Bio

Bio


John P.A. Ioannidis holds the C.F. Rehnborg Chair in Disease Prevention at Stanford University and is Professor of Medicine, Professor of Health Research and Policy, and Director of the Stanford Prevention Research Center (SPRC) at Stanford University School of Medicine, Professor of Statistics (by courtesy) at Stanford University School of Humanities and Sciences, Director of the Meta-Research Innovation Center at Stanford (METRICS), member of the Stanford Cancer Institute, the Stanford Cardiovascular Institute, affiliate in the Stanford Center on Longevity, and affiliated faculty of the Woods Institute for the Environment.

He was born in New York, NY in 1965 and grew up in Athens, Greece. He was Valedictorian of his class (1984) at Athens College and won a number of early awards, including the National Award of the Greek Mathematical Society, in 1984. He graduated in the top rank of his class from the School of Medicine, University of Athens, in 1990 and received also a doctorate in biopathology from the same institution. He trained at Harvard and Tufts, specializing in Internal Medicine and Infectious Diseases, and then held positions at NIH, Johns Hopkins University School of Medicine and Tufts University School of Medicine before returning to Greece in 1999. From 1999 until 2010 he chaired the Department of Hygiene and Epidemiology at the School of Medicine, University of Ioannina in Greece, as a tenured professor since 2003. He has been adjunct faculty for the Tufts University School of Medicine since 1996, with the rank of professor since 2002. In 2008-2010 he led the Genetics/Genomics component of the Tufts Clinical and Translational Science Institute (CTSI) and the Center for Genetic Epidemiology and Modeling (CGEM) of the Tufts Institute for Clinical Research and Health Policy Studies at Tufts Medical Center. He is also adjunct professor of epidemiology at the Harvard School of Public Health and visiting professor of epidemiology and biostatistics at Imperial College London.

Dr. Ioannidis is a member of the executive board of the Human Genome Epidemiology Network, and senior advisor on knowledge integration at the National Cancer Institute, and has served as President of the Society for Research Synthesis Methodology, as a member of the editorial boards of 30 leading international journals (including PLoS Medicine, Lancet, Annals of Internal Medicine, Journal of the National Cancer Institute, Science Translational Medicine, Molecular and Cellular Proteomics, AIDS, International Journal of Epidemiology, Journal of Clinical Epidemiology, Clinical Trials, Cancer Treatment Reviews, and PLoS ONE, among others) and as Editor-in-Chief of the European Journal of Clinical Investigation for the period 2010-2014. He has given more than 300 invited and honorary lectures. He is one of the most-cited scientists worldwide, with indices Hirsch h=112, Hirsch m=6.0, and Schreiber hm=67 per GoogleScholar as of 2/2014 (h=93 per ISI). He has received several awards, including the European Award for Excellence in Clinical Science for 2007, and has been inducted in the Association of American Physicians in 2009 and in the European Academy of Cancer Sciences in 2010. The PLoS Medicine paper on “Why most Published Research Findings are False,” has been the most-accessed article in the history of Public Library of Science (appoximately 1 million hits). The Atlantic selected Ioannidis as the Brave Thinker scientist for 2010 claiming that he “may be one of the most influential scientists alive”. His latest book Toccata for the Girl with the Burnt Face (Kedros 2012, in Greek) was included in the short list for the best book by a new writer Anagnostis award in Greece in 2013. He considers himself privileged to have learnt and to continue to learn from interactions with students and young scientists (of all ages) from all over the world and to be constantly reminded that he knows next to nothing.

Administrative Appointments


  • C.F. Rehnborg Professor in Disease Prevention and Director, Stanford Prevention Research Center (2010 - Present)
  • Director, Meta-Research Innovation Center at Stanford (METRICS) (2013 - Present)
  • Professor of Medicine, Stanford University School of Medicine (2010 - Present)
  • Professor of Health Research and Policy, Stanford University School of Medicine (2011 - Present)
  • Professor of Statistics (by courtesy), Stanford University School of Humanities and Sciences (2011 - Present)
  • Affiliated faculty, Woods Institute for the Environment (2011 - Present)
  • Affiliate, Stanford Center on Longevity (2012 - Present)
  • Member, Stanford Cancer Center (2010 - Present)
  • Member, Stanford Cardiovascular Institute (2010 - Present)
  • Professor of Epidemiology (adjunct), Harvard School of Public Health (2010 - Present)
  • Professor of Medicine (adjunct), Tufts University School of Medicine (2002 - Present)
  • Professor of Epidemiology and Biostatistics (visiting), Imperial College London (2010 - Present)
  • Professor and Chairman, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine (1999 - 2010)
  • Editor-in-chief, European Journal of Clinical Investigation (2010 - Present)

Honors & Awards


  • European Award for Excellence in Clinical Science, European Society for Clinical Investigation (2007)
  • Executive board member and center director, Human Genome Epidemiology Network (2004-)
  • President, Society for Research Synthesis Methodology (2009-2010)
  • Elected member, Association of American Physicians (2009-)
  • Elected fellow, European Academy of Cancer Sciences (2010-)

Professional Education


  • Fellowship, New England Medical Center, Tufts University School of Medicine, Infectious Diseases (1996)
  • Residency, New England Deaconess Hospital, Harvard Medical School, Internal Medicine (1993)
  • DSc, University of Athens School of Medicine, Athens, Greece, Biopathology (1996)
  • MD, University of Athens School of Medicine, Athens, Greece, Medicine (1990)

Research & Scholarship

Current Research and Scholarly Interests


I have worked in the fields of evidence-based medicine, clinical investigation, clinical and molecular epidemiology, clinical research methodology, empirical research methods, statistics, and genomics. I have a strong interest in large-scale evidence (in particular randomized trials and meta-analyses) and in appraisal and control of diverse biases in biomedical research. I am interested in developing and applying new research methods, and in the interdisciplinary enhancement of existing research methods for study design and analysis in biomedicine. Some of my most influential papers in terms of citations are those addressing issues of replication validity of genetic association studies, biases in biomedical research, research synthesis methods, extensions of meta-analysis, genome-wide association studies and agnostic evaluation of associations, and validity of randomized trials and observational research. I have also designed, steered and participated in influential randomized trials (in particular, the major trials that changed decisively the management and outcome of HIV infection, but also trials in nephrology, and in antibiotic use in the community), and large international consortia that have helped transform the efficiency of research in diverse fields of genomic, molecular and clinical epidemiology. I enjoy working with a diverse array of colleagues from very diverse disciplines and to have an opportunity to learn from both senior and junior investigators, and particularly students at all levels.

Clinical Trials


  • Personal Genomics for Preventive Cardiology Not Recruiting

    The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.

    Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.

    View full details

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Improving the drug development process: more not less randomized trials. JAMA : the journal of the American Medical Association Djulbegovic, B., Hozo, I., Ioannidis, J. P. ; 311 (4): 355-6

    View details for DOI 10.1001/jama.2013.283742

    View details for PubMedID 24449311

  • Increasing value and reducing waste in research design, conduct, and analysis. Lancet Ioannidis, J. P., Greenland, S., Hlatky, M. A., Khoury, M. J., Macleod, M. R., Moher, D., Schulz, K. F., Tibshirani, R. 2014; 383 (9912): 166-175

    Abstract

    Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

    View details for DOI 10.1016/S0140-6736(13)62227-8

    View details for PubMedID 24411645

  • Implausible results in human nutrition research BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. P. 2013; 347

    View details for DOI 10.1136/bmj.f6698

    View details for Web of Science ID 000327155000004

    View details for PubMedID 24231028

  • US studies may overestimate effect sizes in softer research PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Ioannidis, J. P. 2013; 110 (37): 15031-15036

    Abstract

    Many biases affect scientific research, causing a waste of resources, posing a threat to human health, and hampering scientific progress. These problems are hypothesized to be worsened by lack of consensus on theories and methods, by selective publication processes, and by career systems too heavily oriented toward productivity, such as those adopted in the United States (US). Here, we extracted 1,174 primary outcomes appearing in 82 meta-analyses published in health-related biological and behavioral research sampled from the Web of Science categories Genetics & Heredity and Psychiatry and measured how individual results deviated from the overall summary effect size within their respective meta-analysis. We found that primary studies whose outcome included behavioral parameters were generally more likely to report extreme effects, and those with a corresponding author based in the US were more likely to deviate in the direction predicted by their experimental hypotheses, particularly when their outcome did not include additional biological parameters. Nonbehavioral studies showed no such "US effect" and were subject mainly to sampling variance and small-study effects, which were stronger for non-US countries. Although this latter finding could be interpreted as a publication bias against non-US authors, the US effect observed in behavioral research is unlikely to be generated by editorial biases. Behavioral studies have lower methodological consensus and higher noise, making US researchers potentially more likely to express an underlying propensity to report strong and significant findings.

    View details for DOI 10.1073/pnas.1302997110

    View details for Web of Science ID 000324125100053

    View details for PubMedID 23980165

  • The effects of excluding treatments from network meta-analyses: survey BMJ-BRITISH MEDICAL JOURNAL Mills, E. J., Kanters, S., Thorlund, K., Chaimani, A., Veroniki, A., Ioannidis, J. P. 2013; 347

    Abstract

    To examine whether the exclusion of individual treatment comparators, including placebo/no treatment, affects the results of network meta-analysis.Survey of networks with individual trial data.PubMed and communication with authors of network meta-analyses.We included networks that had five or more treatments, contained at least two closed loops, had at least twice as many studies as treatments, and had trial level data available. Investigators abstracted information about study design, participants, outcomes, network geometry, and the exclusion of eligible treatments.Among 18 eligible networks involving 757 randomised controlled trials with 750 possible treatment comparisons, 11 had upfront decided not to consider all treatment comparators and only 10 included placebo/no treatment nodes. In 7/18 networks, there was at least one node whose removal caused a more than 1.10-fold average relative change in the estimated treatments effects, and switches in the top three treatments were observed in 9/18 networks. Removal of placebo/no treatment caused large relative changes of the treatment effects (average change 1.16-3.10-fold) for four of the 10 networks that had originally included placebo/no treatment nodes. Exclusion of current uncommonly used drugs resulted in substantial changes of the treatment effects (average 1.21-fold) in one of three networks on systemic treatments for advanced malignancies.Excluding treatments in network meta-analyses sometimes can have important effects on their results and can diminish the usefulness of the research to clinicians if important comparisons are missing.

    View details for DOI 10.1136/bmj.f5195

    View details for Web of Science ID 000324216500001

    View details for PubMedID 24009242

  • Overlapping meta-analyses on the same topic: survey of published studies BMJ-BRITISH MEDICAL JOURNAL Siontis, K. C., Hernandez-Boussard, T., Ioannidis, J. P. 2013; 347

    Abstract

    To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic.Survey of published meta-analyses.PubMed.Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013.Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

    View details for DOI 10.1136/bmj.f4501

    View details for Web of Science ID 000322247400002

    View details for PubMedID 23873947

  • Evaluation of excess significance bias in animal studies of neurological diseases. PLoS biology Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Al-Shahi Salman, R., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)

    Abstract

    Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10(-9)). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.

    View details for DOI 10.1371/journal.pbio.1001609

    View details for PubMedID 23874156

  • Meta-analysis methods for genome-wide association studies and beyond. Nature reviews. Genetics Evangelou, E., Ioannidis, J. P. 2013; 14 (6): 379-389

    Abstract

    Meta-analysis of genome-wide association studies (GWASs) has become a popular method for discovering genetic risk variants. Here, we overview both widely applied and newer statistical methods for GWAS meta-analysis, including issues of interpretation and assessment of sources of heterogeneity. We also discuss extensions of these meta-analysis methods to complex data. Where possible, we provide guidelines for researchers who are planning to use these methods. Furthermore, we address special issues that may arise for meta-analysis of sequencing data and rare variants. Finally, we discuss challenges and solutions surrounding the goals of making meta-analysis data publicly available and building powerful consortia.

    View details for DOI 10.1038/nrg3472

    View details for PubMedID 23657481

  • How to use a subgroup analysis: users' guide to the medical literature. JAMA : the journal of the American Medical Association Sun, X., Ioannidis, J. P., Agoritsas, T., Alba, A. C., Guyatt, G. ; 311 (4): 405-11

    Abstract

    Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

    View details for DOI 10.1001/jama.2013.285063

    View details for PubMedID 24449319

  • A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. Journal of medical genetics Oei, L., Hsu, Y., Styrkarsdottir, U., Eussen, B. H., de Klein, A., Peters, M. J., Halldorsson, B., Liu, C., Alonso, N., Kaptoge, S. K., Thorleifsson, G., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Kruk, M., Lewis, J. R., Patel, M. S., Scollen, S., Svensson, O., Trompet, S., van Schoor, N. M., Zhu, K., Buckley, B. M., Cooper, C., Ford, I., Goltzman, D., González-Macías, J., Langdahl, B. L., Leslie, W. D., Lips, P., Lorenc, R. S., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Slagboom, P. E., Garcia-Ibarbia, C., Ingvarsson, T., Johannsdottir, H., Luben, R., Medina-Gómez, C., Arp, P., Nandakumar, K., Palsson, S. T., Sigurdsson, G., van Meurs, J. B., Zhou, Y., Hofman, A., Jukema, J. W., Pols, H. A., Prince, R. L., Cupples, L. A., Marshall, C. R., Pinto, D., Sato, D., Scherer, S. W., Reeve, J., Thorsteinsdottir, U., Karasik, D., Richards, J. B., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F., Estrada, K. 2014; 51 (2): 122-131

    Abstract

    Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.To identify CNVs associated with osteoporotic bone fracture risk.We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

    View details for DOI 10.1136/jmedgenet-2013-102064

    View details for PubMedID 24343915

  • Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses. Clinical microbiology and infection Kanters, S., Mills, E. J., Thorlund, K., Bucher, H. C., Ioannidis, J. P. 2014; 20 (2): 114-122

    Abstract

    There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

    View details for DOI 10.1111/1469-0691.12475

    View details for PubMedID 24274661

  • Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus BONE Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gomez, C., Vandenput, L., Kim, G. S., Lee, S. H., Castano-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellstrom, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, O., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2014; 59: 20-27

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for DOI 10.1016/j.bone.2013.10.015

    View details for Web of Science ID 000329558600004

    View details for PubMedID 24516880

  • Biomedical research: increasing value, reducing waste. Lancet Macleod, M. R., Michie, S., Roberts, I., Dirnagl, U., Chalmers, I., Ioannidis, J. P., Al-Shahi Salman, R., Chan, A., Glasziou, P. 2014; 383 (9912): 101-104

    View details for DOI 10.1016/S0140-6736(13)62329-6

    View details for PubMedID 24411643

  • How to increase value and reduce waste when research priorities are set. Lancet Chalmers, I., Bracken, M. B., Djulbegovic, B., Garattini, S., Grant, J., Gülmezoglu, A. M., Howells, D. W., Ioannidis, J. P., Oliver, S. 2014; 383 (9912): 156-165

    Abstract

    The increase in annual global investment in biomedical research--reaching US$240 billion in 2010--has resulted in important health dividends for patients and the public. However, much research does not lead to worthwhile achievements, partly because some studies are done to improve understanding of basic mechanisms that might not have relevance for human health. Additionally, good research ideas often do not yield the anticipated results. As long as the way in which these ideas are prioritised for research is transparent and warranted, these disappointments should not be deemed wasteful; they are simply an inevitable feature of the way science works. However, some sources of waste cannot be justified. In this report, we discuss how avoidable waste can be considered when research priorities are set. We have four recommendations. First, ways to improve the yield from basic research should be investigated. Second, the transparency of processes by which funders prioritise important uncertainties should be increased, making clear how they take account of the needs of potential users of research. Third, investment in additional research should always be preceded by systematic assessment of existing evidence. Fourth, sources of information about research that is in progress should be strengthened and developed and used by researchers. Research funders have primary responsibility for reductions in waste resulting from decisions about what research to do.

    View details for DOI 10.1016/S0140-6736(13)62229-1

    View details for PubMedID 24411644

  • The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of aging Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lin, C., Lohmann, K., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Opala, G., Park, S. S., Petrucci, S., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Tomiyama, H., Uitti, R. J., Valente, E. M., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J., Ross, O. A. 2014; 35 (1): 266 e5-266 e14

    Abstract

    The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

    View details for DOI 10.1016/j.neurobiolaging.2013.07.013

    View details for PubMedID 23962496

  • Discussion: Why "An estimate of the science-wise false discovery rate and application to the top medical literature" is false BIOSTATISTICS Ioannidis, J. P. 2014; 15 (1): 28-36

    Abstract

    Jager and Leek have tried to estimate a false-discovery rate (FDR) in abstracts of articles published in five medical journals during 2000-2010. Their approach is flawed in sampling, calculations, and conclusions. It uses a tiny portion of select papers in highly select journals. Randomized controlled trials and systematic reviews (designs with the lowest anticipated false-positive rates) are 52% of the analyzed papers, while these designs account for only 4% in PubMed in the same period. The FDR calculations consider the entire published literature as equivalent to a single genomic experiment where all performed analyses are reported without selection or distortion. However, the data used are the P-values reported in the abstracts of published papers; these P-values are a highly distorted, highly select sample. Besides selective reporting biases, all other biases, in particular confounding in observational studies, are also ignored, while these are often the main drivers for high false-positive rates in the biomedical literature. A reproducibility check of the raw data shows that much of the data Jager and Leek used are either wrong or make no sense: most of the usable data were missed by their script, 94% of the abstracts that reported ≥2 P-values had high correlation/overlap between reported outcomes, and only a minority of P-values corresponded to relevant primary outcomes. The Jager and Leek paper exemplifies the dreadful combination of using automated scripts with wrong methods and unreliable data. Sadly, this combination is common in the medical literature.

    View details for DOI 10.1093/biostatistics/kxt036

    View details for Web of Science ID 000328286700006

    View details for PubMedID 24068251

  • There are no randomized controlled trials that support the United States Preventive Services Task Force guideline on screening for depression in primary care: a systematic review. BMC medicine Thombs, B. D., Ziegelstein, R. C., Roseman, M., Kloda, L. A., Ioannidis, J. P. 2014; 12 (1): 13-?

    Abstract

    The United States Preventive Services Task Force (USPSTF) recommends screening adults for depression in primary care settings when staff-assisted depression management programs are available. This recommendation, however, is based on evidence from depression management programs conducted with patients already identified as depressed, even though screening is intended to identify depressed patients not already recognized or treated. The objective of this systematic review was to evaluate whether there is evidence from randomized controlled trials (RCTs) that depression screening benefits patients in primary care, using an explicit definition of screening.We re-evaluated RCTs included in the 2009 USPSTF evidence review on depression screening, including only trials that compared depression outcomes between screened and non-screened patients and met the following three criteria: determined patient eligibility and randomized prior to screening; excluded patients already diagnosed with a recent episode of depression or already being treated for depression; and provided the same level of depression treatment services to patients identified as depressed in the screening and non-screening trial arms. We also reviewed studies included in a recent Cochrane systematic review, but not the USPSTF review; conducted a focused search to update the USPSTF review; and reviewed trial registries.Of the nine RCTs included in the USPSTF review, four fulfilled none of three criteria for a test of depression screening, four fulfilled one of three criteria, and one fulfilled two of three criteria. There were two additional RCTs included only in the Cochrane review, and each fulfilled one of three criteria. No eligible RCTs were found via the updated review.The USPSTF recommendation to screen adults for depression in primary care settings when staff-assisted depression management programs are available is not supported by evidence from any RCTs that are directly relevant to the recommendation. The USPSTF should re-evaluate this recommendation.Registration: PROSPERO (#CRD42013004276).

    View details for DOI 10.1186/1741-7015-12-13

    View details for PubMedID 24472580

  • Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses. Annals of oncology Ioannidis, J. P., Zhou, Y., Chang, C. Q., Schully, S. D., Khoury, M. J., Freedman, A. N. 2014; 25 (1): 16-23

    Abstract

    Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.

    View details for DOI 10.1093/annonc/mdt372

    View details for PubMedID 24310915

  • Association between pediatric clinical trials and global burden of disease. Pediatrics Bourgeois, F. T., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2014; 133 (1): 78-87

    Abstract

    The allocation of research resources should favor conditions responsible for the greatest disease burden. This is particularly important in pediatric populations, which have been underrepresented in clinical research. Our aim was to measure the association between the focus of pediatric clinical trials and burden of disease and to identify neglected clinical domains.We performed a cross-sectional study of clinical trials by using trial records in ClinicalTrials.gov. All trials started in 2006 or after and studying patient-level interventions in pediatric populations were included. Age-specific measures of disease burden were obtained for 21 separate conditions for high-, middle-, and low-income countries. We measured the correlation between number of pediatric clinical trials and disease burden for each condition.Neuropsychiatric conditions and infectious diseases were the most studied conditions globally in terms of number of trials (874 and 847 trials, respectively), while intentional injuries (5 trials) and maternal conditions (4 trials) were the least studied. Clinical trials were only moderately correlated with global disease burden (r = 0.58, P = .006). Correlations were also moderate within each of the country income levels, but lowest in low-income countries (r = .47, P = .03). Globally, the conditions most understudied relative to disease burden were injuries (-260 trials for unintentional injuries and -160 trials for intentional injuries), nutritional deficiencies (-175 trials), and respiratory infections (-171 trials).Pediatric clinical trial activity is only moderately associated with pediatric burden of disease, and least associated in low-income countries. The mismatch between clinical trials and disease burden identifies key clinical areas for focus and investment.

    View details for DOI 10.1542/peds.2013-2567

    View details for PubMedID 24344112

  • Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices. Implementation science Prasad, V., Ioannidis, J. P. 2014; 9 (1): 1-?

    Abstract

    Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.

    View details for DOI 10.1186/1748-5908-9-1

    View details for PubMedID 24398253

  • Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement. Journal of clinical epidemiology Iglesias, A. I., Mihaescu, R., Ioannidis, J. P., Khoury, M. J., Little, J., van Duijn, C. M., Janssens, A. C. 2014

    Abstract

    Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement.We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted.Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model.Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models.

    View details for DOI 10.1016/j.jclinepi.2013.10.006

    View details for PubMedID 24411311

  • Research accomplishments that are too good to be true: reply to Ting. Intensive care medicine Ioannidis, J. P. 2014

    View details for DOI 10.1007/s00134-014-3220-0

    View details for PubMedID 24477457

  • Research accomplishments that are too good to be true INTENSIVE CARE MEDICINE Ioannidis, J. P. 2014; 40 (1): 99-101

    View details for DOI 10.1007/s00134-013-3100-z

    View details for Web of Science ID 000328198600013

    View details for PubMedID 24129497

  • Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation A Randomized Clinical Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Katritsis, D. G., Pokushalov, E., Romanov, A., Giazitzoglou, E., Siontis, G. C., Po, S. S., Camm, A. J., Ioannidis, J. P. 2013; 62 (24): 2318-2325

    Abstract

    The aim of this study was to investigate whether the combination of conventional pulmonary vein isolation (PVI) by circumferential antral ablation with ganglionated plexi (GP) modification in a single ablation procedure, yields higher success rates than PVI or GP ablation alone, in patients with paroxysmal atrial fibrillation (PAF).Conventional PVI transects the major left atrial GP, and it is possible that autonomic denervation by inadvertent GP ablation plays a central role in the efficacy of PVI.A total of 242 patients with symptomatic PAF were recruited and randomized as follows: 1) circumferential PVI (n = 78); 2) anatomic ablation of the main left atrial GP (n = 82); or 3) circumferential PVI followed by anatomic ablation of the main left atrial GP (n = 82). The primary endpoint was freedom from atrial fibrillation (AF) or other sustained atrial tachycardia (AT), verified by monthly visits, ambulatory electrocardiographic monitoring, and implantable loop recorders, during a 2-year follow-up period.Freedom from AF or AT was achieved in 44 (56%), 39 (48%), and 61 (74%) patients in the PVI, GP, and PVI+GP groups, respectively (p = 0.004 by log-rank test). PVI+GP ablation strategy compared with PVI alone yielded a hazard ratio of 0.53 (95% confidence interval: 0.31 to 0.91; p = 0.022) for recurrence of AF or AT. Fluoroscopy duration was 16 ± 3 min, 20 ± 5 min, and 23 ± 5 min for PVI, GP, and PVI+GP groups, respectively (p < 0.001). Post-ablation atrial flutter did not differ between groups: 5.1% in PVI, 4.9% in GP, and 6.1% in PVI+GP. No serious adverse procedure-related events were encountered.Addition of GP ablation to PVI confers a significantly higher success rate compared with either PVI or GP alone in patients with PAF.

    View details for DOI 10.1016/j.jacc.2013.06.053

    View details for Web of Science ID 000328073300012

    View details for PubMedID 23973694

  • Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality CANADIAN MEDICAL ASSOCIATION JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 185 (18): E827-E837

    Abstract

    Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

    View details for DOI 10.1503/cmaj.130430

    View details for Web of Science ID 000327902600014

    View details for PubMedID 24144601

  • Joint Linkage and Association Analysis with Exome Sequence Data Implicates SLC25A40 in Hypertriglyceridemia. American journal of human genetics Rosenthal, E. A., Ranchalis, J., Crosslin, D. R., Burt, A., Brunzell, J. D., Motulsky, A. G., Nickerson, D. A., Wijsman, E. M., Jarvik, G. P. 2013; 93 (6): 1035-1045

    Abstract

    Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

    View details for DOI 10.1016/j.ajhg.2013.10.019

    View details for PubMedID 24268658

  • Endgame: engaging the tobacco industry in its own elimination. European journal of clinical investigation Ioannidis, J. P., Henriksen, L., Prochaska, J. J. 2013; 43 (12): 1366-1370

    Abstract

    A billion deaths from tobacco are expected by 2100. Many policy interventions such as increased taxation, restrictions on advertisement, smoking bans, as well as behavioral interventions, such as pharmacological and psychological treatments for smoking cessation, decrease tobacco use, but they reach their limits. Endgame scenarios focusing on tobacco supply rather than demand are increasingly discussed, but meet with resistance by the industry and even by many tobacco control experts. A main stumbling block that requires more attention is what to do with the tobacco industry in endgame scenarios. This industry has employed notoriously talented experts in law, business, organization, marketing, advertising, strategy, policy, and statistics and has tremendous lobbying power. Performance-based regulatory approaches can pose a legal obligation on manufacturers to decrease - and eventually - eliminate tobacco products according to specified schedules. Penalties and rewards can make such plans both beneficial for public health and attractive to the companies that do the job well. We discuss caveats and reality checks of engaging the tobacco industry to eliminate its current market and change focus. Brainstorming is warranted to entice the industry to abandon tobacco for other profit goals. To get the dialogue started, we propose the wild possibility of hiring former tobacco companies to reduce the costs of healthcare, thereby addressing concurrently two major challenges to public health.

    View details for DOI 10.1111/eci.12172

    View details for PubMedID 24117211

  • Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey. International journal of epidemiology Patel, C. J., Rehkopf, D. H., Leppert, J. T., Bortz, W. M., Cullen, M. R., Chertow, G. M., Ioannidis, J. P. 2013; 42 (6): 1795-1810

    Abstract

    Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

    View details for DOI 10.1093/ije/dyt208

    View details for PubMedID 24345851

  • Empirical evidence for low reproducibility indicates low pre-study odds. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (12): 877-?

    View details for DOI 10.1038/nrn3475-c6

    View details for PubMedID 24149186

  • Collaborative cancer epidemiology in the 21st century: the model of cancer consortia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Burgio, M. R., Ioannidis, J. P., Kaminski, B. M., Derycke, E., Rogers, S., Khoury, M. J., Seminara, D. 2013; 22 (12): 2148-2160

    Abstract

    During the last two decades, epidemiology has undergone a rapid evolution toward collaborative research. The proliferation of multi-institutional, interdisciplinary consortia has acquired particular prominence in cancer research. Herein, we describe the characteristics of a network of 49 established cancer epidemiology consortia (CEC) currently supported by the Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI). This collection represents the largest disease-based research network for collaborative cancer research established in population sciences. We describe the funding trends, geographic distribution, and areas of research focus. The CEC have been partially supported by 201 grants and yielded 3,876 publications between 1995 and 2011. We describe this output in terms of interdisciplinary collaboration and translational evolution. We discuss challenges and future opportunities in the establishment and conduct of large-scale team science within the framework of CEC, review future prospects for this approach to large-scale, interdisciplinary cancer research, and describe a model for the evolution of an integrated Network of Cancer Consortia optimally suited to address and support 21st-century epidemiology.

    View details for DOI 10.1158/1055-9965.EPI-13-0591

    View details for PubMedID 24045926

  • Geometry of the Randomized Evidence for Treatments of Pulmonary Hypertension CARDIOVASCULAR THERAPEUTICS Tonelli, A. R., Zein, J., Ioannidis, J. P. 2013; 31 (6): E138-E146

    Abstract

    We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication.We searched MEDLINE, Embase and Cochrane Library Databases for published studies. We queried clinicaltrials.gov and WHO International Clinical Trials Registry platform for non-published studies.We found 75 randomized trials (41 published [n = 4136 participants] and 34 registered unpublished [planned n = 3470 participants]). Of the published randomized studies, all used placebo as the comparator arm except for two nonindustry-sponsored comparisons between phosphodiestearase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERA), and one study comparing two different regimens of treprostinil. Similarly, only five unpublished/ongoing trials used an active PH treatment as comparator (PDE-5 inhibitors versus ERA (n = 3), different doses of sildenafil (n = 1) and two formulations of epoprostenol (n = 1). Of the 75 trials, 47 were sponsored by the manufacturer of the tested active product(s), and only two trials were sponsored by two companies comparing their products.The relative merits of different treatment options are not directly known, as there are very few head-to-head comparisons. A limited number of ongoing studies are using active FDA-approved PH-treatments for comparison. This lack of information can be overcome by carefully designing comparative effectiveness trials.

    View details for DOI 10.1111/1755-5922.12050

    View details for Web of Science ID 000327423800012

    View details for PubMedID 24112824

  • A list of highly influential biomedical researchers, 1996-2011. European journal of clinical investigation Boyack, K. W., Klavans, R., Sorensen, A. A., Ioannidis, J. P. 2013; 43 (12): 1339-1365

    Abstract

    We have generated a list of highly influential biomedical researchers based on Scopus citation data from the period 1996-2011. Of the 15,153,100 author identifiers in Scopus, approximately 1% (n=149,655) have an h-index >=20. Of those, we selected 532 authors who belonged to the 400 with highest total citation count (>=25,142 citations) and/or the 400 with highest h-index (>=76). Of those, we selected the top-400 living core biomedical researchers based on a normalized score combining total citations and h-index. Another 62 authors whose focus is outside biomedicine had a normalized score that was at least as high as the score of the 400th core biomedical researcher. We provide information on the profile of these most influential authors, including the most common Medical Subject Heading terms in their articles that are also specific to their work, most common journals where they publish, number of papers with over 100 citations that they have published as first/single, last, or middle authors, and impact score adjusted for authorship positions, given that crude citation indices and authorship positions are almost totally orthogonal. We also show for each researcher the distribution of their papers across 4 main levels (basic-to-applied) of research. We discuss technical issues, limitations and caveats, comparisons against other lists of highly-cited researchers, and potential uses of this resource.

    View details for DOI 10.1111/eci.12171

    View details for PubMedID 24134636

  • Raw data from clinical trials: within reach? Trends in pharmacological sciences Doshi, P., Goodman, S. N., Ioannidis, J. P. 2013; 34 (12): 645-647

    Abstract

    Making raw data from clinical trials widely publically available should reduce selective reporting biases and enhance the reproducibility of and trust in clinical research. The optimal procedures for data sharing are hotly debated. Some of the caveats and limitations in proposed data-sharing policies are potentially restrictive, and we argue in favor of more widespread availability of data from clinical research.

    View details for DOI 10.1016/j.tips.2013.10.006

    View details for PubMedID 24295825

  • Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nature reviews. Rheumatology Ioannidis, J. P., Karassa, F. B., Druyts, E., Thorlund, K., Mills, E. J. 2013; 9 (11): 665-673

    Abstract

    Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

    View details for DOI 10.1038/nrrheum.2013.134

    View details for PubMedID 23999553

  • Prevention and management of non-communicable disease: the IOC consensus statement, Lausanne 2013 BRITISH JOURNAL OF SPORTS MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Borjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 47 (16): 1003-U56

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology and design thinking. The purpose of this paper is to summarise the results of a consensus meeting on NCD prevention sponsored by the IOC in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within healthcare systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: (1) Focus on behavioural change as the core component of all clinical programmes for the prevention and management of chronic disease. (2) Establish actual centres to design, implement, study and improve preventive programmes for chronic disease. (3) Use human-centred design in the creation of prevention programmes with an inclination to action, rapid prototyping and multiple iterations. (4) Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programmes for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. (5) Mobilise resources and leverage networks to scale and distribute programmes of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programmes within healthcare. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1136/bjsports-2013-093034

    View details for Web of Science ID 000325530900002

    View details for PubMedID 24115479

  • Prevention and Management of Non-Communicable Disease: The IOC Consensus Statement, Lausanne 2013. Sports medicine Matheson, G. O., Klügl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Börjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 43 (11): 1075-1088

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April, 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioural change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centres to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad-hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1007/s40279-013-0104-3

    View details for PubMedID 24129783

  • Prevention and Management of Noncommunicable Disease: The IOC Consensus Statement, Lausanne 2013 CLINICAL JOURNAL OF SPORT MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Boerjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 23 (6): 419-429
  • A common biological basis of obesity and nicotine addiction TRANSLATIONAL PSYCHIATRY Thorgeirsson, T. E., Gudbjartsson, D. F., Sulem, P., Besenbacher, S., Styrkarsdottir, U., Thorleifsson, G., Walters, G. B., Furberg, H., Sullivan, P. F., Marchini, J., McCarthy, M. I., Steinthorsdottir, V., Thorsteinsdottir, U., Stefansson, K. 2013; 3

    Abstract

    Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

    View details for DOI 10.1038/tp.2013.81

    View details for Web of Science ID 000327472800001

    View details for PubMedID 24084939

  • Mortality in persons with mental disorders is substantially overestimated using inpatient psychiatric diagnoses. Journal of psychiatric research Crump, C., Ioannidis, J. P., Sundquist, K., Winkleby, M. A., Sundquist, J. 2013; 47 (10): 1298-1303

    Abstract

    Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N = 7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001-2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85-5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08-5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (∼20-30%) or excluded (∼25-40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies.

    View details for DOI 10.1016/j.jpsychires.2013.05.034

    View details for PubMedID 23806577

  • Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium. Movement disorders Heckman, M. G., Soto-Ortolaza, A. I., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Carr, J., Chartier-Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Boczarska-Jedynak, M., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Petrucci, S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, E. M., Van Broeckhoven, C., van de Loo, S., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Hentati, F., Farrer, M. J., Ross, O. A. 2013; 28 (12): 1740-1744

    Abstract

    Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society.

    View details for DOI 10.1002/mds.25600

    View details for PubMedID 23913756

  • In reply II-Reversal of Medical Practices MAYO CLINIC PROCEEDINGS Ioannidis, J. P. 2013; 88 (10): 1184-1184

    View details for DOI 10.1016/j.mayocp.2013.08.014

    View details for Web of Science ID 000325470800029

    View details for PubMedID 24079693

  • Mining the human phenome using allelic scores that index biological intermediates. PLoS genetics Evans, D. M., Brion, M. J., Paternoster, L., Kemp, J. P., McMahon, G., Munafò, M., Whitfield, J. B., Medland, S. E., Montgomery, G. W., Timpson, N. J., St Pourcain, B., Lawlor, D. A., Martin, N. G., Dehghan, A., Hirschhorn, J., Davey Smith, G. 2013; 9 (10)

    Abstract

    It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.

    View details for DOI 10.1371/journal.pgen.1003919

    View details for PubMedID 24204319

  • Ensuring the integrity of clinical practice guidelines: a tool for protecting patients BMJ-BRITISH MEDICAL JOURNAL Lenzer, J., Hoffman, J. R., Furberg, C. D., Ioannidis, J. P. 2013; 347

    View details for DOI 10.1136/bmj.f5535

    View details for Web of Science ID 000324828300004

    View details for PubMedID 24046286

  • Association Between Obesity and Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Operations: A Systematic Review and Meta-Analysis ANNALS OF THORACIC SURGERY Hernandez, A. V., Kaw, R., Pasupuleti, V., Bina, P., Ioannidis, J. P., Bueno, H., Boersma, E., Gillinov, M. 2013; 96 (3): 1104-1116

    Abstract

    In a systematic review and random-effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac operations. We selected 18 observational studies until December 2011 that excluded patients with preoperative AF (n=36,147). Obese patients had a modest higher risk of POAF compared with nonobese (odds ratio, 1.12; 95% confidence interval, 1.04 to 1.21; p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac operation, study design, or year of publication. POAF was significantly associated with a higher risk of stroke, respiratory failure, and operative death.

    View details for DOI 10.1016/j.athoracsur.2013.04.029

    View details for Web of Science ID 000323940200076

    View details for PubMedID 23932258

  • Optimal type I and type II error pairs when the available sample size is fixed JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Hozo, I., Djulbegovic, B. 2013; 66 (8): 903-910

    Abstract

    OBJECTIVE: To model how to select the optimal pair of type I and type II errors that maximize study value when there are constrains on the available study sample size. STUDY DESIGN AND SETTING: Correct inferences [true positives (TPs) and true negatives (TNs)] increase and wrong inferences (false positives and false negatives) decrease the value of a study. We model the composite value of a study based on these four inferences, their relative importance, and relative frequency using multiplicative and additive models. Numerical examples are presented for randomized trials, epidemiologic studies, and agnostic omics investigations with massive testing and variable sample size constraints. RESULTS: The optimal choice of type I and type II errors varies a lot according to the available sample size and the plausible effect sizes in each field. We show how equations can be streamlined for special applications: when the value of all four inferences is considered equal, when the identification of TNs carries no value, and when a study carries no value unless at least one TP is discovered. CONCLUSION: The proposed optimization equations can be used to guide the selection of the optimal type I and type II errors of future studies in which sample size is constrained.

    View details for DOI 10.1016/j.jclinepi.2013.03.002

    View details for Web of Science ID 000322207300013

    View details for PubMedID 23664493

  • To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication? CIRCULATION-CARDIOVASCULAR GENETICS Ioannidis, J. P. 2013; 6 (4): 413-418
  • Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases PLOS BIOLOGY Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Salman, R. A., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)
  • The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males. Annals of the rheumatic diseases Evangelou, E., Valdes, A. M., Castano-Betancourt, M. C., Doherty, M., Doherty, S., Esko, T., Ingvarsson, T., Ioannidis, J. P., Kloppenburg, M., Metspalu, A., Ntzani, E. E., Panoutsopoulou, K., Slagboom, P. E., Southam, L., Spector, T. D., Styrkarsdottir, U., Stefanson, K., Uitterlinden, A. G., wheeler, M., Zeggini, E., Meulenbelt, I., van Meurs, J. B. 2013; 72 (7): 1264-1265

    View details for DOI 10.1136/annrheumdis-2012-203182

    View details for PubMedID 23505243

  • Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus HUMAN GENETICS Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 132 (5): 495-508

    Abstract

    Diseases such as type 2 diabetes (T2D) result from environmental and genetic factors, and risk varies considerably in the population. T2D-related genetic loci discovered to date explain only a small portion of the T2D heritability. Some heritability may be due to gene-environment interactions. However, documenting these interactions has been difficult due to low availability of concurrent genetic and environmental measures, selection bias, and challenges in controlling for multiple hypothesis testing. Through genome-wide association studies (GWAS), investigators have identified over 90 single nucleotide polymorphisms (SNPs) associated to T2D. Using a method analogous to GWAS [environment-wide association study (EWAS)], we found five environmental factors associated with the disease. By focusing on risk factors that emerge from GWAS and EWAS, it is possible to overcome difficulties in uncovering gene-environment interactions. Using data from the National Health and Nutrition Examination Survey (NHANES), we screened 18 SNPs and 5 serum-based environmental factors for interaction in association to T2D. We controlled for multiple hypotheses using false discovery rate (FDR) and Bonferroni correction and found four interactions with FDR <20 %. The interaction between rs13266634 (SLC30A8) and trans-?-carotene withstood Bonferroni correction (corrected p = 0.006, FDR <1.5 %). The per-risk-allele effect sizes in subjects with low levels of trans-?-carotene were 40 % greater than the marginal effect size [odds ratio (OR) 1.8, 95 % CI 1.3-2.6]. We hypothesize that impaired function driven by rs13266634 increases T2D risk when combined with serum levels of nutrients. Unbiased consideration of environmental and genetic factors may help identify larger and more relevant effect sizes for disease associations.

    View details for DOI 10.1007/s00439-012-1258-z

    View details for Web of Science ID 000317691100002

    View details for PubMedID 23334806

  • Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Stamatakis, E., Weiler, R., Ioannidis, J. P. 2013; 43 (5): 469-475

    Abstract

    Expenditure on industry products (mostly drugs and devices) has spiraled over the last 15 years and accounts for substantial part of healthcare expenditure. The enormous financial interests involved in the development and marketing of drugs and devices may have given excessive power to these industries to influence medical research, policy, and practice.Review of the literature and analysis of the multiple pathways through which the industry has directly or indirectly infiltrated the broader healthcare systems. We present the analysis of the industry influences at the following levels: (i) evidence base production, (ii) evidence synthesis, (iii) understanding of safety and harms issues, (iv) cost-effectiveness evaluation, (v) clinical practice guidelines formation, (vi) healthcare professional education, (vii) healthcare practice, (viii) healthcare consumer's decisions.We located abundance of consistent evidence demonstrating that the industry has created means to intervene in all steps of the processes that determine healthcare research, strategy, expenditure, practice and education. As a result of these interferences, the benefits of drugs and other products are often exaggerated and their potential harms are downplayed, and clinical guidelines, medical practice, and healthcare expenditure decisions are biased.To serve its interests, the industry masterfully influences evidence base production, evidence synthesis, understanding of harms issues, cost-effectiveness evaluations, clinical practice guidelines and healthcare professional education and also exerts direct influences on professional decisions and health consumers. There is an urgent need for regulation and other action towards redefining the mission of medicine towards a more objective and patient-, population- and society-benefit direction that is free from conflict of interests.

    View details for DOI 10.1111/eci.12074

    View details for Web of Science ID 000317983300005

    View details for PubMedID 23521369

  • Pancreatitis Potentially Associated Drugs as a Risk Factor for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis A Prospective Cohort Study PANCREAS Sigounas, D. E., Christodoulou, D. K., Tatsioni, A., Katsanos, K. H., Baltayiannis, G., Kappas, A., Ioannidis, J. P., Tsianos, E. V. 2013; 42 (4): 601-606

    Abstract

    The aim of this study was to assess the role of known risk factors and specifically evaluate the role of pancreatitis potentially associated drugs as potential risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).This was a prospective, single-center cohort study conducted in a tertiary university hospital. All eligible ERCP procedures within a 16-month period were evaluated, and all interventions, patient characteristics, and medications used were documented. The association of potential risk factor with PEP was investigated with univariable analyses. Those statistically significant were entered in a multivariable regression model.Three hundred eighteen ERCP procedures were studied. Post-ERCP pancreatitis occurred in 28 patients (8.8%). Twenty-three potential risk factors were studied in univariable analyses, and 3 of them were found to be nominally statistically significant. These 3 factors were independently associated with PEP in the multivariable model and included the use of pancreatitis potentially associated drugs, belonging to Badalov classes I or II, during the last month before ERCP (odds ratio [OR], 4.39; 95% confidence interval [CI], 1.70-5.47; P = 0.003), more than 1 guide-wire insertions in the pancreatic duct (OR, 5.00; 95% CI, 1.97-12.81; P = 0.001) and bile duct stone extraction (OR, 0.12; CI, 0.05-0.32; P < 0.001).Pancreatitis potentially associated drugs used before ERCP seem to increase the risk for PEP.

    View details for DOI 10.1097/MPA.0b013e31827309fd

    View details for Web of Science ID 000317655200007

    View details for PubMedID 23548878

  • Power failure: why small sample size undermines the reliability of neuroscience NATURE REVIEWS NEUROSCIENCE Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafo, M. R. 2013; 14 (5): 365-376

    Abstract

    A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.

    View details for DOI 10.1038/nrn3475

    View details for Web of Science ID 000317913900012

    View details for PubMedID 23571845

  • Mega-Randomized Clinical Trials for Blockbuster Drugs Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (16): 1683-1683

    View details for Web of Science ID 000317906700018

    View details for PubMedID 23613069

  • Bias in associations of emerging biomarkers with cardiovascular disease. JAMA internal medicine Tzoulaki, I., Siontis, K. C., Evangelou, E., Ioannidis, J. P. 2013; 173 (8): 664-671

    Abstract

    IMPORTANCE Numerous cardiovascular biomarkers are proposed as potential predictors of cardiovascular risk. OBJECTIVE To evaluate whether there is evidence for biases favoring statistically significant results and inflating associations in this literature. DESIGN AND SETTING PubMed search for meta-analyses of cardiovascular biomarkers that are not part of the Framingham Risk Score. MAIN OUTCOME MEASURES We estimated summary effects and between-study heterogeneity (considered "very large" for I2 > 75%). We evaluated whether large studies had significantly more conservative results than smaller studies (small-study effects) and whether there were too many studies with statistically significant results compared with what would be expected on the basis of the findings of the largest study in each meta-analysis. RESULTS Of 56 eligible meta-analyses, 49 had statistically significant results. Very large heterogeneity and small-study effects were seen in 9 and 13 meta-analyses, respectively. In 29 meta-analyses (52%), there was a significant excess of studies with statistically significant results. Only 13 of the statistically significant meta-analyses had more than 1000 cases and no hints of large heterogeneity, small-study effects, or excess significance. These included the associations of glomerular filtration rate and albumin to creatinine ratio in general and high-risk populations with cardiovascular disease mortality and of non-high-density lipoprotein cholesterol, serum albumin, Chlamydia pneumoniae IgG, glycosylated hemoglobin, nonfasting insulin, apolipoprotein B/AI ratio, erythrocyte sedimentation rate, and lipoprotein-associated phospholipase mass or activity with coronary heart disease. CONCLUSIONS AND RELEVANCE Selective reporting biases may be common in the evidence on emerging cardiovascular biomarkers. Most of the proposed associations of these biomarkers may be inflated.

    View details for DOI 10.1001/jamainternmed.2013.3018

    View details for PubMedID 23529078

  • Are Mortality Differences Detected by Administrative Data Reliable and Actionable? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (13): 1410-1411

    View details for Web of Science ID 000316934500032

    View details for PubMedID 23549588

  • Seven new loci associated with age-related macular degeneration NATURE GENETICS Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Buitendijk, G. H., Sim, X., Weeks, D. E., Guymer, R. H., Merriam, J. E., Francis, P. J., Hannum, G., Agarwal, A., Armbrecht, A. M., Audo, I., Aung, T., Barile, G. R., Benchaboune, M., Bird, A. C., Bishop, P. N., Branham, K. E., Brooks, M., Brucker, A. J., Cade, W. H., Cain, M. S., Campochiaroll, P. A., Chan, C., Cheng, C., Chew, E. Y., Chin, K. A., Chowers, I., Clayton, D. G., Cojocaru, R., Conley, Y. P., Cornes, B. K., Daly, M. J., Dhillon, B., Edwards, A., Evangelou, E., Fagemess, J., Ferreyra, H. A., Friedman, J. S., Geirsdottir, A., George, R. J., Gieger, C., Gupta, N., Hagstrom, S. A., Harding, S. P., Haritoglou, C., Heckenlively, J. R., Hoz, F. G., Hughes, G., Ioannidis, J. P., Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., Keilhauer, C. N., Khan, J. C., Kim, I. K., Kiyohara, Y., Klein, B. E., Klein, R., Kovach, J. L., Kozak, I., Lee, C. J., Lee, K. E., Lichtner, P., Lotery, A. J., Meitinger, T., Mitchell, P., Mohand-Saied, S., Moore, A. T., Morgan, D. J., Morrison, M. A., Myers, C. E., Naj, A. C., Nakamura, Y., Okada, Y., Orlin, A., Ortube, M. C., Othman, M. I., Pappas, C., Park, K. H., Pauer, G. J., Peachey, N. S., Poch, O., Priya, R. R., Reynolds, R., Richardson, A. J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J., Schaumberg, D. A., Scholl, H. P., Schwartz, S. G., Scott, W. K., Shahid, H., Sigurdsson, H., Silvestri, G., Sivakumaran, T. A., Smith, R. T., Sobrin, L., Souied, E. H., Stambolian, D. E., Stefansson, H., Sturgill-Short, G. M., Takahashi, A., Tosakulwong, N., Truitt, B. J., Tsironi, E. E., Uitterlinden, A. G., van Duijn, C. M., Vijaya, L., Vingerling, J. R., Vithana, E. N., Webster, A. R., Wichmann, H., Winkler, T. W., Wong, T. Y., Wright, A. F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M. L., Hageman, G. S., Lathrop, G. M., Stefansson, K., Allikmets, R., Baird, P. N., Gorin, M. B., Wang, J. J., Klaver, C. C., Seddon, J. M., Pericak-Vance, M. A., Iyengar, S. K., Yates, J. R., Swaroop, A., Weber, B. H., Kubo, M., DeAngelis, M. M., Leveillard, T., Thorsteinsdottir, U., Haines, J. L., Farrer, L. A., Heid, I. M., Abecasis, G. R. 2013; 45 (4): 433-439

    Abstract

    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

    View details for DOI 10.1038/ng.2578

    View details for Web of Science ID 000316840600015

    View details for PubMedID 23455636

  • Technical aspects and inter-laboratory variability in native peptide profiling: The CE-MS experience CLINICAL BIOCHEMISTRY Mischak, H., Vlahou, A., Ioannidis, J. P. 2013; 46 (6): 432-443

    Abstract

    Mass spectrometry platforms have attracted a lot of interest in the last 2 decades as profiling tools for native peptides and proteins with clinical potential. However, limitations associated with reproducibility and analytical robustness, especially pronounced with the initial SELDI systems, hindered the application of such platforms in biomarker qualification and clinical implementation. The scope of this article is to give a short overview on data available on performance and on analytical robustness of the different platforms for peptide profiling. Using the CE-MS platform as a paradigm, data on analytical performance are described including reproducibility (short-term and intermediate repeatability), stability, interference, quantification capabilities (limits of detection), and inter-laboratory variability. We discuss these issues by using as an example our experience with the development of a 273-peptide marker for chronic kidney disease. Finally, we discuss pros and cons and means for improvement and emphasize the need to test in terms of comparative clinical performance and impact, different platforms that pass reasonably well analytical validation tests.

    View details for DOI 10.1016/j.clinbiochem.2012.09.025

    View details for Web of Science ID 000317155800005

    View details for PubMedID 23041249

  • Transforming Epidemiology for 21st Century Medicine and Public Health CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Khoury, M. J., Lam, T. K., Ioannidis, J. P., Hartge, P., Spitz, M. R., Buring, J. E., Chanock, S. J., Croyle, R. T., Goddard, K. A., Ginsburg, G. S., Herceg, Z., Hiatt, R. A., Hoover, R. N., Hunter, D. J., Kramer, B. S., Lauer, M. S., Meyerhardt, J. A., Olopade, O. I., Palmer, J. R., Sellers, T. A., Seminara, D., Ransohoff, D. F., Rebbeck, T. R., Tourassi, G., Winn, D. M., Zauber, A., Schully, S. D. 2013; 22 (4): 508-516

    Abstract

    In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.

    View details for DOI 10.1158/1055-9965.EPI-13-0146

    View details for Web of Science ID 000317960900005

    View details for PubMedID 23462917

  • Most meta-analyses of drug interventions have narrow scopes and many focus on specific agents JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A., Pilalas, D., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 66 (4): 371-378

    Abstract

    To assess the extent to which meta-analysis publications of drugs and biologics focus on specific named agents or even only a single agent, and identify characteristics associated with such focus.We evaluated 499 articles with meta-analyses published in 2010 and estimated how many did not cover all the available comparisons of tested interventions for a given condition (not all-inclusive); focused on specific named agent(s), or focused strictly on comparisons of only one specific active agent vs. placebo/no treatment or different doses/schedules.Of 499 eligible articles, 403 (80.8%) were not all-inclusive, 214 (42.9%) covered only specific named agent(s), and 74 (14.8%) examined only comparisons with one active agent vs. placebo/no treatment or different doses/schedules. Only 39 articles (7.8%) covered all possible indications for the examined agent(s). After adjusting for type of treatment/field, focus on specific named agent(s) was associated with publication in journal venues (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.17-3.26) vs. Cochrane, industry sponsoring (OR: 3.94; 95% CI: 1.66-10.66), and individual patient data analyses (OR: 6.59; 95% CI: 2.24-19.39). Individual patient data analyses primarily (29/34) focused on specific named agent(s).The scope of meta-analysis publications frequently is narrow and shaped to serve particular agents.

    View details for DOI 10.1016/j.jclinepi.2012.10.014

    View details for Web of Science ID 000315935100006

    View details for PubMedID 23384590

  • Limitations of Medical Research and Evidence at the Patient-Clinician Encounter Scale CHEST Morris, A. H., Ioannidis, J. P. 2013; 143 (4): 1127-1135

    Abstract

    We explore some philosophical and scientific underpinnings of clinical research and evidence at the patient-clinician encounter scale. Insufficient evidence and a common failure to use replicable and sound research methods limit us. Both patients and health care may be, in part, complex nonlinear chaotic systems, and predicting their outcomes is a challenge. When trustworthy (credible) evidence is lacking, making correct clinical choices is often a low-probability exercise. Thus, human (clinician) error and consequent injury to patients appear inevitable. Individual clinician decision-makers operate under the philosophical influence of Adam Smith's "invisible hand" with resulting optimism that they will eventually make the right choices and cause health benefits. The presumption of an effective "invisible hand" operating in health-care delivery has supported a model in which individual clinicians struggle to practice medicine, as they see fit based on their own intuitions and preferences (and biases) despite the obvious complexity, errors, noise, and lack of evidence pervading the system. Not surprisingly, the "invisible hand" does not appear to produce the desired community health benefits. Obtaining a benefit at the patient-clinician encounter scale requires human (clinician) behavior modification. We believe that serious rethinking and restructuring of the clinical research and care delivery systems is necessary to assure the profession and the public that we continue to do more good than harm. We need to evaluate whether, and how, detailed decision-support tools may enable reproducible clinician behavior and beneficial use of evidence.

    View details for DOI 10.1378/chest.12-1908

    View details for Web of Science ID 000317871500037

    View details for PubMedID 23546485

  • Informed Consent, Big Data, and the Oxymoron of Research That Is Not Research AMERICAN JOURNAL OF BIOETHICS Ioannidis, J. P. 2013; 13 (4): 40-42

    View details for DOI 10.1080/15265161.2013.768864

    View details for Web of Science ID 000316391200014

    View details for PubMedID 23514395

  • Observational studies often make clinical practice recommendations: an empirical evaluation of authors' attitudes JOURNAL OF CLINICAL EPIDEMIOLOGY Prasad, V., Jorgenson, J., Ioannidis, J. P., Cifu, A. 2013; 66 (4): 361-366

    Abstract

    Although observational studies provide useful descriptive and correlative information, their role in the evaluation of medical interventions remains contentious. There has been no systematic evaluation of authors' attitudes toward their own nonrandomized studies and how often they recommend specific medical practices.We reviewed all original articles of nonrandomized studies published in 2010 in New England Journal of Medicine, Lancet, Journal of the American Medical Association, and Annals of Internal Medicine. We classified articles based on whether authors recommend a medical practice and whether they state that a randomized trial is needed to support their recommendation. We also examined the types of logical extrapolations used by authors who did advance recommendations.Of the 631 original articles published in 2010, 298 (47%) articles were eligible observational studies. In 167 (56%) of 298 studies, authors recommended a medical practice based on their results. Only 24 (14%) of 167 studies stated that a randomized controlled trial (RCT) should be done to validate the recommendation, whereas the other 143 articles made a total of 149 logical extrapolations to recommend specific medical practices. Recommendations without a call for a randomized trial were most common in studies of modifiable factors (59%), but they were also common in studies reporting incidence or prevalence (51%), studies examining novel tests (41%), and association studies of nonmodifiable factors (32%).The authors of observational studies often extrapolate their results to make recommendations concerning a medical practice, typically without first calling for a RCT.

    View details for DOI 10.1016/j.jclinepi.2012.11.005

    View details for Web of Science ID 000315935100004

    View details for PubMedID 23384591

  • Patient Safety Strategies Targeted at Diagnostic Errors A Systematic Review ANNALS OF INTERNAL MEDICINE McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-?

    Abstract

    Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient-related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings.

    View details for Web of Science ID 000316058600004

    View details for PubMedID 23460094

  • Emergence of Large Treatment Effects From Small Trials Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Pereira, T. V., Horwitz, R. I. 2013; 309 (8): 768-769

    View details for Web of Science ID 000315332200015

    View details for PubMedID 23443435

  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment BRITISH MEDICAL JOURNAL Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Rehnborg, C. F. 2013; 346

    Abstract

    To compare treatment effects from randomised trials conducted in more developed versus less developed countries.Meta-epidemiological study.Cochrane Database of Systematic Reviews (August 2012).Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I(2)=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.

    View details for DOI 10.1136/bmj.f707

    View details for Web of Science ID 000315087700003

    View details for PubMedID 23403829

  • Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study PLOS ONE Stefanaki, I., Panagiotou, O. A., Kodela, E., Gogas, H., Kypreou, K. P., Chatzinasiou, F., Nikolaou, V., Plaka, M., Kalfa, I., Antoniou, C., Ioannidis, J. P., Evangelou, E., Stratigos, A. J. 2013; 8 (2)

    Abstract

    Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982--SLC45A2, rs12203592--IRF4, rs258322--CDK10, rs1805007--MC1R, rs1805008--MC1R, rs910873--PIGU, rs17305573--PIGU, and rs1885120--MTAP) and higher for one SNP (rs6001027--PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r?=?0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22-2.10; P?=?0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34-0.76; P?=?0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03-9.43; P?=?2×10??). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p?=?0.66).Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.

    View details for DOI 10.1371/journal.pone.0055712

    View details for Web of Science ID 000314692800051

    View details for PubMedID 23393597

  • Assessment of systematic effects of methodological characteristics on candidate genetic associations HUMAN GENETICS Aljasir, B., Ioannidis, J. P., Yurkiewich, A., Moher, D., Higgins, J. P., Arora, P., Little, J. 2013; 132 (2): 167-178

    Abstract

    Candidate genetic association studies have been found to have a low replication rate in the past. Here, we aimed to assess whether aspects of reported methodological characteristics in genetic association studies may be related to the magnitude of effects observed. An observational, literature-based investigation of 511 case-control studies of genetic association studies indexed in 2007, was undertaken. Meta-regression analyses were used to assess the relationship between 23 reported methodological characteristics and the magnitude of genetic associations. The 511 studies had been conducted in 52 countries and were published in 220 journals (median impact factor 5.1). The multivariate meta-regression model of methodological characteristics plus disease category accounted for 17.2 % of the between-study variance in the magnitude of the reported genetic associations. Our findings are consistent with the view that better conducted and better reported genetic association research may lead to less inflated results.

    View details for DOI 10.1007/s00439-012-1237-4

    View details for Web of Science ID 000313518900006

    View details for PubMedID 23095857

  • Distinguishing true from false positives in genomic studies: p values EUROPEAN JOURNAL OF EPIDEMIOLOGY Broer, L., Lill, C. M., Schuur, M., Amin, N., Roehr, J. T., Bertram, L., Ioannidis, J. P., van Duijn, C. M. 2013; 28 (2): 131-138

    Abstract

    Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the "Venice" criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most "positive" findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10(-3), a p value of 1 × 10(-5) yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10(-5) gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10(-4); genome-wide association studies for instance) 1 × 10(-7) may serve as a useful threshold to declare significance.

    View details for DOI 10.1007/s10654-012-9755-x

    View details for Web of Science ID 000316638900003

    View details for PubMedID 23371043

  • Effect of left ventricular ejection fraction and QRS duration on the survival benefit of implantable cardioverter-defibrillators: Meta-analysis of primary prevention trials HEART RHYTHM Katritsis, D. G., Siontis, K. C., Bigger, J. T., Kadish, A. H., Steinman, R., Zareba, W., Siontis, G. C., Bardy, G. H., Ioannidis, J. P. 2013; 10 (2): 200-206

    Abstract

    Implantable cardioverter-defibrillators (ICDs) are recommended for the primary prevention of sudden cardiac death in patients with left ventricular dysfunction, but it is unclear whether treatment benefits are diminished in patients with very low baseline left ventricular ejection fraction (LVEF) (<25%) or increased in those with prolonged QRS duration (>120 ms).To study the effects of very low LVEF and prolonged QRS duration on the mortality benefits of ICD therapy.We performed a meta-analysis of primary prevention randomized controlled trials comparing ICD and standard medical therapy. All-cause mortality hazard ratios (HRs) in subgroups according to thresholds of 25% for LVEF and 120 ms for QRS duration were extracted from published reports or contributed by trial investigators and synthesized.There was no significant difference of ICD effectiveness in LVEF subgroups of 25%-35% (random effects HR 0.81; 95% confidence interval [CI] 0.70-0.94) vs<25% (HR 0.71; 95% CI 0.55-0.93). Results were also similar in the narrow and wide QRS subgroups (HR 0.78; 95% CI 0.68-0.90 and HR 0.70; 95% CI 0.51-0.95, respectively). Within the LVEF<25% and wide QRS subgroups, there was large heterogeneity driven by the Defibrillator in Acute Myocardial Infarction Trial that included patients with early post-myocardial infarction and its results (HR 1.49; 95% CI 0.84-2.68 and HR 1.51; 95% CI 0.83-2.83, respectively) differed significantly from other trials (P = .008 and P = .01, respectively).LVEF values and QRS duration do not appear to directly modify the survival benefit of ICD in patients with baseline LVEF<35%. However, patients with a recent myocardial infarction do not benefit from ICD, especially when they have LVEF<25% and/or wide QRS.

    View details for DOI 10.1016/j.hrthm.2012.10.039

    View details for Web of Science ID 000315110500014

    View details for PubMedID 23107652

  • Opportunities and Challenges for Selected Emerging Technologies in Cancer Epidemiology: Mitochondrial, Epigenomic, Metabolomic, and Telomerase Profiling CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Verma, M., Khoury, M. J., Ioannidis, J. P. 2013; 22 (2): 189-200

    Abstract

    Remarkable progress has been made in the last decade in new methods for biologic measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, miRNAs, and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g., systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytic and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies.

    View details for DOI 10.1158/1055-9965.EPI-12-1263

    View details for Web of Science ID 000314700800002

    View details for PubMedID 23242141

  • Mega-Trials for Blockbusters JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (3): 239-240

    View details for Web of Science ID 000313546800020

    View details for PubMedID 23321760

  • Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants NATURE Fu, W., O'Connor, T. D., Jun, G., Kang, H. M., Abecasis, G., Leal, S. M., Gabriel, S., Altshuler, D., Shendure, J., Nickerson, D. A., Bamshad, M. J., Akey, J. M. 2013; 493 (7431): 216-220

    Abstract

    Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000?years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

    View details for DOI 10.1038/nature11690

    View details for Web of Science ID 000313259600038

    View details for PubMedID 23201682

  • NIH funding: the critics respond NATURE Ioannidis, J. P., Nicholson, J. M. 2013; 493 (7430): 26-26

    View details for Web of Science ID 000312933800016

    View details for PubMedID 23282353

  • Knowledge Integration in Cancer: Current Landscape and Future Prospects CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ioannidis, J. P., Schully, S. D., Lam, T. K., Khoury, M. J. 2013; 22 (1): 3-10

    Abstract

    Knowledge integration includes knowledge management, synthesis, and translation processes. It aims to maximize the use of collected scientific information and accelerate translation of discoveries into individual and population health benefits. Accumulated evidence in cancer epidemiology constitutes a large share of the 2.7 million articles on cancer in PubMed. We examine the landscape of knowledge integration in cancer epidemiology. Past approaches have mostly used retrospective efforts of knowledge management and traditional systematic reviews and meta-analyses. Systematic searches identify 2,332 meta-analyses, about half of which are on genetics and epigenetics. Meta-analyses represent 1:89-1:1162 of published articles in various cancer subfields. Recently, there are more collaborative meta-analyses with individual-level data, including those with prospective collection of measurements [e.g., genotypes in genome-wide association studies (GWAS)]; this may help increase the reliability of inferences in the field. However, most meta-analyses are still done retrospectively with published information. There is also a flurry of candidate gene meta-analyses with spuriously prevalent "positive" results. Prospective design of large research agendas, registration of datasets, and public availability of data and analyses may improve our ability to identify knowledge gaps, maximize and accelerate translational progress or-at a minimum-recognize dead ends in a more timely fashion.

    View details for DOI 10.1158/1055-9965.EPI-12-1144

    View details for Web of Science ID 000313531900001

    View details for PubMedID 23093546

  • Practices and impact of primary outcome adjustment in randomized controlled trials: meta-epidemiologic study. BMJ (Clinical research ed.) Saquib, N., Saquib, J., Ioannidis, J. P. 2013; 347: f4313

    Abstract

    To assess adjustment practices for primary outcomes of randomized controlled trials and their impact on the results.Meta-epidemiologic study.25 biomedical journals with the highest impact factor according to Journal Citation Reports 2009.Randomized controlled trials published in print in 2009 that reported primary outcomes. The search yielded 684 eligible papers of randomized controlled trials, of which 200 were randomly selected.Two researchers independently extracted data on study population, intervention, primary outcome, and the adjustment plan for primary outcomes. They also recorded the magnitude and statistical significance of the intervention effect with and without adjustments, and estimated whether adjustment made a difference in the level of nominal significance. They also compared the analysis plan for model adjustment in the published trial versus the trial protocol with information on the protocol collected from registries, design papers, and communication with all corresponding authors.54% of the trials used stratified randomization, 96% presented baseline characteristics in the compared arms, and 46% also evaluated differences in baseline factors with statistical testing. Half of the trials performed adjusted analyses for the main outcome, as the sole analysis (29%) or along with unadjusted analyses (21%). Adjustment for stratification variables and for baseline variables was performed in 39% (42/108) and 42% (84/199) of the trials, respectively. Among 40 comparisons with both adjusted and unadjusted analyses, 43% had statistically significant effects, 40% had non-significant effects, and 18% had significant effects with only one of the two analyses, but not with the other. Information on analysis plan regarding model adjustment was available in 6% (9/162) of trial registry entries, 78% (21/27) of design papers, and 74% (40/54) of protocols obtained from authors. The analysis plan disagreed between the published trial and the registry, protocol, or design paper in 47% (28/60) of the studies.There is large diversity on whether and how analyses of primary outcomes are adjusted in randomized controlled trials and these choices can sometimes change the nominal significance of the results. Registered protocols should explicitly specify adjustments plans for main outcomes and analysis should follow these plans.

    View details for PubMedID 23851720

  • Is everything we eat associated with cancer? A systematic cookbook review AMERICAN JOURNAL OF CLINICAL NUTRITION Schoenfeld, J. D., Loannidis, J. P. 2013; 97 (1): 127-134

    Abstract

    Nutritional epidemiology is a highly prolific field. Debates on associations of nutrients with disease risk are common in the literature and attract attention in public media.We aimed to examine the conclusions, statistical significance, and reproducibility in the literature on associations between specific foods and cancer risk.We selected 50 common ingredients from random recipes in a cookbook. PubMed queries identified recent studies that evaluated the relation of each ingredient to cancer risk. Information regarding author conclusions and relevant effect estimates were extracted. When >10 articles were found, we focused on the 10 most recent articles.Forty ingredients (80%) had articles reporting on their cancer risk. Of 264 single-study assessments, 191 (72%) concluded that the tested food was associated with an increased (n = 103) or a decreased (n = 88) risk; 75% of the risk estimates had weak (0.05 > P ? 0.001) or no statistical (P > 0.05) significance. Statistically significant results were more likely than nonsignificant findings to be published in the study abstract than in only the full text (P < 0.0001). Meta-analyses (n = 36) presented more conservative results; only 13 (26%) reported an increased (n = 4) or a decreased (n = 9) risk (6 had more than weak statistical support). The median RRs (IQRs) for studies that concluded an increased or a decreased risk were 2.20 (1.60, 3.44) and 0.52 (0.39, 0.66), respectively. The RRs from the meta-analyses were on average null (median: 0.96; IQR: 0.85, 1.10).Associations with cancer risk or benefits have been claimed for most food ingredients. Many single studies highlight implausibly large effects, even though evidence is weak. Effect sizes shrink in meta-analyses.

    View details for DOI 10.3945/ajcn.112.047142

    View details for Web of Science ID 000313135600018

    View details for PubMedID 23193004

  • Confidence and precision increase with high statistical power. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (8): 585

    View details for PubMedID 23820778

  • Demystifying trial networks and network meta-analysis. BMJ (Clinical research ed.) Mills, E. J., Thorlund, K., Ioannidis, J. P. 2013; 346: f2914-?

    View details for DOI 10.1136/bmj.f2914

    View details for PubMedID 23674332

  • Appropriate vs Clinically Useful Diagnostic Tests. JAMA internal medicine Ioannidis, J. P. 2013

    View details for PubMedID 23877418

  • Expressing Death Risk as Condensed Life Experience and Death Intensity. Medical decision making : an international journal of the Society for Medical Decision Making Ioannidis, J. P. 2013

    Abstract

    Some risk exposures, including many medical and surgical procedures, typically carry hazards of death that are difficult to convey and appreciate in absolute terms. I propose presenting the death risk as a condensed life experience (i.e., the equivalent amount of life T that would carry the same cumulative mortality hazard for a person of the same age and sex based on life tables). For example, if the risk of death during an elective 1-hour procedure is 0.01%, and same-age and same-sex people have a 0.01% death risk over 1 month, one can inform the patient that "this procedure carries the same death risk as living 1 month of normal life." Comparative standards from other risky activities or from a person with the same disease at the same stage and same predictive profile could also be used. A complementary metric that may be useful to consider is the death intensity. The death intensity ? is the hazard function that shows the fold-risk estimate of dying compared with the reference person. The death intensity can vary substantially for different phases of the event, operation, or procedure (e.g., intraoperative, early postoperative, late postoperative), and this variability may also be useful to convey. T will vary depending on the time window for which it is computed. I present examples for calculating T and ? using literature data on accidents, ascent to Mount Everest, and medical and surgical procedures.

    View details for PubMedID 23579043

  • Are randomized trials obsolete or more important than ever in the genomic era? Genome medicine Ioannidis, J. P., Khoury, M. J. 2013; 5 (4): 32

    View details for PubMedID 23673134

  • Trends in citations to books on epidemiological and statistical methods in the biomedical literature. PloS one Porta, M., Vandenbroucke, J. P., Ioannidis, J. P., Sanz, S., Fernandez, E., Bhopal, R., Morabia, A., Victora, C., Lopez, T. 2013; 8 (5)

    Abstract

    There are no analyses of citations to books on epidemiological and statistical methods in the biomedical literature. Such analyses may shed light on how concepts and methods changed while biomedical research evolved. Our aim was to analyze the number and time trends of citations received from biomedical articles by books on epidemiological and statistical methods, and related disciplines.The data source was the Web of Science. The study books were published between 1957 and 2010. The first year of publication of the citing articles was 1945. We identified 125 books that received at least 25 citations. Books first published in 1980-1989 had the highest total and median number of citations per year. Nine of the 10 most cited texts focused on statistical methods. Hosmer & Lemeshow's Applied logistic regression received the highest number of citations and highest average annual rate. It was followed by books by Fleiss, Armitage, et al., Rothman, et al., and Kalbfleisch and Prentice. Fifth in citations per year was Sackett, et al., Evidence-based medicine. The rise of multivariate methods, clinical epidemiology, or nutritional epidemiology was reflected in the citation trends. Educational textbooks, practice-oriented books, books on epidemiological substantive knowledge, and on theory and health policies were much less cited. None of the 25 top-cited books had the theoretical or sociopolitical scope of works by Cochrane, McKeown, Rose, or Morris.Books were mainly cited to reference methods. Books first published in the 1980s continue to be most influential. Older books on theory and policies were rooted in societal and general medical concerns, while the most modern books are almost purely on methods.

    View details for DOI 10.1371/journal.pone.0061837

    View details for PubMedID 23667447

  • The Power of Meta-Analysis in Genome-Wide Association Studies ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 14 Panagiotou, O. A., Willer, C. J., Hirschhorn, J. N., Ioannidis, J. P. 2013; 14: 441-465

    Abstract

    Meta-analysis of multiple genome-wide association (GWA) studies has become common practice over the past few years. The main advantage of this technique is the maximization of power to detect subtle genetic effects for common traits. Moreover, one can use meta-analysis to probe and identify heterogeneity in the effect sizes across the combined studies. In this review, we systematically appraise and evaluate the characteristics of GWA meta-analyses with 10,000 or more subjects published up to June 2012. We provide an overview of the current landscape of variants discovered by GWA meta-analyses, and we discuss and assess with extrapolations from empirical data the value of larger meta-analyses for the discovery of additional genetic associations and new biology in the future. Finally, we discuss some emerging logistical and practical issues related to the conduct of meta-analysis of GWA studies. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

    View details for DOI 10.1146/annurev-genom-091212-153520

    View details for Web of Science ID 000326658500020

    View details for PubMedID 23724904

  • Evaluating Health System Processes With Randomized Controlled Trials. JAMA internal medicine Ioannidis, J. P., Prasad, V. 2013: 1-2

    View details for PubMedID 23689271

  • The geometric increase in meta-analyses from china in the genomic era. PloS one Ioannidis, J. P., Chang, C. Q., Lam, T. K., Schully, S. D., Khoury, M. J. 2013; 8 (6)

    Abstract

    Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.

    View details for DOI 10.1371/journal.pone.0065602

    View details for PubMedID 23776510

  • Meta-analyses of hydroxyethyl starch for volume resuscitation. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013; 309 (21): 2209

    View details for PubMedID 23736722

  • Biomarker Failures CLINICAL CHEMISTRY Ioannidis, J. P. 2013; 59 (1): 202-204

    View details for DOI 10.1373/clinchem.2012.185801

    View details for Web of Science ID 000313535100033

    View details for PubMedID 22997282

  • This I believe in genetics: discovery can be a nuisance, replication is science, implementation matters. Frontiers in genetics Ioannidis, J. P. 2013; 4: 33-?

    View details for DOI 10.3389/fgene.2013.00033

    View details for PubMedID 23505393

  • Assessment of osteoarthritis candidate genes in a meta-analysis of 9 genome-wide association studies. Arthritis and rheumatism Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garces, C. M., Gomez-Reino, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2013

    Abstract

    Objectives: To assess osteoarthritis (OA) candidate genes for identification of promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods: 199 published candidate genes for OA were obtained from the HuGe Navigator. All their SNPs with allele frequency >5% were assessed with fixed effect meta-analysis of 9 genome-wide association studies (GWAS) including 5 636 knee OA patients and 16 972 controls, and 4 349 hip OA patients and 17 836 controls of European ancestry. Additional 5 921 individuals were studied for top SNPs in the meta-analysis. Significance was corrected for the number of independent tests at p < 1.58 x 10(-5) . Results: SNPs at only two of the 199 candidate genes were associated with OA in the meta-analysis. They were associated with hip OA, COL11A1 showing two independent associations in the combined analysis (rs4907986, p = 1.29 x 10(-5) , OR = 1.12; 95 % CI = 1.06-1.17; and rs1241164, p = 1.47 x 10(-5) , OR = 0.82, CI = 0.74-0.89) and a SNP in linkage disequilibrium with rs4907986 in the female-specific analysis (rs4908291, p = 1.29 x 10(-5) , OR = 0.87, CI = 0.82-0.92), and VEGF associated in male-specific analysis (rs833058, p = 1.35 x 10(-5) , OR = 0.85, CI = 0.79-0.91). After genotyping additional samples, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion: Two candidate genes were significantly associated with OA in this focused meta-analysis COL11A1 and VEGF. The remaining candidate genes were not associated. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24338622

  • Potential reporting bias in FMRI studies of the brain. PloS one David, S. P., Ware, J. J., Chu, I. M., Loftus, P. D., Fusar-Poli, P., Radua, J., Munafò, M. R., Ioannidis, J. P. 2013; 8 (7)

    Abstract

    Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation.There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.

    View details for DOI 10.1371/journal.pone.0070104

    View details for PubMedID 23936149

  • A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. Annals of the rheumatic diseases Evangelou, E., Kerkhof, H. J., Styrkarsdottir, U., Ntzani, E. E., Bos, S. D., Esko, T., Evans, D. S., Metrustry, S., Panoutsopoulou, K., Ramos, Y. F., Thorleifsson, G., Tsilidis, K. K., Arden, N., Aslam, N., Bellamy, N., Birrell, F., Blanco, F. J., Carr, A., Chapman, K., Day-Williams, A. G., Deloukas, P., Doherty, M., Engström, G., Helgadottir, H. T., Hofman, A., Ingvarsson, T., Jonsson, H., Keis, A., Keurentjes, J. C., Kloppenburg, M., Lind, P. A., McCaskie, A., Martin, N. G., Milani, L., Montgomery, G. W., Nelissen, R. G., Nevitt, M. C., Nilsson, P. M., Ollier, W. E., Parimi, N., Rai, A., Ralston, S. H., Reed, M. R., Riancho, J. A., Rivadeneira, F., Rodriguez-Fontenla, C., Southam, L., Thorsteinsdottir, U., Tsezou, A., Wallis, G. A., Wilkinson, J. M., Gonzalez, A., Lane, N. E., Lohmander, L. S., Loughlin, J., Metspalu, A., Uitterlinden, A. G., Jonsdottir, I., Stefansson, K., Slagboom, P. E., Zeggini, E., Meulenbelt, I., Ioannidis, J. P., Spector, T. D., van Meurs, J. B., Valdes, A. M. 2013

    Abstract

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

    View details for DOI 10.1136/annrheumdis-2012-203114

    View details for PubMedID 23989986

  • Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human brain mapping Fusar-Poli, P., Radua, J., Frascarelli, M., Mechelli, A., Borgwardt, S., Di Fabio, F., Biondi, M., Ioannidis, J. P., David, S. P. 2013

    Abstract

    To evaluate whether biases may influence the findings of whole-brain structural imaging literature.Forty-seven whole-brain voxel-based meta-analyses including voxel-based morphometry (VBM) studies in neuropsychiatric conditions were included, for a total of 324 individual VBM studies. The total sample size, the overall number of foci, and different moderators were extracted both at the level of the individual studies and at the level of the meta-analyses.Sample size ranged from 12 to 545 (median n = 47) per VBM study. The median number of reported foci per study was six. VBM studies with larger sample sizes reported only slightly more abnormalities than smaller studies (2% increase in the number of foci per 10-patients increase in sample size). A similar pattern was seen in several analyses according to different moderator variables with some possible modulating evidence for the statistical threshold employed, publication year and number of coauthors. Whole-brain meta-analyses (median sample size n = 534) found fewer foci (median = 3) than single studies and overall they showed no significant increase in the number of foci with increasing sample size. Meta-analyses with ≥10 VBM studies reported a median of three foci and showed a significant increase with increasing sample size, while there was no relationship between sample size and number of foci (median = 5) in meta-analyses with <10 VBM studies.The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.22384

    View details for PubMedID 24123491

  • More Than a Billion People Taking Statins?: Potential Implications of the New Cardiovascular Guidelines. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013

    View details for DOI 10.1001/jama.2013.284657

    View details for PubMedID 24296612

  • Systematic identification of interaction effects between validated genome- and environment-wide associations on Type 2 Diabetes Mellitus. AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 2013: 135-?

    View details for PubMedID 24303322

  • Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ (Clinical research ed.) Naci, H., Ioannidis, J. P. 2013; 347: f5577

    Abstract

    To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11, 1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

    View details for PubMedID 24473061

  • Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. Human molecular genetics Gordon, A. S., Tabor, H. K., Johnson, A. D., Snively, B. M., Assimes, T. L., Auer, P. L., Ioannidis, J. P., Peters, U., Robinson, J. G., Sucheston, L. E., Wang, D., Sotoodehnia, N., Rotter, J. I., Psaty, B. M., Jackson, R. D., Herrington, D. M., O'Donnell, C. J., Reiner, A. P., Rich, S. S., Rieder, M. J., Bamshad, M. J., Nickerson, D. A. 2013

    Abstract

    The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

    View details for DOI 10.1093/hmg/ddt588

    View details for PubMedID 24282029

  • How Many Contemporary Medical Practices Are Worse Than Doing Nothing or Doing Less? Mayo Clinic proceedings. Mayo Clinic Ioannidis, J. P. 2013

    View details for PubMedID 23871231

  • Narrow band imaging to differentiate neoplastic and non-neoplastic colorectal polyps in real time: a meta-analysis of diagnostic operating characteristics. Gut McGill, S. K., Evangelou, E., Ioannidis, J. P., Soetikno, R. M., Kaltenbach, T. 2013

    Abstract

    PURPOSE: Many studies have reported on the use of narrow band imaging (NBI) colonoscopy to differentiate neoplastic from non-neoplastic colorectal polyps. It has potential to replace pathological diagnosis of diminutive polyps. We aimed to perform a systematic review and meta-analysis on the real-time diagnostic operating characteristics of NBI colonoscopy. METHODS: We searched PubMed, SCOPUS and Cochrane databases and abstracts. We used a two-level bivariate meta-analysis following a random effects model to summarise the data and fit hierarchical summary receiver-operating characteristic (HSROC) curves. The area under the HSROC curve serves as an indicator of the diagnostic test strength. We calculated summary sensitivity, specificity and negative predictive value (NPV). We assessed agreement of surveillance interval recommendations based on endoscopic diagnosis compared to pathology. RESULTS: For NBI diagnosis of colorectal polyps, the area under the HSROC curve was 0.92 (95% CI 0.90 to 0.94), based on 28 studies involving 6280 polyps in 4053 patients. The overall sensitivity was 91.0% (95% CI 87.6% to 93.5%) and specificity was 82.6% (95% CI 79.0% to 85.7%). In eight studies (n=2146 polyps) that used high-confidence diagnostic predictions, sensitivity was 93.8% and specificity was 83.3%. The NPVs exceeded 90% when 60% or less of all polyps were neoplastic. Surveillance intervals based on endoscopic diagnosis agreed with those based on pathology in 92.6% of patients (95% CI 87.9% to 96.3%). CONCLUSIONS: NBI diagnosis of colorectal polyps is highly accurate-the area under the HSROC curve exceeds 0.90. High-confidence predictions provide >90% sensitivity and NPV. It shows high potential for real-time endoscopic diagnosis.

    View details for PubMedID 23300139

  • Research grants: Conform and be funded. Nature Nicholson, J. M., Ioannidis, J. P. 2012; 492 (7427): 34-36

    View details for DOI 10.1038/492034a

    View details for PubMedID 23222591

  • Scientific inbreeding and same-team replication: Type D personality as an example JOURNAL OF PSYCHOSOMATIC RESEARCH Ioannidis, J. P. 2012; 73 (6): 408-410

    Abstract

    Replication is essential for validating correct results, sorting out false-positive early discoveries, and improving the accuracy and precision of estimated effects. However, some types of seemingly successful replication may foster a spurious notion of increased credibility, if they are performed by the same team and propagate or extend the same errors made by the original discoveries. Besides same-team replication, replication by other teams may also succumb to inbreeding, if it cannot fiercely maintain its independence. These patterns include obedient replication and obliged replication. I discuss these replication patterns in the context of associations and effects in the psychological sciences, drawing from the criticism of Coyne and de Voogd of the proposed association between type D personality and cardiovascular mortality and other empirical examples.

    View details for DOI 10.1016/j.jpsychores.2012.09.014

    View details for Web of Science ID 000311465500002

    View details for PubMedID 23148806

  • METRADISC-XL: A program for meta-analysis of multidimensional ranked discovery oriented datasets including microarrays COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Zintzaras, E., Ioannidis, J. P. 2012; 108 (3): 1243-1246

    Abstract

    A comprehensive software for performing meta-analysis of ranked discovery oriented datasets, such as those derived from microarrays or other high throughput technologies, and for testing between-study heterogeneity for biological variables (gene expression, microRNA, proteomic, or other high-dimensional data) is presented. The software can identify biological probes that have either very high average ranks (e.g. consistently over-expressed genes) or very low average ranks (e.g. consistently under-expressed genes). The program tests each probe's average rank and the between-study heterogeneity of the study-specific ranks. Furthermore, it performs heterogeneity analyses restricted to probes with similar average ranks. The program allows both unweighted and weighted analysis. Statistical inferences are based on Monte Carlo permutation tests.

    View details for DOI 10.1016/j.cmpb.2012.08.001

    View details for Web of Science ID 000311976100033

    View details for PubMedID 22959629

  • Reproducibility concerns NATURE MEDICINE Ioannidis, J. P., Nosek, B., Iorns, E. 2012; 18 (12): 1736-1736

    View details for DOI 10.1038/nm.3020

    View details for Web of Science ID 000311999800011

    View details for PubMedID 23223056

  • Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Staines-Urias, E., Paez, M. C., Doyle, P., Dudbridge, F., Serrano, N. C., Ioannidis, J. P., Keating, B. J., Hingorani, A. D., Casas, J. P. 2012; 41 (6): 1764-1775

    Abstract

    Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies.To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia.For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models.Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations.To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.

    View details for DOI 10.1093/ije/dys162

    View details for Web of Science ID 000313128000033

    View details for PubMedID 23132613

  • Perceived information gain from randomized trials correlates with publication in high-impact factor journals JOURNAL OF CLINICAL EPIDEMIOLOGY Evangelou, E., Siontis, K. C., Pfeiffer, T., Ioannidis, J. P. 2012; 65 (12): 1274-1281

    Abstract

    To examine whether perceived information gain (IG) drives the publication of randomized trials in high-impact factor (IF) journals.We estimated IG as the Kullback-Leibler divergence, quantifying how much a new finding changes established knowledge. We used 67 meta-analyses (964 randomized trials) that include one or more trials from any of the three highest IF general medical journals (NEJM, JAMA, and Lancet). We calculated IG for the presence of a non-null effect (IG(1)) and IG for the effect size magnitude (IG(2)).Across meta-analyses, the summary correlation coefficient of IF was 0.23 (95% confidence interval [CI]: 0.14, 0.31) for IG(1) and 0.35 (95% CI: 0.25, 0.46) for IG(2). IF also correlated with the P-value of the results (r=0.18), order of publication (r=-0.13), and number of events in the trial (r=0.36). Multivariate regression including IG, order of publication, P-value, and the number of events showed that IG is an independent correlate of IF. IG(2) explained a substantially larger proportion of the variance in IF than IG(1).Publication in journals with high IF is driven by how extensively the results of a study change prior perceptions of the evidence, independently of the statistical significance and size of the study.

    View details for DOI 10.1016/j.jclinepi.2012.06.009

    View details for Web of Science ID 000310669400009

    View details for PubMedID 22959593

  • Calculating additive treatment effects from multiple randomized trials provides useful estimates of combination therapies JOURNAL OF CLINICAL EPIDEMIOLOGY Mills, E. J., Thorlund, K., Ioannidis, J. P. 2012; 65 (12): 1282-1288

    Abstract

    Many clinicians and decision makers want to know the combined effects of treatments that have not been evaluated in combination. It is possible to determine such treatment effects by making assumptions about the additive effects. We discuss here the prerequisites and methods of applying additivity assumptions in synthesizing the evidence from randomized trials and multiple treatment meta-analyses.Using statistical approaches, we demonstrate the utility of additivity of both pairwise randomized trials and multiple treatment comparison meta-analyses.We present illustratively an example on estimating the treatment effects of drug combinations for chronic obstructive pulmonary disease. We confirm the additive treatment effects by comparing with direct combination treatment trial results.Additive effects may be a useful tool to estimate the effectiveness of treatment combinations.

    View details for DOI 10.1016/j.jclinepi.2012.07.012

    View details for Web of Science ID 000310669400010

    View details for PubMedID 22981250

  • Evaluation of Excess Statistical Significance in Meta-analyses of 98 Biomarker Associations with Cancer Risk JOURNAL OF THE NATIONAL CANCER INSTITUTE Tsilidis, K. K., Papatheodorou, S. I., Evangelou, E., Ioannidis, J. P. 2012; 104 (24): 1867-1878

    Abstract

    Numerous biomarkers have been associated with cancer risk. We assessed whether there is evidence for excess statistical significance in results of cancer biomarker studies, suggesting biases.We systematically searched PubMed for meta-analyses of nongenetic biomarkers and cancer risk. The number of observed studies with statistically significant results was compared with the expected number, based on the statistical power of each study under different assumptions for the plausible effect size. We also evaluated small-study effects using asymmetry tests. All statistical tests were two-sided.We included 98 meta-analyses with 847 studies. Forty-three meta-analyses (44%) found nominally statistically significant summary effects (random effects). The proportion of meta-analyses with statistically significant effects was highest for infectious agents (86%), inflammatory (67%), and insulin-like growth factor (IGF)/insulin system (52%) biomarkers. Overall, 269 (32%) individual studies observed nominally statistically significant results. A statistically significant excess of the observed over the expected number of studies with statistically significant results was seen in 20 meta-analyses. An excess of observed vs expected was observed in studies of IGF/insulin (P ? .04) and inflammation systems (P ? .02). Only 12 meta-analyses (12%) had a statistically significant summary effect size, more than 1000 case patients, and no hints of small-study effects or excess statistical significance; only four of them had large effect sizes, three of which pertained to infectious agents (Helicobacter pylori, hepatitis and human papilloma viruses).Most well-documented biomarkers of cancer risk without evidence of bias pertain to infectious agents. Conversely, an excess of statistically significant findings was observed in studies of IGF/insulin and inflammation systems, suggesting reporting biases.

    View details for DOI 10.1093/jnci/djs437

    View details for Web of Science ID 000312891200007

    View details for PubMedID 23090067

  • There is nothing personal-reply. Archives of internal medicine Ioannidis, J. P. 2012; 172 (21): 1691-1692

    View details for DOI 10.1001/2013.jamainternmed.13

    View details for PubMedID 23753076

  • A Nutrient-Wide Association Study on Blood Pressure CIRCULATION Tzoulaki, I., Patel, C. J., Okamura, T., Chan, Q., Brown, I. J., Miura, K., Ueshima, H., Zhao, L., Van Horn, L., Daviglus, M. L., Stamler, J., Butte, A. J., Ioannidis, J. P., Elliott, P. 2012; 126 (21): 2456-2464

    Abstract

    A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner.Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP.We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

    View details for DOI 10.1161/CIRCULATIONAHA.112.114058

    View details for Web of Science ID 000311342600010

    View details for PubMedID 23093587

  • Content area experts as authors: helpful or harmful for systematic reviews and meta-analyses? BRITISH MEDICAL JOURNAL Gotzsche, P. C., Ioannidis, J. P. 2012; 345

    View details for DOI 10.1136/bmj.e7031

    View details for Web of Science ID 000310779000003

    View details for PubMedID 23118303

  • Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J. H., Boletis, J., Cervera, R., Doerner, T., Doria, A., Ferrario, F., Floege, J., Houssiau, F. A., Ioannidis, J. P., Isenberg, D. A., Kallenberg, C. G., Lightstone, L., Marks, S. D., Martini, A., Moroni, G., Neumann, I., Praga, M., Schneider, M., Starra, A., Tesar, V., Vasconcelos, C., Van Vollenhoven, R. F., Zakharova, H., Haubitz, M., Gordon, C., Jayne, D., Boumpas, D. T. 2012; 71 (11): 1771-1782

    Abstract

    To develop recommendations for the management of adult and paediatric lupus nephritis (LN).The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

    View details for DOI 10.1136/annrheumdis-2012-201940

    View details for Web of Science ID 000309654900004

    View details for PubMedID 22851469

  • To Correct or Not to Correct-and How EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 912-913

    View details for DOI 10.1097/EDE.0b013e31826cc1b3

    View details for Web of Science ID 000309965800024

    View details for PubMedID 23038115

  • Correction of Phenotype Misclassification Based on High-Discrimination Genetic Predictive Risk Models EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 902-909

    Abstract

    Misclassification of phenotype status can seriously affect accuracy in association studies, including studies of genetic risk factors. A common problem is the classification of participants as nondiseased because of insufficient diagnostic workup or because participants have not been followed up long enough to develop disease. Some validated predictive models may have high discrimination in predicting disease. We suggest that information from such models can be used to predict the risk that a nondiseased participant will eventually develop disease and to recode the status of participants predicted to be at highest risk. We evaluate conditions under which recoding results in a maximal net improvement in the accuracy of phenotype classification. Net improvement is expected only when the positive likelihood ratio of the predictive model is larger than the inverse of the odds of disease among apparently nondiseased controls. We conducted simulations to probe the impact of reclassification on the power to detect new risk factors under several scenarios of classification accuracy of the previously developed models. We also apply this framework to a validated model of progression to advanced age-related macular degeneration that uses genetic and nongenetic variables (area under the curve = 0.915). In the training cohort (n = 2,937) and a separate validation cohort (n = 1,227), 195-272 and 78-91 nonprogressor participants, respectively, were reclassified as progressors. Correction of phenotype misclassification based on highly informative predictive models may be helpful in identifying additional genetic and other risk factors, when there are validated risk factors that provide strong discriminating ability.

    View details for DOI 10.1097/EDE.0b013e31826c3129

    View details for Web of Science ID 000309965800022

    View details for PubMedID 23023008

  • A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants JOURNAL OF MEDICAL GENETICS Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Bertram, L., Bozi, M., Barcikowska, M., Crosiers, D., Clarke, C. E., Facheris, M. F., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Guell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B. S., Jamrozik, Z., Krygowska-Wajs, A., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Libioulle, C., Murata, M., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Meitnger, T., Zimprich, A., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Strom, T. M., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Van Broeckhoven, C., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yomono, H. S., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 49 (11): 721-726

    Abstract

    Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

    View details for DOI 10.1136/jmedgenet-2012-101155

    View details for Web of Science ID 000310632800008

    View details for PubMedID 23125461

  • Empirical Evaluation of Very Large Treatment Effects of Medical Interventions JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pereira, T. V., Horwitz, R. I., Ioannidis, J. P. 2012; 308 (16): 1676-1684

    Abstract

    Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms.To evaluate the frequency and features of very large effects in medicine.Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7).We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ?5). We also sampled randomly 250 topics from each group for further in-depth evaluation.We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses.Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns).Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

    View details for Web of Science ID 000310434100022

    View details for PubMedID 23093165

  • Neglected tropical diseases: survey and geometry of randomised evidence BRITISH MEDICAL JOURNAL Kappagoda, S., Ioannidis, J. P. 2012; 345

    Abstract

    To assess the quantity and distribution of evidence from randomised controlled trials for the treatment of the major neglected tropical diseases and to identify gaps in the evidence with network analysis.Systematic review and network analysis.Cochrane Central Register of Controlled Trials and PubMed from inception to 31 August 2011.Randomised controlled trials that examined treatment of 16 neglected tropical diseases or complications thereof published in English, French, Spanish, Portuguese, German, or Dutch.We identified 971 eligible randomised trials. Leishmaniasis (184 trials, 23,039 participants) and geohelminth infections; 160 trials, 46,887 participants) were the most studied, while dracunculiasis (nine trials, 798 participants) and Buruli ulcer (five trials, 337 participants) were least studied. Relative to its global burden of disease, lymphatic filariasis had the fewest trials and participants. Only 11% of trials were industry funded. Either a single trial or trials with fewer than 100 participants comprised the randomised evidence for first or second line treatments for Buruli ulcer, human African trypanosomiasis, American trypanosomiasis, cysticercosis, rabies, echinococcosis, New World cutaneous leishmaniasis, and each of the foodborne trematode infections. Among the 10 disease categories with more than 40 trials, five lacked sufficient head to head comparisons between first or second line treatments.There is considerable variation in the amount of evidence from randomised controlled trials for each of the 16 major neglected tropical diseases. Even in diseases with substantial evidence, such as leishmaniasis and geohelminth infections, some recommended treatments have limited supporting data and lack head to head comparisons.

    View details for DOI 10.1136/bmj.e6512

    View details for Web of Science ID 000310426900001

    View details for PubMedID 23089149

  • Sex-specific differences in effect size estimates at established complex trait loci INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Orozco, G., Ioannidis, J. P., Morris, A., Zeggini, E. 2012; 41 (5): 1376-1382

    Abstract

    Genetic differences between men and women may contribute to sex differences in prevalence and progression of many common complex diseases. Using the WTCCC GWAS, we analysed whether there are sex-specific differences in effect size estimates at 142 established loci for seven complex diseases: rheumatoid arthritis, type 1 diabetes (T1D), Crohn's disease, type 2 diabetes (T2D), hypertension, coronary artery disease and bipolar disorder.For each Single nucleotide polymorphism (SNP), we calculated the per-allele odds ratio for each sex and the relative odds ratios (RORs; the effect size is higher in men with ROR greater than one). RORs were then meta-analysed across loci within each disease and across diseases.For each disease, summary RORs were not different from one, but there was between-SNP heterogeneity in the RORs for T1D and T2D. Four loci in T1D, three in Crohn's disease and three in T2D showed differences in the genetic effect between men and women (P<0.05). We probed these differences in additional independent replication samples for T1D and T2D. The differences remained for the T1D loci CTSH, 17q21 and 20p13 and the T2D locus BCL11A, when WTCCC data and replication data were meta-analysed. Only CTSH showed different genetic effect between men and women in the replication data alone.Our results exclude the presence of large and frequent differences in the effect size estimates between men and women for the established loci in the seven common diseases explored. Documenting small differences in genetic effects between men and women requires large studies and systematic evaluation.

    View details for DOI 10.1093/ije/dys104

    View details for Web of Science ID 000309922700023

    View details for PubMedID 22825589

  • Assessment of gene-by-sex interaction effect on bone mineral density JOURNAL OF BONE AND MINERAL RESEARCH Liu, C., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., Minster, R. L., Carless, M. A., Kammerer, C. M., Oei, L., Zhou, Y., Alonso, N., Dailiana, Z., Eriksson, J., Garcia-Giralt, N., Giroux, S., Husted, L. B., Khusainova, R. I., Koromila, T., Kung, A. W., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nogues, X., Patel, M. S., Prezelj, J., Richards, J. B., Sham, P. C., Spector, T., Vandenput, L., Xiao, S., Zheng, H., Zhu, K., Balcells, S., Brandi, M. L., Frost, M., Goltzman, D., Gonzalez-Macias, J., Karlsson, M., Khusnutdinova, E. K., Kollia, P., Langdahl, B. L., Ljunggren, O., Lorentzon, M., Marc, J., Mellstroem, D., Ohlsson, C., Olmos, J. M., Ralston, S. H., Riancho, J. A., Rousseau, F., Urreizti, R., Van Hul, W., Zarrabeitia, M. T., Castano-Betancourt, M., Demissie, S., Grundberg, E., Herrera, L., Kwan, T., Medina-Gomez, C., Pastinen, T., Sigurdsson, G., Thorleifsson, G., Vanmeurs, J. B., Blangero, J., Hofman, A., Liu, Y., Mitchell, B. D., O'Connell, J. R., Oostra, B. A., Rotter, J. I., Stefansson, K., Streeten, E. A., Styrkarsdottir, U., Thorsteinsdottir, U., Tylavsky, F. A., Uitterlinden, A., Cauley, J. A., Harris, T. B., Ioannidis, J. P., Psaty, B. M., Robbins, J. A., Zillikens, M. C., Vanduijn, C. M., Prince, R. L., Karasik, D., Rivadeneira, F., Kiel, D. P., Cupples, L. A., Hsu, Y. 2012; 27 (10): 2051-2064

    Abstract

    Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p?

    View details for DOI 10.1002/jbmr.1679

    View details for Web of Science ID 000308925800003

    View details for PubMedID 22692763

  • How to use an article reporting a multiple treatment comparison meta-analysis. JAMA : the journal of the American Medical Association Mills, E. J., Ioannidis, J. P., Thorlund, K., Schünemann, H. J., Puhan, M. A., Guyatt, G. H. 2012; 308 (12): 1246-1253

    Abstract

    Multiple treatment comparison (MTC) meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining. This article uses the existing Users' Guides format to address study validity, interpretation of results, and application to a patient scenario.

    View details for PubMedID 23011714

  • Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials ANNALS OF INTERNAL MEDICINE Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Jueni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N. J., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 157 (6): 429-U97

    Abstract

    Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

    View details for Web of Science ID 000308912800017

    View details for PubMedID 22945832

  • Extrapolating from Animals to Humans SCIENCE TRANSLATIONAL MEDICINE Ioannidis, J. P. 2012; 4 (151)

    Abstract

    Because of a variety of caveats, the safety and effectiveness of interventions in human subjects can only be speculated from animal studies. Careful synthesis of data from multiple animal studies is needed to begin to assess the likelihood of successful cross-species translation (Fay et al., this issue).

    View details for DOI 10.1126/scitranslmed.3004631

    View details for Web of Science ID 000308806000002

    View details for PubMedID 22972841

  • Implementation of proteomic biomarkers: making it work EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Mischak, H., Ioannidis, J. P., Argiles, A., Attwood, T. K., Bongcam-Rudloff, E., Broenstrup, M., Charonis, A., Chrousos, G. P., Delles, C., Dominiczak, A., Dylag, T., Ehrich, J., Egido, J., Findeisen, P., Jankowski, J., Johnson, R. W., Julien, B. A., Lankisch, T., Leung, H. Y., Maahs, D., Magni, F., Manns, M. P., Manolis, E., Mayer, G., Navis, G., Novak, J., Ortiz, A., Persson, F., Peter, K., Riese, H. H., Rossing, P., Sattar, N., Spasovski, G., Thongboonkerd, V., Vanholder, R., Schanstra, J. P., Vlahou, A. 2012; 42 (9): 1027-1036

    Abstract

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

    View details for DOI 10.1111/j.1365-2362.2012.02674.x

    View details for Web of Science ID 000307473300014

    View details for PubMedID 22519700

  • Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study LANCET Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N. W., Day-Williams, A. G., Lopes, M. C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J. J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H. J., Kloppenburg, M., Bos, S. D., Mangino, M., Metrustry, S., Slagboom, P. E., Thorleifsson, G., Raine, E. V., Ratnayake, M., Ricketts, M., Beazley, C., Blackburn, H., Bumpstead, S., Elliott, K. S., Hunt, S. E., Potter, S. C., Shin, S., Yadav, V. K., Zhai, G., Sherburn, K., Dixon, K., Arden, E., Aslam, N., Battley, P., Carluke, I., Doherty, S., Gordon, A., Joseph, J., Keen, R., Koller, N. C., Mitchell, S., O'Neill, F., Paling, E., Reed, M. R., Rivadeneira, F., Swift, D., Walker, K., Watkins, B., Wheeler, M., Birrell, F., Ioannidis, J. P., Meulenbelt, I., Metspalu, A., Rai, A., Salter, D., Stefansson, K., Styrkarsdottir, U., Uitterlinden, A. G., van Meurs, J. B., Chapman, K., Deloukas, P., Ollier, W. E., Wallis, G. A., Arden, N., Carr, A., Doherty, M., McCaskie, A., Wilkinson, J. M., Ralston, S. H., Valdes, A. M., Spector, T. D., Loughlin, J. 2012; 380 (9844): 815-823

    Abstract

    Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.We identified five genome-wide significant loci (binomial test p?5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.arcOGEN was funded by a special purpose grant from Arthritis Research UK.

    View details for DOI 10.1016/S0140-6736(12)60681-3

    View details for Web of Science ID 000308396300030

    View details for PubMedID 22763110

  • Replication and meta-analysis of TMEM132D gene variants in panic disorder TRANSLATIONAL PSYCHIATRY Erhardt, A., Akula, N., Schumacher, J., Czamara, D., Karbalai, N., Mueller-Myhsok, B., Mors, O., Borglum, A., Kristensen, A. S., Woldbye, D. P., Koefoed, P., Eriksson, E., Maron, E., Metspalu, A., Nurnberger, J., Philibert, R. A., Kennedy, J., Domschke, K., Reif, A., Deckert, J., Otowa, T., Kawamura, Y., Kaiya, H., Okazaki, Y., Tanii, H., Tokunaga, K., Sasaki, T., Ioannidis, J. P., McMahon, F. J., Binder, E. B. 2012; 2

    Abstract

    A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

    View details for DOI 10.1038/tp.2012.85

    View details for Web of Science ID 000312900000001

    View details for PubMedID 22948381

  • Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies HEALTH TECHNOLOGY ASSESSMENT Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Juni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 16 (35): 1-?

    Abstract

    The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.To examine the influence of unclear or inadequate random sequence generation and allocation concealment, and unclear or absent double blinding, on intervention effect estimates and between-trial heterogeneity, and whether or not these influences vary with type of clinical area, intervention, comparison and outcome measure.Data were combined from seven contributing meta-epidemiological studies (collections of meta-analyses in which trial characteristics are assessed and results recorded). The resulting database was used to identify and remove overlapping meta-analyses. Outcomes were coded such that odds ratios < 1 correspond to beneficial intervention effects. Outcome measures were classified as mortality, other objective or subjective. We examined agreement between assessments of trial characteristics in trials assessed in more than one contributing study. We used hierarchical Bayesian bias models to estimate the effect of trial characteristics on average bias [quantified as ratios of odds ratios (RORs) with 95% credible intervals (CrIs) comparing trials with and without a characteristic] and in increasing between-trial heterogeneity.The analysis data set contained 1973 trials included in 234 meta-analyses. Median kappa statistics for agreement between assessments of trial characteristics were: sequence generation 0.60, allocation concealment 0.58 and blinding 0.87. Intervention effect estimates were exaggerated by an average 11% in trials with inadequate or unclear (compared with adequate) sequence generation (ROR 0.89, 95% CrI 0.82 to 0.96); between-trial heterogeneity was higher among such trials. Bias associated with inadequate or unclear sequence generation was greatest for subjective outcomes (ROR 0.83, 95% CrI 0.74 to 0.94) and the increase in heterogeneity was greatest for such outcomes [standard deviation (SD) 0.20, 95% CrI 0.03 to 0.32]. The effect of inadequate or unclear (compared with adequate) allocation concealment was greatest among meta-analyses with a subjectively assessed outcome intervention effect (ROR 0.85, 95% CrI 0.75 to 0.95), and the increase in between-trial heterogeneity was also greatest for such outcomes (SD 0.20, 95% CrI 0.02 to 0.33). Lack of, or unclear, double blinding (compared with double blinding) was associated with an average 13% exaggeration of intervention effects (ROR 0.87, 95% CrI 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD 0.14, 95% CrI 0.02 to 0.30). Average bias (ROR 0.78, 95% CrI 0.65 to 0.92) and between-trial heterogeneity (SD 0.37, 95% CrI 0.19 to 0.53) were greatest for meta-analyses assessing subjective outcomes. Among meta-analyses with subjectively assessed outcomes, the effect of lack of blinding appeared greater than the effect of inadequate or unclear sequence generation or allocation concealment.Bias associated with specific reported study design characteristics leads to exaggeration of beneficial intervention effect estimates and increases in between-trial heterogeneity. For each of the three characteristics assessed, these effects were greatest for subjectively assessed outcomes. Assessments of the risk of bias in RCTs should account for these findings. Further research is needed to understand the effects of attrition bias, as well as the relative importance of blinding of patients, care-givers and outcome assessors, and thus separate the effects of performance and detection bias.National Institute for Health Research Health Technology Assessment programme.

    View details for DOI 10.3310/hta16350

    View details for Web of Science ID 000311662000001

    View details for PubMedID 22989478

  • Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-related Macular Degeneration Subtypes OPHTHALMOLOGY Sobrin, L., Ripke, S., Yu, Y., Fagerness, J., Bhangale, T. R., Tan, P. L., Souied, E. H., Buitendijk, G. H., Merriam, J. E., Richardson, A. J., Raychaudhuri, S., Reynolds, R., Chin, K. A., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, P., Smith, R. T., Barile, G. R., Hogg, R. E., Chakravarthy, U., Behrens, T. W., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Brantley, M. A., Baird, P. N., Klaver, C. C., Allikmets, R., Katsanis, N., Graham, R. R., Ioannidis, J. P., Daly, M. J., Seddon, J. M. 2012; 119 (9): 1874-1885

    Abstract

    To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.Sibling correlation study and genome-wide association study (GWAS).For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

    View details for DOI 10.1016/j.ophtha.2012.03.014

    View details for Web of Science ID 000310581200023

    View details for PubMedID 22705344

  • STrengthening the Reporting of OBservational studies in Epidemiology: Molecular Epidemiology STROBE-ME. An extension of the STROBE statement JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 66 (9): 844-854

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1136/jech-2011-200318

    View details for Web of Science ID 000307101800014

    View details for PubMedID 22025194

  • The Importance of Potential Studies That Have Not Existed and Registration of Observational Data Sets JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 308 (6): 575-576

    View details for Web of Science ID 000307228400022

    View details for PubMedID 22871867

  • TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome NATURE GENETICS Boileau, C., Guo, D., Hanna, N., Regalado, E. S., Detaint, D., Gong, L., Varret, M., Prakash, S. K., Li, A. H., d'Indy, H., Braverman, A. C., Grandchamp, B., Kwartler, C. S., Gouya, L., Santos-Cortez, R. L., Abifadel, M., Leal, S. M., Muti, C., Shendure, J., Gross, M., Rieder, M. J., Vahanian, A., Nickerson, D. A., Michel, J. B., Jondeau, G., Milewicz, D. M. 2012; 44 (8): 916-?

    Abstract

    A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-?2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-?2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-?2 levels leading to a secondary increase in TGF-?2 production in the diseased aorta.

    View details for DOI 10.1038/ng.2348

    View details for Web of Science ID 000306854700018

    View details for PubMedID 22772371

  • Large-scale replication and heterogeneity in Parkinson disease genetic loci NEUROLOGY Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Van Broeckhoven, C., Bertram, L., Bozi, M., Crosiers, D., Clarke, C., Facheris, M., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Gueell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 79 (7): 659-667

    Abstract

    Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

    View details for Web of Science ID 000307475200013

    View details for PubMedID 22786590

  • Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nature genetics Emond, M. J., Louie, T., Emerson, J., Zhao, W., Mathias, R. A., Knowles, M. R., Wright, F. A., Rieder, M. J., Tabor, H. K., Nickerson, D. A., Barnes, K. C., Gibson, R. L., Bamshad, M. J. 2012; 44 (8): 886-889

    Abstract

    Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.

    View details for DOI 10.1038/ng.2344

    View details for PubMedID 22772370

  • Pediatric Versus Adult Drug Trials for Conditions With High Pediatric Disease Burden PEDIATRICS Bourgeois, F. T., Murthy, S., Pinto, C., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2012; 130 (2): 285-292

    Abstract

    Optimal treatment decisions in children require sufficient evidence on the safety and efficacy of pharmaceuticals in pediatric patients. However, there is concern that not enough trials are conducted in children and that pediatric trials differ from those performed in adults. Our objective was to measure the prevalence of pediatric studies among clinical drug trials and compare trial characteristics and quality indicators between pediatric and adult drug trials.For conditions representing a high burden of pediatric disease, we identified all drug trials registered in ClinicalTrials.gov with start dates between 2006 and 2011 and tracked the resulting publications. We measured the proportion of pediatric trials and subjects for each condition and compared pediatric and adult trial characteristics and quality indicators.For the conditions selected, 59.9% of the disease burden was attributable to children, but only 12.0% (292/2440) of trials were pediatric (P < .001). Among pediatric trials, 58.6% were conducted without industry funding compared with 35.0% of adult trials (P < .001). Fewer pediatric compared with adult randomized trials examined safety outcomes (10.1% vs 16.9%, P = .008). Pediatric randomized trials were slightly more likely to be appropriately registered before study start (46.9% vs 39.3%, P = .04) and had a modestly higher probability of publication in the examined time frame (32.8% vs 23.2%, P = .04).There is substantial discrepancy between pediatric burden of disease and the amount of clinical trial research devoted to pediatric populations. This may be related in part to trial funding, with pediatric trials relying primarily on government and nonprofit organizations.

    View details for DOI 10.1542/peds.2012-0139

    View details for Web of Science ID 000307123000049

    View details for PubMedID 22826574

  • Estimating the contribution of genetic variants to difference in incidence of disease between population groups EUROPEAN JOURNAL OF HUMAN GENETICS Moonesinghe, R., Ioannidis, J. P., Flanders, W. D., Yang, Q., Truman, B. I., Khoury, M. J. 2012; 20 (8): 831-836

    Abstract

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

    View details for DOI 10.1038/ejhg.2012.15

    View details for Web of Science ID 000306556600007

    View details for PubMedID 22333905

  • Concordance of Sleep and Pain Outcomes of Diverse Interventions: An Umbrella Review PLOS ONE Doufas, A. G., Panagiotou, O. A., Ioannidis, J. P. 2012; 7 (7)

    Abstract

    Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep.We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes.151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P?=?0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r?=?0.17, P?=?0.092).Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.

    View details for DOI 10.1371/journal.pone.0040891

    View details for Web of Science ID 000306507000039

    View details for PubMedID 22815856

  • Time to compare impact and feasibility of prediction models in real life reply BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    View details for DOI 10.1136/bmj.e4360

    View details for Web of Science ID 000306274800015

  • Consistency of genome-wide associations across major ancestral groups HUMAN GENETICS Ntzani, E. E., Liberopoulos, G., Manolio, T. A., Ioannidis, J. P. 2012; 131 (7): 1057-1071

    Abstract

    It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance (p ? 5 × 10(-8)) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects' estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n = 624; Asian, n = 217; African, n = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with >10% absolute differences in 75-89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons' correlation coefficients: 0.20-0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups.

    View details for DOI 10.1007/s00439-011-1124-4

    View details for Web of Science ID 000305195400004

    View details for PubMedID 22183176

  • Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly A critical review and re-analysis of 15 meta-analyses HUMAN VACCINES & IMMUNOTHERAPEUTICS Manzoli, L., Ioannidis, J. P., Flacco, M. E., De Vito, C., Villari, P. 2012; 8 (7): 851-862

    Abstract

    Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines--seasonal, H5N1 and 2009 (H1N1)--in various age-classes (healthy children, adults or elderly). These meta-analyses have often adopted different analyses and study selection criteria. Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic reviews, we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings (or their interpretation) across previously published meta-analyses. For each age group, we performed analyses that included all trials that had been included in at least one relevant meta-analysis, also exploring whether effect sizes changed over time. Although we identified several discrepancies among the meta-analyses on seasonal vaccines for children and elderly, overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases. The available evidence on parenteral inactivated vaccines for children aged < 2 y remains scarce. Pre-pandemic "avian" H5N1 and pandemic 2009 (H1N1) vaccines can achieve satisfactory immunogenicity, but no meta-analysis has addressed H1N1 vaccination impact on clinical outcomes. Data on harms are overall reassuring, but their value is diminished by inconsistent reporting.

    View details for DOI 10.4161/hv.19917

    View details for Web of Science ID 000307107600010

    View details for PubMedID 22777099

  • Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists JOURNAL OF CLINICAL EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 65 (7): 740-747

    Abstract

    To assess the interpretation of a highly heterogeneous meta-analysis by authors of primary studies and by methodologists.We surveyed the authors of studies on the association between insulin-like growth factor 1 (IGF-1) and prostate cancer, and 20 meta-analysis methodologists. Authors and methodologists presented with the respective meta-analysis results were queried about the effect size and potential causality of the association. We evaluated whether author responses correlated with the number of IGF-related articles they had published and their study results included in the meta-analysis. We also compared authors' and methodologists' responses.Authors who had published more IGF-related papers offered more generous effect size estimates for the association (?(s)=0.61, P=0.01) and higher likelihood that the odds ratio (OR) was greater than 1.20 (?(s)=0.63, P=0.01). Authors who had published themselves studies with statistically significant effects for a positive association were more likely to believe that the true OR is greater than 1.20 compared with methodologists (median likelihood 50% versus 2.5%, P=0.01).Researchers are influenced by their own investment in the field, when interpreting a meta-analysis that includes their own study. Authors who published significant results are more likely to believe that a strong association exists compared with methodologists.

    View details for DOI 10.1016/j.jclinepi.2012.01.008

    View details for Web of Science ID 000305357300006

    View details for PubMedID 22537426

  • Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipid levels INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patel, C. J., Cullen, M. R., Ioannidis, J. P., Butte, A. J. 2012; 41 (3): 828-843

    Abstract

    Both genetic and environmental factors contribute to triglyceride, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) levels. Although genome-wide association studies are currently testing the genetic factors systematically, testing and reporting one or a few factors at a time can lead to fragmented literature for environmental chemical factors. We screened for correlation between environmental factors and lipid levels, utilizing four independent surveys with information on 188 environmental factors from the Centers of Disease Control, National Health and Nutrition Examination Survey, collected between 1999 and 2006.We used linear regression to correlate each environmental chemical factor to triglycerides, LDL-C and HDL-C adjusting for age, age(2), sex, ethnicity, socio-economic status and body mass index. Final estimates were adjusted for waist circumference, diabetes status, blood pressure and survey. Multiple comparisons were controlled for by estimating the false discovery rate and significant findings were tentatively validated in an independent survey.We identified and validated 29, 9 and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Findings include hydrocarbons and nicotine associated with lower HDL-C and vitamin E (?-tocopherol) associated with unfavourable lipid levels. Higher triglycerides and lower HDL-C were correlated with higher levels of fat-soluble contaminants (e.g. polychlorinated biphenyls and dibenzofurans). Nutrients and vitamin markers (e.g. vitamins B, D and carotenes), were associated with favourable triglyceride and HDL-C levels.Our systematic association study has enabled us to postulate about broad environmental correlation to lipid levels. Although subject to confounding and reverse causality bias, these findings merit evaluation in additional cohorts.

    View details for DOI 10.1093/ije/dys003

    View details for Web of Science ID 000306417300030

    View details for PubMedID 22421054

  • Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376
  • Standard 6: Age Groups for Pediatric Trials PEDIATRICS Williams, K., Thomson, D., Seto, I., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Hartling, L., Klassen, T. 2012; 129: S153-S160

    View details for DOI 10.1542/peds.2012-0055I

    View details for Web of Science ID 000307396800008

    View details for PubMedID 22661762

  • Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Boffetta, P., Winn, D. M., Ioannidis, J. P., Thomas, D. C., Little, J., Smith, G. D., Cogliano, V. J., Hecht, S. S., Seminara, D., Vineis, P., Khoury, M. J. 2012; 41 (3): 686-704

    Abstract

    We propose guidelines to evaluate the cumulative evidence of gene-environment (G?×?E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G?×?E interactions, discovery and modelling methods for G?×?E interactions, and issues in systematic reviews of evidence for G?×?E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.

    View details for DOI 10.1093/ije/dys010

    View details for Web of Science ID 000306417300018

    View details for PubMedID 22596931

  • Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses PEDIATRICS Contopoulos-Ioannidis, D. G., Seto, I., Hamm, M. P., Thomson, D., Hartling, L., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Klassen, T., Williams, K. 2012; 129: S161-S184

    Abstract

    An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed.We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported.The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8-10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance.We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

    View details for DOI 10.1542/peds.2012-0055J

    View details for Web of Science ID 000307396800009

    View details for PubMedID 22661763

  • Comparisons of established risk prediction models for cardiovascular disease: systematic review BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    Abstract

    To evaluate the evidence on comparisons of established cardiovascular risk prediction models and to collect comparative information on their relative prognostic performance.Systematic review of comparative predictive model studies.Medline and screening of citations and references.Studies examining the relative prognostic performance of at least two major risk models for cardiovascular disease in general populations.Information on study design, assessed risk models, and outcomes. We examined the relative performance of the models (discrimination, calibration, and reclassification) and the potential for outcome selection and optimism biases favouring newly introduced models and models developed by the authors.20 articles including 56 pairwise comparisons of eight models (two variants of the Framingham risk score, the assessing cardiovascular risk to Scottish Intercollegiate Guidelines Network to assign preventative treatment (ASSIGN) score, systematic coronary risk evaluation (SCORE) score, Prospective Cardiovascular Münster (PROCAM) score, QRESEARCH cardiovascular risk (QRISK1 and QRISK2) algorithms, Reynolds risk score) were eligible. Only 10 of 56 comparisons exceeded a 5% relative difference based on the area under the receiver operating characteristic curve. Use of other discrimination, calibration, and reclassification statistics was less consistent. In 32 comparisons, an outcome was used that had been used in the original development of only one of the compared models, and in 25 of these comparisons (78%) the outcome-congruent model had a better area under the receiver operating characteristic curve. Moreover, authors always reported better area under the receiver operating characteristic curves for models that they themselves developed (in five articles on newly introduced models and in three articles on subsequent evaluations).Several risk prediction models for cardiovascular disease are available and their head to head comparisons would benefit from standardised reporting and formal, consistent statistical comparisons. Outcome selection and optimism biases apparently affect this literature.

    View details for DOI 10.1136/bmj.e3318

    View details for Web of Science ID 000304591600005

    View details for PubMedID 22628003

  • Invited commentary-Genetic prediction for common diseases. Archives of internal medicine Ioannidis, J. P. 2012; 172 (9): 744-746

    View details for DOI 10.1001/archinternmed.2012.931

    View details for PubMedID 22782208

  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture NATURE GENETICS Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y., Duncan, E. L., Ntzani, E. E., Oei, L., Albagha, O. M., Amin, N., Kemp, J. P., Koller, D. L., Li, G., Liu, C., Minster, R. L., Moayyeri, A., Vandenput, L., Willner, D., Xiao, S., Yerges-Armstrong, L. M., Zheng, H., Alonso, N., Eriksson, J., Kammerer, C. M., Kaptoge, S. K., Leo, P. J., Thorleifsson, G., Wilson, S. G., Wilson, J. F., Aalto, V., Alen, M., Aragaki, A. K., Aspelund, T., Center, J. R., Dailiana, Z., Duggan, D. J., Garcia, M., Garcia-Giralt, N., Giroux, S., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Khusainova, R., Kim, G. S., Kooperberg, C., Koromila, T., Kruk, M., Laaksonen, M., LaCroix, A. Z., Lee, S. H., Leung, P. C., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nguyen, T. V., Nogues, X., Patel, M. S., Prezelj, J., Rose, L. M., Scollen, S., Siggeirsdottir, K., Smith, A. V., Svensson, O., Trompet, S., Trummer, O., van Schoor, N. M., Woo, J., Zhu, K., Balcells, S., Brandi, M. L., Buckley, B. M., Cheng, S., Christiansen, C., Cooper, C., Dedoussis, G., Ford, I., Frost, M., Goltzman, D., Gonzalez-Macias, J., Kahonen, M., Karlsson, M., Khusnutdinova, E., Koh, J., Kollia, P., Langdahl, B. L., Leslie, W. D., Lips, P., Ljunggren, O., Lorenc, R. S., Marc, J., Mellstrom, D., Obermayer-Pietsch, B., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Ridker, P. M., Rousseau, F., Slagboom, P. E., Tang, N. L., Urreizti, R., Van Hul, W., Viikari, J., Zarrabeitia, M. T., Aulchenko, Y. S., Castano-Betancourt, M., Grundberg, E., Herrera, L., Ingvarsson, T., Johannsdottir, H., Kwan, T., Li, R., Luben, R., Medina-Gomez, C., Palsson, S. T., Reppe, S., Rotter, J. I., Sigurdsson, G., van Meurs, J. B., Verlaan, D., Williams, F. M., Wood, A. R., Zhou, Y., Gautvik, K. M., Pastinen, T., Raychaudhuri, S., Cauley, J. A., Chasman, D. I., Clark, G. R., Cummings, S. R., Danoy, P., Dennison, E. M., Eastell, R., Eisman, J. A., Gudnason, V., Hofman, A., Jackson, R. D., Jones, G., Jukema, J. W., Khaw, K., Lehtimaki, T., Liu, Y., Lorentzon, M., McCloskey, E., Mitchell, B. D., Nandakumar, K., Nicholson, G. C., Oostra, B. A., Peacock, M., Pols, H. A., Prince, R. L., Raitakari, O., Reid, I. R., Robbins, J., Sambrook, P. N., Sham, P. C., Shuldiner, A. R., Tylavsky, F. A., van Duijn, C. M., Wareham, N. J., Cupples, L. A., Econs, M. J., Evans, D. M., Harris, T. B., Kung, A. W., Psaty, B. M., Reeve, J., Spector, T. D., Streeten, E. A., Zillikens, M. C., Thorsteinsdottir, U., Ohlsson, C., Karasik, D., Richards, J. B., Brown, M. A., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F. 2012; 44 (5): 491-?

    Abstract

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

    View details for DOI 10.1038/ng.2249

    View details for Web of Science ID 000303416300007

    View details for PubMedID 22504420

  • Methodological Standards and Patient-Centeredness in Comparative Effectiveness Research The PCORI Perspective JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Basch, E., Aronson, N., Berg, A., Flum, D., Gabriel, S., Goodman, S. N., Helfand, M., Ioannidis, J. P., Lauer, M., Meltzer, D., Mittman, B., Newhouse, R., Normand, S., Schneeweiss, S., Slutsky, J., Tinetti, M., Yancy, C. 2012; 307 (15): 1636-1640

    Abstract

    Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

    View details for Web of Science ID 000302896100026

    View details for PubMedID 22511692

  • A Multidimensional Prognostic Index in Common Conditions Leading to Death in Older Patients reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (7): 594-595
  • Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Nair, V. S., Maeda, L. S., Ioannidis, J. P. 2012; 104 (7): 528-540

    Abstract

    MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -

    View details for DOI 10.1093/jnci/djs027

    View details for Web of Science ID 000302293200008

    View details for PubMedID 22395642

  • Research needs grants, funding and money - missing something? EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P. 2012; 42 (4): 349-351
  • Are Medical Conferences Useful? And for Whom? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 307 (12): 1257-1258

    View details for Web of Science ID 000301978400018

    View details for PubMedID 22453564

  • Re-rethinking the article by Thombs and colleagues Response CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 438-439
  • Rethinking recommendations for screening for depression in primary care CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 413-418

    View details for DOI 10.1503/cmaj.111035

    View details for Web of Science ID 000301465400009

    View details for PubMedID 21930744

  • Minimal and Null Predictive Effects for the Most Popular Blood Biomarkers of Cardiovascular Disease CIRCULATION RESEARCH Ioannidis, J. P., Tzoulaki, I. 2012; 110 (5): 658-662

    View details for DOI 10.1161/RES.0b013e31824da8ad

    View details for Web of Science ID 000301045500006

    View details for PubMedID 22383708

  • The effectiveness of long-term psychoanalytic psychotherapy-A meta-analysis of randomized controlled trials CLINICAL PSYCHOLOGY REVIEW Smit, Y., Huibers, M. J., Ioannidis, J. P., Van Dyck, R., van Tilburg, W., Arntz, A. 2012; 32 (2): 81-92

    Abstract

    The effectiveness of psychoanalysis and long-term psychoanalytic psychotherapy (LTPP) is debated. We evaluated the effectiveness of LTPP, compared to other treatments or no treatment, in patients with clearly defined metal disorders. We selected randomised or quasi-randomised controlled trials on LTPP. Two authors independently identified trials for inclusion. Eleven trials were eligible. The risk difference for recovery (primary outcome) at the longest available follow-up was 0.00 (95% CI: -0.17 to 0.17; p=0.96; I-squared: 58%). The combined Hedges' g, at the longest follow-up for each study, were: for target problems: -0.05 (95% CI -0.55 to 0.46; p=0.86; I-squared=88%); general psychiatric symptoms: 0.69 (95% CI -0.19 to 1.57; p=0.13; I-squared=96%); personality pathology: 0.17 (95% CI: -0.25 to 0.59; p=0.42; I-squared=41%); social functioning: 0.20 (95% CI -0.10 to 0.50; p=0.19; I-squared=53%); overall effectiveness: 0.33 (95% CI -0.31 to 0.96; p=0.32; I-squared=94%); and quality of life: -0.37 (95% CI: -0.78 to 0.04; p=0.08; I-squared=55%). A subgroup analysis of the domain target problem showed that LTPP did significantly better when compared to control treatments without a specialized psychotherapy component, but not when compared to various specialized psychotherapy control treatments. An exploratory meta-regression indicated that there might be a relation between the difference in treatment intensity between the intervention and control group (session ratio) and effect size. We came to conclude that the recovery rate of various mental disorders was equal after LTPP or various control treatments, including treatment as usual. The effect sizes of the individual trials varied substantially in direction and magnitude. In contrast to previous reviews, we found the evidence for the effectiveness of LTPP to be limited and at best conflicting.

    View details for DOI 10.1016/j.cpr.2011.11.003

    View details for Web of Science ID 000300033800001

    View details for PubMedID 22227111

  • Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database PLOS GENETICS Lill, C. M., Roehr, J. T., McQueen, M. B., Kavvoura, F. K., Bagade, S., Schjeide, B. M., Schjeide, L. M., Meissner, E., Zauft, U., Allen, N. C., Liu, T., Schilling, M., Anderson, K. J., Beecham, G., Berg, D., Biernacka, J. M., Brice, A., DeStefano, A. L., Do, C. B., Eriksson, N., Factor, S. A., Farrer, M. J., Foroud, T., Gasser, T., Hamza, T., Hardy, J. A., Heutink, P., Hill-Burns, E. M., Klein, C., Latourelle, J. C., Maraganore, D. M., Martin, E. R., Martinez, M., Myers, R. H., Nalls, M. A., Pankratz, N., Payami, H., Satake, W., Scott, W. K., Sharma, M., Singleton, A. B., Stefansson, K., Toda, T., Tung, J. Y., Vance, J., Wood, N. W., Zabetian, C. P., Young, P., Tanzi, R. E., Khoury, M. J., Zipp, F., Lehrach, H., Ioannidis, J. P., Bertram, L. 2012; 8 (3)

    Abstract

    More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P? =? 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

    View details for DOI 10.1371/journal.pgen.1002548

    View details for Web of Science ID 000302254800024

    View details for PubMedID 22438815

  • Claims for improved survival from systemic corticosteroids in diverse conditions: an umbrella review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2012; 42 (3): 233-244

    Abstract

    Systemic corticosteroids have been proposed for numerous indications and there are many claims that corticosteroids can reduce mortality in diverse conditions.We performed an umbrella, agenda-wide review of the evidence on systemic corticosteroids and mortality, focusing primarily on large trials (defined as those with > 100 deaths) and meta-analyses. Searches were performed in PubMed and Cochrane Central Register of Controlled Trials (last update February 2011). We also examined whether spurious subset analyses may be responsible for claims of survival benefits in indications where only small trials had been available.Among 257 identified randomized trials with mortality data in their abstract, we found 14 large trials pertaining to 10 different indications. Although 10 of these 14 trials have reported statistically significant survival differences in subset analyses, none shows a nominally statistically significant (P < 0·05) decrease in death risk for any of the tested conditions when all deaths on all randomized patients are analysed. Meta-analyses for these conditions show statistically significant reductions in mortality only with antenatal corticosteroids for preterm labour (relative risk 0·77, 95% CI, 0·67-0·89) and in tuberculous meningitis (relative risk 0·78, 95% CI, 0·67-0·91). For conditions without any large trials, statistically significant reductions in mortality in meta-analyses were noted for Pneumocystis pneumonia (relative risk 0·54, 95% CI, 0·38-0·79) and alcoholic hepatitis (relative risk 0·63, 95% CI, 0·50-0·80). Many small trials that claim significant benefits, even those for classic indications such as typhoid fever and tetanus, have shown these benefits only in subset analyses.Corticosteroids have been documented to decrease mortality in some indications, in particular, antenatal use for preterm labour, tuberculous meningitis, Pneumocystis pneumonia, and alcoholic hepatitis. Many postulated benefits of corticosteroids on mortality may reflect 'vibration of treatment effects' leading to false-positive claims from spurious subset analyses and even for standard indications, such biases may have inflated the treatment effect estimates. More large trials are needed for serious, common conditions where use of corticosteroids is proposed.

    View details for DOI 10.1111/j.1365-2362.2011.02584.x

    View details for Web of Science ID 000299832800002

    View details for PubMedID 21880039

  • What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 41 (1): 273-286

    Abstract

    Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ? 5 × 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance.We defined as 'borderline' associations those with P > 5 × 10(-8) and P ? 1 × 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ? 5 × 10(-8) with inclusion of additional data from subsequent GWA studies.Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ? 5 × 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10(-8). If the seven associations that did not reach P ? 5 × 10(-8) when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10(-6) [corresponding false-discovery rate 19% (95% CI 7-39%)].A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold.

    View details for DOI 10.1093/ije/dyr178

    View details for Web of Science ID 000302026800032

    View details for PubMedID 22253303

  • The Clinical Utility of Prognostic Indices: The Proof of the Pudding Is in the Eating reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (2): 195-195
  • Reversals of Established Medical Practices Evidence to Abandon Ship JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Prasad, V., Cifu, A., Ioannidis, J. P. 2012; 307 (1): 37-38

    View details for DOI 10.1001/jama.2011.1960

    View details for Web of Science ID 000298792300016

    View details for PubMedID 22215160

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 42 (1): 1-16

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1111/j.1365-2362.2011.02561.x

    View details for Web of Science ID 000297738500001

    View details for PubMedID 22023344

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement MUTAGENESIS Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 27 (1): 17-29

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and / or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1093/mutage/ger039

    View details for Web of Science ID 000298385400002

    View details for PubMedID 22027842

  • Obtaining evidence by a single well-powered trial or several modestly powered trials. Statistical methods in medical research Inthout, J., Ioannidis, J. P., Borm, G. F. 2012

    Abstract

    There is debate whether clinical trials with suboptimal power are justified and whether results from large studies are more reliable than the (combined) results of smaller trials. We quantified the error rates for evaluations based on single conventionally powered trials (80% or 90% power) versus evaluations based on the random-effects meta-analysis of a series of smaller trials. When a treatment was assumed to have no effect but heterogeneity was present, the error rates for a single trial were increased more than 10-fold above the nominal rate, even for low heterogeneity. Conversely, for meta-analyses on a series of trials, the error rates were correct. When selective publication was present, the error rates were always increased, but they still tended to be lower for a series of trials than single trials. We conclude that evidence of efficacy based on a series of (smaller) trials, may lower the error rates compared with using a single well-powered trial. Only when both heterogeneity and selective publication can be excluded, a single trial is able to provide conclusive evidence.

    View details for PubMedID 23070590

  • Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination PLOS ONE Ioannidis, J. P., Manzoli, L., De Vito, C., D'Addario, M., Villari, P. 2011; 6 (12)

    Abstract

    Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics with new emerging infectious agents. We carried out an observational survey to evaluate how many randomized controlled trials testing 2009 H1N1 vaccines were published among those registered, and what was the time lag from their start to publication and from their completion to publication.PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting.73 eligible trials were identified that had been registered in 2009-2010. By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published less rapidly (hazard ratio 0.42 per month; 95% Confidence Interval: 0.27 to 0.64; p<0.001). Similarly, trials completed later were published less rapidly (hazard ratio 0.43 per month; 95% CI: 0.27 to 0.67; p<0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published.Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature.

    View details for DOI 10.1371/journal.pone.0028346

    View details for Web of Science ID 000298171400075

    View details for PubMedID 22164274

  • Improving Validation Practices in "Omics" Research SCIENCE Ioannidis, J. P., Khoury, M. J. 2011; 334 (6060): 1230-1232

    Abstract

    "Omics" research poses acute challenges regarding how to enhance validation practices and eventually the utility of this rich information. Several strategies may be useful, including routine replication, public data and protocol availability, funding incentives, reproducibility rewards or penalties, and targeted repeatability checks.

    View details for DOI 10.1126/science.1211811

    View details for Web of Science ID 000297553600037

    View details for PubMedID 22144616

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology STROBE-ME: an extension of the STROBE statement JOURNAL OF CLINICAL EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 64 (12): 1350-1363

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1016/j.jclinepi.2011.07.010

    View details for Web of Science ID 000296995000014

    View details for PubMedID 22030070

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement PREVENTIVE MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Loannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 53 (6): 377-387

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrenghtening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1016/j.ypmed.2011.08.007

    View details for Web of Science ID 000298073500005

    View details for PubMedID 22029945

  • Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study BRITISH MEDICAL JOURNAL Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2011; 343

    Abstract

    To compare the reported effect sizes of cardiovascular biomarkers in datasets from observational studies with those in datasets from randomised controlled trials.Review of meta-analyses.Meta-analyses of emerging cardiovascular biomarkers (not part of the Framingham risk score) that included datasets from at least one observational study and at least one randomised controlled trial were identified through Medline (last update, January 2011).Study-specific risk ratios were extracted from all identified meta-analyses and synthesised with random effects for (a) all studies, and (b) separately for observational and for randomised controlled trial populations for comparison.31 eligible meta-analyses were identified. For seven major biomarkers (C reactive protein, non-HDL cholesterol, lipoprotein(a), post-load glucose, fibrinogen, B-type natriuretic peptide, and troponins), the prognostic effect was significantly stronger in datasets from observational studies than in datasets from randomised controlled trials. For five of the biomarkers the effect was less than half as strong in the randomised controlled trial datasets. Across all 31 meta-analyses, on average datasets from observational studies suggested larger prognostic effects than those from randomised controlled trials; from a random effects meta-analysis, the estimated average difference in the effect size was 24% (95% CI 7% to 40%) of the overall biomarker effect.Cardiovascular biomarkers often have less promising results in the evidence derived from randomised controlled trials than from observational studies.

    View details for DOI 10.1136/bmj.d6829

    View details for Web of Science ID 000297057800012

    View details for PubMedID 22065657

  • First-trimester ductus venosus screening for cardiac defects: a meta-analysis BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY Papatheodorou, S. I., Evangelou, E., Makrydimas, G., Ioannidis, J. P. 2011; 118 (12): 1438-1445

    Abstract

    Heart defects are the most common congenital abnormalities.We aimed to evaluate in a meta-analysis the screening performance of abnormal ductus venosus (DV) Doppler waveform for detection of congenital heart disease (CHD) in chromosomally normal fetuses.Studies were retrieved from a search of MEDLINE, ISI, SCOPUS and EMBASE (from 1999 to March 2011) using the keywords 'ductus venosus', 'DV', 'chromosomal abnormalities', 'congenital heart disease' and 'nuchal translucency'.We considered all studies that examined the diagnostic performance of DV in the first trimester for CHD in chromosomally normal fetuses. We included studies that were limited to fetuses with increased nuchal translucency (NT), normal NT, and studies that examined fetuses regardless of NT status.Seven studies (n = 50,354) regardless of the NT status, nine studies (n = 2908) with increased NT and seven studies (n = 47,610) with normal NT were included in the meta-analysis. We drew hierarchical summary receiver operating characteristic (HSROC) curves using the parameters of the fitted models.In populations including participants regardless of NT status, the summary sensitivity and specificity of DV for detecting CHD were 50 and 93%, respectively. In participants with increased NT, the summary sensitivity and specificity were 83 and 80%, and in those with normal NT, they were 19 and 96%, respectively.The estimated performance of DV assessment for detection of CHD in chromosomally normal fetuses can be considered in evaluating the potential use and limitations of this screening test.

    View details for DOI 10.1111/j.1471-0528.2011.03029.x

    View details for Web of Science ID 000296203900004

    View details for PubMedID 21668765

  • Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease NEUROBIOLOGY OF AGING Sharma, M., Maraganore, D. M., Ioannidis, J. P., Riess, O., Aasly, J. O., Annesi, G., Abahuni, N., Bentivoglio, A. R., Brice, A., Van Broeckhoven, C., Chartier-Harlin, M., Destee, A., Djarmati, A., Elbaz, A., Farrer, M., Ferrarese, C., Gibson, J. M., Gispert, S., Hattori, N., Jasinska-Myga, B., Klein, C., Lesage, S., Lynch, T., Lichtner, P., Lambert, J., Lang, A. E., Mellick, G. D., de Nigris, F., Opala, G., Quattrone, A., Riva, C., Rogaeva, E., Ross, O. A., Satake, W., Silburn, P. A., Theuns, J., Toda, T., Tomiyama, H., Uitti, R. J., Wirdefeldt, K., Wszolek, Z., Gasser, T., Krueger, R. 2011; 32 (11)

    Abstract

    Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.

    View details for DOI 10.1016/j.neurobiolaging.2011.05.024

    View details for Web of Science ID 000295220700025

    View details for PubMedID 21782285

  • Predicting Death An Empirical Evaluation of Predictive Tools for Mortality ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2011; 171 (19): 1721-1726

    Abstract

    The ability to predict death is crucial in medicine, and many relevant prognostic tools have been developed for application in diverse settings. We aimed to evaluate the discriminating performance of predictive tools for death and the variability in this performance across different clinical conditions and studies.We used Medline to identify studies published in 2009 that assessed the accuracy (based on the area under the receiver operating characteristic curve [AUC]) of validated tools for predicting all-cause mortality. For tools where accuracy was reported in 4 or more assessments, we calculated summary accuracy measures. Characteristics of studies of the predictive tools were evaluated to determine if they were associated with the reported accuracy of the tool.A total of 94 eligible studies provided data on 240 assessments of 118 predictive tools. The AUC ranged from 0.43 to 0.98 (median [interquartile range], 0.77 [0.71-0.83]), with only 23 of the assessments reporting excellent discrimination (10%) (AUC, >0.90). For 10 tools, accuracy was reported in 4 or more assessments; only 1 tool had a summary AUC exceeding 0.80. Established tools showed large heterogeneity in their performance across different cohorts (I(2) range, 68%-95%). Reported AUC was higher for tools published in journals with lower impact factor (P = .01), with larger sample size (P = .01), and for those that aimed to predict mortality among the highest-risk patients (P = .002) and among children (P < .001).Most tools designed to predict mortality have only modest accuracy, and there is large variability across various diseases and populations. Most proposed tools do not have documented clinical utility.

    View details for DOI 10.1001/archinternmed.2011.334

    View details for Web of Science ID 000296198200006

    View details for PubMedID 21788535

  • Magnitude of effects in clinical trials published in high-impact general medical journals INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Siontis, K. C., Evangelou, E., Ioannidis, J. P. 2011; 40 (5): 1280-1291

    Abstract

    Prestigious journals select for publication studies that are considered most important and informative. We aimed to examine whether high-impact general (HIG) medical journals systematically demonstrate more favourable results for experimental interventions compared with the rest of the literature.We scrutinized systematic reviews of the Cochrane Database (Issue 4, 2009) and meta-analyses published in four general journals (2008-09). Eligible articles included ?1 binary outcome meta-analysis(es) pertaining to effectiveness with ?1 clinical trial(s) published in NEJM, JAMA or Lancet. Effect sizes in trials from NEJM, JAMA or Lancet were compared with those from other trials in the same meta-analyses by deriving summary relative odds ratios (sRORs). Additional analyses examined separately early- and late-published trials in HIG journals and journal-specific effects.A total of 79 meta-analyses including 1043 clinical trials were analysed. Trials in HIG journals had similar effects to trials in other journals, when there was large-scale evidence, but showed more favourable results for experimental interventions when they were small. When HIG trials had less than 40 events, the sROR was 1.64 [95% confidence interval (95% CI): 1.23-2.18). The difference was most prominent when small early trials published in HIG journals were compared with subsequent trials [sROR 2.68 (95% CI: 1.33-5.38)]. Late-published HIG trials showed no consistent inflation of effects. The patterns did not differ beyond chance between NEJM, JAMA or Lancet.Small trials published in the most prestigious journals show more favourable effects for experimental interventions, and this is most prominent for early-published trials in such journals. No effect inflation is seen for large trials.

    View details for DOI 10.1093/ije/dyr095

    View details for Web of Science ID 000296634900020

    View details for PubMedID 22039194

  • Risk factors and interventions with statistically significant tiny effects INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Siontis, G. C., Ioannidis, J. P. 2011; 40 (5): 1292-1307

    Abstract

    Large studies may identify postulated risk factors and interventions with very small effect sizes. We aimed to assess empirically a large number of statistically significant relative risks (RRs) of tiny magnitude and their interpretation by investigators.RRs in the range between 0.95 and 1.05 were identified in abstracts of articles of cohort studies; articles published in NEJM, JAMA or Lancet; and Cochrane reviews. For each eligible tiny effect and the respective study, we recorded information on study design, participants, risk factor/intervention, outcome, effect estimates, P-values and interpretation by study investigators. We also calculated the probability that each effect lies outside specific intervals around the null (RR interval 0.97-1.03, 0.95-1.05, 0.90-1.10).We evaluated 51 eligible tiny effects (median sample size 112?786 for risk factors and 36?021 for interventions). Most (37/51) appeared in articles published in 2006-10. The effects pertained to nutrition (n?=?19), genetic and other biomarkers (n?=?8), correlates of health care (n?=?8) and diverse other topics (n?=?16) of clinical or public health importance and mostly referred to major clinical outcomes. A total of 15 of the 51 effects were >80% likely to lie outside the RR interval 0.97-1.03, but only 8 were >40% likely to lie outside the RR interval 0.95-1.05 and none was >1.7% likely to lie outside the RR interval 0.90-1.10. The authors discussed at least one concern for 23 effects (small magnitude n?=?19, residual confounding n?=?11, selection bias n?=?1). No concerns were expressed for 28 effects.Statistically significant tiny effects for risk factors and interventions of clinical or public health importance become more common in the literature. Cautious interpretation is warranted, since most of these effects could be eliminated with even minimal biases and their importance is uncertain.

    View details for DOI 10.1093/ije/dyr099

    View details for Web of Science ID 000296634900021

    View details for PubMedID 21737403

  • Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects JOURNAL OF CLINICAL EPIDEMIOLOGY Pereira, T. V., Ioannidis, J. P. 2011; 64 (10): 1060-1069

    Abstract

    To assess whether nominally statistically significant effects in meta-analyses of clinical trials are true and whether their magnitude is inflated.Data from the Cochrane Database of Systematic Reviews 2005 (issue 4) and 2010 (issue 1) were used. We considered meta-analyses with binary outcomes and four or more trials in 2005 with P<0.05 for the random-effects odds ratio (OR). We examined whether any of these meta-analyses had updated counterparts in 2010. We estimated the credibility (true-positive probability) under different prior assumptions and inflation in OR estimates in 2005.Four hundred sixty-one meta-analyses in 2005 were eligible, and 80 had additional trials included by 2010. The effect sizes (ORs) were smaller in the updating data (2005-2010) than in the respective meta-analyses in 2005 (median 0.85-fold, interquartile range [IQR]: 0.66-1.06), even more prominently for meta-analyses with less than 300 events in 2005 (median 0.67-fold, IQR: 0.54-0.96). Mean credibility of the 461 meta-analyses in 2005 was 63-84% depending on the assumptions made. Credibility estimates changed >20% in 19-31 (24-39%) of the 80 updated meta-analyses.Most meta-analyses with nominally significant results pertain to truly nonnull effects, but exceptions are not uncommon. The magnitude of observed effects, especially in meta-analyses with limited evidence, is often inflated.

    View details for DOI 10.1016/j.jclinepi.2010.12.012

    View details for Web of Science ID 000294526700003

    View details for PubMedID 21454050

  • Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study LANCET NEUROLOGY Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Van Broeckhoven, C., Carr, J., Chartier-Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Ferraris, A., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, E. M., van de Loo, S., Vassilatis, D. K., Vilarino-Gueell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Farrer, M. J. 2011; 10 (10): 898-908

    Abstract

    Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.121 exonic LRRK2 variants were assessed in 15?540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012).The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.Michael J Fox Foundation and National Institutes of Health.

    View details for DOI 10.1016/S1474-4422(11)70175-2

    View details for Web of Science ID 000295814600011

    View details for PubMedID 21885347

  • STrengthening the reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 26 (10): 797-810

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1007/s10654-011-9622-1

    View details for Web of Science ID 000297474500006

    View details for PubMedID 22037796

  • STrengthening the Reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): An Extension of the STROBE Statement PLOS MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 8 (10)

    View details for DOI 10.1371/journal.pmed.1001117

    View details for Web of Science ID 000296552400015

    View details for PubMedID 22039356

  • More time for research: fund people not projects. Nature Ioannidis, J. P. 2011; 477 (7366): 529-531

    View details for DOI 10.1038/477529a

    View details for PubMedID 21956312

  • Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration HUMAN MOLECULAR GENETICS Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H., Reynolds, R., Raychaudhuri, S., Chin, K. A., Sobrin, L., Evangelou, E., Lee, P. H., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, B., Campochiaro, P., Smith, R. T., Barile, G. R., Guymer, R. H., Hogg, R., Chakravarthy, U., Robman, L. D., Gustafsson, O., Sigurdsson, H., Ortmann, W., Behrens, T. W., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Klaver, C. C., Allikmets, R., Brantley, M. A., Baird, P. N., Katsanis, N., Thorsteinsdottir, U., Ioannidis, J. P., Daly, M. J., Graham, R. R., Seddon, J. M. 2011; 20 (18): 3699-3709

    Abstract

    Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

    View details for DOI 10.1093/hmg/ddr270

    View details for Web of Science ID 000294442200016

    View details for PubMedID 21665990

  • Public Availability of Published Research Data in High-Impact Journals PLOS ONE Alsheikh-Ali, A. A., Qureshi, W., Al-Mallah, M. H., Ioannidis, J. P. 2011; 6 (9)

    Abstract

    There is increasing interest to make primary data from published research publicly available. We aimed to assess the current status of making research data available in highly-cited journals across the scientific literature.We reviewed the first 10 original research papers of 2009 published in the 50 original research journals with the highest impact factor. For each journal we documented the policies related to public availability and sharing of data. Of the 50 journals, 44 (88%) had a statement in their instructions to authors related to public availability and sharing of data. However, there was wide variation in journal requirements, ranging from requiring the sharing of all primary data related to the research to just including a statement in the published manuscript that data can be available on request. Of the 500 assessed papers, 149 (30%) were not subject to any data availability policy. Of the remaining 351 papers that were covered by some data availability policy, 208 papers (59%) did not fully adhere to the data availability instructions of the journals they were published in, most commonly (73%) by not publicly depositing microarray data. The other 143 papers that adhered to the data availability instructions did so by publicly depositing only the specific data type as required, making a statement of willingness to share, or actually sharing all the primary data. Overall, only 47 papers (9%) deposited full primary raw data online. None of the 149 papers not subject to data availability policies made their full primary data publicly available.A substantial proportion of original research papers published in high-impact journals are either not subject to any data availability policies, or do not adhere to the data availability instructions in their respective journals. This empiric evaluation highlights opportunities for improvement.

    View details for DOI 10.1371/journal.pone.0024357

    View details for Web of Science ID 000294802500039

    View details for PubMedID 21915316

  • Meta-Analysis of the Immunogenicity and Tolerability of Pandemic Influenza A 2009 (H1N1) Vaccines PLOS ONE Manzoli, L., De Vito, C., Salanti, G., D'Addario, M., Villari, P., Ioannidis, J. P. 2011; 6 (9)

    Abstract

    Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation.We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis.Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (>?=?70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses

    View details for DOI 10.1371/journal.pone.0024384

    View details for Web of Science ID 000294689200040

    View details for PubMedID 21915319

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 41 (9): 1010-1035

    Abstract

    • The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. • Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1111/j.1365-2362.2011.02493.x

    View details for Web of Science ID 000293509200013

    View details for PubMedID 21434890

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 41 (9): 1004-1009

    Abstract

    • The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting vary. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. • A detailed Explanation and Elaboration document is published as an accompanying article [1].

    View details for DOI 10.1111/j.1365-2362.2011.02494.x

    View details for Web of Science ID 000293509200012

    View details for PubMedID 21434891

  • Strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS): explanation and elaboration. Journal of clinical epidemiology Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 64 (8): e1-e22

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1016/j.jclinepi.2011.02.003

    View details for PubMedID 21414753

  • Homophily and co-occurrence patterns shape randomized trials agendas: illustration in antifungal agents JOURNAL OF CLINICAL EPIDEMIOLOGY Rizos, E. C., Salanti, G., Kontoyiannis, D. P., Ioannidis, J. P. 2011; 64 (8): 830-842

    Abstract

    To assess whether there are preferences and avoidances for specific comparisons in a clinical trials agenda.We tested for homophily (preference to compare agents against others in the same class) and co-occurrence (preference or avoidance of specific head-to-head comparisons) in the randomized trials agenda of antifungal agents. We searched MEDLINE and Cochrane Library databases for English language randomized trials evaluating systemic antifungals against Candida or Aspergillus in adults. We extracted data on compared regimens, sample size, publication year, indication (treatment/prophylaxis), and underlying disease.One hundred forty-four trials (74 treatments, 70 prophylaxes) were found (n=27,497 patients). Among polyene and azole groups, agents were compared within the same class more often than across classes (homophily test P<0.001). Lipid amphotericin was compared almost entirely against conventional amphotericin (18 trials), with only three comparisons against azoles. Head-to-head comparisons of newer agents were avoided. Only one of 14 trials for echinocandins compared head-to-head two different echinocandins (P<0.001 for co-occurrence). Of 11 trials on newer azoles, only one compared a newer azole with an echinocandin (P<0.001 for co-occurrence).Trial networks for antifungals show that specific comparisons are preferred and others avoided, generating a potentially biased clinical research agenda.

    View details for DOI 10.1016/j.jclinepi.2010.11.017

    View details for Web of Science ID 000292413400004

    View details for PubMedID 21411286

  • Excess Significance Bias in the Literature on Brain Volume Abnormalities ARCHIVES OF GENERAL PSYCHIATRY Ioannidis, J. P. 2011; 68 (8): 773-780

    Abstract

    Many studies report volume abnormalities in diverse brain structures in patients with various mental health conditions.To evaluate whether there is evidence for an excess number of statistically significant results in studies of brain volume abnormalities that suggest the presence of bias in the literature.PubMed (articles published from January 2006 to December 2009).Recent meta-analyses of brain volume abnormalities in participants with various mental health conditions vs control participants with 6 or more data sets included, excluding voxel-based morphometry.Standardized effect sizes were extracted in each data set, and it was noted whether the results were "positive" (P < .05) or not. For each data set in each meta-analysis, I estimated the power to detect at ? = .05 an effect equal to the summary effect of the respective meta-analysis. The sum of the power estimates gives the number of expected positive data sets. The expected number of positive data sets can then be compared against the observed number.From 8 articles, 41 meta-analyses with 461 data sets were evaluated (median, 10 data sets per meta-analysis) pertaining to 7 conditions. Twenty-one of the 41 meta-analyses had found statistically significant associations, and 142 of 461 (31%) data sets had positive results. Even if the summary effect sizes of the meta-analyses were unbiased, the expected number of positive results would have been only 78.5 compared with the observed number of 142 (P < .001).There are too many studies with statistically significant results in the literature on brain volume abnormalities. This pattern suggests strong biases in the literature, with selective outcome reporting and selective analyses reporting being possible explanations.

    View details for DOI 10.1001/archgenpsychiatry.2011.28

    View details for Web of Science ID 000293359800002

    View details for PubMedID 21464342

  • Comprehensive Field Synopsis and Systematic Meta-analyses of Genetic Association Studies in Cutaneous Melanoma JOURNAL OF THE NATIONAL CANCER INSTITUTE Chatzinasiou, F., Lill, C. M., Kypreou, K., Stefanaki, I., Nicolaou, V., Spyrou, G., Evangelou, E., Roehr, J. T., Kodela, E., Katsambas, A., Tsao, H., Ioannidis, J. P., Bertram, L., Stratigos, A. J. 2011; 103 (16): 1227-1235

    Abstract

    Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported.We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided.Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility.To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.

    View details for DOI 10.1093/jnci/djr219

    View details for Web of Science ID 000294074500008

    View details for PubMedID 21693730

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF HUMAN GENETICS Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 19 (8): 833-836

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies, building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published on the EJHG website.

    View details for DOI 10.1038/ejhg.2011.25

    View details for Web of Science ID 000292957600006

    View details for PubMedID 21407265

  • Use of reclassification for assessment of improved prediction: an empirical evaluation INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2011; 40 (4): 1094-1105

    Abstract

    An increasing number of studies evaluate the ability of predictors to change risk stratification and alter medical decisions, i.e. reclassification performance. We examined the reported design and analysis of recent studies of reclassification and the robustness of their claims for improved reclassification.Two independent investigators searched PubMed and citations to the article that introduced the currently most popular reclassification metric (net reclassification index, NRI) to identify studies performing reclassification analysis (January 2006-January 2010). We focused on articles that included any analyses comparing the performance of a baseline predictive model vs the baseline model plus some additional predictor for a prospectively assessed outcome. We recorded information on the baseline model used, outcomes assessed, choice of risk thresholds and features of reclassification analyses.Of 58 baseline models used in 51 eligible papers, only 14 (24%) were previously described, used as described and had same outcomes as originally intended. Calibration was examined in 53% of the studies. Sixteen studies (31%) provided a reference for the choice of risk thresholds and only six used the previously proposed categories or justified the use of alternative thresholds. Only 14 studies (27%) stated that the chosen risk thresholds had different therapeutic intervention implications. NRI was calculated in 38 studies and was smaller in studies with adequately referenced or justified risk thresholds vs others (P?

    View details for DOI 10.1093/ije/dyr013

    View details for Web of Science ID 000294108700040

    View details for PubMedID 21325392

  • Strengthening the reporting of Genetic RIsk Prediction Studies: the GRIPS Statement JOURNAL OF CLINICAL EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 64 (8): 843-847
  • Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials BRITISH MEDICAL JOURNAL Sterne, J. A., Sutton, A. J., Ioannidis, J. P., Terrin, N., Jones, D. R., Lau, J., Carpenter, J., Ruecker, G., Harbord, R. M., Schmid, C. H., Tetzlaff, J., Deeks, J. J., Peters, J., Macaskill, P., Schwarzer, G., Duval, S., Altman, D. G., Moher, D., Higgins, J. P. 2011; 343

    View details for DOI 10.1136/bmj.d4002

    View details for Web of Science ID 000293169000008

    View details for PubMedID 21784880

  • The False-positive to False-negative Ratio in Epidemiologic Studies EPIDEMIOLOGY Ioannidis, J. P., Tarone, R., McLaughlin, J. K. 2011; 22 (4): 450-456

    Abstract

    The ratio of false-positive to false-negative findings (FP:FN ratio) is an informative metric that warrants further evaluation. The FP:FN ratio varies greatly across different epidemiologic areas. In genetic epidemiology, it has varied from very high values (possibly even >100:1) for associations reported in candidate-gene studies to very low values (1:100 or lower) for associations with genome-wide significance. The substantial reduction over time in the FP:FN ratio in human genome epidemiology has corresponded to the routine adoption of stringent inferential criteria and comprehensive, agnostic reporting of all analyses. Most traditional fields of epidemiologic research more closely follow the practices of past candidate gene epidemiology, and thus have high FP:FN ratios. Further, FP and FN results do not necessarily entail the same consequences, and their relative importance may vary in different settings. This ultimately has implications for what is the acceptable FP:FN ratio and for how the results of published epidemiologic studies should be presented and interpreted.

    View details for DOI 10.1097/EDE.0b013e31821b506e

    View details for Web of Science ID 000291252100001

    View details for PubMedID 21490505

  • Replication of genome-wide discovered breast cancer risk loci in the Cypriot population BREAST CANCER RESEARCH AND TREATMENT Loizidou, M. A., Hadjisavvas, A., Ioannidis, J. P., Kyriacou, K. 2011; 128 (1): 267-272

    Abstract

    Genome-wide association studies (GWAS) have identified associations with robust statistical support for influencing breast cancer susceptibility. Most GWAS and replications have been conducted in Northern European populations and to a lesser extent in Asians, and Ashkenazi Jews. It is important to evaluate whether these variants confer risk across different populations and also to assess the magnitude of risk conferred. The aim of this study was to evaluate previously GWAS-identified breast cancer risk variants in the Cypriot population. Eleven GWAS-discovered single nucleotide polymorphisms (SNPs) were analyzed for association with breast cancer in 1,109 Cypriot female breast cancer patients and 1,177 healthy female controls. Four of the 11 SNPs evaluated were found to be nominally significantly associated (P < 0.05) with breast cancer risk in the Cypriot population. Based on estimated power, five associations would be expected to be nominally significant. The correlation coefficient of effect sizes (per-allele odds ratio) between the Cypriot population and the original GWAS populations where these SNPs had been discovered was 0.58 (P = 0.064), while allele frequencies were very similar (r = 0.88, P < 0.001). Overall, we show modest concordance for breast cancer GWAS-discovered alleles and their effect sizes in the Cypriot population. The effects sizes of GWAS-discovered SNPs need to be verified separately in different populations.

    View details for DOI 10.1007/s10549-010-1319-8

    View details for Web of Science ID 000291656200031

    View details for PubMedID 21210208

  • Individualized Cost-Effectiveness Analysis PLOS MEDICINE Ioannidis, J. P., Garber, A. M. 2011; 8 (7)

    View details for DOI 10.1371/journal.pmed.1001058

    View details for Web of Science ID 000293169700008

    View details for PubMedID 21765810

  • Understanding and Harnessing the Health Effects of Rapid Urbanization in China ENVIRONMENTAL SCIENCE & TECHNOLOGY Zhu, Y., Ioannidis, J. P., Li, H., Jones, K. C., Martin, F. L. 2011; 45 (12): 5099-5104

    Abstract

    China is undergoing a rapid transition from a rural to an urban society. This societal change is a consequence of a national drive toward economic prosperity. Rapid urbanization impacts on infrastructure, environmental health and human wellbeing. Unlike many cases of urban expansion, Chinese urbanization has led to containment, rather than to increase, in the spread of infectious diseases. Conversely, the incidence of chronic conditions such as cardiovascular and metabolic diseases has risen, with higher rates occurring in urban regions. This rural-urban gradient in disease incidence seems not to be a reflection simply of more aggressive diagnosis or healthcare access. Other diseases exhibit little rural versus urban differences (e.g., liver cancer or respiratory disease), or even occur at a higher rate in the rural population (e.g., esophageal cancer). This article examines the impact of this changing demographic on environmental health and human wellbeing in China. Lessons learned from epidemiological studies mostly carried out in Europe and the U.S. may not be directly transferable to China. We advocate that there is now a need to establish robust systems of accurate data collection, a Chinese biobank network to facilitate the profiling of human health effects, and relevant randomized controlled trials to identify effective interventions in the Chinese urbanized setting. Such studies could allow for the future implementation of disease-preventive strategies.

    View details for DOI 10.1021/es2004254

    View details for Web of Science ID 000291422200008

    View details for PubMedID 21542627

  • Different Black Box Warning Labeling for Same-Class Drugs JOURNAL OF GENERAL INTERNAL MEDICINE Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Papanikolaou, P. N., Ntzani, E. E., Ioannidis, J. P. 2011; 26 (6): 603-610

    Abstract

    Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications.We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs.Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months.Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic.

    View details for DOI 10.1007/s11606-011-1633-9

    View details for Web of Science ID 000290576600010

    View details for PubMedID 21286838

  • A roadmap for successful applications of clinical proteomics PROTEOMICS CLINICAL APPLICATIONS Ioannidis, J. P. 2011; 5 (5-6): 241-247

    Abstract

    Despite over 30,000 publications on proteomics in the last decade, and the accumulation of extensive interesting information on the human proteome in diverse observations, the clinical translation of proteomics to-date has had major setbacks. I review here a roadmap for improving the success rate of clinical proteomics. The roadmap includes steps for improvements that need to be made in analytical tools, discovery, validation, clinical application, and post-clinical application appraisal. It is likely that most if not all of the components that are necessary for clinical success are either readily available, or should be possible to put in place with more rigorous research standards and concerted efforts of the research community, clinicians, and health agencies. Enthusiasm for the clinical impact of proteomics may need to be tempered currently until robust evidence can be obtained, but some clinical successes should eventually be feasible.

    View details for DOI 10.1002/prca.201000096

    View details for Web of Science ID 000291087800005

    View details for PubMedID 21523915

  • Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Panagiotou, O. A. 2011; 305 (21): 2200-2210

    Abstract

    Many biomarkers are proposed in highly cited studies as determinants of disease risk, prognosis, or response to treatment, but few eventually transform clinical practice.To examine whether the magnitude of the effect sizes of biomarkers proposed in highly cited studies is accurate or overestimated.We searched ISI Web of Science and MEDLINE until December 2010.We included biomarker studies that had a relative risk presented in their abstract. Eligible articles were those that had received more than 400 citations in the ISI Web of Science and that had been published in any of 24 highly cited biomedical journals. We also searched MEDLINE for subsequent meta-analyses on the same associations (same biomarker and same outcome).In the highly cited studies, data extraction was focused on the disease/outcome, biomarker under study, and first reported relative risk in the abstract. From each meta-analysis, we extracted the overall relative risk and the relative risk in the largest study. Data extraction was performed independently by 2 investigators.We evaluated 35 highly cited associations. For 30 of the 35 (86%), the highly cited studies had a stronger effect estimate than the largest study; for 3 the largest study was also the highly cited study; and only twice was the effect size estimate stronger in the largest than in the highly cited study. For 29 of the 35 (83%) highly cited studies, the corresponding meta-analysis found a smaller effect estimate. Only 15 of the associations were nominally statistically significant based on the largest studies, and of those only 7 had a relative risk point estimate greater than 1.37.Highly cited biomarker studies often report larger effect estimates for postulated associations than are reported in subsequent meta-analyses evaluating the same associations.

    View details for Web of Science ID 000291106300023

    View details for PubMedID 21632484

  • An Epidemic of False Claims SCIENTIFIC AMERICAN Ioannidis, J. P. 2011; 304 (6): 16-16

    View details for Web of Science ID 000290707400014

    View details for PubMedID 21608392

  • Impact of Phenotype Definition on Genome-Wide Association Signals: Empirical Evaluation in Human Immunodeficiency Virus Type 1 Infection AMERICAN JOURNAL OF EPIDEMIOLOGY Evangelou, E., Fellay, J., Colombo, S., Martinez-Picado, J., Obel, N., Goldstein, D. B., Telenti, A., Ioannidis, J. P. 2011; 173 (11): 1336-1342

    Abstract

    Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

    View details for DOI 10.1093/aje/kwr024

    View details for Web of Science ID 000291058400015

    View details for PubMedID 21490045

  • Commentary: Adjusting for bias: a user's guide to performing plastic surgery on meta-analyses of observational studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2011; 40 (3): 777-779

    View details for DOI 10.1093/ije/dyq265

    View details for Web of Science ID 000293618300029

    View details for PubMedID 21233141

  • Guidelines on Chemotherapy in Advanced Stage Gynecological Malignancies: An Evaluation of 224 Professional Societies and Organizations PLOS ONE Polyzos, N. P., Mauri, D., Ioannidis, J. P. 2011; 6 (5)

    Abstract

    Clinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence.We examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed.Among 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p?=?0.033), response rates (p?=?0.024), symptoms relief (p?=?0.005), quality of life (p?=?0.001) and toxicity (p?=?0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy.Clinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence.

    View details for DOI 10.1371/journal.pone.0020106

    View details for Web of Science ID 000290657500042

    View details for PubMedID 21611154

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF HUMAN GENETICS Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 19 (5)

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1038/ejhg.2011.27

    View details for Web of Science ID 000289789500001

    View details for PubMedID 21407270

  • An empirical assessment of validation practices for molecular classifiers BRIEFINGS IN BIOINFORMATICS Castaldi, P. J., Dahabreh, I. J., Ioannidis, J. P. 2011; 12 (3): 189-202

    Abstract

    Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21-61%) and 29% (IQR, 15-65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04-5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice.

    View details for DOI 10.1093/bib/bbq073

    View details for Web of Science ID 000290324500002

    View details for PubMedID 21300697

  • Strengthening the reporting of Genetic Risk Prediction Studies: The GRIPS statement GENETICS IN MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 13 (5): 453-456

    View details for DOI 10.1097/GIM.0b013e318212fa82

    View details for Web of Science ID 000290435700013

    View details for PubMedID 21502867

  • New Prognostic Markers for Outcome of Acute Pancreatitis Overview of Reporting in 184 Studies PANCREAS Sigounas, D. E., Tatsioni, A., Christodoulou, D. K., Tsianos, E. V., Ioannidis, J. P. 2011; 40 (4): 522-532

    Abstract

    The objective of this study was to assess the reporting of studies on new prognostic markers of outcome in acute pancreatitis.We used MEDLINE searches complemented with perusal of review articles' references to identify eligible English-language studies. We included studies evaluating nonroutine markers for acute pancreatitis. Eligible outcomes included Atlanta criteria, Japanese criteria for severity, multiple/single organ failure, complications, interventional treatment, hospitalization length, and death. We generated a 47-item checklist on Acute Pancreatitis Prognosis by adapting a previously constructed reporting guidance instrument for prognostic tumor markers (REMARK [Reporting Recommendations for Tumor Marker Prognostic Studies]). The checklist addresses the reporting of essential information in prognostic studies.The 184 identified eligible studies reported on 196 different prognostic markers. One hundred forty-four studies (78.3%) found at least 1 prognostic marker to be nominally statistically significant. Significant improvements over time were seen in the reporting for 17 items, but major deficiencies were noted even in 2004-2009 studies. Particularly, 12 items were reported in less than 10% of studies overall and even within the most recent studies.Despite some improvements over time, the reporting of important aspects of prognostic studies in acute pancreatitis remains suboptimal. The proposed REMARK-based checklist may help improve the quality and reporting of research in this field.

    View details for DOI 10.1097/MPA.0b013e31820bf8ac

    View details for Web of Science ID 000289404900005

    View details for PubMedID 21343832

  • Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study ANNALS OF THE RHEUMATIC DISEASES Panoutsopoulou, K., Southam, L., Elliott, K. S., Wrayner, N., Zhai, G., Beazley, C., Thorleifsson, G., Arden, N. K., Carr, A., Chapman, K., Deloukas, P., Doherty, M., McCaskie, A., Ollier, W. E., Ralston, S. H., Spector, T. D., Valdes, A. M., Wallis, G. A., Wilkinson, J. M., ARDEN, E., Battley, K., Blackburn, H., Blanco, F. J., Bumpstead, S., Cupples, L. A., Day-Williams, A. G., Dixon, K., Doherty, S. A., Esko, T., Evangelou, E., Felson, D., Gomez-Reino, J. J., Gonzalez, A., Gordon, A., Gwilliam, R., Halldorsson, B. V., Hauksson, V. B., Hofman, A., Hunt, S. E., Ioannidis, J. P., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Keen, R., Kerkhof, H. J., Kloppenburg, M. G., KOLLER, N., Lakenberg, N., Lane, N. E., Lee, A. T., Metspalu, A., Meulenbelt, I., Nevitt, M. C., O'Neill, F., Parimi, N., Potter, S. C., Rego-Perez, I., Riancho, J. A., Sherburn, K., Slagboom, P. E., Stefansson, K., Styrkarsdottir, U., Sumillera, M., Swift, D., Thorsteinsdottir, U., Tsezou, A., Uitterlinden, A. G., van Meurs, J. B., Watkins, B., Wheeler, M., Mitchell, S., Zhu, Y., Zmuda, J. M., Zeggini, E., Loughlin, J. 2011; 70 (5): 864-867

    Abstract

    The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

    View details for DOI 10.1136/ard.2010.141473

    View details for Web of Science ID 000289070500026

    View details for PubMedID 21177295

  • The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance ANNALS OF THE RHEUMATIC DISEASES Valdes, A. M., Evangelou, E., Kerkhof, H. J., Tamm, A., Doherty, S. A., Kisand, K., Tamm, A., Kerna, I., Uitterlinden, A., Hofman, A., Rivadeneira, F., Cooper, C., Dennison, E. M., Zhang, W., Muir, K. R., Ioannidis, J. P., wheeler, M., Maciewicz, R. A., van Meurs, J. B., Arden, N. K., Spector, T. D., Doherty, M. 2011; 70 (5): 873-U308

    View details for DOI 10.1136/ard.2010.134155

    View details for Web of Science ID 000289070500029

    View details for PubMedID 20870806

  • Independent and Joint Effects of the MAPT and SNCA Genes in Parkinson Disease ANNALS OF NEUROLOGY Elbaz, A., Ross, O. A., Ioannidis, J. P., Soto-Ortolaza, A. I., Moisan, F., Aasly, J., Annesi, G., Bozi, M., Brighina, L., Chartier-Harlin, M., Destee, A., Ferrarese, C., Ferraris, A., Gibson, J. M., Gispert, S., Hadjigeorgiou, G. M., Jasinska-Myga, B., Klein, C., Krueger, R., Lambert, J., Lohmann, K., van de Loo, S., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Stefanis, L., Uitti, R. J., Valente, E. M., Vilarino-Gueell, C., Wirdefeldt, K., Wszolek, Z. K., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J. 2011; 69 (5): 778-792

    Abstract

    We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium.Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach.Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.

    View details for DOI 10.1002/ana.22321

    View details for Web of Science ID 000290156300005

    View details for PubMedID 21391235

  • Industry involvement and baseline assumptions of cost-effectiveness analyses: diagnostic accuracy of the Papanicolaou test CANADIAN MEDICAL ASSOCIATION JOURNAL Polyzos, N. P., Valachis, A., Mauri, D., Ioannidis, J. P. 2011; 183 (6): E337-E343

    Abstract

    Industry involvement has been associated with more favourable cost-effectiveness ratios in cost-effectiveness analyses, but the mechanisms for this association are unclear. We evaluated whether the assumed accuracy of the Papanicolaou (Pap) test was correlated with the features of cost-effectiveness analysis studies.We searched PubMed (last updated April 2010) for cost-effectiveness analysis studies in which at least one strategy involved the Pap test for cervical cancer. We assessed the baseline assumed diagnostic sensitivity and specificity of the Pap test in each study and the association of these values with three levels of manufacturer involvement in the study.Among 88 analyzed cost-effectiveness analysis studies, the assumed sensitivity of the Pap test was lower in studies with manufacturer-affiliated authors, manufacturer funding or manufacturer-related competing interests versus studies without (mean sensitivity 60% v. 70%, p < 0.001). The assumed specificity of the Pap test was lower in cost-effectiveness analyses involving new screening tests (mean 93% v. 96%, p = 0.016). The assumed specificity did not differ between trials with manufacturer involvement versus those without (mean 95% v. 95%, p = 0.755).The results of cost-effectiveness analyses may be affected by a downgrading of the assumed diagnostic accuracy of the standard Pap test against which newer tests or interventions are compared. New technology then seems to have more favourable results against a straw-man comparator.

    View details for DOI 10.1503/cmaj.101506

    View details for Web of Science ID 000288872600014

    View details for PubMedID 21402681

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 26 (4): 313-337

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1007/s10654-011-9551-z

    View details for Web of Science ID 000290333700009

    View details for PubMedID 21424820

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement CIRCULATION-CARDIOVASCULAR GENETICS Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 4 (2): 206-209
  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 26 (4): 255-259

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published.

    View details for DOI 10.1007/s10654-011-9552-y

    View details for Web of Science ID 000290333700002

    View details for PubMedID 21431409

  • Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: A systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases AUTOIMMUNITY REVIEWS van Assen, S., Elkayam, O., Agmon-Levin, N., Cervera, R., Doran, M. F., Dougados, M., Emery, P., Geborek, P., Ioannidis, J. P., Jayne, D. R., Kallenberg, C. G., Mueller-Ladner, U., Shoenfeld, Y., Stojanovich, L., Valesini, G., Wulffraat, N. M., Bijl, M. 2011; 10 (6): 341-352

    Abstract

    To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD).AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ? 5 participants. Articles in English and regarding patients ? 16 years of age, were eligible.Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive.Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

    View details for DOI 10.1016/j.autrev.2010.12.003

    View details for Web of Science ID 000290059400009

    View details for PubMedID 21182987

  • Quantifying Selective Reporting and the Proteus Phenomenon for Multiple Datasets with Similar Bias PLOS ONE Pfeiffer, T., Bertram, L., Ioannidis, J. P. 2011; 6 (3)

    Abstract

    Meta-analyses play an important role in synthesizing evidence from diverse studies and datasets that address similar questions. A major obstacle for meta-analyses arises from biases in reporting. In particular, it is speculated that findings which do not achieve formal statistical significance are less likely reported than statistically significant findings. Moreover, the patterns of bias can be complex and may also depend on the timing of the research results and their relationship with previously published work. In this paper, we present an approach that is specifically designed to analyze large-scale datasets on published results. Such datasets are currently emerging in diverse research fields, particularly in molecular medicine. We use our approach to investigate a dataset on Alzheimer's disease (AD) that covers 1167 results from case-control studies on 102 genetic markers. We observe that initial studies on a genetic marker tend to be substantially more biased than subsequent replications. The chances for initial, statistically non-significant results to be published are estimated to be about 44% (95% CI, 32% to 63%) relative to statistically significant results, while statistically non-significant replications have almost the same chance to be published as statistically significant replications (84%; 95% CI, 66% to 107%). Early replications tend to be biased against initial findings, an observation previously termed Proteus phenomenon: The chances for non-significant studies going in the same direction as the initial result are estimated to be lower than the chances for non-significant studies opposing the initial result (73%; 95% CI, 55% to 96%). Such dynamic patterns in bias are difficult to capture by conventional methods, where typically simple publication bias is assumed to operate. Our approach captures and corrects for complex dynamic patterns of bias, and thereby helps generating conclusions from published results that are more robust against the presence of different coexisting types of selective reporting.

    View details for DOI 10.1371/journal.pone.0018362

    View details for Web of Science ID 000289054600050

    View details for PubMedID 21479240

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement ANNALS OF INTERNAL MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 154 (6): 421-W141
  • RE: "THE EMERGENCE OF TRANSLATIONAL EPIDEMIOLOGY: FROM SCIENTIFIC DISCOVERY TO POPULATION HEALTH IMPACT" REPLY AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Gwinn, M., Ioannidis, J. P. 2011; 173 (6): 718-U131

    View details for DOI 10.1093/aje/kwq450

    View details for Web of Science ID 000288274800018

  • EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases ANNALS OF THE RHEUMATIC DISEASES van Assen, S., Agmon-Levin, N., Elkayam, O., Cervera, R., Doran, M. F., Dougados, M., Emery, P., Geborek, P., Ioannidis, J. P., Jayne, D. R., Kallenberg, C. G., Mueller-Ladner, U., Shoenfeld, Y., Stojanovich, L., Valesini, G., Wulffraat, N. M., Bijl, M. 2011; 70 (3): 414-422

    Abstract

    To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD).A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force.Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed.Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

    View details for DOI 10.1136/ard.2010.137216

    View details for Web of Science ID 000286927800003

    View details for PubMedID 21131643

  • Polymorphisms in the 5 ' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies OSTEOPOROSIS INTERNATIONAL Jin, H., Evangelou, E., Ioannidis, J. P., Ralston, S. H. 2011; 22 (3): 911-921

    Abstract

    A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest.Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results.We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture.For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p?=?0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10??) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p?=?0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p?=?0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p?=?0.05) and the -1663indelT (p?=?0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited.The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.

    View details for DOI 10.1007/s00198-010-1364-5

    View details for Web of Science ID 000287101600018

    View details for PubMedID 20798928

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement PLOS MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 8 (3)

    View details for DOI 10.1371/journal.pmed.1000420

    View details for Web of Science ID 000288945200001

    View details for PubMedID 21423587

  • A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease NEUROBIOLOGY OF AGING Krueger, R., Sharma, M., Riess, O., Gasser, T., Van Broeckhoven, C., Theuns, J., Aasly, J., Annesi, G., Bentivoglio, A. R., Brice, A., Djarmati, A., Elbaz, A., Farrer, M., Ferrarese, C., Gibson, J. M., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Klein, C., Lambert, J., Lesage, S., Lin, J., Lynch, T., Mellick, G. D., de Nigris, F., Opala, G., Prigione, A., Quattrone, A., Ross, O. A., Satake, W., Silburn, P. A., Tan, E. K., Toda, T., Tomiyama, H., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Maraganore, D. M. 2011; 32 (3)

    Abstract

    High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.

    View details for DOI 10.1016/j.neurobiolaging.2009.11.021

    View details for Web of Science ID 000289944800028

    View details for PubMedID 20036034

  • Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Siontis, G. C. 2011; 103 (3)

    View details for DOI 10.1093/jnci/djq503

    View details for Web of Science ID 000287027000014

    View details for PubMedID 21163904

  • Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial JOURNAL OF CLINICAL EPIDEMIOLOGY Salanti, G., Ades, A. E., Ioannidis, J. P. 2011; 64 (2): 163-171

    Abstract

    To present some simple graphical and quantitative ways to assist interpretation and improve presentation of results from multiple-treatment meta-analysis (MTM).We reanalyze a published network of trials comparing various antiplatelet interventions regarding the incidence of serious vascular events using Bayesian approaches for random effects MTM, and we explore the advantages and drawbacks of various traditional and new forms of quantitative displays and graphical presentations of results.We present the results under various forms, conventionally based on the mean of the distribution of the effect sizes; based on predictions; based on ranking probabilities; and finally, based on probabilities to be within an acceptable range from a reference. We show how to obtain and present results on ranking of all treatments and how to appraise the overall ranks.Bayesian methodology offers a multitude of ways to present results from MTM models, as it enables a natural and easy estimation of all measures based on probabilities, ranks, or predictions.

    View details for DOI 10.1016/j.jclinepi.2010.03.016

    View details for Web of Science ID 000287281300007

    View details for PubMedID 20688472

  • Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 ANNALS OF THE RHEUMATIC DISEASES Evangelou, E., Valdes, A. M., Kerkhof, H. J., Styrkarsdottir, U., Zhu, Y., Meulenbelt, I., Lories, R. J., Karassa, F. B., Tylzanowski, P., Bos, S. D., Akune, T., Arden, N. K., Carr, A., Chapman, K., Cupples, L. A., Dai, J., Deloukas, P., Doherty, M., Doherty, S., Engstrom, G., Gonzalez, A., Halldorsson, B. V., Hammond, C. L., Hart, D. J., Helgadottir, H., Hofman, A., Ikegawa, S., Ingvarsson, T., Jiang, Q., Jonsson, H., Kaprio, J., Kawaguchi, H., Kisand, K., Kloppenburg, M., Kujala, U. M., Lohmander, L. S., Loughlin, J., Luyten, F. P., Mabuchi, A., McCaskie, A., Nakajima, M., Nilsson, P. M., Nishida, N., Ollier, W. E., Panoutsopoulou, K., Van de Putte, T., Ralston, S. H., Rivadeneira, F., Saarela, J., Schulte-Merker, S., Shi, D., Slagboom, P. E., Sudo, A., Tamm, A., Tamm, A., Thorleifsson, G., Thorsteinsdottir, U., Tsezou, A., Wallis, G. A., Wilkinson, J. M., Yoshimura, N., Zeggini, E., Zhai, G., Zhang, F., Jonsdottir, I., Uitterlinden, A. G., Felson, D. T., van Meurs, J. B., Stefansson, K., Ioannidis, J. P., Spector, T. D. 2011; 70 (2): 349-355

    Abstract

    Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component.A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets.With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10??), thereby confirming its role as a susceptibility locus for OA.The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, ?), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

    View details for DOI 10.1136/ard.2010.132787

    View details for Web of Science ID 000286179000022

    View details for PubMedID 21068099

  • Optimal timing of coronary angiography and potential intervention in non-ST-elevation acute coronary syndromes EUROPEAN HEART JOURNAL Katritsis, D. G., Siontis, G. C., Kastrati, A., van't Hof, A. W., Neumann, F., Siontis, K. C., Ioannidis, J. P. 2011; 32 (1): 32-40

    Abstract

    An invasive approach is superior to medical management for the treatment of patients with acute coronary syndromes without ST-segment elevation (NSTE-ACS), but the optimal timing of coronary angiography and subsequent intervention, if indicated, has not been settled.We conducted a meta-analysis of randomized trials addressing the optimal timing (early vs. delayed) of coronary angiography in NSTE-ACS. Four trials with 4013 patients were eligible (ABOARD, ELISA, ISAR-COOL, TIMACS), and data for longer follow-up periods than those published became available for this meta-analysis by the ELISA and ISAR-COOL investigators. The median time from admission or randomization to coronary angiography ranged from 1.16 to 14 h in the early and 20.8-86 h in the delayed strategy group. No statistically significant difference of risk of death [random effects risk ratio (RR) 0.85, 95% confidence interval (CI) 0.64-1.11] or myocardial infarction (MI) (RR 0.94, 95% CI 0.61-1.45) was detected between the two strategies. Early intervention significantly reduced the risk for recurrent ischaemia (RR 0.59, 95% CI 0.38-0.92, P = 0.02) and the duration of hospital stay (by 28%, 95% CI 22-35%, P < 0.001). Furthermore, decreased major bleeding events (RR 0.78, 95% CI 0.57-1.07, P = 0.13), and less major events (death, MI, or stroke) (RR 0.91, 95% CI 0.82-1.01, P = 0.09) were observed with the early strategy but these differences were not nominally significant.Early coronary angiography and potential intervention reduces the risk of recurrent ischaemia, and shortens hospital stay in patients with NSTE-ACS.

    View details for DOI 10.1093/eurheartj/ehq276

    View details for Web of Science ID 000286006200012

    View details for PubMedID 20709722

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. BMJ (Clinical research ed.) Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 342

    View details for DOI 10.1136/bmj.d631

    View details for PubMedID 21411493

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. Genome medicine Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 3 (3): 16-?

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of genetic risk prediction studies (the GRIPS statement), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published at http://www.plosmedicine.org.

    View details for DOI 10.1186/gm230

    View details for PubMedID 21410995

  • Allergens responsible for allergic contact dermatitis among children: a systematic review and meta-analysis CONTACT DERMATITIS Bonitsis, N. G., Tatsioni, A., Bassioukas, K., Ioannidis, J. P. 2011; 64 (5): 245-257

    Abstract

    Multiple studies have evaluated diverse allergens in paediatric populations. Consensus is still lacking on which allergens are most commonly implicated in allergic contact dermatitis.To evaluate the proportion of positive reactions for allergens tested in children and to identify allergens with positive reactions in at least 1% of them.This was a systematic review of studies in PubMed (1966-2010) investigating allergens in at least 100 enrolled children. Proportions of positive reactions for each allergen were combined with random effects models across studies.We included 49 studies with available data on 170 allergens. Each study tested a median of two allergens. Among the 94 allergens evaluated by at least two studies, 58 had estimates of positive reactions of at least 1% by random effects calculations, and for 21 of them the 95% confidence interval ensured that the proportion of positive reactions was at least 1%. The top five allergens tested by at least two studies included nickel sulfate, ammonium persulfate, gold sodium thiosulfate, thimerosal, and toluene-2,5-diamine (p-toluenediamine). For most allergens, the proportion of positive reactions was higher in studies published after 1995 than in earlier studies (p = 0.0065).This meta-analysis offers guidance on which allergens are most prevalent in the paediatric population and should have priority for inclusion in standardized allergen series.

    View details for DOI 10.1111/j.1600-0536.2010.01860.x

    View details for Web of Science ID 000289474000001

    View details for PubMedID 21480911

  • Combining molecular and genetic data from different sources. IARC scientific publications Ntzani, E. E., Khoury, M. J., Ioannidis, J. P. 2011: 323-336

    Abstract

    The rapidly growing number of molecular epidemiology studies is providing an enormous, often multidimensional, body of evidence on the association of various disease outcomes and biomarkers. The testing and validation of statistical hypotheses in genetic and molecular epidemiology presents a major challenge requiring methodological rigor and analytical power. The non-replication of many genetic and other biomarker association studies suggests that there may be an abundance of spurious findings in the field. This chapter will discuss ways of combining evidence from different sources using meta-analysis methods. Research synthesis not only aims at producing a summary effect estimate for a specific biomarker, but also offers a unique opportunity for a meticulous attempt to critically appraise a research field, identify substantial differences between or within studies, and detect sources of bias. Systematic reviews and meta-analyses in human genome epidemiology are specifically discussed, as they comprise the bulk of the available evidence in molecular epidemiology where these methods have been applied to date. Considered here are issues regarding validity and interpretation in genetic association studies, as well as strategies for developing and integrating evidence through international consortia. Finally, there is a brief look at how combining data through meta-analysis may be applied in other areas of molecular epidemiology.

    View details for PubMedID 22997870

  • EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Ioannidis, J. P., Aringer, M., Bollen, E., Bombardieri, S., Bruce, I. N., Cervera, R., Dalakas, M., DORIA, A., Hanly, J. G., Huizinga, T. W., Isenberg, D., Kallenberg, C., Piette, J. C., Schneider, M., Scolding, N., Smolen, J., Stara, A., Tassiulas, I., Tektonidou, M., Tincani, A., van Buchem, M. A., van Vollenhoven, R., Ward, M., Gordon, C., Boumpas, D. T. 2010; 69 (12): 2074-2082

    Abstract

    To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations.The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design.Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence > 5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1-5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD.Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

    View details for DOI 10.1136/ard.2010.130476

    View details for Web of Science ID 000284407300004

    View details for PubMedID 20724309

  • Is there a glass ceiling for highly cited scientists at the top of research universities? FASEB JOURNAL Ioannidis, J. P. 2010; 24 (12): 4635-4638

    Abstract

    University leaders aim to protect, shape, and promote the missions of their institutions. I evaluated whether top highly cited scientists are likely to occupy these positions. Of the current leaders of 96 U.S. high research activity universities, only 6 presidents or chancellors were found among the 4009 U.S. scientists listed in the ISIHighlyCited.com database. Of the current leaders of 77 UK universities, only 2 vice-chancellors were found among the 483 UK scientists listed in the same database. In a sample of 100 top-cited clinical medicine scientists and 100 top-cited biology and biochemistry scientists, only 1 and 1, respectively, had served at any time as president of a university. Among the leaders of 25 U.S. universities with the highest citation volumes, only 12 had doctoral degrees in life, natural, physical or computer sciences, and 5 of these 12 had a Hirsch citation index m < 1.0. The participation of highly cited scientists in the top leadership of universities is limited. This could have consequences for the research and overall mission of universities.

    View details for DOI 10.1096/fj.10-162974

    View details for Web of Science ID 000284824400004

    View details for PubMedID 20686108

  • Laboratory Mouse Models for the Human Genome-Wide Associations PLOS ONE Kitsios, G. D., Tangri, N., Castaldi, P. J., Ioannidis, J. P. 2010; 5 (11)

    Abstract

    The agnostic screening performed by genome-wide association studies (GWAS) has uncovered associations for previously unsuspected genes. Knowledge about the functional role of these genes is crucial and laboratory mouse models can provide such information. Here, we describe a systematic juxtaposition of human GWAS-discovered loci versus mouse models in order to appreciate the availability of mouse models data, to gain biological insights for the role of these genes and to explore the extent of concordance between these two lines of evidence. We perused publicly available data (NHGRI database for human associations and Mouse Genome Informatics database for mouse models) and employed two alternative approaches for cross-species comparisons, phenotype- and gene-centric. A total of 293 single gene-phenotype human associations (262 unique genes and 69 unique phenotypes) were evaluated. In the phenotype-centric approach, we identified all mouse models and related ortholog genes for the 51 human phenotypes with a comparable phenotype in mice. A total of 27 ortholog genes were found to be associated with the same phenotype in humans and mice, a concordance that was significantly larger than expected by chance (p<0.001). In the gene-centric approach, we were able to locate at least 1 knockout model for 60% of the 262 genes. The knockouts for 35% of these orthologs displayed pre- or post-natal lethality. For the remaining non-lethal orthologs, the same organ system was involved in mice and humans in 71% of the cases (p<0.001). Our project highlights the wealth of available information from mouse models for human GWAS, catalogues extensive information on plausible physiologic implications for many genes, provides hypothesis-generating findings for additional GWAS analyses and documents that the concordance between human and mouse genetic association is larger than expected by chance and can be informative.

    View details for DOI 10.1371/journal.pone.0013782

    View details for Web of Science ID 000283645700007

    View details for PubMedID 21072174

  • Science mapping analysis characterizes 235 biases in biomedical research JOURNAL OF CLINICAL EPIDEMIOLOGY Chavalarias, D., Ioannidis, J. P. 2010; 63 (11): 1205-1215

    Abstract

    Many different types of bias have been described. Some biases may tend to coexist or be associated with specific research settings, fields, and types of studies. We aimed to map systematically the terminology of bias across biomedical research.We used advanced text-mining and clustering techniques to evaluate 17,265,924 items from PubMed (1958-2008). We considered 235 bias terms and 103 other terms that appear commonly in articles dealing with bias.Forty bias terms were used in the title or abstract of more than 100 articles each. Pseudo-inclusion clustering identified 252 clusters of terms. The clusters were organized into macroscopic maps that cover a continuum of research fields. The resulting maps highlight which types of biases tend to co-occur and may need to be considered together and what biases are commonly encountered and discussed in specific fields. Most of the common bias terms have had continuous use over time since their introduction, and some (in particular confounding, selection bias, response bias, and publication bias) show increased usage through time.This systematic mapping offers a dynamic classification of biases in biomedical investigation and related fields and can offer insights for the multifaceted aspects of bias.

    View details for DOI 10.1016/j.jclinepi.2009.12.011

    View details for Web of Science ID 000282861600006

    View details for PubMedID 20400265

  • Genome-wide Significant Associations for Variants With Minor Allele Frequency of 5% or Less - An Overview: A HuGE Review AMERICAN JOURNAL OF EPIDEMIOLOGY Panagiotou, O. A., Evangelou, E., Ioannidis, J. P. 2010; 172 (8): 869-889

    Abstract

    The authors survey uncommon variants (minor allele frequency, ?5%) that have reached genome-wide significance (P ? 10??) in genome-wide association study(ies) (GWAS). They examine the typical effect sizes of these associations; whether they have arisen in multiple GWAS on the same phenotype; and whether they pertain to genetic loci that have other variants discovered through GWAS, perceived biologic plausibility from the candidate gene era, or known mutations associated with related phenotypes. Forty-three associations with minor allele frequency of 5% or less and P ? 10?? were studied, 12 of which involved nonsynonymous variants. Per-allele odds ratios ranged from 1.03 to 22.11. Thirty-two associations had P ? 10??. Eight uncommon variants were identified in multiple GWAS. For 14 associations, also other common polymorphisms with genome-wide significance were identified in the same loci. Thirteen associations pertained to genetic loci considered to have biologic plausibility for association in the candidate gene era, and mutations with related phenotypic effects were identified for 11 associations. Twenty-five uncommon variants are common in at least 1 of the 4 different ancestry samples of the International HapMap Project. Although the number of uncommon variants with genome-wide significance is still limited, these data suggest a possible confluence of rare/uncommon and common genetic variation on the same genetic loci.

    View details for DOI 10.1093/aje/kwq234

    View details for Web of Science ID 000283089700001

    View details for PubMedID 20876667

  • Evaluating novel agent effects in multiple-treatments meta-regression STATISTICS IN MEDICINE Salanti, G., Dias, S., Welton, N. J., Ades, A. E., Golfinopoulos, V., Kyrgiou, M., Mauri, D., Ioannidis, J. P. 2010; 29 (23): 2369-2383

    Abstract

    Multiple-treatments meta-analyses are increasingly used to evaluate the relative effectiveness of several competing regimens. In some fields which evolve with the continuous introduction of new agents over time, it is possible that in trials comparing older with newer regimens the effectiveness of the latter is exaggerated. Optimism bias, conflicts of interest and other forces may be responsible for this exaggeration, but its magnitude and impact, if any, needs to be formally assessed in each case. Whereas such novelty bias is not identifiable in a pair-wise meta-analysis, it is possible to explore it in a network of trials involving several treatments. To evaluate the hypothesis of novel agent effects and adjust for them, we developed a multiple-treatments meta-regression model fitted within a Bayesian framework. When there are several multiple-treatments meta-analyses for diverse conditions within the same field/specialty with similar agents involved, one may consider either different novel agent effects in each meta-analysis or may consider the effects to be exchangeable across the different conditions and outcomes. As an application, we evaluate the impact of modelling and adjusting for novel agent effects for chemotherapy and other non-hormonal systemic treatments for three malignancies. We present the results and the impact of different model assumptions to the relative ranking of the various regimens in each network. We established that multiple-treatments meta-regression is a good method for examining whether novel agent effects are present and estimation of their magnitude in the three worked examples suggests an exaggeration of the hazard ratio by 6 per cent (2-11 per cent).

    View details for DOI 10.1002/sim.4001

    View details for Web of Science ID 000282622200001

    View details for PubMedID 20687172

  • Assessment of cumulative evidence for the association between glutathione S-transferase polymorphisms and lung cancer: application of the Venice interim guidelines PHARMACOGENETICS AND GENOMICS Langevin, S. M., Ioannidis, J. P., Vineis, P., Taioli, E. 2010; 20 (10): 586-597

    Abstract

    There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines.Information from the literature was enriched with an updated meta-analysis and a pooled analysis using data from the Genetic Susceptibility to Environmental Carcinogens database.There was a significant association between GSTM1 null and lung cancer for the meta-analysis (meta odds ratio=1.17, 95% confidence interval: 1.10-1.25) and pooled analysis (adjusted odds ratio=1.10, 95% confidence interval: 1.04-1.16), although substantial heterogeneity was present. No overall association between lung cancer and GSTT1 null or GSTP1 Ile105Val was found. When the Venice criteria was applied, cumulative evidence for all associations were considered 'weak', with the exception of East Asian carriers of the G allele of GSTP1 Ile105Val, which was graded as 'moderate' evidence.Despite the large amounts of studies, and several statistically significant summary estimates produced by meta-analyses, the application of the Venice criteria suggests extensive heterogeneity and susceptibility to bias for the studies on association of common genetic polymorphisms, such as with GST variants and lung cancer.

    View details for DOI 10.1097/FPC.0b013e32833c3892

    View details for Web of Science ID 000281830900002

    View details for PubMedID 20729793

  • The need to consider the wider agenda in systematic reviews and meta-analyses: breadth, timing, and depth of the evidence BRITISH MEDICAL JOURNAL Ioannidis, J. P., Karassa, F. B. 2010; 341

    View details for DOI 10.1136/bmj.c4875

    View details for Web of Science ID 000282089500010

    View details for PubMedID 20837576

  • The Emergence of Translational Epidemiology: From Scientific Discovery to Population Health Impact AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Gwinn, M., Ioannidis, J. P. 2010; 172 (5): 517-524

    Abstract

    Recent emphasis on translational research (TR) is highlighting the role of epidemiology in translating scientific discoveries into population health impact. The authors present applications of epidemiology in TR through 4 phases designated T1-T4, illustrated by examples from human genomics. In T1, epidemiology explores the role of a basic scientific discovery (e.g., a disease risk factor or biomarker) in developing a "candidate application" for use in practice (e.g., a test used to guide interventions). In T2, epidemiology can help to evaluate the efficacy of a candidate application by using observational studies and randomized controlled trials. In T3, epidemiology can help to assess facilitators and barriers for uptake and implementation of candidate applications in practice. In T4, epidemiology can help to assess the impact of using candidate applications on population health outcomes. Epidemiology also has a leading role in knowledge synthesis, especially using quantitative methods (e.g., meta-analysis). To explore the emergence of TR in epidemiology, the authors compared articles published in selected issues of the Journal in 1999 and 2009. The proportion of articles identified as translational doubled from 16% (11/69) in 1999 to 33% (22/66) in 2009 (P = 0.02). Epidemiology is increasingly recognized as an important component of TR. By quantifying and integrating knowledge across disciplines, epidemiology provides crucial methods and tools for TR.

    View details for DOI 10.1093/aje/kwq211

    View details for Web of Science ID 000281324100003

    View details for PubMedID 20688899

  • Expectations, validity, and reality in omics JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2010; 63 (9): 945-949

    Abstract

    Diverse methods of large-scale measurements of biological processes have emerged in the last 15 years and their list is growing rapidly. Almost invariably, these advances in omics have been associated with major expectations of transforming not only biological knowledge but also medicine and health. However, practical applications of omics in biomedicine have often suffered from poor attention to issues of validity. As a consequence, major promises of personalized medicine have not yet materialized in improving patient or population outcomes. Several omics fields increasingly realize the need to safeguard the validity of their efforts, make reporting more transparent, and improve the translational potential of their studies. Many discoveries point indeed toward a highly individualized profile of health and disease, where each case is different, but this is currently difficult to translate into more effective personalized treatment or prevention. Given the exponential growth of collected data, understanding is often drowning in the sea of measurements.

    View details for DOI 10.1016/j.jclinepi.2010.04.002

    View details for Web of Science ID 000280746000002

    View details for PubMedID 20573481

  • Published articles should not be dead and buried: introducing research updates EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (9): 767-769
  • Fifty-Year Fate and Impact of General Medical Journals PLOS ONE Ioannidis, J. P., Belbasis, L., Evangelou, E. 2010; 5 (9)

    Abstract

    Influential medical journals shape medical science and practice and their prestige is usually appraised by citation impact metrics, such as the journal impact factor. However, how permanent are medical journals and how stable is their impact over time?We evaluated what happened to general medical journals that were publishing papers half a century ago, in 1959. Data were retrieved from ISI Web of Science for citations and PubMed (Journals function) for journal history. Of 27 eligible journals publishing in 1959, 4 have stopped circulation (including two of the most prestigious journals in 1959) and another 7 changed name between 1959 and 2009. Only 6 of these 27 journals have been published continuously with their initial name since they started circulation. The citation impact of papers published in 1959 gives a very different picture from the current journal impact factor; the correlation between the two is non-significant and very close to zero. Only 13 of the 5,223 papers published in 1959 received at least 5 citations in 2009.Journals are more permanent entities than single papers, but they are also subject to major change and their relative prominence can change markedly over time.

    View details for DOI 10.1371/journal.pone.0012531

    View details for Web of Science ID 000281456100023

    View details for PubMedID 20824146

  • Partisan Perspectives in the Medical Literature: A Study of High Frequency Editorialists Favoring Hormone Replacement Therapy JOURNAL OF GENERAL INTERNAL MEDICINE Tatsioni, A., Siontis, G. C., Ioannidis, J. P. 2010; 25 (9): 914-919

    Abstract

    Unfavorable results of major studies have led to a large shrinkage of the market for hormone replacement therapy (HRT) in the last 6 years. Some scientists continue to strongly support the use of HRT.We analyzed a sample of partisan editorializing articles on HRT to examine their arguments, the reporting of competing interests, the journal venues and their sponsoring societies.Through Thomson ISI database, we selected articles without primary data written by the five most prolific editorialists that addressed clinical topics pertaining to HRT and that were published in regular journal issues in 2002-2008.We recorded the number of articles with a partisan stance and their arguments, the number of partisan articles that reported conflicting interests, and the journal venues and their sponsoring societies publishing the partisan editorials.We analyzed 114 eligible articles (58 editorials, 16 guidelines, 37 reviews, 3 letters), of which 110 (96%) had a partisan stance favoring HRT. Typical arguments were benefits for menopausal and related symptoms (64.9%), criticism of unfavorable studies (78.9%), preclinical data that showed favorable effects of HRT (50%), and benefits for major outcomes such as osteoporosis and fractures (49.1%), cardiovascular disease (31.6%), dementia (24.6%) or colorectal cancer (20.2%), but also even breast cancer (4.4%). All 5 prolific editorialists had financial relationships with hormone manufacturers, but these were reported in only 6 of the 110 partisan articles. Four journals published 15-37 partisan articles each. The medical societies of these journals reported on their websites that several pharmaceutical companies sponsored them or their conferences.There is a considerable body of editorializing articles favoring HRT use and very few of these articles report conflicts of interest. Full disclosure of conflicts of interest is needed, especially for articles without primary data.

    View details for DOI 10.1007/s11606-010-1360-7

    View details for Web of Science ID 000280728300011

    View details for PubMedID 20425148

  • Recommendations for Biomarker Identification and Qualification in Clinical Proteomics SCIENCE TRANSLATIONAL MEDICINE Mischak, H., Allmaier, G., Apweiler, R., Attwood, T., Baumann, M., Benigni, A., Bennett, S. E., Bischoff, R., Bongcam-Rudloff, E., Capasso, G., Coon, J. J., D'Haese, P., Dominiczak, A. F., Dakna, M., Dihazi, H., Ehrich, J. H., Fernandez-Llama, P., Fliser, D., Frokiaer, J., Garin, J., Girolami, M., Hancock, W. S., Haubitz, M., Hochstrasser, D., Holman, R. R., Ioannidis, J. P., Jankowski, J., Julian, B. A., Klein, J. B., Kolch, W., Luider, T., Massy, Z., Mattes, W. B., Molina, F., Monsarrat, B., Novak, J., Peter, K., Rossing, P., Sanchez-Carbayo, M., Schanstra, J. P., Semmes, O. J., Spasovski, G., Theodorescu, D., Thongboonkerd, V., Vanholder, R., Veenstra, T. D., Weissinger, E., Yamamoto, T., Vlahou, A. 2010; 2 (46)

    Abstract

    Clinical proteomics has yielded some early positive results-the identification of potential disease biomarkers-indicating the promise for this analytical approach to improve the current state of the art in clinical practice. However, the inability to verify some candidate molecules in subsequent studies has led to skepticism among many clinicians and regulatory bodies, and it has become evident that commonly encountered shortcomings in fundamental aspects of experimental design mainly during biomarker discovery must be addressed in order to provide robust data. In this Perspective, we assert that successful studies generally use suitable statistical approaches for biomarker definition and confirm results in independent test sets; in addition, we describe a brief set of practical and feasible recommendations that we have developed for investigators to properly identify and qualify proteomic biomarkers, which could also be used as reporting requirements. Such recommendations should help put proteomic biomarker discovery on the solid ground needed for turning the old promise into a new reality.

    View details for DOI 10.1126/scitranslmed.3001249

    View details for Web of Science ID 000288435800002

    View details for PubMedID 20739680

  • Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal TRIALS Kent, D. M., Rothwell, P. M., Ioannidis, J. P., Altman, D. G., Hayward, R. A. 2010; 11

    Abstract

    Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.

    View details for DOI 10.1186/1745-6215-11-85

    View details for Web of Science ID 000282599100001

    View details for PubMedID 20704705

  • Comparative Effectiveness of Medical Interventions in Adults Versus Children JOURNAL OF PEDIATRICS Contopoulos-Ioannidis, D. G., Baltogianni, M. S., Ioannidis, J. P. 2010; 157 (2): 322-330

    Abstract

    To estimate the comparative effectiveness of medical interventions in adults versus children.We identified from the Cochrane Database of Systematic Reviews (Issue 1, 2007) meta-analyses with data on at least 1 adult and 1 pediatric randomized trial with binary primary efficacy outcome. For each meta-analysis, we calculated the summary odds ratio of the adult trials and the pediatric trials, respectively; the relative odds ratio (ROR) of the adult versus pediatric odds ratios per meta-analysis; and the summary ROR across all meta-analyses. ROR <1 means that the experimental intervention is more unfavorable in children than adults.Across 128 eligible meta-analyses (1051 adult and 343 pediatric trials), the summary ROR did not show a statistically significant difference between adults and children (0.96; 95% confidence intervals, 0.86 to 1.08). However, in all meta-analyses except for 1, the individual ROR's 95% confidence intervals could not exclude a relative difference in efficacy over 20%. In two-thirds, the relative difference in observed point estimates exceeded 50%. Nine statistically significant discrepancies were identified; 4 of them were also clinically important.Treatment effects are on average similar in adults and children, but available evidence leaves large uncertainty about their relative efficacy. Clinically important discrepancies may occur.

    View details for DOI 10.1016/j.jpeds.2010.02.011

    View details for Web of Science ID 000279871700031

    View details for PubMedID 20434730

  • Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies EUROPEAN JOURNAL OF HUMAN GENETICS Siontis, K. C., Patsopoulos, N. A., Ioannidis, J. P. 2010; 18 (7): 832-837

    Abstract

    Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10(-3) for association and 41 had P<10(-7). A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82-4.6) and median minor allele frequency=0.17 (IQR: 0.12-0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10(-7) discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18-1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15-0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.

    View details for DOI 10.1038/ejhg.2010.26

    View details for Web of Science ID 000278838800016

    View details for PubMedID 20234392

  • A Compendium of Genome-Wide Associations for Cancer: Critical Synopsis and Reappraisal JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Castaldi, P., Evangelou, E. 2010; 102 (12): 846-858

    Abstract

    Since 2007, genome-wide association (GWA) studies have identified numerous well-supported, novel genetic risk loci for common cancers; however, there are concerns that this technology is reaching its limits. We provide an overview of GWA-identified genetic associations with solid tumors. We simulated the distribution of population risk alleles for colorectal, prostate, testicular, and thyroid cancers based on genetic variants identified in GWA studies. We also evaluated whether statistical power to detect typical genetic effects could be improved with studies performing GWA analyses of all available samples rather than multistage designs. Fifty-six eligible articles yielded 92 eligible associations between cancer phenotypes and genetic variants with a median per-allele odds ratio (OR) of 1.22 (interquartile range = 1.15-1.36). Half of the associations pertained to prostate, colorectal, or breast cancer. Individuals at the upper quartile of simulated risk had only 2.1- to 4.2-fold higher relative risk than those in the lower quartile. Comprehensive evaluation of currently available samples with GWA platforms would yield few additional variants with per-allele OR = 1.4, but many more variants with OR = 1.2 could be detected; statistical power to detect weak associations (OR = 1.07) would still be negligible. The GWA approach is effective in identifying common genetic variants with moderate effect; however, identifying loci with very small effects and rare variants will require major new efforts. At present, the utility of GWA-identified risk loci in risk stratification for cancer is limited.

    View details for DOI 10.1093/jnci/djq173

    View details for Web of Science ID 000279925200006

    View details for PubMedID 20505153

  • Authors Response INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Ioannidis, J. P. 2010; 39 (3): 933-933

    View details for DOI 10.1093/ije/dyp158

    View details for Web of Science ID 000278438500035

  • Home Blood Pressure as a Cardiovascular Outcome Predictor It's Time to Take This Method Seriously HYPERTENSION Stergiou, G. S., Siontis, K. C., Ioannidis, J. P. 2010; 55 (6): 1301-1303
  • Evaluation of Association of HNF1B Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies PLOS ONE Elliott, K. S., Zeggini, E., McCarthy, M. I., Gudmundsson, J., Sulem, P., Stacey, S. N., Thorlacius, S., Amundadottir, L., Groenberg, H., Xu, J., Gaborieau, V., Eeles, R. A., Neal, D. E., Donovan, J. L., Hamdy, F. C., Muir, K., Hwang, S., Spitz, M. R., Zanke, B., Carvajal-Carmona, L., Brown, K. M., Hayward, N. K., Macgregor, S., Tomlinson, I. P., Lemire, M., Amos, C. I., Murabito, J. M., Isaacs, W. B., Easton, D. F., Brennan, P., Barkardottir, R. B., Gudbjartsson, D. F., Rafnar, T., Hunter, D. J., Chanock, S. J., Stefansson, K., Ioannidis, J. P. 2010; 5 (5)

    Abstract

    Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association.The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.

    View details for DOI 10.1371/journal.pone.0010858

    View details for Web of Science ID 000278222100002

    View details for PubMedID 20526366

  • Selection and Presentation of Imaging Figures in the Medical Literature PLOS ONE Siontis, G. C., Patsopoulos, N. A., Vlahos, A. P., Ioannidis, J. P. 2010; 5 (5)

    Abstract

    Images are important for conveying information, but there is no empirical evidence on whether imaging figures are properly selected and presented in the published medical literature. We therefore evaluated the selection and presentation of radiological imaging figures in major medical journals.We analyzed articles published in 2005 in 12 major general and specialty medical journals that had radiological imaging figures. For each figure, we recorded information on selection, study population, provision of quantitative measurements, color scales and contrast use. Overall, 417 images from 212 articles were analyzed. Any comment/hint on image selection was made in 44 (11%) images (range 0-50% across the 12 journals) and another 37 (9%) (range 0-60%) showed both a normal and abnormal appearance. In 108 images (26%) (range 0-43%) it was unclear whether the image came from the presented study population. Eighty-three images (20%) (range 0-60%) had any quantitative or ordered categorical value on a measure of interest. Information on the distribution of the measure of interest in the study population was given in 59 cases. For 43 images (range 0-40%), a quantitative measurement was provided for the depicted case and the distribution of values in the study population was also available; in those 43 cases there was no over-representation of extreme than average cases (p = 0.37).The selection and presentation of images in the medical literature is often insufficiently documented; quantitative data are sparse and difficult to place in context.

    View details for DOI 10.1371/journal.pone.0010888

    View details for Web of Science ID 000278222100017

    View details for PubMedID 20526360

  • RE: "UNDERLYING GENETIC MODELS OF INHERITANCE IN ESTABLISHED TYPE 2 DIABETES ASSOCIATIONS" - THREE AUTHORS REPLY AMERICAN JOURNAL OF EPIDEMIOLOGY Salanti, G., Zeggini, E., Ioannidis, J. P. 2010; 171 (10): 1155-1156

    View details for DOI 10.1093/aje/kwq059

    View details for Web of Science ID 000277728400013

  • Genome-wide meta-analyses identify multiple loci associated with smoking behavior NATURE GENETICS Furberg, H., Kim, Y., Dackor, J., Boerwinkle, E., Franceschini, N., Ardissino, D., Bernardinelli, L., Mannucci, P. M., Mauri, F., Merlini, P. A., Absher, D., Assimes, T. L., Fortmann, S. P., Iribarren, C., Knowles, J. W., Quertermous, T., Ferrucci, L., Tanaka, T., Bis, J. C., Furberg, C. D., Haritunians, T., McKnight, B., Psaty, B. M., Taylor, K. D., Thacker, E. L., Almgren, P., Groop, L., Ladenvall, C., Boehnke, M., Jackson, A. U., Mohlke, K. L., Stringham, H. M., Tuomilehto, J., Benjamin, E. J., Hwang, S., Levy, D., Preis, S. R., Vasan, R. S., Duan, J., Gejman, P. V., Levinson, D. F., Sanders, A. R., Shi, J., Lips, E. H., McKay, J. D., Agudo, A., Barzan, L., Bencko, V., Benhamou, S., Castellsague, X., Canova, C., Conway, D. I., Fabianova, E., Foretova, L., Janout, V., Healy, C. M., Holcatova, I., Kjaerheim, K., Lagiou, P., Lissowska, J., Lowry, R., Macfarlane, T. V., Mates, D., Richiardi, L., Rudnai, P., Szeszenia-Dabrowska, N., Zaridze, D., Znaor, A., Lathrop, M., Brennan, P., Bandinelli, S., Frayling, T. M., Guralnik, J. M., Milaneschi, Y., Perry, J. R., Altshuler, D., Elosua, R., Kathiresan, S., Lucas, G., Melander, O., O'Donnell, C. J., Salomaa, V., Schwartz, S. M., Voight, B. F., Penninx, B. W., Smit, J. H., Vogelzangs, N., Boomsma, D. I., de Geus, E. J., Vink, J. M., Willemsen, G., Chanock, S. J., Gu, F., Hankinson, S. E., Hunter, D. J., Hofman, A., Tiemeier, H., Uitterlinden, A. G., van Duijn, C. M., Walter, S., Chasman, D. I., Everett, B. M., Pare, G., Ridker, P. M., Li, M. D., Maes, H. H., Audrain-McGovern, J., Posthuma, D., Thornton, L. M., Lerman, C., Kaprio, J., Rose, J. E., Ioannidis, J. P., Kraft, P., Lin, D., Sullivan, P. F. 2010; 42 (5): 441-U134

    Abstract

    Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

    View details for DOI 10.1038/ng.571

    View details for Web of Science ID 000277179500017

    View details for PubMedID 20418890

  • Sources of funding for Nobel Prize-winning work: public or private? FASEB JOURNAL Tatsioni, A., Vavva, E., Ioannidis, J. P. 2010; 24 (5): 1335-1339

    Abstract

    Funding is important for scientists' work and may contribute to exceptional research outcomes. We analyzed the funding sources reported in the landmark scientific papers of Nobel Prize winners. Between 2000 and 2008, 70 Nobel laureates won recognition in medicine, physics, and chemistry. Sixty five (70%) of the 93 selected papers related to the Nobel-awarded work reported some funding source including U.S. government sources in 53 (82%), non-U.S. government sources in 19 (29%), and nongovernment sources in 33 (51%). A substantial portion of this exceptional work was unfunded. We contacted Nobel laureates whose landmark papers reported no funding. Thirteen Nobel laureates responded and offered their insights about the funding process and difficulties inherent in funding. Overall, very diverse sources amounting to a total of 64 different listed sponsors supported Nobel-related work. A few public institutions, in particular the U.S. National Institutes of Health (with n=26 funded papers) and the National Science Foundation (with n=17 papers), stood out for their successful record for funding exceptional research. However, Nobel-level work arose even from completely unfunded research, especially when institutions offered a protected environment for dedicated scientists.

    View details for DOI 10.1096/fj.09-148239

    View details for Web of Science ID 000277158900006

    View details for PubMedID 20056712

  • What Makes a Good Predictor? The Evidence Applied to Coronary Artery Calcium Score JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Tzoulaki, I. 2010; 303 (16): 1646-1647

    View details for Web of Science ID 000277085200030

    View details for PubMedID 20424257

  • Assessing Predictive Performance Beyond the Framingham Risk Score Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2010; 303 (14): 1369-1369
  • Validation of the Greek translation of the Dundee Ready Education Environment Measure (DREEM). Education for health (Abingdon, England) Dimoliatis, I. D., Vasilaki, E., ANASTASSOPOULOS, P., Ioannidis, J. P., Roff, S. 2010; 23 (1): 348-?

    Abstract

    The educational environment makes an important contribution to student learning. The DREEM questionnaire is a validated tool assessing the environment.To translate and validate the DREEM into Greek.Forward translations from English were produced by three independent Greek translators and then back translations by five independent bilingual translators. The Greek DREEM.v0 that was produced was administered to 831 undergraduate students from six Greek medical schools. Cronbach's alpha and test-retest correlation were used to evaluate reliability and factor analysis was used to assess validity. Questions that increased alpha if deleted and/or sorted unexpectedly in factor analysis were further checked through two focus groups.Questionnaires were returned by 487 respondents (59%), who were representative of all surveyed students by gender but not by year of study or medical school. The instrument's overall alpha was 0.90, and for the learning, teachers, academic, atmosphere and social subscales the alphas were 0.79 (expected 0.69), 0.78 (0.67), 0.69 (0.60), 0.68 (0.69), 0.48 (0.57), respectively. In a subset of the whole sample, test and retest alphas were both 0.90, and mean item scores highly correlated (p<0.001). Factor analysis produced meaningful subscales but not always matching the original ones. Focus group evaluation revealed possible misunderstanding for questions 17, 25, 29 and 38, which were revised in the DREEM.Gr.v1. The group mean overall scale score was 107.7 (SD 20.2), with significant differences across medical schools (p<0.001).Alphas and test-retest correlation suggest the Greek translated and validated DREEM scale is a reliable tool for assessing the medical education environment and for informing policy. Factor analysis and focus group input suggest it is a valid tool. Reasonable school differences suggest the instrument's sensitivity.

    View details for PubMedID 20589604

  • Who is afraid of reviewers' comments? Or, why anything can be published and anything can be cited EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (4): 285-287
  • Correspondence to Sand et Al. "Critical reappraisal of a catechol-o-methyltransferase transversion variant in schizophrenia". Biological psychiatry Lill, C. M., Schjeide, B. M., Roehr, J. T., Zauft, U., Allen, N. C., Zipp, F., McQueen, M. B., Kavvoura, F. K., Ioannidis, J. P., Khoury, M. J., Tanzi, R. E., Bertram, L. 2010; 67 (7): e45-8

    View details for DOI 10.1016/j.biopsych.2010.02.003

    View details for PubMedID 20303423

  • Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis ANNALS OF THE RHEUMATIC DISEASES Patsopoulos, N. A., Ioannidis, J. P. 2010; 69 (3): 561-566

    Abstract

    Genome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions.To carry out a meta-analysis of the available evidence for the association of polymorphisms in the TRAF1-C5 locus and 6q23 region with rheumatoid arthritis.Data were synthesised for four polymorphisms: rs3761847 (n=13 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. Meta-analyses for subgroups defined by anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status were also performed.The polymorphism rs6920220 reached genome-wide statistical significance with p=7.9 x 10(-17) and an allelic odds ratio of 1.24 (95% CI 1.18 to 1.30) and no between-study heterogeneity (I(2)=0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with RF. The other three variants showed large between-study heterogeneity across datasets (I(2) range 74-82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220).Genetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and RF profile. With the exception of rs6920220, which shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognised phenotypic or genetic variability (eg, gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.

    View details for DOI 10.1136/ard.2009.109447

    View details for Web of Science ID 000275458700016

    View details for PubMedID 19401279

  • Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer TRENDS IN GENETICS Galvan, A., Ioannidis, J. P., Dragani, T. A. 2010; 26 (3): 132-141

    Abstract

    Genome-wide association studies (GWAS) using population-based designs have identified many genetic loci associated with risk of a range of complex diseases including cancer; however, each locus exerts a very small effect and most heritability remains unexplained. Family-based pedigree studies have also suggested tentative loci linked to increased cancer risk, often characterized by pedigree-specificity. However, comparison between the results of population- and family-based studies shows little concordance. Explanations for this unidentified genetic 'dark matter' of cancer include phenotype ascertainment issues, limited power, gene-gene and gene-environment interactions, population heterogeneity, parent-of-origin-specific effects, and rare and unexplored variants. Many of these reasons converge towards the concept of genetic heterogeneity that might implicate hundreds of genetic variants in regulating cancer risk. Dissecting the dark matter is a challenging task. Further insights can be gained from both population association and pedigree studies.

    View details for DOI 10.1016/j.tig.2009.12.008

    View details for Web of Science ID 000275272600007

    View details for PubMedID 20106545

  • Associations of polymorphisms of eight muscle- or metabolism-related genes with performance in Mount Olympus marathon runners JOURNAL OF APPLIED PHYSIOLOGY Tsianos, G. I., Evangelou, E., Boot, A., Zillikens, M. C., van Meurs, J. B., Uitterlinden, A. G., Ioannidis, J. P. 2010; 108 (3): 567-574

    Abstract

    Athletic endurance performance is probably partly under genetic control, but genetic association studies have yielded inconclusive results. The objective of the present study was to evaluate the association of polymorphisms in eight muscle- or metabolism-related genes with endurance performance in participants of the Olympus Marathon running race. We recruited 438 athletes who participated in the 2007 and 2008 annual running events of the Olympus Marathon: a 43.8-km race with an ascent from sea level to 2,690-m altitude and then a descent to 300 m. Phenotypes of interest were the competitive event time at the specific Olympus Marathon where the athlete was enrolled, the fastest reported timing ever achieved in an Olympus Marathon, and how many kilometers per week the athlete ran during the previous year. Eleven polymorphisms in alpha(3)-actinin (ACTN3), AMP deaminase-1 (AMPD1), bradykinin B(2) receptor (BDKRB2), beta(2)-adrenergic receptor (ADRB2), peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 alpha (PPARGC1A), PPAR-alpha (PPARA), PPAR-delta (PPARD), and apoliprotein E (APOE) were evaluated. Hardy-Weinberg equilibrium testing on the overall cohort of male athletes showed a significant deviation for BDKRB2 rs1799722 (P = 0.018; P = 0.006 when limited to 316 habitual male runners) with an excess of the TT genotype. Across all athletes, no associations showed nominal statistical significance for any of the three phenotypes, and the same was true when analyses were limited to men (n = 417). When limited to 316 male athletes who identified running as their preferred sport, ADRB2 rs1042713 had nominally significant associations with faster times for the minor (A) allele for the fastest time ever (P = 0.01). The direction of effect was identical as previously postulated only for BDKRB2 rs1799722 and ADRB2 rs1042713, indicating consistency. BDKRB2 rs1799722 and ADRB2 rs1042713 have some support for being implicated in endurance performance among habitual runners and require further investigation.

    View details for DOI 10.1152/japplphysiol.00780.2009

    View details for Web of Science ID 000275670400018

    View details for PubMedID 20044476

  • Industry sponsorship and selection of comparators in randomized clinical trials EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Lathyris, D. N., Patsopoulos, N. A., Salanti, G., Ioannidis, J. P. 2010; 40 (2): 172-182

    Abstract

    Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products.Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period.Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors.Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition.

    View details for DOI 10.1111/j.1365-2362.2009.02240.x

    View details for Web of Science ID 000273602200011

    View details for PubMedID 20050879

  • A Genome-Wide Association Study Identifies an Osteoarthritis Susceptibility Locus on Chromosome 7q22 ARTHRITIS AND RHEUMATISM Kerkhof, H. J., Lories, R. J., Meulenbelt, I., Jonsdottir, I., Valdes, A. M., Arp, P., Ingvarsson, T., Jhamai, M., Jonsson, H., Stolk, L., Thorleifsson, G., Zhai, G., Zhang, F., Zhu, Y., van der Breggen, R., Carr, A., Doherty, M., Doherty, S., Felson, D. T., Gonzalez, A., Halldorsson, B. V., Hart, D. J., Hauksson, V. B., Hofman, A., Ioannidis, J. P., Kloppenburg, M., Lane, N. E., Loughlin, J., Luyten, F. P., Nevitt, M. C., Parimi, N., Pols, H. A., Rivadeneira, F., Slagboom, E. P., Styrkarsdottir, U., Tsezou, A., Van de Putte, T., Zmuda, J., Spector, T. D., Stefansson, K., Uitterlinden, A. G., van Meurs, J. B. 2010; 62 (2): 499-510

    Abstract

    To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study.We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10(-7) considered genome-wide significant.The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.

    View details for DOI 10.1002/art.27184

    View details for Web of Science ID 000279432100028

    View details for PubMedID 20112360

  • A vision for the European Journal of Clinical Investigation: note from the new editors EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (1): 1-3
  • Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece. Clinical ophthalmology (Auckland, N.Z.) Kitsos, G., Petrou, Z., Grigoriadou, M., Samples, J. R., Hewitt, A. W., Kokotas, H., Giannoulia-Karantana, A., Mackey, D. A., Wirtz, M. K., Moschou, M., Ioannidis, J. P., Petersen, M. B. 2010; 4: 171-178

    Abstract

    Mutations in the MYOC gene have been shown to explain 5% of unrelated primary open angle glaucoma (POAG) in different populations. In particular, the T377M MYOC mutation has arisen at least three separate times in history, in Great Britain, India, and Greece. The purpose of this study is to investigate the distribution of the mutation among different population groups in the northwestern region of Greece.We explored the distribution of the "Greek" T377M founder mutation in the Epirus region in Northwestern Greece, which could be its origin. Genotyping was performed in POAG cases and controls by PCR amplification of the MYOC gene, followed by digestion with restriction enzyme. Statistical analyses were performed by an exact test, the Kaplan-Meier method and the t-test.In the isolated Chrysovitsa village in the Pindus Mountains, a large POAG family demonstrated the T377M mutation in 20 of 66 family members while no controls from the Epirus region (n = 124) carried this mutation (P < 0.001). Among other POAG cases from Epirus, 2 out of 14 familial cases and 1 out of 80 sporadic cases showed the mutation (P = 0.057). The probability of POAG diagnosis with advancing age among mutation carriers was 23% at age 40, and reached 100% at age 75. POAG patients with the T377M mutation were diagnosed at a mean age of 51 years (SD +/- 13.9), which is younger than the sporadic or familial POAG cases: 63.1 (SD +/- 11) and 66.8 (SD +/- 9.8) years, respectively.The T377M mutation was found in high proportion in members of the Chrysovitsa family (30.3%), in lower proportion in familial POAG cases (14.2%) and seems rare in sporadic POAG cases (1.2%), while no controls (0%) from the Epirus region carried the mutation. Historical and geographical data may explain the distribution of this mutation within Greece and worldwide.

    View details for PubMedID 20390039

  • Non-Replication of Association for Six Polymorphisms From Meta-Analysis of Genome-Wide Association Studies of Parkinson's Disease: Large-Scale Collaborative Study AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Evangelou, E., Maraganore, D. M., Annesi, G., Brijhina, L., Brice, A., Elbaz, A., Ferrarese, C., Hadjigeorgiou, G. M., Krueger, R., Lambert, J., Lesage, S., Markopoulou, K., Mellick, G. D., Meeus, B., Pedersen, N. L., Quattrone, A., Van Broeckhoven, C., Sharma, M., Silburn, P. A., Tan, E., Wirdefeldt, K., Ioannidis, J. P. 2010; 153B (1): 220-228

    Abstract

    Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.

    View details for DOI 10.1002/ajmg.b.30980

    View details for Web of Science ID 000273440500025

    View details for PubMedID 19475631

  • Synopsis of Preterm Birth Genetic Association Studies: The Preterm Birth Genetics Knowledge Base (PTBGene) PUBLIC HEALTH GENOMICS Dolan, S. M., Hollegaard, M. V., Merialdi, M., Betran, A. P., Allen, T., Abelow, C., Nace, J., Lin, B. K., Khoury, M. J., Ioannidis, J. P., Bagade, S., Zheng, X., Dubin, R. A., Bertram, L., Edwards, D. R., Menon, R. 2010; 13 (7-8): 514-523

    Abstract

    Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data.We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene (http://ric.einstein.yu.edu/ptbgene/index.html) and report on a structured synopsis thereof as of December 1, 2008.Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility.After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups.

    View details for DOI 10.1159/000294202

    View details for Web of Science ID 000285011900015

    View details for PubMedID 20484876

  • Using Lifetime Risk Estimates in Personal Genomic Profiles: Estimation of Uncertainty AMERICAN JOURNAL OF HUMAN GENETICS Yang, Q., Flanders, W. D., Moonesinghe, R., Ioannidis, J. P., Guessous, I., Khoury, M. J. 2009; 85 (6): 786-800

    Abstract

    Personal genome tests are now offered direct-to-consumer (DTC) via genetic variants identified by genome-wide association studies (GWAS) for common diseases. Tests report risk estimates (age-specific and lifetime) for various diseases based on genotypes at multiple loci. However, uncertainty surrounding such risk estimates has not been systematically investigated. With breast cancer as an example, we examined the combined effect of uncertainties in population incidence rates, genotype frequency, effect sizes, and models of joint effects among genetic variants on lifetime risk estimates. We performed simulations to estimate lifetime breast cancer risk for carriers and noncarriers of genetic variants. We derived population-based cancer incidence rates from Surveillance, Epidemiology, and End Results (SEER) Program and comparative international data. We used data for non-Hispanic white women from 2003 to 2005. We derived genotype frequencies and effect sizes from published GWAS and meta-analyses. For a single genetic variant in FGFR2 gene (rs2981582), combination of uncertainty in these parameters produced risk estimates where upper and lower 95% simulation intervals differed by more than 3-fold. Difference in population incidence rates was the largest contributor to variation in risk estimates. For a panel of five genetic variants, estimated lifetime risk of developing breast cancer before age 80 for a woman that carried all risk variants ranged from 6.1% to 21%, depending on assumptions of additive or multiplicative joint effects and breast cancer incidence rates. Epidemiologic parameters involved in computation of disease risk have substantial uncertainty, and cumulative uncertainty should be properly recognized. Reliance on point estimates alone could be seriously misleading.

    View details for DOI 10.1016/j.ajhg.2009.10.017

    View details for Web of Science ID 000272797100003

    View details for PubMedID 19931039

  • Assessment of Claims of Improved Prediction Beyond the Framingham Risk Score JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2009; 302 (21): 2345-2352

    Abstract

    With heightened interest in predictive medicine, many studies try to document information that can improve prediction of major clinical outcomes.To evaluate the reported design and analysis of studies that examined whether additional predictors improve predictive performance when added to the Framingham risk score (FRS), one of the most widely validated and cited clinical prediction scores.Two independent investigators searched 1908 articles citing the article that described the FRS in 1998 until September 2009 through the ISI Web of Knowledge database. Articles were eligible if they included any analyses comparing the predictive performance of the FRS vs the FRS plus some additional predictor for a prospectively assessed outcome. Data Analyses We recorded information on FRS calculation, modeling of additional predictors, outcomes assessed, population evaluated, subgroup analysis documentation, and flaws in the methods that may have affected the reported improvements in predictive ability. We also evaluated the correlation of reported design and analysis features with the predictive model discrimination and improvements with the additional predictors.We evaluated 79 eligible articles. Forty-nine studies (62%) did not calculate the FRS as it has been proposed, 15 (19%) modeled the additional predictor in more than 1 way and presented only the best-fit or area-under-the-curve (AUC) results for only 1 model, 41 (52%) did not examine the original outcome that the FRS was developed for, 33 (42%) studied a population different from what the FRS was intended for, and 25 (32%) claimed improved prediction in 1 subgroup but only 7 (9%) formally tested subgroup differences. Evaluation of independence in multivariable regressions, discrimination in AUC, calibration, and reclassification were reported in 77, 36, 7, and 7 studies, respectively, but these methods were adequately documented in only 60, 13, 4, and 2 studies, respectively. Overall, 63 studies (80%) claimed some improved prediction. Increase in AUC was larger when the predictive performance of the FRS was lower (rho = -0.57, P < .001). Increase in AUC was significantly larger when evaluation of independence in multivariable regression or discrimination in AUC analysis was not adequately documented and when the additional predictor had been modeled in more than 1 way and only 1 model was reported for AUC.The majority of examined studies claimed that they found factors that could offer additional predictive value beyond what the FRS could achieve; however, most had flaws in their design, analyses, and reporting that cast some doubt on the reliability of the claims for improved prediction.

    View details for Web of Science ID 000272239000023

    View details for PubMedID 19952321

  • Heterogeneous views on heterogeneity INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Evangelou, E., Ioannidis, J. P. 2009; 38 (6): 1740-1742

    View details for DOI 10.1093/ije/dyn235

    View details for Web of Science ID 000272464700042

    View details for PubMedID 18940836

  • Researching Genetic Versus Nongenetic Determinants of Disease: A Comparison and Proposed Unification SCIENCE TRANSLATIONAL MEDICINE Ioannidis, J. P., Loy, E. Y., Poulton, R., Chia, K. S. 2009; 1 (7)

    Abstract

    Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limits. Studies are needed that massively measure genotypes, nongenetic exposures, and outcomes concurrently.

    View details for DOI 10.1126/scitranslmed.3000247

    View details for Web of Science ID 000277262200001

    View details for PubMedID 20368180

  • Discovery Properties of Genome-wide Association Signals From Cumulatively Combined Data Sets AMERICAN JOURNAL OF EPIDEMIOLOGY Pereira, T. V., Patsopoulos, N. A., Salanti, G., Ioannidis, J. P. 2009; 170 (10): 1197-1206

    Abstract

    Genetic effects for common variants affecting complex disease risk are subtle. Single genome-wide association (GWA) studies are typically underpowered to detect these effects, and combination of several GWA data sets is needed to enhance discovery. The authors investigated the properties of the discovery process in simulated cumulative meta-analyses of GWA study-derived signals allowing for potential genetic model misspecification and between-study heterogeneity. Variants with null effects on average (but also between-data set heterogeneity) could yield false-positive associations with seemingly homogeneous effects. Random effects had higher than appropriate false-positive rates when there were few data sets. The log-additive model had the lowest false-positive rate. Under heterogeneity, random-effects meta-analyses of 2-10 data sets averaging 1,000 cases/1,000 controls each did not increase power, or the meta-analysis was even less powerful than a single study (power desert). Upward bias in effect estimates and underestimation of between-study heterogeneity were common. Fixed-effects calculations avoided power deserts and maximized discovery of association signals at the expense of much higher false-positive rates. Therefore, random- and fixed-effects models are preferable for different purposes (fixed effects for initial screenings, random effects for generalizability applications). These results may have broader implications for the design and interpretation of large-scale multiteam collaborative studies discovering common gene variants.

    View details for DOI 10.1093/aje/kwp262

    View details for Web of Science ID 000271379800002

    View details for PubMedID 19808636

  • The elderly were under-represented in osteoarthritis clinical trials JOURNAL OF CLINICAL EPIDEMIOLOGY Liberopoulos, G., Trikalinos, N. A., Ioannidis, J. P. 2009; 62 (11): 1218-1223

    Abstract

    Osteoarthritis is the most common disease affecting joints in the elderly. We aimed to evaluate if elderly patients are properly represented in clinical trials of diverse osteoarthritis interventions.Clinical trials of osteoarthritis interventions were retrieved from Cochrane Library systematic reviews (2006, issue 2). We examined the age distribution of the trial participants and eligibility criteria.We analyzed data from 219 eligible trials from 18 systematic reviews. The average mean age of the participants was 63 years. Only 13 trials (6.4%) had a mean age between 71 and 80 years and only one trial had a mean age exceeding 80 years. Among trials where the age range of participants was available or could be approximately inferred, we estimated that 66 (38%) trials had not included any patients over 80 years old. Only 23 trials specifically excluded patients over 70 based on reported eligibility criteria, but 168 trials excluded patients with various comorbidities and 142 trials excluded patients receiving other specific treatments.Elderly patients are considerably under-represented in clinical trials of osteoarthritis. This causes an important deficit in the utility, relevance, and generalizability of trial results for this very common condition.

    View details for DOI 10.1016/j.jclinepi.2008.12.009

    View details for Web of Science ID 000270758900016

    View details for PubMedID 19356899

  • Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies NATURE GENETICS Rivadeneira, F., Styrkarsdottir, U., Estrada, K., Halldorsson, B. V., Hsu, Y., Richards, J. B., Zillikens, M. C., Kavvoura, F. K., Amin, N., Aulchenko, Y. S., Cupples, L. A., Deloukas, P., Demissie, S., Grundberg, E., Hofman, A., Kong, A., Karasik, D., van Meurs, J. B., Oostra, B., Pastinen, T., Pols, H. A., Sigurdsson, G., Soranzo, N., Thorleifsson, G., Thorsteinsdottir, U., Williams, F. M., Wilson, S. G., Zhou, Y., Ralston, S. H., van Duijn, C. M., Spector, T., Kiel, D. P., Stefansson, K., Ioannidis, J. P., Uitterlinden, A. G. 2009; 41 (11): 1199-U58

    Abstract

    Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.

    View details for DOI 10.1038/ng.446

    View details for Web of Science ID 000271247600012

    View details for PubMedID 19801982

  • STrengthening the REporting of Genetic Association Studies (STREGA)-An Extension of the STROBE Statement GENETIC EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A., Birkett, N. 2009; 33 (7): 581-598

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1002/gepi.20410

    View details for Web of Science ID 000271406100003

    View details for PubMedID 19278015

  • Replication in Genome-Wide Association Studies STATISTICAL SCIENCE Kraft, P., Zeggini, E., Ioannidis, J. P. 2009; 24 (4): 561-573

    Abstract

    Replication helps ensure that a genotype-phenotype association observed in a genome-wide association (GWA) study represents a credible association and is not a chance finding or an artifact due to uncontrolled biases. We discuss prerequisites for exact replication; issues of heterogeneity; advantages and disadvantages of different methods of data synthesis across multiple studies; frequentist vs. Bayesian inferences for replication; and challenges that arise from multi-team collaborations. While consistent replication can greatly improve the credibility of a genotype-phenotype association, it may not eliminate spurious associations due to biases shared by many studies. Conversely, lack of replication in well-powered follow-up studies usually invalidates the initially proposed association, although occasionally it may point to differences in linkage disequilibrium or effect modifiers across studies.

    View details for DOI 10.1214/09-STS290

    View details for Web of Science ID 000277257000013

    View details for PubMedID 20454541

  • Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis CANCER TREATMENT REVIEWS Golfinopoulos, V., Pentheroudakis, G., Salanti, G., Nearchou, A. D., Ioannidis, J. P., Pavlidis, N. 2009; 35 (7): 570-573

    Abstract

    To synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP).PubMed and the Cochrane Library Central Registry of Controlled Trials.We retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals.Ten articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane).No type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing.

    View details for DOI 10.1016/j.ctrv.2009.05.005

    View details for Web of Science ID 000272098400006

    View details for PubMedID 19539430

  • Adverse Events in Randomized Trials Neglected, Restricted, Distorted, and Silenced ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. P. 2009; 169 (19): 1737-1739

    View details for Web of Science ID 000271163800001

    View details for PubMedID 19858427

  • Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture ANNALS OF INTERNAL MEDICINE Richards, J. B., Kavvoura, F. K., Rivadeneira, F., Styrkarsdottir, U., Estrada, K., Halldorsson, B. V., Hsu, Y., Zillikens, M. C., Wilson, S. G., Mullin, B. H., Amin, N., Aulchenko, Y. S., Cupples, L. A., Deloukas, P., Demissie, S., Hofman, A., Kong, A., Karasik, D., van Meurs, J. B., Oostra, B. A., Pols, H. A., Sigurdsson, G., Thorsteinsdottir, U., Soranzo, N., Williams, F. M., Zhou, Y., Ralston, S. H., Thorleifsson, G., van Duijn, C. M., Kiel, D. P., Stefansson, K., Uitterlinden, A. G., Ioannidis, J. P., Spector, T. D. 2009; 151 (8): 528-U32

    Abstract

    Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.Large-scale meta-analysis of genome-wide association data.5 international, multicenter, population-based studies.Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

    View details for Web of Science ID 000271386200002

    View details for PubMedID 19841454

  • Integration of evidence from multiple meta-analyses: a primer on umbrella reviews, treatment networks and multiple treatments meta-analyses CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P. 2009; 181 (8): 488-493

    View details for DOI 10.1503/cmaj.081086

    View details for Web of Science ID 000270712800009

    View details for PubMedID 19654195

  • Population-Wide Generalizability of Genome-Wide Discovered Associations JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P. 2009; 101 (19): 1297-1299

    View details for DOI 10.1093/jnci/djp298

    View details for Web of Science ID 000270709900004

    View details for PubMedID 19726754

  • Double Versus Single Stenting for Coronary Bifurcation Lesions A Meta-Analysis CIRCULATION-CARDIOVASCULAR INTERVENTIONS Katritsis, D. G., Siontis, G. C., Ioannidis, J. P. 2009; 2 (5): 409-U76

    Abstract

    Several trials have addressed whether bifurcation lesions require stenting of both the main vessel and side branch, but uncertainty remains on the benefits of such double versus single stenting of the main vessel only.We have conducted a meta-analysis of randomized trials including patients with coronary bifurcation lesions who were randomly selected to undergo percutaneous coronary intervention by either double or single stenting. Six studies (n=1642 patients) were eligible. There was increased risk of myocardial infarction with double stenting (risk ratio, 1.78; P=0.001 by fixed effects; risk ratio, 1.49 with Bayesian meta-analysis). The summary point estimate suggested also an increased risk of stent thrombosis with double stenting, but the difference was not nominally significant given the sparse data (risk ratio, 1.85; P=0.19). No obvious difference was seen for death (risk ratio, 0.81; P=0.66) and target lesion revascularization (risk ratio, 1.09; P=0.67).Stenting of both the main vessel and side branch in bifurcation lesions may increase myocardial infarction and stent thrombosis risk compared with stenting of the main vessel only.

    View details for DOI 10.1161/CIRCINTERVENTIONS.109.868091

    View details for Web of Science ID 000276068800007

    View details for PubMedID 20031750

  • Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations AMERICAN JOURNAL OF EPIDEMIOLOGY Salanti, G., Southam, L., Altshuler, D., Ardlie, K., Barroso, I., Boehnke, M., Cornelis, M. C., Frayling, T. M., Grallert, H., Grarup, N., Groop, L., Hansen, T., Hattersley, A. T., Hu, F. B., Hveem, K., Illig, T., Kuusisto, J., Laakso, M., Langenberg, C., Lyssenko, V., McCarthy, M. I., Morris, A., Morris, A. D., Palmer, C. N., Payne, F., Platou, C. G., Scott, L. J., Voight, B. F., Wareham, N. J., Zeggini, E., Ioannidis, J. P. 2009; 170 (5): 537-545

    Abstract

    For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.

    View details for DOI 10.1093/aje/kwp145

    View details for Web of Science ID 000269195000001

    View details for PubMedID 19602701

  • Prognostic factors and outcomes for osteosarcoma: An international collaboration EUROPEAN JOURNAL OF CANCER Pakos, E. E., Nearchou, A. D., Grimer, R. J., Koumoullis, H. D., Abudu, A., Bramer, J. A., Jeys, L. M., Franchi, A., Scoccianti, G., Campanacci, D., Capanna, R., Aparicio, J., Tabone, M., Holzer, G., Abdolvahab, F., Funovics, P., Dominkus, M., Ilhan, I., Berrak, S. G., Patino-Garcia, A., Sierrasesumaga, L., San-Julian, M., Garraus, M., Petrili, A. S., Garcia Filho, R. J., Pacheco Donato Macedo, C. R., de Seixas Alves, M. T., Seiwerth, S., Nagarajan, R., Cripe, T. P., Ioannidis, J. P. 2009; 45 (13): 2367-2375

    Abstract

    We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.

    View details for DOI 10.1016/j.ejca.2009.03.005

    View details for Web of Science ID 000270645700026

    View details for PubMedID 19349163

  • The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration ANNALS OF INTERNAL MEDICINE Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 151 (4): W65-W94

    Abstract

    Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement-a reporting guideline published in 1999-there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (www.prisma-statement.org) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for Web of Science ID 000269038900004

    View details for PubMedID 19622512

  • The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health-Centers for Disease Control and Prevention Multidisciplinary Workshop GENETICS IN MEDICINE Khoury, M. J., McBride, C. M., Schully, S. D., Ioannidis, J. P., Feero, W. G., Janssens, A. C., Gwinn, M., Simons-Morton, D. G., Bernhardt, J. M., Cargill, M., Chanock, S. J., Church, G. M., Coates, R. J., Collins, F. S., Croyle, R. T., Davis, B. R., Downing, G. J., DuRoss, A., Friedman, S., Gail, M. H., Ginsburg, G. S., Green, R. C., Greene, M. H., Greenland, P., Gulcher, J. R., Hsu, A., Hudson, K. L., Kardia, S. L., Kimmel, P. L., Lauer, M. S., Miller, A. M., Offit, K., Ransohoff, D. F., Roberts, J. S., Rasooly, R. S., Stefansson, K., Terry, S. F., Teutsch, S. M., Trepanier, A., Wanke, K. L., Witte, J. S., Xu, J. 2009; 11 (8): 559-567

    Abstract

    The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

    View details for DOI 10.1097/GIM.0b013e3181b13a6c

    View details for Web of Science ID 000269273900001

    View details for PubMedID 19617843

  • Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Bertram, L., Boffetta, P., Butterworth, A. S., Chanock, S. J., Dolan, S. M., Fortier, I., Garcia-Closas, M., Gwinn, M., Higgins, J. P., Janssens, A. C., Ostell, J., Owen, R. P., Pagon, R. A., Rebbeck, T. R., Rothman, N., Bernstein, J. L., Burton, P. R., Campbell, H., Chockalingam, A., Furberg, H., Little, J., O'Brien, T. R., Seminara, D., Vineis, P., Winn, D. M., Yu, W., Ioannidis, J. P. 2009; 170 (3): 269-279

    Abstract

    Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues -- especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10(-7)). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.

    View details for DOI 10.1093/aje/kwp119

    View details for Web of Science ID 000268330300001

    View details for PubMedID 19498075

  • Immunogenicity and adverse events of avian influenza A H5N1 vaccine in healthy adults: multiple-treatments meta-analysis LANCET INFECTIOUS DISEASES Manzoli, L., Salanti, G., De Vito, C., Boccia, A., Ioannidis, J. P., Villari, P. 2009; 9 (8): 482-492

    Abstract

    Influenza H5N1 is thought to be a likely causative agent for a future human influenza pandemic. Several types of H5N1 vaccine have been tested, including different doses and adjuvants, and a meta-analysis is needed to identify the best formulation. We searched Medline, Embase, the Cochrane Library, and other online databases to February, 2009, in any language for randomised trials comparing different H5N1 vaccines with or without placebo in healthy adults. Primary outcomes were seroconversion, seroresponse, or both according to haemagglutination-inhibition and microneutralisation. Secondary outcomes were adverse events. Because of the large number of compared formulations, multiple-treatments meta-analysis was used for primary outcomes. Direct-comparison meta-analyses were also done. We included 13 trials, which assessed 58 groups. With non-aluminium adjuvant, sufficiently high immunogenicity (greater than 70%) was achieved even at 12 microg or less (given as two doses of 6 microg or less), and higher doses did not provide major improvements. Immunogenicity for non-adjuvanted and aluminium-adjuvanted formulations increased with increasing dose, but was not sufficiently high. No serious vaccine-related adverse events were reported across 9600 participants. Currently, H5N1 influenza vaccines with non-aluminium adjuvants might represent the best available option in a pandemic. Large-scale studies are needed to verify the high immunogenicity of non-aluminium-adjuvanted vaccines that use very low doses of antigen.

    View details for Web of Science ID 000268625400016

    View details for PubMedID 19628173

  • The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration BRITISH MEDICAL JOURNAL Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 339

    Abstract

    Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement-a reporting guideline published in 1999-there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for DOI 10.1136/bmj.b2700

    View details for Web of Science ID 000268351400023

    View details for PubMedID 19622552

  • The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration PLOS MEDICINE Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 6 (7)

    Abstract

    Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users.Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement--a reporting guideline published in 1999--there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions.The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for DOI 10.1371/journal.pmed.1000100

    View details for Web of Science ID 000268452400006

    View details for PubMedID 19621070

  • STrengthening the REporting of Genetic Association studies (STREGA)-an extension of the strengthening the reporting, of observational studies in epidemiology (STROBE) statement JOURNAL OF CLINICAL EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 62 (6): 597-608

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence, the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association (STREGA) studies initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1016/j.jclinepi.2008.12.004

    View details for Web of Science ID 000266291600009

    View details for PubMedID 19217256

  • Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand ARTHRITIS AND RHEUMATISM Evangelou, E., Chapman, K., Meulenbelt, I., Karassa, F. B., Loughlin, J., Carr, A., Doherty, M., Doherty, S., Gomez-Reino, J. J., Gonzalez, A., Halldorsson, B. V., Hauksson, V. B., Hofman, A., Hart, D. J., Ikegawa, S., Ingvarsson, T., Jiang, Q., Jonsdottir, I., Jonsson, H., Kerkhof, H. J., Kloppenburg, M., Lane, N. E., Li, J., Lories, R. J., van Meurs, J. B., Nakki, A., Nevitt, M. C., Rodriguez-Lopez, J., Shi, D., Slagboom, E., Stefansson, K., Tsezou, A., Wallis, G. A., Watson, C. M., Spector, T. D., Uitterlinden, A. G., Valdes, A. M., Ioannidis, J. P. 2009; 60 (6): 1710-1721

    Abstract

    GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P=9.4x10(-7)), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P=0.016]) or absent (for OA of the hand [P=0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P=0.019).Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.

    View details for DOI 10.1002/art.24524

    View details for Web of Science ID 000267116800021

    View details for PubMedID 19479880

  • Ranking antidepressants LANCET Ioannidis, J. P. 2009; 373 (9677): 1759-1760

    View details for Web of Science ID 000266337300019

    View details for PubMedID 19465221

  • Validating, augmenting and refining genome-wide association signals. Nature reviews. Genetics Ioannidis, J. P., Thomas, G., Daly, M. J. 2009; 10 (5): 318-329

    Abstract

    Studies using genome-wide platforms have yielded an unprecedented number of promising signals of association between genomic variants and human traits. This Review addresses the steps required to validate, augment and refine such signals to identify underlying causal variants for well-defined phenotypes. These steps include: large-scale exact replication across both similar and diverse populations; fine mapping and resequencing; determination of the most informative markers and multiple independent informative loci; incorporation of functional information; and improved phenotype mapping of the implicated genetic effects. Even in cases for which replication proves that an effect exists, confident localization of the causal variant often remains elusive.

    View details for DOI 10.1038/nrg2544

    View details for PubMedID 19373277

  • STrengthening the REporting of Genetic Association studies (STREGA) - an extension of the STROBE statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 39 (4): 247-266

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.

    View details for DOI 10.1111/j.1365-2362.2009.02125.x

    View details for Web of Science ID 000264021800001

    View details for PubMedID 19297801

  • EULAR points to consider for conducting clinical trials in systemic lupus erythematosus: literature based evidence for the selection of endpoints ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I. M., Houssiau, F., Huizinga, T., Isenberg, D., Kallenberg, C. G., Khamashta, M., Piette, J. C., Schneider, M., Smolen, J., Sturfelt, G., Tincani, A., van Vollenhoven, R., Boumpas, D. T., Gordon, C. 2009; 68 (4): 477-483

    Abstract

    To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE.The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists.Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken.This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.

    View details for DOI 10.1136/ard.2007.083030

    View details for Web of Science ID 000264196000005

    View details for PubMedID 18434449

  • EULAR points to consider for conducting clinical trials in systemic lupus erythematosus ANNALS OF THE RHEUMATIC DISEASES Gordon, C., Bertsias, G., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I., Houssiau, F., Huizinga, T. W., Isenberg, D., Kallenberg, C. G., Khamashta, M. A., Piette, J., Schneider, M., Smolen, J. S., Sturfelt, G., Tincani, A., van Vollenhoven, R., Boumpas, D. T. 2009; 68 (4): 470-476

    Abstract

    Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions.ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE.The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE.The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications.Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.

    View details for DOI 10.1136/ard.2007.083022

    View details for Web of Science ID 000264196000004

    View details for PubMedID 18388158

  • Overinterpretation of Clinical Applicability in Molecular Diagnostic Research CLINICAL CHEMISTRY Lumbreras, B., Parker, L. A., Porta, M., Pollan, M., Ioannidis, J. P., Hernandez-Aguado, I. 2009; 55 (4): 786-794

    Abstract

    We evaluated whether articles on molecular diagnostic tests interpret appropriately the clinical applicability of their results.We selected original-research articles published in 2006 that addressed the diagnostic value of a molecular test. We defined overinterpretation of clinical applicability by means of prespecified rules that evaluated study design, conclusions regarding applicability, presence of statements suggesting the need for further clinical evaluation of the test, and diagnostic accuracy. Two reviewers independently evaluated the articles; consensus was reached after discussion and arbitration by a third reviewer.Of 108 articles included in the study, 82 (76%) used a design that used healthy controls or alternative-diagnosis controls, only 15 (11%) addressed a clinically relevant population similar to that in which the test might be applied in practice, 104 articles (96%) made definitely favorable or promising statements regarding clinical applicability, and 61 (56%) of the articles apparently overinterpreted the clinical applicability of their findings. Articles published in journals with higher impact factors were more likely to overinterpret their results than those with lower impact factors (adjusted odds ratio, 1.71 per impact factor quartile; 95% CI, 1.09-2.69; P = 0.020). Overinterpretation was more common when authors were based in laboratories than in clinical settings (adjusted odds ratio, 18.7; 95% CI, 1.41-249; P = 0.036).Although expectations are high for new diagnostic tests based on molecular techniques, the majority of published research has involved preclinical phases of research. Overinterpretation of the clinical applicability of findings for new molecular diagnostic tests is common.

    View details for DOI 10.1373/clinchem.2008.121517

    View details for Web of Science ID 000264774200024

    View details for PubMedID 19233907

  • Persistent reservations against contradicted percutaneous coronary intervention indications: Citation content analysis AMERICAN HEART JOURNAL Siontis, G. C., Tatsioni, A., Katritsis, D. G., Ioannidis, J. P. 2009; 157 (4): 695-701

    Abstract

    Two large trials, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Occluded Artery Trial (OAT), found no benefits of percutaneous coronary intervention (PCI) versus optimal medical therapy in chronic stable coronary artery disease and chronic total occlusion.We examined the stance of articles citing COURAGE and OAT to determine whether some authors continue to defend PCI despite this evidence, what persisting counterarguments are raised to express reservations, and whether specific characteristics of the citations are associated with reservations. We evaluated all citing articles entered in the Web of Science until February 1, 2008. Specific characteristics were recorded for each eligible citation, and a citation content analysis was performed. Counterarguments were categorized on participants, interventions, comparisons, and outcomes.Of 54 articles citing COURAGE and 33 articles citing OAT, 10 (19%) and 5 (15%), respectively, had an overall reserved stance. Alluded reservations included lack of power, eroded effects from crossover, selective inclusion and exclusion of specific types of patients, suboptimal clinical setting, use of bare-metal stents, suspiciously good results in the conservative treatment arm, and suboptimal outcome choices or definitions. Reserved articles were more likely than unreserved ones to have an interventional cardiologist as corresponding author (odds ratio 5.2, 95% confidence interval 1.6-17.1; P = .007) and to be commentaries focusing on one of these trials (odds ratio 3.3, 95% confidence interval 1.0-11.0; P = .05).Despite strong randomized evidence, a fraction of the literature, mostly corresponded by interventional cardiologists, continues to raise reservations about recently contradicted indications of PCI.

    View details for DOI 10.1016/j.ahj.2008.11.023

    View details for Web of Science ID 000265110100017

    View details for PubMedID 19332198

  • Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement HUMAN GENETICS Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 125 (2): 131-151

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1007/s00439-008-0592-7

    View details for Web of Science ID 000263496900003

    View details for PubMedID 19184668

  • An empirical comparison of meta-analyses of published gene-disease associations versus consortium analyses GENETICS IN MEDICINE Janssens, A. C., Ladd, A. M., Lopez-Leon, S., Ioannidis, J. P., Oostra, B. A., Khoury, M. J., van Duijn, C. M. 2009; 11 (3): 153-162

    Abstract

    Consortia of investigators currently compile sufficiently large sample sizes to investigate the effects of low-risk susceptibility genetic variants. It is not clear how the results obtained by consortia compare with those derived from meta-analyses of published studies.We performed meta-analyses of published data for 16 genetic polymorphisms investigated by the Breast Cancer Association Consortium, and compared sample sizes, heterogeneity, and effect sizes. PubMed, Web of Science, and Human Genome Epidemiology Network databases were searched for breast cancer case-control association studies.We found that meta-analyses of published data and consortium analyses were based on substantially different data. Published data by non-consortium teams amounted on average to 26.9% of all available data (range 3.0 -50.0%). Both approaches showed statistically significant decreased breast cancer risks for CASP8 D302H. The meta-analyses of published data demonstrated statistically significant results for five other genes and the consortium analyses for two other genes, but the strength of this evidence, evaluated on the basis of the Venice criteria, was not strong.Because both approaches identified the same gene out of 16 candidates, the methods can be complimentary. The expense and complexity of consortium-based studies should be considered vis-à-vis the potential methodological limitations of synthesis of published studies.

    View details for DOI 10.1097/GIM.0b013e3181929237

    View details for Web of Science ID 000264468300003

    View details for PubMedID 19367188

  • STrengthening the REporting of Genetic Association Studies (STREGA): An Extension of the STROBE Statement ANNALS OF INTERNAL MEDICINE Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 150 (3): 206-?

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information into the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and issues of data volume that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for Web of Science ID 000263029600008

    View details for PubMedID 19189911

  • Synthesis of observational studies should consider credibility ceilings JOURNAL OF CLINICAL EPIDEMIOLOGY Salanti, G., Ioannidis, J. P. 2009; 62 (2): 115-122

    Abstract

    Meta-analyses of observational studies often get spuriously precise results. We aimed to factor this skepticism in meta-analysis calculations.We developed a simple sensitivity analysis starting from the assumption that any single observational study cannot give us more than a maximum certainty c% (called credibility ceiling) that an effect is in a particular direction and not in the other. Each study included in meta-analysis is adjusted for different credibility ceilings c and the consistency of the conclusion examined. We applied the method in three meta-analyses of observational studies with nominally statistically significant summary effects (mortality with teaching versus nonteaching health care; risk of non-Hodgkin's lymphoma with hair dyes; mortality with omega-3 fatty acids).Between-study heterogeneity I(2) estimates dropped from 36%-72% without a ceiling effect to 0% with ceilings of 9%, 4%, and 4% in the three meta-analyses, respectively. Nominal statistical significance was lost with ceilings of 10%, 8%, and 11%, respectively. The likelihood ratios suggested that even with minimal ceiling effects, there was no strong support for the credibility of each of these three associations.Consideration of credibility ceilings allows conservative interpretation of observational evidence and can be applied routinely to meta-analyses of observational studies.

    View details for DOI 10.1016/j.jclinepi.2008.05.014

    View details for Web of Science ID 000262574100001

    View details for PubMedID 19131013

  • Repeatability of published microarray gene expression analyses NATURE GENETICS Ioannidis, J. P., Allison, D. B., Ball, C. A., Coulibaly, I., Cui, X., Culhane, A. C., Falchi, M., Furlanello, C., Game, L., Jurman, G., Mangion, J., Mehta, T., Nitzberg, M., Page, G. P., Petretto, E., van Noort, V. 2009; 41 (2): 149-155

    Abstract

    Given the complexity of microarray-based gene expression studies, guidelines encourage transparent design and public data availability. Several journals require public data deposition and several public databases exist. However, not all data are publicly available, and even when available, it is unknown whether the published results are reproducible by independent scientists. Here we evaluated the replication of data analyses in 18 articles on microarray-based gene expression profiling published in Nature Genetics in 2005-2006. One table or figure from each article was independently evaluated by two teams of analysts. We reproduced two analyses in principle and six partially or with some discrepancies; ten could not be reproduced. The main reason for failure to reproduce was data unavailability, and discrepancies were mostly due to incomplete data annotation or specification of data processing and analysis. Repeatability of published microarray studies is apparently limited. More strict publication rules enforcing public data availability and explicit description of data processing and analysis should be considered.

    View details for DOI 10.1038/ng.295

    View details for Web of Science ID 000263091300011

    View details for PubMedID 19174838

  • Prediction of Cardiovascular Disease Outcomes and Established Cardiovascular Risk Factors by Genome-Wide Association Markers CIRCULATION-CARDIOVASCULAR GENETICS Ioannidis, J. P. 2009; 2 (1): 7-15

    Abstract

    Genome-wide association (GWA) platforms have yielded a rapidly increasing number of new genetic markers. The ability of these markers to improve prediction of clinically important outcomes is debated.A systematic review was performed of GWA-derived markers associated with cardiovascular outcomes or other phenotypes that represent common established risk factors for cardiovascular outcomes. Sources of information included the National Human Genome Research Institute catalog of published GWA studies, and perusal of the eligible GWA articles, meta-analyses on the respective associations, and articles on the incremental predictive performance of common variants in the GWA era. A total of 95 eligible associations were retrieved from the National Human Genome Research Institute catalogue of published GWA studies as of September 2008. Of those 36 have statistical support of P<10(-7). In depth evaluation of the respective articles shows 28 independent associations with such statistical support, pertaining to coronary artery disease, myocardial infarction, atrial fibrillation/flutter, prolongation of QT interval, as well as type 2 diabetes, body mass index, high-density lipoprotein levels, low-density lipoprotein levels, and nicotine dependence. Between-study heterogeneity is not taken into account usually, but it seems common and it would pose a challenge to generalizability across different populations for these markers. Still limited data are available in non-white populations. Effect sizes are small and may be even smaller in subsequent replications and meta-analysis. Population attributable fractions are substantial, given the large frequency of the risk alleles. However, individualized risk measures are typically very small (proportion of variance explained <1% per marker). When used in conjunction with traditional predictors, improvement in overall prediction (eg, area under the curve) or risk reclassification is limited, and subject to methodological caveats.Despite very promising signals in terms of statistical significance, evidence for improvement in cardiovascular prediction by currently available markers derived from GWA studies is sparse. Clinical use of such markers currently would be premature.

    View details for DOI 10.1161/CIRCGENETICS.108.833392

    View details for Web of Science ID 000275960100003

    View details for PubMedID 20031562

  • STrengthening the REporting of Genetic Association Studies (STREGA) - An Extension of the STROBE Statement PLOS MEDICINE Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 6 (2): 151-163

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1371/journal.pmed.1000022

    View details for Web of Science ID 000263600000009

    View details for PubMedID 19192942

  • Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Thorlund, K., Devereaux, P. J., Wetterslev, J., Guyatt, G., Ioannidis, J. P., Thabane, L., Gluud, L., Als-Nielsen, B., Gluud, C. 2009; 38 (1): 276-286

    Abstract

    Results from apparently conclusive meta-analyses may be false. A limited number of events from a few small trials and the associated random error may be under-recognized sources of spurious findings. The information size (IS, i.e. number of participants) required for a reliable and conclusive meta-analysis should be no less rigorous than the sample size of a single, optimally powered randomized clinical trial. If a meta-analysis is conducted before a sufficient IS is reached, it should be evaluated in a manner that accounts for the increased risk that the result might represent a chance finding (i.e. applying trial sequential monitoring boundaries).We analysed 33 meta-analyses with a sufficient IS to detect a treatment effect of 15% relative risk reduction (RRR). We successively monitored the results of the meta-analyses by generating interim cumulative meta-analyses after each included trial and evaluated their results using a conventional statistical criterion (alpha = 0.05) and two-sided Lan-DeMets monitoring boundaries. We examined the proportion of false positive results and important inaccuracies in estimates of treatment effects that resulted from the two approaches.Using the random-effects model and final data, 12 of the meta-analyses yielded P > alpha = 0.05, and 21 yielded P alpha = 0.05. The monitoring boundaries eliminated all false positives. Important inaccuracies in estimates were observed in 6 out of 21 meta-analyses using the conventional P

    View details for DOI 10.1093/ije/dyn179

    View details for Web of Science ID 000263164400037

    View details for PubMedID 18824467

  • Meta-analysis in genome-wide association studies PHARMACOGENOMICS Zeggini, E., Ioannidis, J. P. 2009; 10 (2): 191-201

    Abstract

    The advent of genome-wide association studies has allowed considerable progress in the identification and robust replication of common gene variants that confer susceptibility to common diseases and other phenotypes of interest. These genetic effect sizes are almost invariably moderate to small in magnitude and single studies, even if large, are underpowered to detect them with confidence. Meta-analysis of many genome-wide association studies improves the power to detect more associations, and to investigate the consistency or heterogeneity of these associations across diverse datasets and study populations. In this review, we discuss the key methodological issues in the set-up, information gathering and processing, and analysis of meta-analyses of genome-wide association datasets. We illustrate, as an example, the application of meta-analysis methods in the elucidation of common genetic variants associated with Type 2 diabetes. Finally, we discuss the prospects and caveats for future application of meta-analysis methods in the genome-wide setting.

    View details for DOI 10.2217/14622416.10.2.191

    View details for Web of Science ID 000263811400005

    View details for PubMedID 19207020

  • How to Use an Article About Genetic Association C: What Are the Results and Will They Help Me in Caring for My Patients? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (3): 304-308

    Abstract

    In the first 2 articles of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies, and we enumerated the major issues in judging the validity of these studies. In this third article, we review the issues relating to the applicability of the results in the clinical situation. How large and precise are the associations? Many genetic effects are expected to be smaller in magnitude than traditional risk factors. Does the genetic association improve predictive power beyond easily measured clinical variables? In some cases, the additional genetic information adds only a small increment in the predictive ability of a diagnostic or prognostic test. What are the absolute vs relative effects? Even if the genetic risk is high in relative terms, the baseline risk may be very low in absolute terms. Is the risk-associated allele likely to be present in my patient? A risk allele may have a strong effect but be rare in a particular ethnic group. Is the patient likely better off knowing the genetic information? Given that genes cannot be modified, one must weigh whether the genetic information is likely to be helpful in planning other health interventions or initiating behavior change.

    View details for Web of Science ID 000262518700021

    View details for PubMedID 19155457

  • Personalized Genetic Prediction: Too Limited, Too Expensive, or Too Soon? ANNALS OF INTERNAL MEDICINE Ioannidis, J. P. 2009; 150 (2): 139-141

    View details for Web of Science ID 000262655200009

    View details for PubMedID 19153414

  • How to Use an Article About Genetic Association B: Are the Results of the Study Valid? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (2): 191-197

    Abstract

    In the first article of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies. In this second article, we enumerate the major issues in judging the validity of these studies, framed as critical appraisal questions. Was the disease phenotype properly defined and accurately recorded by someone blind to the genetic information? Have any potential differences between disease and nondisease groups, particularly ethnicity, been properly addressed? In genetic studies, one potential cause of spurious associations is differences between cases and controls in ethnicity, a situation termed population stratification. Was measurement of the genetic variants unbiased and accurate? Methods for determining DNA sequence variation are not perfect and may have some measurement error. Do the genotype proportions observe Hardy-Weinberg equilibrium? This simple mathematic rule about the distribution of genetic groups may be one way to check for errors in reading DNA information. Have the investigators adjusted their inferences for multiple comparisons? Given the thousands of genetic markers tested in genome-wide association studies, the potential for false-positive and false-negative results is much higher than in traditional medical studies, and it is particularly important to look for replication of results.

    View details for Web of Science ID 000262405500021

    View details for PubMedID 19141767

  • Reporting and interpretation of SF-36 outcomes in randomised trials: systematic review BRITISH MEDICAL JOURNAL Contopoulos-Ioannidis, D. G., Karvouni, A., Kouri, I., Ioannidis, J. P. 2009; 338

    Abstract

    To determine how often health surveys and quality of life evaluations reach different conclusions from those of primary efficacy outcomes and whether discordant results make a difference in the interpretation of trial findings.Systematic review.PubMed, contact with authors for missing information, and author survey for unpublished SF-36 data.Randomised trials with SF-36 outcomes (the most extensively validated and used health survey instrument for appraising quality of life) that were published in 2005 in 22 journals with a high impact factor.Analyses on the two composite and eight subdomain SF-36 scores that corresponded to the time and mode of analysis of the primary efficacy outcome.Of 1057 screened trials, 52 were identified as randomised trials with SF-36 results (66 separate comparisons). Only eight trials reported all 10 SF-36 scores in the published articles. For 21 of the 66 comparisons, SF-36 results were discordant for statistical significance compared with the results for primary efficacy outcomes. Of 17 statistically significant SF-36 scores where primary outcomes were not also statistically significant in the same direction, the magnitude of effect was small in six, moderate in six, large in three, and not reported in two. Authors modified the interpretation of study findings based on SF-36 results in only two of the 21 discordant cases. Among 100 additional randomly selected trials not reporting any SF-36 information, at least five had collected SF-36 data but only one had analysed it.SF-36 measurements sometimes produce different results from those of the primary efficacy outcomes but rarely modify the overall interpretation of randomised trials. Quality of life and health related survey information should be utilised more systematically in randomised trials.

    View details for DOI 10.1136/bmj.a3006

    View details for Web of Science ID 000263192800001

    View details for PubMedID 19139138

  • How to Use an Article About Genetic Association A: Background Concepts JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (1): 74-81

    Abstract

    This is the first in a series of 3 articles serving as an introduction to clinicians wishing to read and critically appraise genetic association studies. We summarize the key concepts in genetics that clinicians must understand to review these studies, including the structure of DNA, transcription and translation, patterns of inheritance, Hardy-Weinberg equilibrium, and linkage disequilibrium. We review the types of DNA variation, including single-nucleotide polymorphisms (SNPs), insertions, and deletions, and how these can affect protein function. We introduce the idea of genetic association for both single-candidate gene and genome-wide association studies, in which thousands of genetic variants are tested for association with disease. We use the APOE polymorphism and its association with dementia as a case study to demonstrate the concepts and introduce the terminology used in this field. The second and third articles will focus on issues of validity and applicability.

    View details for Web of Science ID 000262220400022

    View details for PubMedID 19126812

  • A Field Synopsis on Low-Penetrance Variants in DNA Repair Genes and Cancer Susceptibility JOURNAL OF THE NATIONAL CANCER INSTITUTE Vineis, P., Manuguerra, M., Kavvoura, F. K., Guarrera, S., Allione, A., Rosa, F., Di Gregorio, A., Polidoro, S., Saletta, F., Ioannidis, J. P., Matullo, G. 2009; 101 (1): 24-36

    Abstract

    Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair.We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided.Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P

    View details for DOI 10.1093/jnci/djn437

    View details for Web of Science ID 000262333500009

    View details for PubMedID 19116388

  • The use of older studies in meta-analyses of medical interventions: a survey. Open medicine : a peer-reviewed, independent, open-access journal Patsopoulos, N. A., Ioannidis, J. P. 2009; 3 (2): e62-8

    Abstract

    Evidence for medical interventions sometimes derives from data that are no longer up to date. These data can influence the outcomes of meta-analyses, yet do not always reflect current clinical practice. We examined the age of the data used in meta-analyses contained within systematic reviews of medical interventions, and investigated whether authors consider the age of these data in their interpretations.From Issue 4, 2005, of the Cochrane Database of Systematic Reviews we randomly selected 10% of systematic reviews containing at least 1 meta-analysis. From this sample we extracted 1 meta-analysis per primary outcome. We calculated the number of years between the study's publication and 2005 (the year that the systematic review was published), as well as the number of years between the study's publication and the year of the literature search conducted in the study. We assessed whether authors discussed the implications of including less recent data, and, for systematic reviews containing meta-analyses of studies published before 1996, we calculated whether excluding the findings of those studies changed the significance of the outcomes. We repeated these calculations and assessments for 22 systematic reviews containing meta-analyses published in 6 high-impact general medical journals in 2005.For 157 meta-analyses (n = 1149 trials) published in 2005, the median year of the most recent literature search was 2003 (interquartile range [IQR] 2002-04). Two-thirds of these meta-analyses (103/157, 66%) involved no trials published in the preceding 5 years (2001-05). Forty-seven meta-analyses (30%) included no trials published in the preceding 10 years (1996-2005). In another 16 (10%), the statistical significance of the outcomes would have been different had the studies been limited to those published between 1996 and 2005, although in some cases this change in significance would have been due to loss of power. Only 12 (8%) of the meta-analyses discussed the potential implications of including older studies. Among the 22 meta-analyses considered in high-impact general medical journals, 2 included no studies published in the 5 years prior to the reference year (2005), and 18 included at least 1 study published before 1996. Only 4 meta-analyses discussed the implications of including older studies.In most systematic reviews containing meta-analyses of evidence for health care interventions, very recent studies are rare. Researchers who conduct systematic reviews with meta-analyses, and clinicians who read the outcomes of these studies, should be made aware of the potential implications of including less recent data.

    View details for PubMedID 19946395

  • Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 24 (1): 37-55

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1007/s10654-008-9302-y

    View details for Web of Science ID 000263362000006

    View details for PubMedID 19189221

  • Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term COCHRANE DATABASE OF SYSTEMATIC REVIEWS Sotiriadis, A., Makrydimas, G., Papatheodorou, S., Ioannidis, J. P. 2009

    Abstract

    Infants born at term by elective caesarean delivery are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications.The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications.We searched the Cochrane Pregnancy and Chilbirth Group's Trials Register (30 June 2009).Randomised and quasi-randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation).The co-authors assessed the results of the only available trial independently to retrieve data on perinatal outcomes. Results were expressed as risk ratio (RR) or mean differences (MD), together with their 95% confidence intervals (CI).One study comparing prophylactic administration of betamethasone (N = 467) versus usual treatment without steroids (N = 475) in term elective caesarean section was included in the review. Women randomised to treatment group received two intramuscular doses of betamethasone in the 48 hours before delivery, whereas the control group received treatment as usual.Prophylactic betamethasone appeared to significantly decrease the risk of admission to the neonatal intensive care unit for respiratory morbidity (RR 0.15; 95% CI 0.03 to 0.64). However, no statistically significant reduction was found in the incidence of neonatal respiratory distress syndrome (RR 0.32; 95% CI 0.07 to 1.58), transient tachypnoea of the newborn (RR 0.52; 95% CI 0.25 to 1.11), need for mechanical ventilation (RR 4.07; 95% CI 0.46 to 36.27) and length of stay in neonatal intensive care unit (MD) -2.14 days; 95% CI -5.58 to 1.30).There were no reported events of neonatal sepsis, perinatal deaths or maternal trauma infection, therefore results on these outcomes are non-estimable. The study did not provide data on other pre-defined outcomes.The results from the single trial are promising, but more studies with larger samples are needed to investigate the effect of prophylactic steroids in the incidence of neonatal complications per se. Also more data and longer follow up would be needed for potential harms and complications.

    View details for DOI 10.1002/14651858.CD006614.pub2

    View details for Web of Science ID 000270686900058

    View details for PubMedID 19821379

  • Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Polyzos, N. P., Salanti, G., Pavlidis, N., Ioannidis, J. P. 2008; 100 (24): 1780-1791

    Abstract

    Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival.We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973-2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab).We identified 370 eligible randomized trials (54,189 patients), of which 172 (31,552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26,031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%-33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57-0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55-0.81] for single-drug taxane, 0.64 [0.53-0.78] for combination of anthracyclines with taxane, 0.49 [0.37-0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (<5% difference in HR) as first- and subsequent-line therapies.Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer. Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles.

    View details for DOI 10.1093/jnci/djn414

    View details for Web of Science ID 000261902100013

    View details for PubMedID 19066278

  • Expectations and challenges stemming from genome-wide association studies MUTAGENESIS Vineis, P., Brennan, P., Canzian, F., Ioannidis, J. P., Matullo, G., Ritchie, M., Stromberg, U., Taioli, E., Thompson, J. 2008; 23 (6): 439-444

    Abstract

    There are considerable expectations about the ability of genome-wide association (GWA) studies to make exciting discoveries about the role of genes in common diseases. GWA studies may allow researchers to identify causal pathways that have not been unveiled before, thus opening new avenues to disease understanding, prevention and therapy. However, there are still many open challenges. One is how to analyse these studies. The problem of false positives and false negatives provides an interesting methodological stimulus to find optimal solutions. Once main genetic effects have been concretely documented, the next question is how to proceed with the investigation of gene-gene and gene-environment interactions. It is possible that what really counts is not the main effect of genes but complex interactions. Finding and interpreting such interactions is not straightforward. Finally, continuous updated integration of all evidence, from both old studies, current GWA investigations and future replication studies, and careful interpretation of the strength of the evidence are crucial to maximize transparency and lead to informative selection of the next steps of research in this field. The present Commentary is a report of an Environmental Cancer Risk, Nutrition and Individual Susceptibility network Workshop held in Venice in October 2007 and discusses some of the problems outlined above, with examples.

    View details for DOI 10.1093/mutage/gen042

    View details for Web of Science ID 000260557900002

    View details for PubMedID 18765424

  • Evaluation of the Potential Excess of Statistically Significant Findings in Published Genetic Association Studies: Application to Alzheimer's Disease AMERICAN JOURNAL OF EPIDEMIOLOGY Kavvoura, F. K., McQueen, M. B., Khoury, M. J., Tanzi, R. E., Bertram, L., Ioannidis, J. P. 2008; 168 (8): 855-865

    Abstract

    The authors evaluated whether there is an excess of statistically significant results in studies of genetic associations with Alzheimer's disease reflecting either between-study heterogeneity or bias. Among published articles on genetic associations entered into the comprehensive AlzGene database (www.alzgene.org) through January 31, 2007, 1,348 studies included in 175 meta-analyses with 3 or more studies each were analyzed. The number of observed studies (O) with statistically significant results (P = 0.05 threshold) was compared with the expected number (E) under different assumptions for the magnitude of the effect size. In the main analysis, the plausible effect size of each association was the summary effect presented in the respective meta-analysis. Overall, 19 meta-analyses (all with eventually nonsignificant summary effects) had a documented excess of O over E: Typically single studies had significant effects pointing in opposite directions and early summary effects were dissipated over time. Across the whole domain, O was 235 (17.4%), while E was 164.8 (12.2%) (P < 10(-6)). The excess showed a predilection for meta-analyses with nonsignificant summary effects and between-study heterogeneity. The excess was seen for all levels of statistical significance and also for studies with borderline P values (P = 0.05-0.10). The excess of significant findings may represent significance-chasing biases in a setting of massive testing.

    View details for DOI 10.1093/aje/kwn206

    View details for Web of Science ID 000259965800001

    View details for PubMedID 18779388

  • Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level BEHAVIORAL AND BRAIN FUNCTIONS Stefanis, N. C., Trikalinos, T. A., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., Ntzani, E. E., Hatzimanolis, A., Ioannidis, J. P., Stefanis, C. N. 2008; 4

    Abstract

    While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level.Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts.SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model).Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders.

    View details for DOI 10.1186/1744-9081-4-46

    View details for Web of Science ID 000260435200001

    View details for PubMedID 18834502

  • Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Evangelou, E., Ioannidis, J. P. 2008; 37 (5): 1148-1157

    Abstract

    Several approaches are available for evaluating heterogeneity in meta-analysis. Sensitivity analyses are often used, but these are often implemented in various non-standardized ways.We developed and implemented sequential and combinatorial algorithms that evaluate the change in between-study heterogeneity as one or more studies are excluded from the calculations. The algorithms exclude studies aiming to achieve either the maximum or the minimum final I(2) below a desired pre-set threshold. We applied these algorithms in databases of meta-analyses of binary outcome and >/=4 studies from Cochrane Database of Systematic Reviews (Issue 4, 2005, n = 1011) and meta-analyses of genetic associations (n = 50). Two I(2) thresholds were used (50% and 25%).Both algorithms have succeeded in achieving the pre-specified final I(2) thresholds. Differences in the number of excluded studies varied from 0% to 6% depending on the database and the heterogeneity threshold, while it was common to exclude different specific studies. Among meta-analyses with initial I(2) > 50%, in the large majority [19 (90.5%) and 208 (85.9%) in genetic and Cochrane meta-analyses, respectively] exclusion of one or two studies sufficed to decrease I(2) < 50%. Similarly, among meta-analyses with initial I(2) > 25%, in most cases [16 (57.1%) and 382 (81.3%), respectively) exclusion of one or two studies sufficed to decrease heterogeneity even <25%. The number of excluded studies correlated modestly with initial estimated I(2) (correlation coefficients 0.52-0.68 depending on algorithm used).The proposed algorithms can be routinely applied in meta-analyses as standardized sensitivity analyses for heterogeneity. Caution is needed evaluating post hoc which specific studies are responsible for the heterogeneity.

    View details for DOI 10.1093/ije/dyn065

    View details for Web of Science ID 000259771500031

    View details for PubMedID 18424475

  • Why Current Publication Practices May Distort Science PLOS MEDICINE Young, N. S., Ioannidis, J. P., Al-Ubaydi, O. 2008; 5 (10): 1418-1422

    View details for DOI 10.1371/journal.pmed.0050201

    View details for Web of Science ID 000260424100003

    View details for PubMedID 18844432

  • Interpretation of tests of heterogeneity and bias in meta-analysis JOURNAL OF EVALUATION IN CLINICAL PRACTICE Ioannidis, J. P. 2008; 14 (5): 951-957

    Abstract

    Statistical tests of heterogeneity and bias, in particular publication bias, are very popular in meta-analyses. These tests use statistical approaches whose limitations are often not recognized. Moreover, it is often implied with inappropriate confidence that these tests can provide reliable answers to questions that in essence are not of statistical nature. Statistical heterogeneity is only a correlate of clinical and pragmatic heterogeneity and the correlation may sometimes be weak. Similarly, statistical signals may hint to bias, but seen in isolation they cannot fully prove or disprove bias in general, let alone specific causes of bias, such as publication bias in particular. Both false-positive and false-negative signals of heterogeneity and bias can be common and their prevalence may be anticipated based on some rational considerations. Here I discuss the major common challenges and flaws that emerge in using and interpreting statistical tests of heterogeneity and bias in meta-analyses. I discuss misinterpretations that can occur at the level of statistical inference, clinical/pragmatic inference and specific cause attribution. Suggestions are made on how to avoid these flaws, use these tests properly and learn from them.

    View details for DOI 10.1111/j.1365-2753.2008.00986.x

    View details for Web of Science ID 000260544400050

    View details for PubMedID 19018930

  • Calibration of credibility of agnostic genome-wide associations AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Ioannidis, J. P. 2008; 147B (6): 964-972

    Abstract

    Genome-wide testing platforms are increasingly used to promote "agnostic" approaches to the discovery of gene variants associated with the risk of many common diseases and quantitative traits. The early track record of genome-wide association (GWA) studies suggests that some proposed associations are replicated quite consistently with large-scale subsequent evidence from multiple studies, others have a more inconsistent replication record, some have failed to be replicated by independent investigators and many more early proposed associations await further replication. An important question is how to calibrate the credibility of these postulated associations. A simple Bayesian method is applied here to achieve such calibration. The variability of the estimated credibility is examined under different assumptions. Empirical examples are drawn from existing GWA studies. It is demonstrated that the credibility of different proposed associations can cover a very wide range. The credibility of specific associations usually remains relatively robust when different plausible assumptions are made (within a reasonable range) for the prior odds of an association being true, or the magnitude of the anticipated effect size for genetic associations. Heterogeneity and bias assumptions can have a more major impact on the credibility estimates and thus they need very careful consideration in each case. Credibility calibration may be used in conjunction with qualitative criteria for the appraisal of the cumulative evidence that take into consideration the amount, consistency, and protection from bias in the data.

    View details for DOI 10.1002/ajmg.b.30721

    View details for Web of Science ID 000259050100040

    View details for PubMedID 18361430

  • Medicine - Life cycle of translational research for medical interventions SCIENCE Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2008; 321 (5894): 1298-1299

    View details for DOI 10.1126/science.1160622

    View details for Web of Science ID 000258914300031

    View details for PubMedID 18772421

  • Mortality in systemic sclerosis CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Karassa, F. B., Ioannidis, J. P. 2008; 26 (5): S85-S93

    Abstract

    Systemic sclerosis is a rare and potentially devastating connective tissue disease. It is highly heterogeneous in terms of clinical presentation, extent and severity of organ involvement, immunologic abnormalities, and clinical course. Although clinical outcomes appear to have improved in recent years, the disease continues to cause substantial excess mortality. In this review, we have systematically collected the published studies addressing the mortality burden in patients with scleroderma in comparison with the general population, as well as studies exploring the most important potential predictors of mortality. Results of these studies are presented and discussed, with emphasis on methodological limitations. Suggestions are made for the design, conduct, and reporting of further research on these themes.

    View details for Web of Science ID 000260467300011

    View details for PubMedID 19026149

  • Why most discovered true associations are inflated EPIDEMIOLOGY Ioannidis, J. P. 2008; 19 (5): 640-648

    Abstract

    Newly discovered true (non-null) associations often have inflated effects compared with the true effect sizes. I discuss here the main reasons for this inflation. First, theoretical considerations prove that when true discovery is claimed based on crossing a threshold of statistical significance and the discovery study is underpowered, the observed effects are expected to be inflated. This has been demonstrated in various fields ranging from early stopped clinical trials to genome-wide associations. Second, flexible analyses coupled with selective reporting may inflate the published discovered effects. The vibration ratio (the ratio of the largest vs. smallest effect on the same association approached with different analytic choices) can be very large. Third, effects may be inflated at the stage of interpretation due to diverse conflicts of interest. Discovered effects are not always inflated, and under some circumstances may be deflated-for example, in the setting of late discovery of associations in sequentially accumulated overpowered evidence, in some types of misclassification from measurement error, and in conflicts causing reverse biases. Finally, I discuss potential approaches to this problem. These include being cautious about newly discovered effect sizes, considering some rational down-adjustment, using analytical methods that correct for the anticipated inflation, ignoring the magnitude of the effect (if not necessary), conducting large studies in the discovery phase, using strict protocols for analyses, pursuing complete and transparent reporting of all results, placing emphasis on replication, and being fair with interpretation of results.

    View details for DOI 10.1097/EDE.0b013e31818131e7

    View details for Web of Science ID 000258712000001

    View details for PubMedID 18633328

  • Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias PLOS ONE Dwan, K., Altman, D. G., Arnaiz, J. A., Bloom, J., Chan, A., Cronin, E., Decullier, E., Easterbrook, P. J., von Elm, E., Gamble, C., Ghersi, D., Ioannidis, J. P., Simes, J., Williamson, P. R. 2008; 3 (8)

    Abstract

    The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention.We review and summarise the evidence from a series of cohort studies that have assessed study publication bias and outcome reporting bias in randomised controlled trials. Sixteen studies were eligible of which only two followed the cohort all the way through from protocol approval to information regarding publication of outcomes. Eleven of the studies investigated study publication bias and five investigated outcome reporting bias. Three studies have found that statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). In comparing trial publications to protocols, we found that 40-62% of studies had at least one primary outcome that was changed, introduced, or omitted. We decided not to undertake meta-analysis due to the differences between studies.Recent work provides direct empirical evidence for the existence of study publication bias and outcome reporting bias. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. Publications have been found to be inconsistent with their protocols. Researchers need to be aware of the problems of both types of bias and efforts should be concentrated on improving the reporting of trials.

    View details for DOI 10.1371/journal.pone.0003081

    View details for Web of Science ID 000264796600003

    View details for PubMedID 18769481

  • Effect of formal statistical significance on the credibility of observational associations AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2008; 168 (4): 374-383

    Abstract

    The author evaluated the implications of nominal statistical significance for changing the credibility of null versus alternative hypotheses across a large number of observational associations for which formal statistical significance (p < 0.05) was claimed. Calculation of the Bayes factor (B) under different assumptions was performed on 272 observational associations published in 2004-2005 and a data set of 50 meta-analyses on gene-disease associations (752 studies) for which statistically significant associations had been claimed (p < 0.05). Depending on the formulation of the prior, statistically significant results offered less than strong support to the credibility (B > 0.10) for 54-77% of the 272 epidemiologic associations for diverse risk factors and 44-70% of the 50 associations from genetic meta-analyses. Sometimes nominally statistically significant results even decreased the credibility of the probed association in comparison with what was thought before the study was conducted. Five of six meta-analyses with less than substantial support (B > 0.032) lost their nominal statistical significance in a subsequent (more recent) meta-analysis, while this did not occur in any of seven meta-analyses with decisive support (B < 0.01). In these large data sets of observational associations, formal statistical significance alone failed to increase much the credibility of many postulated associations. Bayes factors may be used routinely to interpret "significant" associations.

    View details for DOI 10.1093/aje/kwn156

    View details for Web of Science ID 000258329700004

    View details for PubMedID 18611956

  • Measuring Co-Authorship and Networking-Adjusted Scientific Impact PLOS ONE Ioannidis, J. P. 2008; 3 (7)

    Abstract

    Appraisal of the scientific impact of researchers, teams and institutions with productivity and citation metrics has major repercussions. Funding and promotion of individuals and survival of teams and institutions depend on publications and citations. In this competitive environment, the number of authors per paper is increasing and apparently some co-authors don't satisfy authorship criteria. Listing of individual contributions is still sporadic and also open to manipulation. Metrics are needed to measure the networking intensity for a single scientist or group of scientists accounting for patterns of co-authorship. Here, I define I(1) for a single scientist as the number of authors who appear in at least I(1) papers of the specific scientist. For a group of scientists or institution, I(n) is defined as the number of authors who appear in at least I(n) papers that bear the affiliation of the group or institution. I(1) depends on the number of papers authored N(p). The power exponent R of the relationship between I(1) and N(p) categorizes scientists as solitary (R>2.5), nuclear (R = 2.25-2.5), networked (R = 2-2.25), extensively networked (R = 1.75-2) or collaborators (R<1.75). R may be used to adjust for co-authorship networking the citation impact of a scientist. I(n) similarly provides a simple measure of the effective networking size to adjust the citation impact of groups or institutions. Empirical data are provided for single scientists and institutions for the proposed metrics. Cautious adoption of adjustments for co-authorship and networking in scientific appraisals may offer incentives for more accountable co-authorship behaviour in published articles.

    View details for DOI 10.1371/journal.pone.0002778

    View details for Web of Science ID 000264302900048

    View details for PubMedID 18648663

  • Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database NATURE GENETICS Allen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., Bertram, L. 2008; 40 (7): 827-834

    Abstract

    In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.

    View details for DOI 10.1038/ng.171

    View details for Web of Science ID 000257166500015

    View details for PubMedID 18583979

  • Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: The case of rosiglitazone AMERICAN HEART JOURNAL Hernandez, A. V., Walker, E., Ioannidis, J. P., Kattan, M. W. 2008; 156 (1): 23-30

    Abstract

    Rare cardiovascular events of commonly used drugs are important to document and investigate, but single trials are notoriously underpowered to provide conclusive evidence. Recently, meta-analyses have been used to improve on the power. A recent rosiglitazone meta-analysis heightened the debate about the usefulness and limitations of meta-analysis in this setting. In this review, we examined the methods used in previous published meta-analyses for harmful cardiovascular events, with special attention to the rosiglitazone meta-analyses, and give suggestions for the improvement of methods and interpretation of such meta-analyses. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on harms, and statistical expertise. There are important decisions that need to be made about selecting the appropriate analytical methods and performing sensitivity analyses to evaluate whether the results are robust to different analytical choices.

    View details for DOI 10.1016/j.ahj.2008.03.002

    View details for Web of Science ID 000257329900004

    View details for PubMedID 18585493

  • Interpretation of research results: An indispensable mission impossible? SEMINARS IN HEMATOLOGY Ioannidis, J. P. 2008; 45 (3): 133-134
  • Perfect study, poor evidence: Interpretation of biases preceding study design SEMINARS IN HEMATOLOGY Ioannidis, J. P. 2008; 45 (3): 160-166

    Abstract

    In the interpretation of research evidence, data that have been accumulated in a specific isolated study are typically examined. However, important biases may precede the study design. A study may be misleading, useless, or even harmful, even though it seems to be perfectly designed, conducted, analyzed, and reported. Some biases pertain to setting the wider research agenda and include poor scientific relevance, minimal clinical utility, or failure to consider prior evidence (non-consideration of prior evidence, biased consideration of prior evidence, or consideration of biased prior evidence). Other biases reflect issues in setting the specific research questions: examples include straw man effects, avoidance of head-to-head comparisons, head-to-head comparisons bypassing demonstration of effectiveness, overpowered studies, unilateral aims (focusing on benefits and neglecting harms), and the approach of the industry towards research as bulk advertisement (including ghost management of the literature). The concerted presence of such biases may have a multiplicative, detrimental impact on the scientific literature. These issues should be considered carefully when interpreting research results.

    View details for DOI 10.1053/j.seminhematol.2008.04.010

    View details for Web of Science ID 000257501600005

    View details for PubMedID 18582622

  • Reasons or excuses for avoiding meta-analysis in forest plots. BMJ (Clinical research ed.) Ioannidis, J. P., Patsopoulos, N. A., Rothstein, H. R. 2008; 336 (7658): 1413-1415

    View details for DOI 10.1136/bmj.a117

    View details for PubMedID 18566080

  • Doctors' versus patients' global assessments of treatment effectiveness: empirical survey of diverse treatments in clinical trials BRITISH MEDICAL JOURNAL Evangelou, E., Tsianos, G., Ioannidis, J. P. 2008; 336 (7656): 1287-?

    Abstract

    To examine whether doctors' global assessments of treatment effects agree with patients' global assessments.Survey of trials included in systematic reviews of treatments for diverse conditions.Cochrane database of systematic reviews. Data extracted Data on patients' global assessments and on doctors' global assessment for the same treatment against the same comparator.Relative odds ratio (ratio of odds ratios of global improvement with the experimental intervention versus control according to doctors compared with patients), and improvement rates according to doctors and patients.Doctors' global assessments were compared with patients' global assessments for 63 different treatment comparisons (240 trials) in 18 conditions. The summary relative odds ratio across the comparisons was not significant (0.98, 95% confidence interval 0.88 to 1.08; I(2)=0%, 95% confidence interval 0% to 30%). In 62 of the 63 comparisons the effects of treatment rated by patients and by doctors did not differ beyond chance, but for single comparisons the confidence intervals were large. Rates of improvement on average did not differ between doctors' assessments and patients' assessments (summary relative odds ratio 0.98, 0.88 to 1.06; I(2)=0%, 0% to 24%).Doctors' global assessments of the effects of treatments are on average similar to those of patients.

    View details for DOI 10.1136/bmj.39560.759572.BE

    View details for Web of Science ID 000256705900032

    View details for PubMedID 18495634

  • Evaluation of networks of randomized trials STATISTICAL METHODS IN MEDICAL RESEARCH Salanti, G., Higgins, J. P., Ades, A. E., Ioannidis, J. P. 2008; 17 (3): 279-301

    Abstract

    Randomized trials may be designed and interpreted as single experiments or they may be seen in the context of other similar or relevant evidence. The amount and complexity of available randomized evidence vary for different topics. Systematic reviews may be useful in identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, and planning future trials. A new, promising, but also very much debated extension of systematic reviews, mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTC meta-analysis may have value in interpreting the available randomized evidence from networks of trials and can rank many different treatments, going beyond focusing on simple pairwise-comparisons. Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, we review the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency and methods that have been proposed to evaluate it as well as the methodological gaps that remain. We introduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation of the asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetry in informing the planning of future trials.

    View details for DOI 10.1177/0962280207080643

    View details for Web of Science ID 000257244300006

    View details for PubMedID 17925316

  • Inflated numbers of authors over time have not been just due to increasing research complexity JOURNAL OF CLINICAL EPIDEMIOLOGY Papatheodorou, S. I., Trikalinos, T. A., Ioannidis, J. P. 2008; 61 (6): 546-551

    Abstract

    To examine trends in and determinants of the number of authors in clinical studies.We analyzed determinants of the number of authors in 633 articles of randomized trials and 313 articles of nonrandomized studies included in large meta-analyses (seven and six topics, respectively). Analyses were adjusted for topic. We also evaluated 310 randomly sampled case reports that had an abstract and described a single case.After adjusting for topic and other determinants, for both randomized trials and nonrandomized studies, the number of authors increased by 0.8 per decade (P<0.001). Topic was a strong determinant of the number of authors; other independent factors included journal impact factor, multinational authorship, and (for randomized trials) article length and sample size. Trials from South Europe (+1.1 authors) and North America (+0.9) and nonrandomized studies from South Europe (+1.8) had more authors than studies from North Europe (P<0.001). For case reports, only geographic location and article length were significantly related with author numbers.The number of authors in articles of randomized and nonrandomized studies has increased over time, even after adjusting for the topic, size, and visibility of a study. The academic coinage of authorship may be suffering from inflation.

    View details for DOI 10.1016/j.jclinepi.2007.07.017

    View details for Web of Science ID 000256164700006

    View details for PubMedID 18471658

  • F-18-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: A meta-analysis JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Evangelou, E., Denaxa-Kyza, D., Ioannidis, J. P. 2008; 100 (10): 712-720

    Abstract

    Positron emission tomography using 18F-fluorodeoxyglucose (18F-FDG PET) has been proposed to enhance preoperative assessment of cervical lymph node status in patients with head and neck squamous cell carcinoma (HNSCC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to assess the diagnostic accuracy of 18F-FDG PET in detecting lymph node metastases in patients with HNSCC.We performed a meta-analysis of all available studies of the diagnostic performance of 18F-FDG PET in patients with HNSCC. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves using hierarchical regression models. We also compared the performance of 18F-FDG PET with that of conventional diagnostic methods (ie, computed tomography, magnetic resonance imaging, and ultrasound with fine-needle aspiration) by analyzing studies that had also used these diagnostic methods on the same patients.Across 32 studies (1236 patients), 18F-FDG PET sensitivity was 79% (95% confidence interval [CI] = 72% to 85%) and specificity was 86% (95% CI = 83% to 89%). For cN0 patients, sensitivity of 18F-FDG PET was only 50% (95% CI = 37% to 63%), whereas specificity was 87% (95% CI = 76% to 93%). Overall, LR+ was 5.84 (95% CI = 4.59 to 7.42) and LR- was 0.24 (95% CI = 0.17 to 0.33). In studies in which both 18F-FDG PET and conventional diagnostic tests were performed, sensitivity and specificity of 18F-FDG PET were 80% and 86%, respectively, and of conventional diagnostic tests were 75% and 79%, respectively.18F-FDG PET has good diagnostic performance in the overall pretreatment evaluation of patients with HNSCC but still does not detect disease in half of the patients with metastasis and cN0.

    View details for DOI 10.1093/jnci/djn125

    View details for Web of Science ID 000256172400008

    View details for PubMedID 18477804

  • Reporting of human genome epidemiology (HuGE) association studies: An empirical assessment BMC MEDICAL RESEARCH METHODOLOGY Yesupriya, A., Evangelou, E., Kavvoura, F. K., Patsopoulos, N. A., Clyne, M., Walsh, M. C., Lin, B. K., Yu, W., Gwinn, M., Ioannidis, J. P., Khoury, M. J. 2008; 8

    Abstract

    Several thousand human genome epidemiology association studies are published every year investigating the relationship between common genetic variants and diverse phenotypes. Transparent reporting of study methods and results allows readers to better assess the validity of study findings. Here, we document reporting practices of human genome epidemiology studies.Articles were randomly selected from a continuously updated database of human genome epidemiology association studies to be representative of genetic epidemiology literature. The main analysis evaluated 315 articles published in 2001-2003. For a comparative update, we evaluated 28 more recent articles published in 2006, focusing on issues that were poorly reported in 2001-2003.During both time periods, most studies comprised relatively small study populations and examined one or more genetic variants within a single gene. Articles were inconsistent in reporting the data needed to assess selection bias and the methods used to minimize misclassification (of the genotype, outcome, and environmental exposure) or to identify population stratification. Statistical power, the use of unrelated study participants, and the use of replicate samples were reported more often in articles published during 2006 when compared with the earlier sample.We conclude that many items needed to assess error and bias in human genome epidemiology association studies are not consistently reported. Although some improvements were seen over time, reporting guidelines and online supplemental material may help enhance the transparency of this literature.

    View details for DOI 10.1186/1471-2288-8-31

    View details for Web of Science ID 000256664800001

    View details for PubMedID 18492284

  • Large-scale analysis of association between polymorphisms in the transfonning growth factor beta 1 gene (TGFB1) and osteoporosis: The GENOMOS study BONE Langdahl, B. L., Uitterlinden, A. G., Ralston, S. H., Trikalinos, T. A., Balcells, S., Brandi, M. L., Scollen, S., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Reid, D. M., Armas, J. B., Arp, P. P., Bassiti, A., Bustamante, M., Husted, L. B., Carey, A. H., Cano, R. P., Dobnig, H., Dunning, A. M., Fahrleitner-Pammer, A., Falchetti, A., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., Masi, L., van Meurs, J. B., Mangion, J., McGuigan, F. E., Mellibovsky, L., Mosekilde, L., Nogues, X., Pols, H. A., Reeve, J., Renner, W., Rivadeneira, F., van Schoor, N. M., Ioannidis, J. P. 2008; 42 (5): 969-981

    Abstract

    The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results.We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures.There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05.This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.

    View details for DOI 10.1016/j.bone.2007.11.007

    View details for Web of Science ID 000255260100016

    View details for PubMedID 18284942

  • Falsified papers in high-impact journals were slow to retract and indistinguishable from nonfraudulent papers JOURNAL OF CLINICAL EPIDEMIOLOGY Trikalinos, N. A., Evangelou, E., Ioannidis, J. P. 2008; 61 (5): 464-470

    Abstract

    The aim was to evaluate papers retracted due to falsification in high-impact journals.We selected articles retracted due to allegations of falsification in January 1, 1980 to March 1, 2006 from journals with impact factor >10 and >30,000 annual citations. We evaluated characteristics of these papers and misconduct-involved authors and assessed whether they correlated with time to retraction. We also compared retracted articles vs. matched nonretracted articles in the same journals.Fourteen eligible journals had 63 eligible retracted articles. Median time from publication to retraction was 28 months; it was 79 months for articles where a senior researcher was implicated in the misconduct vs. 22 months when junior researchers were implicated (log-rank P<0.001). For the 25 implicated authors, the median time from the first publication of a fraudulent paper to the first retraction was 34 months, again with a clear difference according to researcher rank (log-rank P=0.001). Retracted articles didn't differ from matched nonretracted papers in citations received within 12 months, number of authors, country, funding, or field, but were twofold more likely to have multinational authorship (P=0.049).Retractions due to falsification can take a long time, especially when senior researchers are implicated. Fraudulent articles are not obviously distinguishable from nonfraudulent ones.

    View details for DOI 10.1016/j.jclinepi.2007.11.019

    View details for Web of Science ID 000254978200008

    View details for PubMedID 18394539

  • Genome-wide association studies for complex traits: consensus, uncertainty and challenges NATURE REVIEWS GENETICS McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P., Hirschhorn, J. N. 2008; 9 (5): 356-369

    Abstract

    The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.

    View details for DOI 10.1038/nrg2344

    View details for Web of Science ID 000255057300012

    View details for PubMedID 18398418

  • Exploring the geometry of treatment networks ANNALS OF INTERNAL MEDICINE Salanti, G., Kavvoura, F. K., Ioannidis, J. P. 2008; 148 (7): 544-553

    Abstract

    Several treatment options exist for many conditions. Randomized trial evidence on the relative merits of various options may be missing or biased.To examine the patterns of trial evidence (network geometry) and explain their implications for the interpretation of the existing evidence on a treatment's relative effectiveness.PubMed and Thompson ISI Web of Knowledge (last search April 2007).Published networks of randomized trials that included at least 4 treatments were identified.For each network, data on the number of studies per treatment comparison were extracted by one investigator and verified by a second investigator.Indices were adopted from the ecological literature that measure diversity (number of treatments and how often they were tested) and co-occurrence (whether some treatment comparisons were preferred and others avoided). Eighteen eligible treatment networks were identified for different diseases, involving 4 to 16 alternative treatments and 10 to 84 trials. Networks in which 1 option (placebo or no treatment) was the typical comparator were star-shaped, even though several treatments might have had proven effectiveness. Other networks had different shapes. Some showed important co-occurrence that avoided specific head-to-head comparisons. Comparison choices sometimes seemed justified, such as when newer treatments were not compared with older ones already shown to be inferior, whereas other choices seemed to reflect preference bias.Networks evolve over time as new trials accumulate, and their geometry may change. Statistical testing for co-occurrence is underpowered when few trials exist.Evaluation of the geometry of a treatment network can offer valuable insights for the interpretation of total evidence when many treatment options are available.

    View details for Web of Science ID 000254701000007

    View details for PubMedID 18378949

  • Percutaneous coronary intervention after myocardial infarction and the late open artery hypothesis AMERICAN HEART JOURNAL Ioannidis, J. P., Katritsis, D. G. 2008; 155 (4)
  • Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION van Meurs, J. B., Trikalinos, T. A., Ralston, S. H., Balcells, S., Brandi, M. L., Brixen, K., Kiel, D. P., Langdahl, B. L., Lips, P., Ljunggren, O., Lorenc, R., Obermayer-Pietsch, B., Ohlsson, C., Pettersson, U., Reid, D. M., Rousseau, F., Scollen, S., Van Hul, W., Agueda, L., Akesson, K., Benevolenskaya, L. I., Ferrari, S. L., Hallmans, G., Hofman, A., Husted, L. B., Kruk, M., Kaptoge, S., Karasik, D., Karlsson, M. K., Lorentzon, M., Masi, L., McGuigan, F. E., Mellstrom, D., Mosekilde, L., Nogues, X., Pols, H. A., Reeve, J., Renner, W., Rivadeneira, F., van Schoor, N. M., Weber, K., Ioannidis, J. P., Uitterlinden, A. G. 2008; 299 (11): 1277-1290

    Abstract

    Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

    View details for Web of Science ID 000254079100019

    View details for PubMedID 18349089

  • Assessment of cumulative evidence on genetic associations: interim guidelines INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Boffetta, P., Little, J., O'Brien, T. R., Uitterlinden, A. G., Vineis, P., Balding, D. J., Chokkalingam, A., Dolan, S. M., Flanders, W. D., Higgins, J. P., McCarthy, M. I., McDermott, D. H., Page, G. P., Rebbeck, T. R., Seminara, D., Khoury, M. J. 2008; 37 (1): 120-132

    Abstract

    Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors.

    View details for DOI 10.1093/ije/dym159

    View details for Web of Science ID 000252906600022

    View details for PubMedID 17898028

  • Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls HUMAN GENETICS Kavvoura, F. K., Ioannidis, J. P. 2008; 123 (1): 1-14

    Abstract

    Meta-analysis offers the opportunity to combine evidence from retrospectively accumulated or prospectively generated data. Meta-analyses may provide summary estimates and can help in detecting and addressing potential inconsistency between the combined datasets. Application of meta-analysis in genetic associations presents considerable potential and several pitfalls. In this review, we present basic principles of meta-analytic methods, adapted for human genome epidemiology. We describe issues that arise in the retrospective or the prospective collection of relevant data through various sources, common traps to consider in the appraisal of evidence and potential biases that may interfere. We describe the relative merits and caveats for common methods used to trace inconsistency across studies along with possible reasons for non-replication of proposed associations. Different statistical models may be employed to combine data and some common misconceptions may arise in the process. Several meta-analysis diagnostics are often applied or misapplied in the literature, and we comment on their use and limitations. An alternative to overcome limitations arising from retrospective combination of data from published studies is to create networks of research teams working in the same field and perform collaborative meta-analyses of individual participant data, ideally on a prospective basis. We discuss the advantages and the challenges inherent in such collaborative approaches. Meta-analysis can be a useful tool in dissecting the genetics of complex diseases and traits, provided its methods are properly applied and interpreted.

    View details for DOI 10.1007/s00439-007-0445-9

    View details for Web of Science ID 000252799200001

    View details for PubMedID 18026754

  • Meta-analysis for ranked discovery datasets: theoretical framework and empirical demonstration for microarrays. Computational biology and chemistry Zintzaras, E., Ioannidis, J. P. 2008; 32 (1): 38-46

    Abstract

    The combination of results from different large-scale datasets of multidimensional biological signals (such as gene expression profiling) presents a major challenge. Methodologies are needed that can efficiently combine diverse datasets, but can also test the extent of diversity (heterogeneity) across the combined studies. We developed METa-analysis of RAnked DISCovery datasets (METRADISC), a generalized meta-analysis method for combining information across discovery-oriented datasets and for testing between-study heterogeneity for each biological variable of interest. The method is based on non-parametric Monte Carlo permutation testing. The tested biological variables are ranked in each study according to the level of statistical significance. METRADISC tests for each biological variable of interest its average rank and the between-study heterogeneity of the study-specific ranks. After accounting for ties and differences in tested variables across studies, we randomly permute the ranks of each study and the simulated metrics of average rank and heterogeneity are calculated. The procedure is repeated to generate null distributions for the metrics. The use of METRADISC is demonstrated empirically using gene expression data from seven studies comparing prostate cancer cases and normal controls. We offer a new tool for combining complex datasets derived from massive testing, discovery-oriented research and for examining the diversity of results across the combined studies.

    View details for PubMedID 17988949

  • EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics ANNALS OF THE RHEUMATIC DISEASES Bertsias, G., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I. M., Houssiau, F., Huizinga, T., Isenberg, D., Kallenberg, C. G., Khamashta, M., Piette, J. C., Schneider, M., Smolen, J., Sturfelt, G., Tincani, A., van Vollenhoven, R., Gordon, C., Boumpas, D. T. 2008; 67 (2): 195-205

    Abstract

    Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE.The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists.Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10.Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.

    View details for DOI 10.1136/ard.2007.070367

    View details for Web of Science ID 000252301700010

    View details for PubMedID 17504841

  • Meta-analysis for ranked discovery datasets: Theoretical framework and empirical demonstration for microarrays COMPUTATIONAL BIOLOGY AND CHEMISTRY Zintzaras, E., Ioannidis, J. P. 2008; 32 (1): 39-47
  • Required sample size and nonreplicability thresholds for heterogeneous genetic associations PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Moonesinghe, R., Khoury, M. J., Liu, T., Ioannidis, J. P. 2008; 105 (2): 617-622

    Abstract

    Many gene-disease associations proposed to date have not been consistently replicated across different populations. Nonreplication often reflects false positives in the original claims. However, occasionally, nonreplication may be due to heterogeneity due to biases or even genuine diversity of the genetic effects in different populations. Here, we propose methods for estimating the required sample size to replicate an association across many studies with different amounts of between-study heterogeneity, when data are summarized through metaanalysis. We demonstrate thresholds of between-study heterogeneity (tau(0)(2)) above which one cannot reach adequate power to replicate a proposed association at a specified level of statistical significance when k studies are performed (regardless of how large these studies are). Based on empirical evidence from 91 proposed gene-disease associations (50 on candidate genes and 41 from genome-wide association efforts), the observed between-study heterogeneity is often close to or even surpasses nonreplicability thresholds. With more modest between-study heterogeneity, the required sample size increases considerably compared with when no between-study heterogeneity exists. Increases are steep as tau(0)(2) is approached. Therefore, some true associations may not be practically possible to replicate with consistency, no matter how large studies are conducted. Efforts should be made to minimize between-study heterogeneity in targeted genetic effects.

    View details for DOI 10.1073/pnas.0705554105

    View details for Web of Science ID 000252551100041

    View details for PubMedID 18174335

  • Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials? Philosophy, ethics, and humanities in medicine : PEHM Ioannidis, J. P. 2008; 3: 14-?

    Abstract

    Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence.

    View details for DOI 10.1186/1747-5341-3-14

    View details for PubMedID 18505564

  • Meta-Analysis Methods GENETIC DISSECTION OF COMPLEX TRAITS, 2ND EDITION Trikalinos, T. A., Salanti, G., Zintzaras, E., Ioannidis, J. P. 2008; 60: 311-334

    Abstract

    Meta-analysis is the quantitative synthesis of information from several studies. It is applicable to a variety of study designs in genetics, from family-based linkage studies and population-based association studies to genome-wide scans and genome-wide association studies. By combining relevant evidence from many studies, statistical power is increased and more precise estimates may be obtained. Most importantly, meta-analysis provides a framework for the appreciation and assessment of between-study heterogeneity, that is, the methodological, epidemiological, clinical, and biological dissimilarity across the various studies. Being a retrospective research design in most cases, meta-analysis is subject to a variety of selection biases that may undermine its validity. A major challenge is to differentiate genuine between-study heterogeneity from systematic errors and biases.

    View details for DOI 10.1016/S0065-2660(07)00413-0

    View details for Web of Science ID 000280575900015

    View details for PubMedID 18358326

  • Nested Randomized trials in large cohorts and biobanks - Studying the health effects of lifestyle factors EPIDEMIOLOGY Ioannidis, J. P., Adami, H. 2008; 19 (1): 75-82

    Abstract

    Most diseases are likely to result largely from the interplay of lifestyle and genetic factors. However, both observational studies and randomized trials have faced major limitations in trying to address the impact of lifestyle on health. As large cohorts and biobanks are being developed, we need to find novel, efficient ways to address the effects of lifestyle interventions. We propose that this could be done using multiple lifestyle factorial experimental designs that combine characteristics of randomized trials and epidemiologic studies. Randomized trials of simple lifestyle interventions can be nested within large cohorts linked to reliable registries of outcomes. Participants can choose from a long list of simple lifestyle randomization options and many interventions may be tested concurrently with factorial randomization. Participants can tailor their own personal trial choosing several items among long laundry lists of randomization options. Participants are citizen-scientists rather than passive subjects and this may be attractive in modern societies of health-conscious people. These trials can use the existing machinery of the cohort for data collection and outcome linkage at no or minimal additional cost. We discuss a number of issues on the implementation of multiple lifestyle factorial experimental designs, as compared with the usual observational studies and randomized trials. These include participation, the number of allowed randomizations per participant, compliance/adherence, power, false-negatives, false-positives, composite lifestyle effects, selection of outcomes, follow-up and monitoring, masking and allocation concealment, age of participants, confounding, and cost. The aim should be to combine carefully the strengths of both observational epidemiology and randomized research without compounding their limitations.

    View details for DOI 10.1097/EDE.0b013e31815be01c

    View details for Web of Science ID 000251889400013

    View details for PubMedID 18090999

  • Some main problems eroding the credibility and relevance of randomized trials. Bulletin of the NYU hospital for joint diseases Ioannidis, J. P. 2008; 66 (2): 135-139

    Abstract

    Randomized trials are an excellent research design with major advantages. However, randomized trials are not immune to biases, and inferences from them may be sometimes flawed or irrelevant. The present review addresses, in brief, some of the major threats to the credibility and relevance of the results of clinical trials: power problems, biases affecting internal validity (poor design, conduct, and analysis), biases affecting the total randomized evidence on a specific topic (publication bias and selective outcome and analysis reporting bias), lack of relevance, poor generalizability, and biases in the interpretation of the results.

    View details for PubMedID 18537784

  • Claims of sex-gene interactions - Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Tatsioni, A., Ioannidis, J. P. 2007; 298 (23): 2742-2742
  • Persistence of contradicted claims in the literature JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tatsioni, A., Bonitsis, N. G., Ioannidis, J. P. 2007; 298 (21): 2517-2526

    Abstract

    Some research findings based on observational epidemiology are contradicted by randomized trials, but may nevertheless still be supported in some scientific circles.To evaluate the change over time in the content of citations for 2 highly cited epidemiological studies that proposed major cardiovascular benefits associated with vitamin E in 1993; and to understand how these benefits continued being defended in the literature, despite strong contradicting evidence from large randomized clinical trials (RCTs). To examine the generalizability of these findings, we also examined the extent of persistence of supporting citations for the highly cited and contradicted protective effects of beta-carotene on cancer and of estrogen on Alzheimer disease.For vitamin E, we sampled articles published in 1997, 2001, and 2005 (before, early, and late after publication of refuting evidence) that referenced the highly cited epidemiological studies and separately sampled articles published in 2005 and referencing the major contradicting RCT (HOPE trial). We also sampled articles published in 2006 that referenced highly cited articles proposing benefits associated with beta-carotene for cancer (published in 1981 and contradicted long ago by RCTs in 1994-1996) and estrogen for Alzheimer disease (published in 1996 and contradicted recently by RCTs in 2004).The stance of the citing articles was rated as favorable, equivocal, and unfavorable to the intervention. We also recorded the range of counterarguments raised to defend effectiveness against contradicting evidence.For the 2 vitamin E epidemiological studies, even in 2005, 50% of citing articles remained favorable. A favorable stance was independently less likely in more recent articles, specifically in articles that also cited the HOPE trial (odds ratio for 2001, 0.05 [95% confidence interval, 0.01-0.19; P < .001] and the odds ratio for 2005, 0.06 [95% confidence interval, 0.02-0.24; P < .001], as compared with 1997), and in general/internal medicine vs specialty journals. Among articles citing the HOPE trial in 2005, 41.4% were unfavorable. In 2006, 62.5% of articles referencing the highly cited article that had proposed beta-carotene and 61.7% of those referencing the highly cited article on estrogen effectiveness were still favorable; 100% and 96%, respectively, of the citations appeared in specialty journals; and citations were significantly less favorable (P = .001 and P = .009, respectively) when the major contradicting trials were also mentioned. Counterarguments defending vitamin E or estrogen included diverse selection and information biases and genuine differences across studies in participants, interventions, cointerventions, and outcomes. Favorable citations to beta-carotene, long after evidence contradicted its effectiveness, did not consider the contradicting evidence.Claims from highly cited observational studies persist and continue to be supported in the medical literature despite strong contradictory evidence from randomized trials.

    View details for Web of Science ID 000251361900017

    View details for PubMedID 18056905

  • Percutaneous coronary intervention for late reperfusion after myocardial infarction in stable patients AMERICAN HEART JOURNAL Ioannidis, J. P., Katritsis, D. G. 2007; 154 (6): 1065-1071

    Abstract

    Results of randomized trials that have compared mechanical coronary artery recanalization versus medical therapy for total occlusion late after myocardial infarction (MI) have been conflicting.We performed a meta-analysis of randomized trials comparing percutaneous coronary intervention (PCI) with medical therapy in stable patients with an occluded artery 1 to 45 days after MI. Six trials and one substudy were included with data on 2617 patients for the clinical outcomes and 653 patients for determination of ejection fraction (EF) during follow-up. Outcomes included death, MI, death or MI, congestive heart failure (CHF), and change in left ventricular EF.There were no statistically significant differences for any clinical outcome, with trends for an increase in MI (risk ratio 1.26, P = .19) and decrease in CHF (risk ratio 0.67, P = .19) in the PCI arm. The PCI arm showed a slight superiority in left ventricular EF (2%, 95% CI 0.1%-2.8%). Early smaller studies showed formally statistically significant benefits for CHF and EF, but the much larger Occluded Artery Trial and Total Occlusion Study of Canada 2 found no benefit. For CHF, the difference between early smaller studies and Occluded Artery Trial was beyond chance (P = .02).Percutaneous coronary intervention does not seem to confer any benefits when used for late revascularization of occluded arteries after MI in stable patients.

    View details for DOI 10.1016/j.ahj.2007.07.049

    View details for Web of Science ID 000251396200010

    View details for PubMedID 18035076

  • Osteomyelitis: Antigranulocyte scintigraphy with Tc-99m radiolabeled monoclonal antibodies for diagnosis-meta-analysis RADIOLOGY Pakos, E. E., Koumoulis, H. D., Fotopoulos, A. D., Ioannidis, J. P. 2007; 245 (3): 732-741

    Abstract

    To perform a meta-analysis of the sensitivity and specificity of antigranulocyte scintigraphy with monoclonal antibodies (MoAbs) in the diagnosis of osteomyelitis across different patient groups and clinical settings.MEDLINE and EMBASE searches were conducted. Data on the diagnostic performance of antigranulocyte scintigraphy with MoAbs were combined. Weighted sensitivities and specificities were estimated by using a random-effects model that incorporated between-study heterogeneity and by constructing summary receiver operating characteristic (ROC) curves. The weighted positive and negative likelihood ratios (LRs) across studies were estimated. Data syntheses were performed for all patients and for various subgroups. The reference standard used in each individual study was accepted.Nineteen nonoverlapping studies with a total of 714 examinations and reference standards of cell culture, histologic examination, clinical follow-up, and radiologic examination were eligible. The independent random-effects summary estimates of sensitivity and specificity were 81% (95% confidence interval [CI]: 70%, 88%) and 77% (95% CI: 66%, 86%), respectively, with statistically significant between-study heterogeneity (exact P < .001 for both metrics). In the summary ROC curve, a sensitivity of 81% corresponded to a specificity of 86%, and a specificity of 77% corresponded to a sensitivity of 87%. The weighted positive LR was 3.02 (95% CI: 2.07, 4.42), and the weighted negative LR was 0.26 (95% CI: 0.17, 0.39), with statistically significant between-study heterogeneity (exact P < .001 for both metrics). Sensitivity was better for peripheral than for axial skeleton lesions (87% vs 53%).Antigranulocyte scintigraphy with MoAbs has a sensitivity of 81% and a specificity of 77% in the diagnosis of osteomyelitis.

    View details for DOI 10.1148/radiol.2452061877

    View details for Web of Science ID 000251070700014

    View details for PubMedID 17898328

  • Uncertainty in heterogeneity estimates in meta-analyses BRITISH MEDICAL JOURNAL Ioannidis, J. P., Patsopoulos, N. A., Evangelou, E. 2007; 335 (7626): 914-916

    View details for Web of Science ID 000250848300029

    View details for PubMedID 17974687

  • Almost all articles on cancer prognostic markers report statistically significant results EUROPEAN JOURNAL OF CANCER Kyzas, P. A., Denaxa-Kyza, D., Ioannidis, J. P. 2007; 43 (17): 2559-2579

    Abstract

    We aimed to understand the extent of the pursuit for statistically significant results in the prognostic literature of cancer. We evaluated 340 articles included in prognostic marker meta-analyses (Database 1) and 1575 articles on cancer prognostic markers published in 2005 (Database 2). For each article, we examined whether the abstract reported any statistically significant prognostic effect for any marker and any outcome ('positive' articles). 'Negative' articles were further examined for statements made by the investigators to overcome the absence of prognostic statistical significance. We also examined how the articles of Database 1 had presented the relative risks that were included in the respective meta-analyses. 'Positive' prognostic articles comprised 90.6% and 95.8% in Databases 1 and 2, respectively. Most of the 'negative' prognostic articles claimed significance for other analyses, expanded on non-significant trends or offered apologies that were occasionally remote from the original study aims. Only five articles in Database 1 (1.5%) and 21 in Database 2 (1.3%) were fully 'negative' for all presented results in the abstract and without efforts to expand on non-significant trends or to defend the importance of the marker with other arguments. Of the statistically non-significant relative risks in the meta-analyses, 25% had been presented as statistically significant in the primary papers using different analyses compared with the respective meta-analysis. We conclude that almost all articles on cancer prognostic marker studies highlight some statistically significant results. Under strong reporting bias, statistical significance loses its discriminating ability for the importance of prognostic markers.

    View details for DOI 10.1016/j.ejca.2007.08.030

    View details for Web of Science ID 000251706000027

    View details for PubMedID 17981458

  • International ranking systems for universities and institutions: a critical appraisal BMC MEDICINE Ioannidis, J. P., Patsopoulos, N. A., Kavvoura, F. K., Tatsioni, A., Evangelou, E., Kouri, I., Contopoulos-Ioannidis, D. G., Liberopoulos, G. 2007; 5

    Abstract

    Ranking of universities and institutions has attracted wide attention recently. Several systems have been proposed that attempt to rank academic institutions worldwide.We review the two most publicly visible ranking systems, the Shanghai Jiao Tong University 'Academic Ranking of World Universities' and the Times Higher Education Supplement 'World University Rankings' and also briefly review other ranking systems that use different criteria. We assess the construct validity for educational and research excellence and the measurement validity of each of the proposed ranking criteria, and try to identify generic challenges in international ranking of universities and institutions.None of the reviewed criteria for international ranking seems to have very good construct validity for both educational and research excellence, and most don't have very good construct validity even for just one of these two aspects of excellence. Measurement error for many items is also considerable or is not possible to determine due to lack of publication of the relevant data and methodology details. The concordance between the 2006 rankings by Shanghai and Times is modest at best, with only 133 universities shared in their top 200 lists. The examination of the existing international ranking systems suggests that generic challenges include adjustment for institutional size, definition of institutions, implications of average measurements of excellence versus measurements of extremes, adjustments for scientific field, time frame of measurement and allocation of credit for excellence.Naïve lists of international institutional rankings that do not address these fundamental challenges with transparent methods are misleading and should be abandoned. We make some suggestions on how focused and standardized evaluations of excellence could be improved and placed in proper context.

    View details for DOI 10.1186/1741-7015-5-30

    View details for Web of Science ID 000252409300001

    View details for PubMedID 17961208

  • Turning the pump handle: Evolving methods for integrating the evidence on gene-disease association AMERICAN JOURNAL OF EPIDEMIOLOGY Higgins, J. P., Little, J., Ioannidis, J. P., Bray, M. S., Manolio, T. A., Smeeth, L., Sterne, J. A., Anagnostelis, B., Butterworth, A. S., Danesh, J., Dezateux, C., Gallacher, J. E., Gwinn, M., Lewis, S. J., Minelli, C., Pharoah, P. D., Salanti, G., Sanderson, S., Smith, L. A., Taioli, E., Thompson, J. R., Thompson, S. G., Walker, N., Zimmern, R. L., Khoury, M. J. 2007; 166 (8): 863-866

    View details for DOI 10.1093/aje/kwm248

    View details for Web of Science ID 000250143200001

    View details for PubMedID 17804859

  • Effects of glycoprotein IIb/IIIa blockers - Reply HEART Hernandez, A. V., Westerhout, C. M., Steyerberg, E. W., Ioannidis, J. P., Bueno, H., White, H., Theroux, P., Moliterno, D. J., Armstrong, P. W., Califf, R. M., Wallentin, L. C., Simoons, M. L., Boersma, E. 2007; 93 (10): 1293-1293
  • Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level BIOLOGICAL PSYCHIATRY Stefanis, N. C., Trikalinos, T. A., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., Ntzani, E. E., Ioannidis, J. P., Stefanis, C. N. 2007; 62 (7): 784-792

    Abstract

    Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia.We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated.The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected.The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

    View details for DOI 10.1016/j.biopsych.2006.11.015

    View details for Web of Science ID 000249511500010

    View details for PubMedID 17336946

  • Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis LANCET ONCOLOGY Golfinopoulos, V., Salanti, G., Pavlidis, N., Ioannidis, J. P. 2007; 8 (10): 898-911

    Abstract

    Many randomised trials have compared different systemic treatment regimens in patients with advanced colorectal cancer. While survival advances have apparently been achieved, the magnitude of these incremental benefits across diverse regimens is less clear. The aim of our study was to estimate the magnitude of survival and disease progression benefits with the use of different regimens in patients with advanced colorectal cancer.We systematically reviewed randomised trials comparing systemic treatment regimens in advanced colorectal cancer. Treatment was categorised by use of or no use of fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab. We used multiple-treatment meta-analysis methodology to combine information from direct comparisons (ie, treatments compared within a randomised trial) and indirect comparisons (ie, treatments compared between trials by combining results on how effective they are against a common comparator treatment) of different chemotherapy regimens. The primary endpoint was death and the secondary endpoint was disease progression. Monte Carlo simulations were used to establish which regimen offered the most benefit for these endpoints. We did analyses of all trials and analysed separately trials that studied first-line treatments and non-first-line treatments.242 trials published in 1967-2007 (N=56 677 patients) involved 137 different chemotherapy regimens. 37 of these trials were eligible for the multiple-treatment meta-analysis, according to our categorisation, including 47 comparisons of data on death (N=13 875 patients) and 48 comparisons of data on disease progression (N=15 158 patients). Compared with fluorouracil plus leucovorin alone, the risk of death was most decreased with the addition of irinotecan plus bevacizumab (hazard ratio [HR] 0.60, 95% credibility intervals (CrI) 0.44-0.84) and considerable benefits were also noted with addition of irinotecan plus oxaliplatin (HR 0.72 [95% CrI 0.54-0.97]); oxaliplatin plus bevacizumab (HR 0.72 [0.57-0.90]); bevacizumab alone (HR 0.78 [0.60-1.03]); and oxaliplatin alone (HR 0.87 [0.78-0.98]). The disease progression benefits were even more prominent for the addition of irinotecan plus bevacizumab (HR 0.41 [0.28-0.60]); irinotecan plus oxaliplatin (0.53 [0.38-0.73]); oxaliplatin plus bevacizumab (0.46 [0.34-0.61]); bevacizumab alone (0.56 [0.41-0.76]); oxaliplatin alone (0.64 [0.56-0.73]); irinotecan plus cetuximab (HR 0.62 [0.42-0.92]); and irinotecan alone (HR 0.73 [0.65-0.82]). Findings were similar for first-line and non-first-line treatment analyses although data were sparse for non-first-line treatment analyses. Compared with a patient with an anticipated 1-year survival who is treated with fluorouracil and leucovorin, the absolute survival benefit is estimated at 8 months' prolongation with addition of irinotecan plus bevacizumab, 4.7 months' prolongation with addition of oxaliplatin plus bevacizumab or irinotecan plus oxaliplatin, and 1-1.8 months' prolongation with addition of irinotecan alone or oxaliplatin alone.Distinct incremental benefits are noted for diverse chemotherapy regimens in patients with advanced colorectal cancer, with more prominent effects on disease progression than on death. More data are needed at least for the newest drugs to estimate more accurately the magnitude of the benefit derived from their use.

    View details for DOI 10.1016/S1470-2045(07)70281-4

    View details for Web of Science ID 000250249000028

    View details for PubMedID 17888735

  • Heterogeneity in Meta-Analyses of Genome-Wide Association Investigations PLOS ONE Ioannidis, J. P., Patsopoulos, N. A., Evangelou, E. 2007; 2 (9)

    Abstract

    Meta-analysis is the systematic and quantitative synthesis of effect sizes and the exploration of their diversity across different studies. Meta-analyses are increasingly applied to synthesize data from genome-wide association (GWA) studies and from other teams that try to replicate the genetic variants that emerge from such investigations. Between-study heterogeneity is important to document and may point to interesting leads.To exemplify these issues, we used data from three GWA studies on type 2 diabetes and their replication efforts where meta-analyses of all data using fixed effects methods (not incorporating between-study heterogeneity) have already been published. We considered 11 polymorphisms that at least one of the three teams has suggested as susceptibility loci for type 2 diabetes. The I2 inconsistency metric (measuring the amount of heterogeneity not due to chance) was different from 0 (no detectable heterogeneity) for 6 of the 11 genetic variants; inconsistency was moderate to very large (I2 = 32-77%) for 5 of them. For these 5 polymorphisms, random effects calculations incorporating between-study heterogeneity revealed more conservative p-values for the summary effects compared with the fixed effects calculations. These 5 associations were perused in detail to highlight potential explanations for between-study heterogeneity. These include identification of a marker for a correlated phenotype (e.g. FTO rs8050136 being associated with type 2 diabetes through its effect on obesity); differential linkage disequilibrium across studies of the identified genetic markers with the respective culprit polymorphisms (e.g., possibly the case for CDKAL1 polymorphisms or for rs9300039 and markers in linkage disequilibrium, as shown by additional studies); and potential bias. Results were largely similar, when we treated the discovery and replication data from each GWA investigation as separate studies.Between-study heterogeneity is useful to document in the synthesis of data from GWA investigations and can offer valuable insights for further clarification of gene-disease associations.

    View details for DOI 10.1371/journal.pone.0000841

    View details for Web of Science ID 000207455500024

    View details for PubMedID 17786212

  • Selective discussion and transparency in microarray research findings for cancer outcomes EUROPEAN JOURNAL OF CANCER Ioannidis, J. P., Polyzos, N. P., Trikalinos, T. A. 2007; 43 (13): 1999-2010

    Abstract

    We examined the interpretation of research findings and public availability of transparent information on data and processing for 46 articles of microarray studies that had addressed major cancer outcomes. Unsupervised and supervised methods selected molecular signatures with a median of 675 and 50 genes, respectively, but only a median of eight genes or groups thereof were further discussed. Across 479 genes or groups thereof discussed in all 46 studies, 65% reflected specific comments (reflecting external relevant data from other studies or other lines of reasoning relevant to the gene of interest), and 59% of the comments were referenced. Among specific comments, supportive ones outnumbered comments against the research findings by nine to one (270 versus 29). Discussion was similarly selective in early studies and in studies published in 2006. Even in 2006 only 10 of 15 studies had publicly deposited data. Only three studies had scanned images, raw and processed data available. Processing details varied. Public transparency and unbiased interpretation of findings can be improved in microarray research.

    View details for DOI 10.1016/j.ejca.2007.05.019

    View details for Web of Science ID 000250128300026

    View details for PubMedID 17629475

  • Genetic and molecular epidemiology JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Ioannidis, J. P. 2007; 61 (9): 757-758

    Abstract

    Genetic and molecular epidemiology covers a vast area of research. Given the rapid changes in this field, discussing a research agenda is a precarious and ambitious task. A representative set of high-priority concepts will be presented here, each of which alone could be the topic of a long series of essays. The wish list includes issues of full transparency and integration of information, dealing efficiently with complex multidimensional biology, juxtaposing the genome and environmental exposures, and using robust randomised trials to advance our knowledge and its application in this field.

    View details for DOI 10.1136/jech.2006.059055

    View details for Web of Science ID 000248743600003

    View details for PubMedID 17699527

  • Claims of sex differences - An empirical assessment in genetic associations JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Tatsioni, A., Ioannidis, J. P. 2007; 298 (8): 880-893

    Abstract

    Many studies try to probe for differences in risks between men and women, and this is a major challenge in the expanding literature of associations between genetic variants and common diseases or traits.To evaluate whether prominently claimed sex differences for genetic effects have sufficient internal and external validity.We searched PubMed through July 6, 2007, for genetic association studies claiming sex-related differences in the articles' titles. Titles and abstracts and, if necessary, the full text of the article were assessed for eligibility.Two hundred fifteen articles were retrieved by the search. We considered eligible all retrieved association studies that claimed different genetic effects across sexes of 1 or more gene variants for any human disease or phenotype. We considered both biallelic and multiallelic markers (including haplotypes) and both binary and continuous phenotypes and traits. We excluded non-English-language studies; studies evaluating only 1 sex; studies in which sex was treated only as an independent predictor of disease; studies that did not address any association of the investigated genetic variant with a disease or trait; studies not involving humans; and studies in which the authors did not claim any sex difference.Two evaluators independently extracted data with a third evaluator arbitrating their discrepancies. Data evaluation included whether analyses were stated to have been specified a priori; whether sex effects were evaluated in the whole study or subgroups thereof; and whether the claims were appropriately documented, insufficiently documented, or spurious. For appropriately and insufficiently documented claims we performed the calculations for gene-sex interaction whenever raw data were available. Finally, we compared the sex-difference claims with the best internal validity against the results of other studies addressing the same interaction.We appraised 432 sex-difference claims in 77 eligible articles. Authors stated that sex comparisons were decided a priori for 286 claims (66.2%), while the entire sample size was used in 210 (48.6%) claims. Appropriate documentation of gene-sex interaction was recorded in 55 claims (12.7%); documentation was insufficient for 303 claims and spurious for the other 74. Data for reanalysis of claims were available for 188 comparisons. Of these, 83 (44.1%) were nominally statistically significant at a P = .05 threshold, and more than half of them (n = 44) had modest P values between .01 and .05. Of 60 claims with seemingly the best internal validity, only 1 was consistently replicated in at least 2 other studies.In this sample of highly prominent claims of sex-related differences in genetic associations, most claims were insufficiently documented or spurious, and claims with documented good internal and external validity were uncommon.

    View details for Web of Science ID 000248880200022

    View details for PubMedID 17712072

  • Pharmacogenetics of the response to beta 2 agonist drugs: a systematic overview of the field. Pharmacogenomics Contopoulos-Ioannidis, D. G., Kouri, I., Ioannidis, J. P. 2007; 8 (8): 933-958

    Abstract

    The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large-scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data.

    View details for PubMedID 17716228

  • Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: A meta-analysis JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P., Ban, Y., Bednarczuk, T., Chistiakova, E. I., Chojm, M., Heward, J. M., Hiratani, H., Juo, S. H., Karabon, L., Katayama, S., Kurihara, S., Liu, R., Miyake, I., Omrani, G. R., Pawlak, E., Taniyama, M., Tozaki, T., Ioannidis, J. P. 2007; 92 (8): 3162-3170

    Abstract

    Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear.The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT.Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed.Association of gene variants and haplotypes with GD and HT was measured.Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) per G allele, respectively] and CT60 [1.45 (P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose-response effect for the G allele of CT60.The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.

    View details for DOI 10.1210/jc.2007-0147

    View details for Web of Science ID 000248570600052

    View details for PubMedID 17504905

  • PCI for stable coronary disease NEW ENGLAND JOURNAL OF MEDICINE Katritsis, D. G., Ioannidis, J. P. 2007; 357 (4): 414-415

    View details for Web of Science ID 000248283500017

    View details for PubMedID 17652659

  • Why most published research findings are false: Author's reply to Goodman and Greenland PLOS MEDICINE Ioannidis, J. P. 2007; 4 (6): 1132-1133

    View details for DOI 10.1371/journal.pmed.0040215

    View details for Web of Science ID 000247476300030

    View details for PubMedID 17593900

  • Reporting of systematic reviews: The challenge of genetic association studies PLOS MEDICINE Khoury, M. J., Little, J., Higgins, J., Ioannidis, J. P., Gwinn, M. 2007; 4 (6): 1129-1129

    View details for DOI 10.1371/journal.pmed.0040211

    View details for Web of Science ID 000247476300024

    View details for PubMedID 17593896

  • Genetic effects versus bias for candidate polymorphisms in myocardial infarction: Case study and overview of large-scale evidence AMERICAN JOURNAL OF EPIDEMIOLOGY Ntzani, E. E., Rizos, E. C., Ioannidis, J. P. 2007; 165 (9): 973-984

    Abstract

    Several genetic polymorphisms have been proposed to be associated with myocardial infarction (MI). The authors examined the evidence and biases underlying such associations using a case-study meta-analysis and an overview of large-scale data. In a meta-analysis of 27 studies addressing the association of the angiotensin type 1 receptor (AT1R)+1166A/C polymorphism with MI (10,180 cases, 17,129 controls), the *C allele conferred an increase in MI risk (odds ratio = 1.13 per allele, p = 0.005). However, there was large between-study heterogeneity; the largest study showed no effect, contradicting smaller studies; and studies with blinded genotyping showed no effect. The authors conducted an overview of meta-analyses of genetic associations for MI or coronary artery disease, including at least three studies and 3,000 subjects. In their latest meta-analysis, another 14 polymorphisms were found to have formally significant associations. If true, these associations would already explain 42% of the MI risk for Caucasian populations. Significant between-study heterogeneity was common. Across the 32 largest studies, only two found formally significant results (nine would be expected if each meta-analysis showed a true association). Even with large-scale evidence from meta-analyses, significant associations for MI may be subject to bias. Large-scale single studies and prospective consortia should be used for detecting and validating the genetic determinants of MI.

    View details for DOI 10.1093/aje/kwk085

    View details for Web of Science ID 000245896900001

    View details for PubMedID 17293603

  • Molecular evidence-based medicine - Evolution and integration of information in the genomic era EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P. 2007; 37 (5): 340-349

    Abstract

    Evidence-based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence-based and molecular medicine are complementary and they should be converging. I define molecular evidence-based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and 'significant' biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace.

    View details for Web of Science ID 000245986300002

    View details for PubMedID 17461979

  • The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P., Trikalinos, T. A. 2007; 176 (8): 1091-1096

    Abstract

    Statistical tests for funnel-plot asymmetry are common in meta-analyses. Inappropriate application can generate misleading inferences about publication bias. We aimed to measure, in a survey of meta-analyses, how frequently the application of these tests would be not meaningful or inappropriate.We evaluated all meta-analyses of binary outcomes with é 3 studies in the Cochrane Database of Systematic Reviews (2003, issue 2). A separate, restricted analysis was confined to the largest meta-analysis in each of the review articles. In each meta-analysis, we assessed whether criteria to apply asymmetry tests were met: no significant heterogeneity, I2 < 50%, é 10 studies (with statistically significant results in at least 1) and ratio of the maximal to minimal variance across studies > 4. We performed a correlation and 2 regression asymmetry tests and evaluated their concordance. Finally, we sampled 60 meta-analyses from print journals in 2005 that cited use of the standard regression test.A total of 366 of 6873 (5%) and 98 of 846 meta-analyses (12%) in the wider and restricted Cochrane data set, respectively, would have qualified for use of asymmetry tests. Asymmetry test results were significant in 7%-18% of the meta-analyses. Concordance between the 3 tests was modest (estimated k 0.33-0.66). Of the 60 journal meta-analyses, 7 (12%) would qualify for asymmetry tests; all 11 claims for identification of publication bias were made in the face of large and significant heterogeneity.Statistical conditions for employing asymmetry tests for publication bias are absent from most meta-analyses; yet, in medical journals these tests are performed often and interpreted erroneously.

    View details for DOI 10.1503/cmaj.060410

    View details for Web of Science ID 000245303100012

    View details for PubMedID 17420491

  • Evidence from crossover trials: empirical evaluation and comparison against parallel arm trials INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Lathyris, D. N., Trikalinos, T. A., Ioannidis, J. P. 2007; 36 (2): 422-430

    Abstract

    We aimed to evaluate empirically how crossover trial results are analysed in meta-analyses of randomized evidence and whether their results agree with parallel arm studies on the same questions.We used a systematic sample of Cochrane meta-analyses including crossover trials. We evaluated the methods of analysis for crossover results and compared the concordance of the estimated effect sizes in crossover vs parallel arm trials.Of 334 screened reviews, 62 had crossover trials. Of those, 33 meta-analyses performed quantitative syntheses involving two-arm two-period crossover trials. There was large variability on how these trials were analysed; only one of the 33 meta-analyses stated that they used the data from both the first and second period with an appropriate paired approach. Nine meta-analyses used the first period data only and 14 gave no information at all on what they had done. Twenty-eight meta-analyses had both crossover (n = 137, sample size n = 7,162) and parallel arm (n = 132, sample size n = 11,398) trials. Effect sizes correlated well with the two types of designs (rho = 0.72). Differences on whether the summary effect had a P < 0.05 or not were common due to limited sample sizes. The summary relative odds ratio for parallel arm vs crossover designs for favourable outcomes was 0.87 (95% CI, 0.74-1.02).Crossover designs may contribute evidence in a fifth of systematic reviews, but few meta-analyses make use of their full data. The results of crossover trials tend to agree with those of parallel arm trials, although there was a trend for more conservative treatment effect estimates in parallel arm trials.

    View details for DOI 10.1093/ije/dym001

    View details for Web of Science ID 000248084200034

    View details for PubMedID 17301102

  • Limitations are not properly acknowledged in the scientific literature JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2007; 60 (4): 324-329

    Abstract

    Limitations are important to understand for placing research findings in context, interpreting the validity of the scientific work, and ascribing a credibility level to the conclusions of published research. This goes beyond listing the magnitude and direction of random and systematic errors and validity problems. Acknowledgment of limitations requires an interpretation of the meaning and influence of errors and validity problems on the published findings. An examination of the full-text files of the first 50 articles published in 2005 in the six most-cited research journals and in two recently launched leading open-access journals showed that only 67 articles (17%) used at least one word denoting limitations in the context of the presented scientific work. Only four articles (1%) used the word limitation in their abstract; none referred to limitations of the present work that materially affected conclusions. Only five articles had a separate section on limitations. Conversely, 243 articles (61%) used words detected by the roots error, valid, bias, reproducib, or false and 289 articles (72%) used words with the root importan. Among the 25 top-cited journals' instructions to the authors and editorial policies, only one encourages discussion of limitations; importance, novelty, and lack of error are typically encouraged. Limitations should be better covered and discussed in research articles. To facilitate this, journals should give better guidance and promote the discussion of limitations. Otherwise, we are facing an important loss of context for the scientific literature.

    View details for DOI 10.1016/j.jclinepi.2006.09.011

    View details for Web of Science ID 000245094200002

    View details for PubMedID 17346604

  • Effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups HEART Hernandez, A. V., Westerhout, C. M., Steyerberg, E. W., Ioannidis, J. P., Bueno, H., White, H., Theroux, P., Moliterno, D. J., Armstrong, P. W., Califf, R. M., Wallentin, L. C., Simoons, M. L., Boersma, E. 2007; 93 (4): 450-455

    Abstract

    To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST elevation acute coronary syndromes (NSTE-ACS) depend on age.A meta-analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE-ACS (PRISM, PRISM-PLUS, PARAGON-A, PURSUIT, PARAGON-B, GUSTO IV-ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non-fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60-69, 70-79, > or =80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH).Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5-4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients > or =80 years had half of the NNT and a third of the NNH of patients <60 years.In patients with NSTE-ACS, the relative reduction of death or non-fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted.

    View details for DOI 10.1136/hrt.2006.098657

    View details for Web of Science ID 000245350000010

    View details for PubMedID 17065179

  • On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Little, J., Gwinn, M., Ioannidis, J. P. 2007; 36 (2): 439-445

    Abstract

    Emerging technologies are allowing researchers to study hundreds of thousands of genetic variants simultaneously as risk factors for common complex diseases. Both theoretical considerations and empirical evidence suggest that specific genetic variants causally associated with common diseases will have small effects (risk ratios mostly <2.0). However, the combination of even a few small effects (e.g. effects of fewer than 20 common genetic variants) could account for a sizeable population attributable fraction of common diseases and shed important light on disease pathogenesis and environmental determinants. Nevertheless, the inauguration of genome-wide association studies only magnifies the challenge of differentiating between the expected, true weak associations from the numerous spurious effects caused by misclassification, confounding and significance-chasing biases. Standards are urgently needed for presenting and interpreting cumulative evidence on gene-disease associations, especially for consistent but weak associations. Criteria for synthesis of the evidence should include sound methods for study conduct and analysis, biological plausibility, experimental evidence and adequate replication in large-scale, collaborative studies. Efforts by the Human Genome Epidemiology Network (HuGENet) are currently ongoing to streamline and operationalize these criteria for data on genetic associations with common diseases.

    View details for DOI 10.1093/ije/dyl253

    View details for Web of Science ID 000248084200036

    View details for PubMedID 17182636

  • Selection in reported epidemiological risks: An empirical assessment PLOS MEDICINE Kavvoura, F. K., Liberopoulos, G., Ioannidis, J. P. 2007; 4 (3): 456-465

    Abstract

    Epidemiological studies may be subject to selective reporting, but empirical evidence thereof is limited. We empirically evaluated the extent of selection of significant results and large effect sizes in a large sample of recent articles.We evaluated 389 articles of epidemiological studies that reported, in their respective abstracts, at least one relative risk for a continuous risk factor in contrasts based on median, tertile, quartile, or quintile categorizations. We examined the proportion and correlates of reporting statistically significant and nonsignificant results in the abstract and whether the magnitude of the relative risks presented (coined to be consistently > or =1.00) differs depending on the type of contrast used for the risk factor. In 342 articles (87.9%), > or =1 statistically significant relative risk was reported in the abstract, while only 169 articles (43.4%) reported > or =1 statistically nonsignificant relative risk in the abstract. Reporting of statistically significant results was more common with structured abstracts, and was less common in US-based studies and in cancer outcomes. Among 50 randomly selected articles in which the full text was examined, a median of nine (interquartile range 5-16) statistically significant and six (interquartile range 3-16) statistically nonsignificant relative risks were presented (p = 0.25). Paradoxically, the smallest presented relative risks were based on the contrasts of extreme quintiles; on average, the relative risk magnitude was 1.41-, 1.42-, and 1.36-fold larger in contrasts of extreme quartiles, extreme tertiles, and above-versus-below median values, respectively (p < 0.001).Published epidemiological investigations almost universally highlight significant associations between risk factors and outcomes. For continuous risk factors, investigators selectively present contrasts between more extreme groups, when relative risks are inherently lower.

    View details for DOI 10.1371/journal.pmed.0040079

    View details for Web of Science ID 000245243700013

    View details for PubMedID 17341129

  • Meta-analysis of fractional flow reserve versus quantitative coronary angiography and noninvasive imaging for evaluation of myocardial ischemia AMERICAN JOURNAL OF CARDIOLOGY Christou, M. A., Siontis, G. C., Katritsis, D. G., Ioannidis, J. P. 2007; 99 (4): 450-456

    Abstract

    We performed a meta-analysis of 31 studies comparing the results of fractional flow reserve (FFR) against quantitative coronary angiography (QCA) and/or noninvasive imaging of the same lesions. Studies were retrieved from PubMed (last search February 2006). Across 18 studies (1,522 lesions), QCA had a random effects sensitivity of 78% (95% confidence interval [CI] 67 to 86) and specificity of 51% (95% CI 40 to 61) against FFR (0.75 cutoff). Overall concordances were 61% for lesions with diameter stenosis 30% to 70%, 67% for stenoses >70%, and 95% for stenoses <30%. Compared with noninvasive imaging (21 studies, 1,249 lesions), FFR had a sensitivity of 76% (95% CI 69 to 82) and specificity of 76% (95% CI 71 to 81) by random effects. Summary receiver-operator characteristic estimates were similar. Most data addressed comparisons with perfusion scintigraphy (976 lesions, sensitivity 75%, specificity 77%), and some data were also available for dobutamine stress echocardiography (273 lesions, sensitivity 82%, specificity 74%). In conclusion, QCA does not predict the functional significance of coronary lesions. FFR shows modest concordance with noninvasive imaging tests. The prognostic implications of discordant FFR and imaging results need further study.

    View details for DOI 10.1016/j.amjcard.2006.09.092

    View details for Web of Science ID 000244514500005

    View details for PubMedID 17293182

  • Bayesian meta-analysis and meta-regression for gene-disease associations and deviations from Hardy-Weinberg equilibrium STATISTICS IN MEDICINE Salanti, G., Higgins, J. P., Trikalinos, T. A., Ioannidis, J. P. 2007; 26 (3): 553-567

    Abstract

    Violation of Hardy-Weinberg equilibrium (HWE) can raise doubts about the validity of the conclusions from genetic association studies. However, for most currently performed gene-disease association studies, the available tests have low power to detect deviations from HWE. We consider this issue from a meta-analysis perspective, and suggest an approach to estimate the deviation and investigate its relationship with the observed genetic effects. Different degrees of deviation from HWE have previously been proposed as a potential source of heterogeneity across studies. We present a hierarchical meta-regression model that can be applied to test this assumption, using the concept of the fixation coefficient. We re-analyse seven meta-analyses to illustrate these methods. The uncertainty in the genetic effect estimate tended to increase once the fixation coefficient was taken into account. Dependence of the genetic effect size on the deviation from HWE was found in one meta-analysis, while in the other six examples, deviations from HWE did not clearly explain between-study heterogeneity in the genetic effects. The proposed hierarchical models allow the synthesis of data across gene-disease association studies with appropriate consideration of HWE issues.

    View details for DOI 10.1002/sim.2575

    View details for Web of Science ID 000243511400007

    View details for PubMedID 16685693

  • Meta-Analysis in Genome-Wide Association Datasets: Strategies and Application in Parkinson Disease PLOS ONE Evangelou, E., Maraganore, D. M., Ioannidis, J. P. 2007; 2 (2)

    Abstract

    Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques.Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1) enhancement of replication data and (2) enhancement of first-stage data, and then, we also considered (3) joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets) on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2) = 0, 0 and 15%, respectively). Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets).Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.

    View details for DOI 10.1371/journal.pone.0000196

    View details for Web of Science ID 000207444300009

    View details for PubMedID 17332845

  • Quality of reporting of cancer prognostic marker studies: Association with reported prognostic effect JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Denaxa-Kyza, D., Ioannidis, J. P. 2007; 99 (3): 236-243

    Abstract

    Issues of reported study quality have not been addressed empirically with large-scale data in the cancer prognostic literature.Eight quality measures pertaining to study design and assay methods (i.e., blinding, prospective versus retrospective design, power calculations, outcomes' definitions, time of enrollment, reporting of variables, assay description, and assay reference) were evaluated in cancer prognostic marker studies included in meta-analyses identified in Medline and EMBASE. To be eligible, meta-analyses had to include at least six studies and to examine binary outcomes. We estimated the ratios of relative risks, which compared the overall prognostic effects (summary relative risks) between poor-quality and good-quality studies for each quality item. Between-study heterogeneity was tested with the Q statistic (statistically significant at P<.10). All statistical tests were two-sided.We identified 20 meta-analyses that included 331 cancer prognostic marker studies published between 1987 and 2005. Only three (0.9%) of the 331 studies presented power calculations, 129 (39.0%) studies stated that analyses were blinded, and 73 (21.5%) stated that they were prospective. Time of enrollment was defined in 232 (70.0%), 234 (70.7%) gave lists of candidate variables, and 254 (76.7%) defined outcomes. The assay used was described in 317 (95.8%), but only 177 (53.5%) provided the assay reference. Estimates of prognostic effects from poor-quality studies varied considerably and could be larger or smaller than summary estimates derived from meta-analyses. Summary ratios of relative risks of poor- versus good-quality studies for the seven quality measures ranged from 0.95 to but 1.26, but none was statistically significantly. There was statistically significant heterogeneity (P<.10) between the ratios of relative risk estimates across meta-analyses for blinding, defining endpoints, and stating variables and assay references.Among cancer prognostic marker studies, reporting quality of design and assay information often appears suboptimal, indicating that this literature may be largely unreliable. Given the potential clinical importance of prognostic marker information, improved design and reporting of these studies are warranted.

    View details for DOI 10.1093/jnci/djk032

    View details for Web of Science ID 000244223400011

    View details for PubMedID 17284718

  • Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass JOURNAL OF BONE AND MINERAL RESEARCH Ioannidis, J. P., Ng, M. Y., Sham, P. C., Zintzaras, E., Lewis, C. M., Deng, H., Econs, M. J., Karasik, D., Devoto, M., Kammerer, C. M., Spector, T., Andrew, T., Cupples, L. A., Duncan, E. L., Foroud, T., Kiel, D. P., Koller, D., Langdahl, B., Mitchell, B. D., Peacock, M., Recker, R., Shen, H., Sol-Church, K., Spotila, L. D., Uitterlinden, A. G., Wilson, S. G., Kung, A. W., Ralston, S. H. 2007; 22 (2): 173-183

    Abstract

    Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.

    View details for DOI 10.1359/JBMR.060806

    View details for Web of Science ID 000243668800001

    View details for PubMedID 17228994

  • Effects of different chemotherapy regimens on survival for advanced cervical cancer: Systematic review and meta-analysis CANCER TREATMENT REVIEWS Tzioras, S., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2007; 33 (1): 24-38

    Abstract

    A large number of trials have assessed various chemotherapy regimens for the treatment of advanced cervical cancer, but there is uncertainty about the magnitude of survival benefits.We searched (last update January 2006) for trials in women with locally advanced or disseminated cervical cancer that compared neo-adjuvant or concurrent chemotherapy plus radiotherapy versus radiotherapy alone; or different chemotherapy regimens among themselves (with or without background radiotherapy in both arms). Sixty-five trials were identified with survival data on 11,180 women. Results for survival were combined with fixed and random effects models and between-study heterogeneity was estimated. Separate results were obtained for different regimens, cycle length, and type of chemotherapy (neo-adjuvant, concurrent, without radiotherapy).Twenty two comparisons had survival data on 3837 women randomized to receive chemotherapy plus radiotherapy versus radiotherapy alone; the summary relative hazard for mortality was 0.95, 95% CI, 0.83-1.08. Modest between-study heterogeneity (I2=38%) seemed to be due to contradictory results in early trials; trials published in the last decade had a summary relative hazard 0.89 (95% CI, 0.78-1.02) and no between-study heterogeneity (I2=0%). Results were similar for neo-adjuvant chemotherapy and for concurrent chemo-radiotherapy. Cisplatin or cisplatin-based combinations had no significant benefit overall, but a potential benefit was seen with short-length cycles (14 days) and a marginally significant harm with longer-length cycles (summary relative hazards 0.80, 95% CI, 0.66-0.99 and 1.18, 95% CI, 1.02-1.38, respectively). The summary relative hazard was 1.02, (95% CI, 0.84-1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI, 0.73-1.00) for trials using concurrent chemotherapy.Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy.

    View details for DOI 10.1016/j.ctrv.2006.09.007

    View details for Web of Science ID 000244178700003

    View details for PubMedID 17112673

  • Open letter to the leader of academic medicine. BMJ (Clinical research ed.) Ioannidis, J. P., Ahmed, T., Awasthi, S., Clarfield, A. M., Clark, J., Dandona, L., Howe, A., Lozano, J. M., Li, Y., Madani, H., Marusic, A., Mohammed, I., Purcell, G. P., Rhoads, M., Sliwa-Hähnle, K., Straus, S. E., Edejer, T. T., Tugwell, P., Ward, R., Wilkes, M. S., Smith, R. 2007; 334 (7586): 191-193

    View details for PubMedID 17255613

  • Re: Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis - Response JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Mauri, D., Polyzos, N. P., Pavlidis, N. 2007; 99 (2): 176-177
  • Genetic predisposition to asthma and atopy RESPIRATION Contopoulos-Ioannidis, D. G., Kouri, I. N., Ioannidis, J. P. 2007; 74 (1): 8-12

    Abstract

    A large number of studies have tried to identify heritable components in the susceptibility to asthma and atopy phenotypes. This review examines the evidence of multigenetic inheritance for these conditions. We identified in the literature at least 372 gene-disease association studies for asthma and 124 for atopy published in the last 6 years. Gene-environment analyses were performed in 41 and 14 articles, respectively, in the same time period. Many postulated associations have been probed with limited sample sizes and will require more extensive replication and large-scale evidence. Meta-analyses have been performed for polymorphisms in 5 genes and provide modest evidence for genetic association of asthma with ADAM33 and TNFA gene polymorphisms. Meta-analyses of linkage studies show that it is unlikely to detect strong linkage peaks for asthma susceptibility. However, linkage was claimed between loci on chromosomes 2, 4, 6, 9, 10, 11 and 15 and total serum IgE levels. Careful definitions and standardization of phenotypes across teams of investigators are important to endorse. New large-scale testing platforms may offer new opportunities for discovering susceptibility gene variants, but they need to be coupled with careful study design, international collaboration, and possibly also dissection of gene-environment interactions.

    View details for DOI 10.1159/000096833

    View details for Web of Science ID 000244565400003

    View details for PubMedID 17190999

  • Is molecular profiling ready for use in clinical decision making? ONCOLOGIST Ioannidis, J. P. 2007; 12 (3): 301-311

    Abstract

    Molecular profiling, the classification of tissue or other specimens for diagnostic, prognostic, and predictive purposes based on multiple gene expression, is a technology that holds major promise for optimizing the management of patients with cancer. However, the use of these tests for clinical decision making presents many challenges to overcome. Assay development and data analysis in this field have been largely exploratory, and leave numerous possibilities for the introduction of bias. Standardization of profiles remains the exception. Classifier performance is usually overinterpreted by presenting the results as p-values or multiplicative effects (e.g., relative risks), while the absolute sensitivity and specificity of classification remain modest at best, especially when tested in large validation samples. Validation has often been done with suboptimal attention to methodology and protection from bias. The postulated classifier performance may be inflated compared to what these profiles can achieve. With the exception of breast cancer, we have little evidence about the incremental discrimination that molecular profiles can provide versus classic risk factors alone. Clinical trials have started to evaluate the utility of using molecular profiles for breast cancer management. Until we obtain data from these trials, the impact of these tests and the net benefit under real-life settings remain unknown. Optimal incorporation into clinical practice is not straightforward. Finally, cost-effectiveness is difficult to appreciate until these other challenges are addressed. Overall, molecular profiling is a fascinating and promising technology, but its incorporation into clinical decision making requires careful planning and robust evidence.

    View details for DOI 10.1634/theoncologist.12-3-301

    View details for Web of Science ID 000245543600008

    View details for PubMedID 17405894

  • An exploratory test for an excess of significant findings CLINICAL TRIALS Ioannidis, J. P., Trikalinos, T. A. 2007; 4 (3): 245-253

    Abstract

    The published clinical research literature may be distorted by the pursuit of statistically significant results.We aimed to develop a test to explore biases stemming from the pursuit of nominal statistical significance.The exploratory test evaluates whether there is a relative excess of formally significant findings in the published literature due to any reason (e.g., publication bias, selective analyses and outcome reporting, or fabricated data). The number of expected studies with statistically significant results is estimated and compared against the number of observed significant studies. The main application uses alpha = 0.05, but a range of alpha thresholds is also examined. Different values or prior distributions of the effect size are assumed. Given the typically low power (few studies per research question), the test may be best applied across domains of many meta-analyses that share common characteristics (interventions, outcomes, study populations, research environment).We evaluated illustratively eight meta-analyses of clinical trials with >50 studies each and 10 meta-analyses of clinical efficacy for neuroleptic agents in schizophrenia; the 10 meta-analyses were also examined as a composite domain. Different results were obtained against commonly used tests of publication bias. We demonstrated a clear or possible excess of significant studies in 6 of 8 large meta-analyses and in the wide domain of neuroleptic treatments.The proposed test is exploratory, may depend on prior assumptions, and should be applied cautiously.An excess of significant findings may be documented in some clinical research fields.

    View details for DOI 10.1177/1740774507079441

    View details for Web of Science ID 000249489200005

    View details for PubMedID 17715249

  • Prosthesis infection: Diagnosis after total joint arthroplasty with antigranulocyte scintigraphy with Tc-99m-labeled monoclonal antibodies - A meta-analysis RADIOLOGY Pakos, E. E., Trikalinos, T. A., Fotopoulos, A. D., Ioannidis, J. P. 2007; 242 (1): 101-108

    Abstract

    To perform a meta-analysis of diagnostic studies regarding the accuracy of antigranulocyte scintigraphy (AGS) with monoclonal antibodies in the identification of prosthesis infection after total hip or knee arthroplasty.PubMed and EMBASE searches were conducted for the identification of relevant studies. Data on the diagnostic performance of AGS with monoclonal antibodies were combined quantitatively across eligible studies, and the overall sensitivity and specificity, along with summary receiver operating characteristic (ROC) curves and likelihood ratios (LRs), were estimated. The above parameters were evaluated for all patients and for various subgroups among the eligible studies. The reference standard used in the individual studies was accepted.Thirteen eligible studies on nonoverlapping patient groups were included in the meta-analysis; there was a total sample size of 522 implants. The independent random effects summary estimates of sensitivity and specificity were 83% and 80%, respectively. The summary ROC curve estimate for weighted analysis was a sensitivity of 90% for a specificity of 80%. LR syntheses gave a weighted positive LR of 3.99 (95% confidence interval [CI]: 3.13, 5.09) and a weighted negative LR of 0.22 (95% CI: 0.15, 0.34); there was no statistically significant between-study heterogeneity for either metric. Various subgroup analyses did not reveal any statistically significant differences.AGS with monoclonal antibodies had a reasonably high discriminating ability to identify prosthesis infection in patients who underwent total joint arthroplasty.

    View details for DOI 10.1148/radiol.2421052011

    View details for Web of Science ID 000243842500014

    View details for PubMedID 17090716

  • The emergence of networks in human genome epidemiology - Challenges and opportunities EPIDEMIOLOGY Seminara, D., Khoury, M. J., O'Brien, T. R., Manolio, T., Gwinn, M. L., Little, J., T Higgins, J. P., Bernstein, J. L., Boffetta, P., Bondy, M., Bray, M. S., Brenchley, P. E., Buffler, P. A., Casas, J. P., Chokkalingam, A. P., Danesh, J., Smith, G. D., Dolan, S., Duncan, R., Gruis, N. A., Hashibe, M., Hunter, D., Jarvelin, M., Malmer, B., Maraganore, D. M., Newton-Bishop, J. A., Riboli, E., Salanti, G., Taioli, E., Timpson, N., Uitterlinden, A. G., Vineis, P., Wareham, N., Winn, D. M., Zimmern, R., Ioannidis, J. P. 2007; 18 (1): 1-8
  • Non-replication and inconsistency in the genome-wide association setting HUMAN HEREDITY Ioannidis, J. P. 2007; 64 (4): 203-213

    Abstract

    Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.

    View details for DOI 10.1159/000103512

    View details for Web of Science ID 000247824800001

    View details for PubMedID 17551261

  • Concentration of the Most-Cited Papers in the Scientific Literature: Analysis of Journal Ecosystems PLOS ONE Ioannidis, J. P. 2006; 1 (1)

    Abstract

    A minority of scientific journals publishes the majority of scientific papers and receives the majority of citations. The extent of concentration of the most influential articles is less well known.The 100 most-cited papers in the last decade in each of 21 scientific fields were analyzed; fields were considered as ecosystems and their "species" (journal) diversity was evaluated. Only 9% of journals in Journal Citation Reports had published at least one such paper. Among this 9%, half of them had published only one such paper. The number of journals that had published a larger number of most-cited papers decreased exponentially according to a Lotka law. Except for three scientific fields, six journals accounted for 53 to 94 of the 100 most-cited papers in their field. With increasing average number of citations per paper (citation density) in a scientific field, concentration of the most-cited papers in a few journals became even more prominent (p<0.001). Concentration was unrelated to the number of papers published or number of journals available in a scientific field. Multidisciplinary journals accounted for 24% of all most-cited papers, with large variability across fields. The concentration of most-cited papers in multidisciplinary journals was most prominent in fields with high citation density (correlation coefficient 0.70, p<0.001). Multidisciplinary journals had published fewer than eight of the 100 most-cited papers in eight scientific fields (none in two fields). Journals concentrating most-cited original articles often differed from those concentrating most-cited reviews. The concentration of the most-influential papers was stronger than the already prominent concentration of papers published and citations received.Despite a plethora of available journals, the most influential papers are extremely concentrated in few journals, especially in fields with high citation density. Existing multidisciplinary journals publish selectively most-cited papers from fields with high citation density.

    View details for DOI 10.1371/journal.pone.0000005

    View details for Web of Science ID 000207443600005

    View details for PubMedID 17183679

  • Evolution and translation of research findings: From to where? PLOS CLINICAL TRIALS Ioannidis, J. P. 2006; 1 (7)

    Abstract

    The credibility and replication of research findings evolve over time, as data accumulate. However, translation of postulated research promises to real-life biomedical applications is uncommon. In some fields of research, we may observe diminishing effects for the strength of research findings and rapid alternations of exaggerated claims and extreme contradictions--the "Proteus Phenomenon." While these phenomena are probably more prominent in the basic sciences, similar manifestations have been documented even in clinical trials and they may undermine the credibility of clinical research. Significance-chasing bias may be in part responsible, but the greatest threat may come from the poor relevance and scientific rationale and thus low pre-study odds of success of research efforts. Given that we currently have too many research findings, often with low credibility, replication and rigorous evaluation become as important as or even more important than discovery. Credibility, replication, and translation are all desirable properties of research findings, but are only modestly correlated. In this essay, I discuss some of the evidence (or lack thereof) for the process of evolution and translation of research findings, with emphasis on the biomedical sciences.

    View details for DOI 10.1371/journal.pctr.0010036

    View details for Web of Science ID 000245239000003

    View details for PubMedID 17111044

  • Survival benefits with diverse chemotherapy regimens for ovarian cancer: Meta-analysis of multiple treatments JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyrgiou, M., Salanti, G., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2006; 98 (22): 1655-1663

    Abstract

    Numerous randomized trials have compared different chemotherapy regimens in women with ovarian cancer. Although ovarian cancer survival has improved in recent years, the magnitude of these incremental benefits across diverse regimens is unclear.We used multiple-treatment meta-analysis methodology to combine information from direct and indirect comparisons of all chemotherapy regimens used in randomized trials of ovarian cancer in the last 40 years. Chemotherapy was categorized by the use or not of platinum and/or taxanes, combinations of agents, and intraperitoneal administration. Monte Carlo simulations were used to determine which regimen most improved survival. Analyses of trials that examined first- and second-line treatments were also performed separately.We found 198 trials (N = 38,440 women) involving 120 different chemotherapy regimens published in 1971-2006. Eighty-two trials compared different types of chemotherapy, among which 60 had usable survival information (N = 15,609 women). Monte Carlo simulations showed a 92% probability that the regimen that best prolonged survival is a platinum and taxane combination with intraperitoneal administration; this regimen resulted in a 55% relative risk reduction (95% confidence interval [CI] = 39% to 67%) for mortality as compared with nonintraperitoneal monotherapy using neither platinum nor taxane. Against that same monotherapy comparator, platinum-based combinations with and without intraperitoneal administration achieved 40% (95% CI = 21% to 54%) and 30% (95% CI = 20% to 38%) relative risk reductions for mortality, respectively, and combinations involving platinum and taxane without intraperitoneal administration achieved a 42% (95% CI = 31% to 51%) relative risk reduction. Results were similar when analyses were limited to first-line treatment. Data on second-line treatment were consistent with the superiority of platinum and taxane combinations.Distinct incremental improvements in survival have been achieved for ovarian cancer chemotherapy over time, with the possibility to achieve a doubling or more of time to mortality with platinum and taxane combinations, especially when intraperitoneal administration is used.

    View details for DOI 10.1093/jnci/djj443

    View details for Web of Science ID 000242379700012

    View details for PubMedID 17105988

  • Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study LANCET NEUROLOGY Elbaz, A., Nelson, L. M., Payami, H., Ioannidis, J. P., Fiske, B. K., Annesi, G., Belin, A. C., Factor, S. A., Ferrarese, C., Hadjigeorgiou, G. M., Higgins, D. S., Kawakami, H., Krueger, R., Marder, K. S., Mayeux, R. P., Mellick, G. D., Nutt, J. G., Ritz, B., Samii, A., Tanner, C. M., Van Broeckhoven, C., Van Den Eeden, S. K., Wirdefeldt, K., Zabetian, C. P., Dehem, M., Montimurro, J. S., Southwick, A., Myers, R. M., Trikalinos, T. A. 2006; 5 (11): 917-923

    Abstract

    A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

    View details for DOI 10.1016/S1474-4422(06)70579-8

    View details for Web of Science ID 000241591600014

    View details for PubMedID 17052658

  • Indirect comparisons: the mesh and mess of clinical trials LANCET Ioannidis, J. P. 2006; 368 (9546): 1470-1472

    View details for Web of Science ID 000241582700005

    View details for PubMedID 17071265

  • Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P. 2006; 98 (19): 1350-1353

    View details for DOI 10.1093/jnci/djj392

    View details for Web of Science ID 000241721200003

    View details for PubMedID 17018776

  • Gene expression profiling for individualized breast cancer chemotherapy: success or not? NATURE CLINICAL PRACTICE ONCOLOGY Ioannidis, J. P. 2006; 3 (10): 538-539

    View details for DOI 10.1038/ncponc0631

    View details for Web of Science ID 000241054700006

    View details for PubMedID 17019431

  • Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A., Khoury, M. J. 2006; 164 (7): 609-614

    Abstract

    Accumulated evidence from searching for candidate gene-disease associations of complex diseases can offer some insights as the field moves toward discovery-oriented approaches with massive genome-wide testing. Meta-analyses of 50 non-human lymphocyte antigen gene-disease associations with documented overall statistical significance (752 studies) show summary odds ratios with a median of 1.43 (interquartile range, 1.28-1.65). Many different biases may operate in this field, for both single studies and meta-analyses, and these biases could invalidate some of these seemingly "validated" associations. Studies with a sample size of >500 show a median odds ratio of only 1.15. The median sample size required to detect the observed summary effects in each population addressed in the 752 studies is estimated to be 3,535 (interquartile range, 1,936-9,119 for cases and controls combined). These estimates are steeply inflated in the presence of modest bias. Population heterogeneity, as well as gene-gene and gene-environment interactions, could steeply increase these estimates and may be difficult to address even by very large biobanks and observational cohorts. The one visible solution is for a large number of teams to join forces on the same research platforms. These collaborative studies ideally should be designed up front to also assess more complex gene-gene and gene-environment interactions.

    View details for DOI 10.1093/aje/kwj259

    View details for Web of Science ID 000240698000001

    View details for PubMedID 16893921

  • Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: A meta-analysis BONE Fang, Y., Rivadeneira, F., van Meurs, J. B., Pols, H. A., Ioannidis, J. P., Uitterlinden, A. G. 2006; 39 (4): 938-945

    Abstract

    Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and osteoporosis, but evidence remains conflicting.We searched published studies from 1996 to September 2005 through PubMed and evaluated the genetic effect of the BsmI and TaqI polymorphism of VDR on fracture risk in a meta-analysis. Thirteen studies with a total of 20 eligible comparisons (1632 fracture cases and 5203 controls) were analyzed with fixed and random effects models.No evidence of relationship between the VDR BsmI or TaqI polymorphism and fracture risk was observed with any genetic model. The odds ratio (95% confidence interval) of b-allele versus B-allele was 0.98 (0.86-1.12) with random effects calculations. There was significant between-study heterogeneity. Small studies did not differ significantly from larger ones.No relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.

    View details for DOI 10.1016/j.bone.2006.04.016

    View details for Web of Science ID 000240792700030

    View details for PubMedID 16769262

  • An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthma treatment PHARMACOGENETICS AND GENOMICS Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2006; 16 (10): 705-711

    Abstract

    Pharmacogenetics promises to individualize therapeutics. Concerns, however, exist about the lack of replication of discoveries. Selective use of different endpoints, times of assessment, types of interventions and genetic groups across studies may lead to spurious results. Here, we examined the variability of definitions of endpoints and analyses reported across studies addressing the association of the Arg16Gly and/or Gln27Glu polymorphisms of the beta2-adrenergic receptor gene with clinical response to beta2-agonist therapy in asthma.We systematically calculated the number and type of endpoints and analyses reported across studies and recorded the appraisal of their statistical significance.Across 21 studies, the total number of probed and reported associations was 487 when the multiple endpoints and types of comparisons presented by multiple comparisons were considered (337 for Arg16Gly, 98 for Gln27Glu and 52 for their haplotypes): 465 (95%) were probed only once; only six associations were probed twice and two associations were probed five times, for the same endpoint, time of assessment, type of interventions and genetic group. Most studies (17/21) claimed at least one significant association. Overall, however, 243/487 (49.9%) probed and reported associations were not statistically significant, 120 (24.6%) were of unspecified statistical significance, 86 (17.7%) were statistically significant only for specific selected genetic contrasts and only 38 (7.8%) were genuinely statistically significant for the comparison between all available genetic groups.The multifarious outcomes in this literature are inconsistent across studies and susceptible to selective reporting. The lack of standardization hinders the evaluation of replication validity for reported discoveries.

    View details for Web of Science ID 000203009100002

    View details for PubMedID 17001289

  • Heterogeneity-based genome search meta-analysis for preeclampsia HUMAN GENETICS Zintzaras, E., Kitsios, G., Harrison, G. A., Laivuori, H., Kivinen, K., Kere, J., Messinis, I., Stefanidis, I., Ioannidis, J. P. 2006; 120 (3): 360-370

    Abstract

    Preeclampsia is a pregnancy-related disorder that causes maternal and fetal morbidity and mortality. Its exact inheritance pattern is still unknown, and genome searches for identifying susceptibility loci for preeclampsia have thus far produced inconclusive or inconsistent results. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) that synthesized the available genome scan data on preeclampsia. HEGESMA identifies genetic regions (bins) that rank highly on average in terms of linkage statistics across genome scans (searches). The significance of each bin's average rank and heterogeneity across scans was calculated using Monte Carlo tests. The meta-analysis involved four genome-scans on general preeclampsia and five scans on severe preeclampsia. In general preeclampsia, 13 bins had significantly high average rank (Prank< 0.05) by either unweighted or weighted analyses, while four of them (2p11.2-2q21.1, 9q21.32-9q31.2, 2p15-2p11.2, 2q32.1-2q35) were formally significant by both analyses. Heterogeneity of bin 2.8 (2q32.1-2q35) was significantly low in both unweighted and weighted analysis (PQ< 0.01). In severe preeclampsia, 10 bins had significantly high average rank by either unweighted or weighted analyses and five of them (3q11.1-3q21.2, 2q37.1-2q37.3, 18p11.32-18p11.22, 2p15-2p11.2, 7q34-7q36.3) were significant by both analyses. Bin 2q37.1-2q37.3 showed marginal low heterogeneity in unweighted and weighted analysis (PQ= 0.06). Results should be interpreted with caution as the p values were modest. Further investigation of these regions by genotyping with additional markers and families may help to direct the identification of candidate genes for preeclampsia.

    View details for DOI 10.1007/s00439-006-0214-1

    View details for Web of Science ID 000240613900004

    View details for PubMedID 16868762

  • Extreme between-study homogeneity in meta-analyses could offer useful insights JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A., Zintzaras, E. 2006; 59 (10): 1023-1032

    Abstract

    Meta-analyses are routinely evaluated for the presence of large between-study heterogeneity. We examined whether it is also important to probe whether there is extreme between-study homogeneity.We used heterogeneity tests with left-sided statistical significance for inference and developed a Monte Carlo simulation test for testing extreme homogeneity in risk ratios across studies, using the empiric distribution of the summary risk ratio and heterogeneity statistic. A left-sided P=0.01 threshold was set for claiming extreme homogeneity to minimize type I error.Among 11,803 meta-analyses with binary contrasts from the Cochrane Library, 143 (1.21%) had left-sided P-value <0.01 for the asymptotic Q statistic and 1,004 (8.50%) had left-sided P-value <0.10. The frequency of extreme between-study homogeneity did not depend on the number of studies in the meta-analyses. We identified examples where extreme between-study homogeneity (left-sided P-value <0.01) could result from various possibilities beyond chance. These included inappropriate statistical inference (asymptotic vs. Monte Carlo), use of a specific effect metric, correlated data or stratification using strong predictors of outcome, and biases and potential fraud.Extreme between-study homogeneity may provide useful insights about a meta-analysis and its constituent studies.

    View details for DOI 10.1016/j.jclinepi.2006.02.013

    View details for Web of Science ID 000241064500003

    View details for PubMedID 16980141

  • Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Pavlidis, N., Polyzos, N. P., Ioannidis, J. P. 2006; 98 (18): 1285-1291

    Abstract

    Aromatase inhibitors and inactivators have been extensively tested in patients with advanced breast cancer, but it is unclear whether they offer any survival benefits compared with standard hormonal treatment with tamoxifen or progestagens. We performed a meta-analysis of randomized controlled trials that compared several generations of aromatase inhibitors and inactivators with standard hormonal treatment in patients with advanced breast cancer.The endpoint that we assessed was survival. Trials were located through searches of PubMed and Cochrane Library (last update March 2006). Relative hazards (RHs) were summarized across trials through fixed- and random-effects analyses, and heterogeneity was assessed with the Q and I2 statistics. All statistical tests were two-sided.Twenty-five different comparisons, with a total of 8504 patients, were included in the meta-analysis. We found statistically significant survival benefits with third-generation aromatase inhibitors and inactivators (vorozole, letrozole, examestane, and anastrazole) (RH = 0.87, 95% confidence interval [CI] = 0.82 to 0.93; P<.001) but not with first-generation (aminoglutethimide) or second-generation (formestane and fadrozole) agents. The difference in the summary effects between these two groups of trials was statistically significant (P = .04). The survival benefit with third-generation agents in first-line trials, in which these agents were compared with tamoxifen (11% RH reduction, 95% CI = 1% to 19%; P = .03), was identical to their benefit in second- and subsequent-line trials in which these agents were compared with other treatments (14% RH reduction, 95% CI = 6% to 21%; P<.001).Inhibition of the aromatase system, in particular with third-generation aromatase inhibitors and inactivators, appears to be associated with statistically significant improved survival of patients with advanced breast cancer compared with standard hormonal treatments.

    View details for DOI 10.1093/jnci/djj357

    View details for Web of Science ID 000241721100008

    View details for PubMedID 16985247

  • The case of the misleading funnel plot. BMJ (Clinical research ed.) Lau, J., Ioannidis, J. P., Terrin, N., Schmid, C. H., Olkin, I. 2006; 333 (7568): 597-600

    View details for PubMedID 16974018

  • Concordance of functional in vitro data and epidemiological associations in complex disease genetics GENETICS IN MEDICINE Ioannidis, J. P., Kavvoura, F. K. 2006; 8 (9): 583-593

    Abstract

    We aimed to assess whether epidemiological evidence on genetic associations for complex diseases concord with in vitro functional data.We examined 36 studies on bi-allelic markers and 23 studies on haplotypes where investigators had addressed both epidemiological associations and the functional effect of the same gene variants in luciferase reporter systems in vitro.There was no correlation between epidemiological odds ratios and luciferase activity ratios (-0.09, P = 0.60). Luciferase activity ratios could not tell whether a probed epidemiologic association would be significant or not (area under receiver operating characteristics curve, 0.52). Luciferase results usually were qualitatively similar across cell lines and experimental conditions, with some exceptions. A luciferase activity ratio of 1.44 adequately separated statistically significant from non-significant functional differences (area under receiver operating characteristics curve, 0.95). Binary and continuous disease outcomes usually gave concordant results; other in vitro methods, in particular EMSA, agreed with luciferase results. Selective reporting and use of different variants and contrasts between functional and epidemiological analyses were common in these studies.In vitro biological data and epidemiology provide independent lines of evidence on complex diseases. We provide suggestions for improving the design and reporting of studies addressing both in vitro and epidemiological effects.

    View details for DOI 10.1097/01.gim.0000237775.93658.0c

    View details for Web of Science ID 000240917600007

    View details for PubMedID 16980815

  • The importance of independent risk-factors for long-term mortality prediction after cardiac surgery EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Toumpoulis, I. K., Anagnostopoulos, C. E., Ioannidis, J. P., Toumpoulis, S. K., Chamogeorgakis, T., Swistel, D. G., DeRose, J. J. 2006; 36 (9): 599-607

    Abstract

    The purpose of the present study was to determine independent predictors for long-term mortality after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to score in-hospital mortality and recent studies have shown its ability to predict long-term mortality as well. We compared forecasts based on EuroSCORE with other models based on independent predictors. Medical records of patients with cardiac surgery who were discharged alive (n = 4852) were retrospectively reviewed. Their operative surgical risks were calculated according to EuroSCORE. Patients were randomly divided into two groups: training dataset (n = 3233) and validation dataset (n = 1619). Long-term survival data (mean follow-up 5.1 years) were obtained from the National Death Index. We compared four models: standard EuroSCORE (M1); logistic EuroSCORE (M2); M2 and other preoperative, intra-operative and post-operative selected variables (M3); and selected variables only (M4). M3 and M4 were determined with multivariable Cox regression analysis using the training dataset. The estimated five-year survival rates of the quartiles in compared models in the validation dataset were: 94.5%, 87.8%, 77.1%, 64.9% for M1; 95.1%, 88.0%, 80.5%, 64.4% for M2; 93.4%, 89.4%, 80.8%, 64.1% for M3; and 95.8%, 90.9%, 81.0%, 59.9% for M4. In the four models, the odds of death in the highest-risk quartile was 8.4-, 8.5-, 9.4- and 15.6-fold higher, respectively, than the odds of death in the lowest-risk quartile (P < 0.0001 for all). EuroSCORE is a good predictor of long-term mortality after cardiac surgery. We developed and validated a model using selected preoperative, intra-operative and post-operative variables that has better discriminatory ability.

    View details for Web of Science ID 000239636000001

    View details for PubMedID 16919041

  • Patient outcomes with teaching versus nonteaching healthcare: A systematic review PLOS MEDICINE Papanikolaou, P. N., Christidi, G. D., Ioannidis, J. P. 2006; 3 (9): 1603-1615

    Abstract

    Extensive debate exists in the healthcare community over whether outcomes of medical care at teaching hospitals and other healthcare units are better or worse than those at the respective nonteaching ones. Thus, our goal was to systematically evaluate the evidence pertaining to this question.We reviewed all studies that compared teaching versus nonteaching healthcare structures for mortality or any other patient outcome, regardless of health condition. Studies were retrieved from PubMed, contact with experts, and literature cross-referencing. Data were extracted on setting, patients, data sources, author affiliations, definition of compared groups, types of diagnoses considered, adjusting covariates, and estimates of effect for mortality and for each other outcome. Overall, 132 eligible studies were identified, including 93 on mortality and 61 on other eligible outcomes (22 addressed both). Synthesis of the available adjusted estimates on mortality yielded a summary relative risk of 0.96 (95% confidence interval [CI], 0.93-1.00) for teaching versus nonteaching healthcare structures and 1.04 (95% CI, 0.99-1.10) for minor teaching versus nonteaching ones. There was considerable heterogeneity between studies (I(2) = 72% for the main analysis). Results were similar in studies using clinical and those using administrative databases. No differences were seen in the 14 studies fully adjusting for volume/experience, severity, and comorbidity (relative risk 1.01). Smaller studies did not differ in their results from larger studies. Differences were seen for some diagnoses (e.g., significantly better survival for breast cancer and cerebrovascular accidents in teaching hospitals and significantly better survival from cholecystectomy in nonteaching hospitals), but these were small in magnitude. Other outcomes were diverse, but typically teaching healthcare structures did not do better than nonteaching ones.The available data are limited by their nonrandomized design, but overall they do not suggest that a healthcare facility's teaching status on its own markedly improves or worsens patient outcomes. Differences for specific diseases cannot be excluded, but are likely to be small.

    View details for DOI 10.1371/journal.pmed.0030341

    View details for Web of Science ID 000241923800028

    View details for PubMedID 16968119

  • The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis ANNALS OF INTERNAL MEDICINE Uitterlinden, A. G., Ralston, S. H., Brandi, M. L., Carey, A. H., Grinberg, D., Langdahl, B. L., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Reeve, J., Reid, D. M., Amidei, A., Bassiti, A., Bustamante, M., Husted, U. B., Diez-Perez, A., Dobnig, H., Dunning, A. M., Enjuanes, A., Fahrleitner-Pammer, A., Fang, Y., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., Mavilia, C., van Meurs, J. B., Mangion, J., McGuigan, F. E., Pols, H. A., Renner, W., Rivadeneira, F., van Schoor, N. M., Scollen, S., Sherlock, R. E., Ioannidis, J. P. 2006; 145 (4): 255-264

    Abstract

    Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.To evaluate the relation between VDR polymorphisms, BMD, and fractures.Prospective multicenter large-scale association study.The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.26,242 participants (18,405 women).Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

    View details for Web of Science ID 000239858800003

    View details for PubMedID 16908916

  • Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Maraganore, D. M., de Andrade, M., Elbaz, A., Farrer, M. J., Ioannidis, J. P., Krueger, R., Rocca, W. A., Schneider, N. K., Lesnick, T. G., Lincoln, S. J., Hulihan, M. M., Aasly, J. O., Ashizawa, T., Chartier-Harlin, M., Checkoway, H., Ferrarese, C., Hadjigeorgiou, G., Hattori, N., Kawakami, H., Lambert, J., Lynch, T., Mellick, G. D., Papapetropoulos, S., Parsian, A., Quattrone, A., Riess, O., Tan, E., Van Broeckhoven, C. 2006; 296 (6): 661-670

    Abstract

    Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking.To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset.We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally.Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset.Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55).This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

    View details for Web of Science ID 000239603800028

    View details for PubMedID 16896109

  • Family-based versus unrelated case-control designs for genetic associations PLOS GENETICS Evangelou, E., Trikalinos, T. A., Salanti, G., Ioannidis, J. P. 2006; 2 (8): 1147-1155

    Abstract

    The most simple and commonly used approach for genetic associations is the case-control study design of unrelated people. This design is susceptible to population stratification. This problem is obviated in family-based studies, but it is usually difficult to accumulate large enough samples of well-characterized families. We addressed empirically whether the two designs give similar estimates of association in 93 investigations where both unrelated case-control and family-based designs had been employed. Estimated odds ratios differed beyond chance between the two designs in only four instances (4%). The summary relative odds ratio (ROR) (the ratio of odds ratios obtained from unrelated case-control and family-based studies) was close to unity (0.96 [95% confidence interval, 0.91-1.01]). There was no heterogeneity in the ROR across studies (amount of heterogeneity beyond chance I(2) = 0%). Differences on whether results were nominally statistically significant (p < 0.05) or not with the two designs were common (opposite classification rates 14% and 17%); this reflected largely differences in power. Conclusions were largely similar in diverse subgroup analyses. Unrelated case-control and family-based designs give overall similar estimates of association. We cannot rule out rare large biases or common small biases.

    View details for DOI 10.1371/journal.pgen.0020123

    View details for Web of Science ID 000240006900004

    View details for PubMedID 16895437

  • Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study BRITISH MEDICAL JOURNAL Tiihonen, J., Wahlbeck, K., Lonnqvist, J., Klaukka, T., Ioannidis, J. P., Volavka, J., Haukka, J. 2006; 333 (7561): 224-227

    Abstract

    To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community.Prospective cohort study using national central registers.Community care in Finland.Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001.Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness.Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276).The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.

    View details for DOI 10.1136/bmj.38881.382755.2F

    View details for Web of Science ID 000239496900018

    View details for PubMedID 16825203

  • Not-so-surprising findings - Response CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P., Papanikolaou, P. 2006; 175 (2): 172-172
  • Commentary: Grading the credibility of molecular evidence for complex diseases INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2006; 35 (3): 572-577

    View details for DOI 10.1093/ije/dyl003

    View details for Web of Science ID 000238763100019

    View details for PubMedID 16540537

  • Origin and funding of the most frequently cited papers in medicine: database analysis BRITISH MEDICAL JOURNAL Patsopoulos, N. A., Analatos, A. A., Ioannidis, J. P. 2006; 332 (7549): 1061-1063

    Abstract

    To evaluate changes in the role of academics and the sources of funding for the medical research cited most frequently over the past decade.Database analysis.Web of Knowledge database.For each year from 1994 to 2003, articles in the domain of clinical medicine that had been cited most often by the end of 2004 were identified. Changes in authors' affiliations and funding sources were evaluated.Of the 289 frequently cited articles, most had at least one author with a university (76%) or hospital (57%) affiliation, and the proportion of articles with each type of affiliation was constant over time. Government or public funding was most common (60% of articles), followed by industry (36%). The proportion of most frequently cited articles funded by industry increased over time (odds ratio 1.17 per year, P = 0.001) and was equal to the proportion funded by government or public sources by 2001. 65 of the 77 most cited randomised controlled trials received funding from industry, and the proportion increased significantly over time (odds ratio 1.59 per year, P = 0.003). 18 of the 32 most cited trials published after 1999 were funded by industry alone.Academic affiliations remain prominent among the authors of the most frequently cited medical research. Such research is increasingly funded by industry, often exclusively so. Academics may be losing control of the clinical research agenda.

    View details for DOI 10.1136/bmj.38768.420139.80

    View details for Web of Science ID 000237518400015

    View details for PubMedID 16547014

  • Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS study PLOS MEDICINE Ralston, S. H., Uitterlinden, A. G., Brandi, M. L., Balcells, S., Langdahl, B. L., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Scollen, S., Bustamante, M., Husted, L. B., Carey, A. H., Diez-Perez, A., Dunning, A. M., Falchetti, A., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., van Meurs, J. B., Mangion, J., McGuigan, F. E., Mellibovsky, L., del Monte, F., Pols, H. A., Reeve, J., Reid, D. M., Renner, W., Rivadeneira, F., van Schoor, N. M., Sherlock, R. E., Ioannidis, J. P. 2006; 3 (4): 515-523

    Abstract

    Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

    View details for DOI 10.1371/journal.pmed.0030090

    View details for Web of Science ID 000237548200020

    View details for PubMedID 16475872

  • Self-reported health in high and very high incomes QUALITY OF LIFE RESEARCH Mantzavinis, G. D., Trikalinos, T. A., Dimoliatis, I. D., Ioannidis, J. P. 2006; 15 (3): 547-558

    Abstract

    The objective of the present study was to investigate whether self-reported health (SRH), an overall health indicator, continues to improve as individual income increases to very high levels or whether there is a threshold above which this relationship changes direction. We used data from the 2003 US Current Population Survey, focusing on the upper income decile. We modelled the relationship between income and SRH before and after adjustment for other socio-demographic parameters that are known to influence SRH. In the unadjusted model, SRH increased with increasing income up to the threshold of $326,000, above which SRH declined. After adjustment for all major socio-demographic parameters (age, gender, race, education, and marital status), the adjusted curve showed monotonically increasing SRH with increasing income. Adjustment for each of these parameters separately revealed that the threshold effect was lost only after adjusting for education. There were more people with low levels of educational attainment among those receiving more than $500,000 per year, compared to other people in the upper income decile. Increasing income does not always improve SRH. People in the very high income bracket tend to report slightly worse health, which may be explained by their lower education.

    View details for DOI 10.1007/s11136-005-1770-x

    View details for Web of Science ID 000236100300024

    View details for PubMedID 16547793

  • Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies CANADIAN MEDICAL ASSOCIATION JOURNAL Papanikolaou, P. N., Christidi, G. D., Ioannidis, J. P. 2006; 174 (5): 635-641

    Abstract

    Information on major harms of medical interventions comes primarily from epidemiologic studies performed after licensing and marketing. Comparison with data from large-scale randomized trials is occasionally feasible. We compared evidence from randomized trials with that from epidemiologic studies to determine whether they give different estimates of risk for important harms of medical interventions.We targeted well-defined, specific harms of various medical interventions for which data were already available from large-scale randomized trials (> 4000 subjects). Nonrandomized studies involving at least 4000 subjects addressing these same harms were retrieved through a search of MEDLINE. We compared the relative risks and absolute risk differences for specific harms in the randomized and nonrandomized studies.Eligible nonrandomized studies were found for 15 harms for which data were available from randomized trials addressing the same harms. Comparisons of relative risks between the study types were feasible for 13 of the 15 topics, and of absolute risk differences for 8 topics. The estimated increase in relative risk differed more than 2-fold between the randomized and nonrandomized studies for 7 (54%) of the 13 topics; the estimated increase in absolute risk differed more than 2-fold for 5 (62%) of the 8 topics. There was no clear predilection for randomized or nonrandomized studies to estimate greater relative risks, but usually (75% [6/8]) the randomized trials estimated larger absolute excess risks of harm than the nonrandomized studies did.Nonrandomized studies are often conservative in estimating absolute risks of harms. It would be useful to compare and scrutinize the evidence on harms obtained from both randomized and nonrandomized studies.

    View details for Web of Science ID 000235402600020

    View details for PubMedID 16505459

  • Adverse events: The more you search, the more you find ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Mulrow, C. D., Goodman, S. N. 2006; 144 (4): 298-300

    View details for Web of Science ID 000235543100010

    View details for PubMedID 16490917

  • Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations AMERICAN JOURNAL OF EPIDEMIOLOGY Trikalinos, T. A., Salanti, G., Khoury, M. J., Ioannidis, J. P. 2006; 163 (4): 300-309

    Abstract

    The authors evaluated whether statistically significant violations of Hardy-Weinberg equilibrium (HWE) or the magnitude of deviations from HWE may contribute to the problem of replicating postulated gene-disease associations across different studies. Forty-two gene-disease associations assessed in meta-analyses of 591 studies were examined. Studies with disease-free controls in which HWE was violated gave significantly different results from HWE-conforming studies in five instances. Exclusion of the former studies resulted in loss of statistical significance of the overall meta-analysis in three instances and more than a 10% change in the summary odds ratio in six. Exclusion of HWE-violating studies changed the formal significance of the estimated between-study heterogeneity in three instances. After adjustment for the magnitude of the deviation from HWE for the controls, formal significance was lost in another three instances. Studies adjusted for the magnitude of deviation from HWE tended to become more heterogeneous among themselves, and, for seven gene-disease associations, between-study heterogeneity became significant, while it was not so in the unadjusted analyses. Gene-disease association studies and meta-analyses thereof should routinely scrutinize the potential impact of HWE violations as well as nonsignificant deviations from the exact frequencies expected under HWE. Postulated genetic associations with modest-sized odds ratios and borderline statistical significance may not be robust in such sensitivity analyses.

    View details for DOI 10.1093/aje/kwj046

    View details for Web of Science ID 000235276600001

    View details for PubMedID 16410351

  • Randomized evidence on chemotherapy and hormonal therapy regimens for advanced endometrial cancer: An overview of survival data EUROPEAN JOURNAL OF CANCER Polyzos, N. P., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2006; 42 (3): 319-326

    Abstract

    Several chemotherapy and hormonal therapy regimens have been used in advanced endometrial cancer. In this review we have systematically evaluated the available data from randomized trials on survival. We searched MEDLINE, EMBASE and the Cochrane Library (last search April 2005) for randomized controlled trials evaluating various chemotherapy or hormonal therapy regimens in locally advanced or metastatic endometrial cancer. We focused on survival outcomes and examined trial characteristics pertaining to quality and potential biases. Across 17 eligible trials (2964 patients randomized), only 4 regimens were involved in more than one trial, and only two trials had used the same comparison of regimens. A statistically significant effect in survival was seen only in one recent trial, but it was borderline (P = 0.032) and amounted to only 3 months difference in median survival. Three more trials reported some survival benefits, but these were seen only after specific adjustments, and the difference was against the experimental arm in one of these three trials. Only four trials (24%) apparently analyzed all randomized patients and none of the trials were blinded. Median survival was seemingly longer in more recent compared with older trials, but this effect was driven by the inclusion of significantly fewer patients with poor performance status in more recent trials (P < 0.001). Overall, randomized evidence on systemic treatment in advanced endometrial cancer is fragmented and survival benefits for specific regimens are questionable.

    View details for DOI 10.1016/j.ejca.2005.09.026

    View details for Web of Science ID 000235508100015

    View details for PubMedID 16376072

  • A heterogeneity-based genome search meta-analysis for autism-spectrum disorders MOLECULAR PSYCHIATRY Trikalinos, T. A., Karvouni, A., Zintzaras, E., Ylisaukko-oja, T., Peltonen, L., Jarvela, I., Ioannidis, J. P. 2006; 11 (1): 29-36

    Abstract

    Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.

    View details for DOI 10.1038/sj.mp.4001750

    View details for Web of Science ID 000233971300007

    View details for PubMedID 16189507

  • Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus - An international meta-analysis ARTHRITIS AND RHEUMATISM Karassa, F. B., Afeltra, A., Ambrozic, A., Chang, D. M., De Keyser, F., DORIA, A., Galeazzi, M., Hirohata, S., Hoffman, I. E., Inanc, M., Massardo, L., Mathieu, A., Mok, C. C., Morozzi, G., Sanna, G., Spindler, A. J., Tzioufas, A. G., Yoshio, T., Ioannidis, J. P. 2006; 54 (1): 312-324

    Abstract

    To quantitatively evaluate the diagnostic accuracy of antibodies to ribosomal P proteins (anti-P) for neuropsychiatric systemic lupus erythematosus (NPSLE) in general, for psychosis, mood disorder, or both, and for other diffuse manifestations.This international meta-analysis combined standardized data from 1,537 lupus patients contributed by 14 research teams. Weighted estimation of sensitivity and specificity with fixed-effects and random-effects models, as well as summary receiver operating characteristic (SROC) curve analysis, was used to summarize test performance. The robustness of the overall estimates was examined in sensitivity analyses that included additional studies published up to November 1, 2004 in the Medline, EMBase, and Cochrane databases.Combining the data from the 14 teams, the weighted sensitivity and specificity estimates for the diagnosis of NPSLE were 26% (95% confidence interval [95% CI] 15-42%) and 80% (95% CI 74-85%), respectively. For psychosis, mood disorder, or both, the sensitivity and specificity were 27% (95% CI 14-47%) and 80% (95% CI 74-85%), respectively. For other diffuse manifestations, the sensitivity was 24% (95% CI 12-42%), and the specificity was 80% (95% CI 73-85%). The proportion of patients with anti-P antibodies did not vary markedly across different presentations of NPSLE. Between-study heterogeneity was substantial, but the SROC curves were consistent with the weighted estimates. In further analyses that included another 24 published studies, only the sensitivity for psychosis and/or mood disorder was slightly improved, but it was still suboptimal (42% [95% CI 30-53%]); the specificity remained essentially the same (81% [95% CI 76-85%]).Anti-P antibody testing has limited diagnostic value for NPSLE, and it is not helpful in differentiating among various disease phenotypes.

    View details for DOI 10.1002/art.21539

    View details for Web of Science ID 000234605200038

    View details for PubMedID 16385548

  • Susceptibility to HIV infection - Disentangling host genetics and host behavior JOURNAL OF INFECTIOUS DISEASES Telenti, A., Ioannidis, J. P. 2006; 193 (1): 4-6

    View details for Web of Science ID 000234182800002

    View details for PubMedID 16323124

  • Journals should publish all "null" results and should sparingly publish "positive" results CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ioannidis, J. P. 2006; 15 (1): 186-186

    View details for Web of Science ID 000234866200038

    View details for PubMedID 16434613

  • A road map for efficient and reliable human genome epidemiology NATURE GENETICS Ioannidis, J. P., Gwinn, M., Little, J., Higgins, J. P., Bernstein, J. L., Boffetta, P., Bondy, M., Bray, M. S., Brenchley, P. E., Buffler, P. A., Casas, J. P., Chokkalingam, A., Danesh, J., Smith, G. D., Dolan, S., DUNCAN, R., Gruis, N. A., Hartge, P., Hashibe, M., Hunter, D. J., Jarvelin, M. R., Malmer, B., Maraganore, D. M., Newton-Bishop, J. A., O'Brien, T. R., Petersen, G., Riboli, E., Salanti, G., Seminara, D., Smeeth, L., Taioli, E., Timpson, N., Uitterlinden, A. G., Vineis, P., Wareham, N., Winn, D. M., Zimmern, R., Khoury, M. J. 2006; 38 (1): 3-5

    Abstract

    Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.

    View details for DOI 10.1038/ng0106-3

    View details for Web of Science ID 000234227200002

    View details for PubMedID 16468121

  • beta(2)-adrenergic receptor polymorphism in asthma: Prospective versus retrospective perspective - Reply JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2006; 117 (1): 222-223
  • Local literature bias in genetic epidemiology: An empirical evaluation of the Chinese literature PLOS MEDICINE Pan, Z. L., Trikalinos, T. A., Kavvoura, F. K., Lau, J., Ioannidis, J. P. 2005; 2 (12): 1309-1317

    Abstract

    Postulated epidemiological associations are subject to several biases. We evaluated whether the Chinese literature on human genome epidemiology may offer insights on the operation of selective reporting and language biases.We targeted 13 gene-disease associations, each already assessed by meta-analyses, including at least 15 non-Chinese studies. We searched the Chinese Journal Full-Text Database for additional Chinese studies on the same topics. We identified 161 Chinese studies on 12 of these gene-disease associations; only 20 were PubMed-indexed (seven English full-text). Many studies (14-35 per topic) were available for six topics, covering diseases common in China. With one exception, the first Chinese study appeared with a time lag (2-21 y) after the first non-Chinese study on the topic. Chinese studies showed significantly more prominent genetic effects than non-Chinese studies, and 48% were statistically significant per se, despite their smaller sample size (median sample size 146 versus 268, p < 0.001). The largest genetic effects were often seen in PubMed-indexed Chinese studies (65% statistically significant per se). Non-Chinese studies of Asian-descent populations (27% significant per se) also tended to show somewhat more prominent genetic effects than studies of non-Asian descent (17% significant per se).Our data provide evidence for the interplay of selective reporting and language biases in human genome epidemiology. These biases may not be limited to the Chinese literature and point to the need for a global, transparent, comprehensive outlook in molecular population genetics and epidemiologic studies in general.

    View details for DOI 10.1371/journal.pmed.0020334

    View details for Web of Science ID 000234714700019

    View details for PubMedID 16285839

  • Unavailability of online supplementary scientific information from articles published in major journals FASEB JOURNAL Evangelou, E., Trikalinos, T. A., Ioannidis, J. P. 2005; 19 (14): 1943-1944

    Abstract

    Printed articles increasingly rely on online supplements to store critical scientific information, but such data may eventually become unavailable. We checked the current availability of online supplementary scientific information published in six top-cited scientific journals (Science, Nature, Cell, New England Journal of Medicine, Lancet, Proceedings of the National Academy of Sciences USA). Here we show that in 4.7% and 9.6% of articles with online supplementary material, some of the supplements became unavailable within 2 and 5 years of their publication, respectively.

    View details for DOI 10.1096/fj.05-4784lsf

    View details for Web of Science ID 000234405500004

    View details for PubMedID 16319137

  • HEGESMA: genome search meta-analysis and heterogeneity testing BIOINFORMATICS Zintzaras, E., Ioannidis, J. P. 2005; 21 (18): 3672-3673

    Abstract

    Heterogeneity and genome search meta-analysis (HEGESMA) is a comprehensive software for performing genome scan meta-analysis, a quantitative method to identify genetic regions (bins) with consistently increased linkage score across multiple genome scans, and for testing the heterogeneity of the results of each bin across scans. The program provides as an output the average of ranks and three heterogeneity statistics, as well as corresponding significance levels. Statistical inferences are based on Monte Carlo permutation tests. The program allows both unweighted and weighted analysis, with the weights for each study as specified by the user. Furthermore, the program performs heterogeneity analyses restricted to the bins with similar average ranks.http://biomath.med.uth.gr.

    View details for DOI 10.1093/bioinformatics/bti536

    View details for Web of Science ID 000231694600015

    View details for PubMedID 15955784

  • Molecular bias EUROPEAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2005; 20 (9): 739-745

    Abstract

    Bias is ubiquitous in research. The advent of the molecular era provides a unique opportunity to study the consequences of bias with large-scale empirical evidence accumulated in the massive data produced by the current discovery-oriented scientific effort, rather than just with theoretical speculations and constructs. Here I discuss some empirical evidence about manifestations of bias in molecular epidemiology. Bias may manifest as either heterogeneity or as deviation from the true estimates. The failure to translate molecular knowledge and the failure to replicate information are some typical hallmarks of bias at action. The acquired knowledge about the behaviour and manifestations of bias in molecular fields can be transferred back also to more traditional fields of epidemiology and medical research. Getting rid of false claims of the past is at least as important as producing new scientific discoveries. In many fields, the observed effects sizes that circulate as established knowledge are practically estimating only the net bias that has operated in the field all along. Issues of plausibility (in particular biological plausibility), replication, and credibility that form the theoretical basis of epidemiology and etiological inference can now be approached with large-scale empirical data.

    View details for DOI 10.1007/s10654-005-2028-1

    View details for Web of Science ID 000231974100001

    View details for PubMedID 16170656

  • A network of investigator networks in human genome epidemiology AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Bernstein, J., Boffetta, P., Danesh, J., Dolan, S., Hartge, P., Hunter, D., Inskip, P., Jarvelin, M. R., Little, J., Maraganore, D. M., Bishop, J. A., O'Brien, T. R., Petersen, G., Riboli, E., Seminara, D., Taioli, E., Uitterlinden, A. G., Vineis, P., Winn, D. M., Salanti, G., Higgins, J. P., Khoury, M. J. 2005; 162 (4): 302-304

    Abstract

    The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort.

    View details for DOI 10.1093/aje/kwi201

    View details for Web of Science ID 000231150600002

    View details for PubMedID 16014777

  • Reply to Badri et al. on 'Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analvsis' AIDS Trikalinos, T. A., Panidou, E. T., Ioannidis, J. P. 2005; 19 (12): 1336-1337

    View details for Web of Science ID 000231316800019

    View details for PubMedID 16052096

  • Why most published research findings are false PLOS MEDICINE Ioannidis, J. P. 2005; 2 (8): 696-701

    Abstract

    There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

    View details for DOI 10.1371/journal.pmed.0020124

    View details for Web of Science ID 000231676900008

    View details for PubMedID 16060722

  • Selective reporting biases in cancer prognostic factor studies JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Loizou, K. T., Ioannidis, J. P. 2005; 97 (14): 1043-1055

    Abstract

    Nonreported and selectively reported information and the use of different definitions may introduce biases in the literature of prognostic factors. We probed these biases in a meta-analysis of a prognostic factor for head and neck squamous cell cancer (HNSCC) mortality that has drawn wide attention--the status of the tumor suppressor protein TP53.We compared results of meta-analyses that included published data plus unpublished data retrieved from investigators; published data; and only published data indexed with "survival" or "mortality" in MEDLINE/EMBASE, with or without standardized definitions. We also evaluated whether previously published meta-analyses on mortality predictors for various malignancies addressed issues of retrieval and standardized information. All statistical tests were two-sided.For the 18 studies with 1364 patients that included published and indexed data, we obtained a highly statistically significant association between TP53 status and mortality. When we used the definitions preferred by each publication, the association was stronger (risk ratio [RR] = 1.38, 95% confidence interval [CI] = 1.13 to 1.67; P = .001) than when we standardized definitions (RR = 1.27, 95% CI = 1.06 to 1.53; P = .011). The addition of 13 studies with 1028 subjects that included published but not indexed data reduced the observed association (RR = 1.23, 95% CI = 1.03 to 1.47; P = .02). Finally, when we obtained data from investigators (11 studies with 996 patients) and analyzed it with all other data, statistical significance was lost (RR = 1.16, 95% CI = 0.99 to 1.35; P = .06). Among 18 published meta-analyses of 37 cancer prognostic factors, 13 (72%) did not use standardized definitions and 16 (89%) did not retrieve additional information.Selective reporting may spuriously inflate the importance of postulated prognostic factors for various malignancies. We recommend that meta-analyses thereof should maximize retrieval of information and standardize definitions.

    View details for DOI 10.1093/jnci/dji184

    View details for Web of Science ID 000230523400009

    View details for PubMedID 16030302

  • Contradicted and initially stronger effects in highly cited clinical research JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2005; 294 (2): 218-228

    Abstract

    Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted. Controversies are most prominent when high-impact research is involved.To understand how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether specific characteristics are associated with such refutation over time.All original clinical research studies published in 3 major general clinical journals or high-impact-factor specialty journals in 1990-2003 and cited more than 1000 times in the literature were examined.The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better controlled designs. The same analysis was also performed comparatively for matched studies that were not so highly cited.Of 49 highly cited original clinical research studies, 45 claimed that the intervention was effective. Of these, 7 (16%) were contradicted by subsequent studies, 7 others (16%) had found effects that were stronger than those of subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely unchallenged. Five of 6 highly-cited nonrandomized studies had been contradicted or had found stronger effects vs 9 of 39 randomized controlled trials (P = .008). Among randomized trials, studies with contradicted or stronger effects were smaller (P = .009) than replicated or unchallenged studies although there was no statistically significant difference in their early or overall citation impact. Matched control studies did not have a significantly different share of refuted results than highly cited studies, but they included more studies with "negative" results.Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

    View details for Web of Science ID 000230406100026

    View details for PubMedID 16014596

  • CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: A HuGE review and meta-analysis AMERICAN JOURNAL OF EPIDEMIOLOGY Kavvoura, F. K., Ioannidis, J. P. 2005; 162 (1): 3-16

    Abstract

    The authors performed a meta-analysis of 33 studies examining the association of type 1 diabetes mellitus with polymorphisms in the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene, including the A49G (29 comparisons), C(-318)T (three comparisons), and (AT)n microsatellite (six comparisons) polymorphisms. The studies included 5,637 cases of type 1 diabetes and 6,759 controls (4,775 and 5,829, respectively, for analysis of the A49G polymorphism). The random-effects odds ratio for the *G (Ala) allele versus the *A (Thr) allele was 1.45 (95% confidence interval (CI): 1.28, 1.65), with significant between-study heterogeneity (p < 0.001). The effect size tended to be higher in type 1 diabetes cases with age of onset <20 years (odds ratio (OR) = 1.61), and there was a significant association between the presence of glutamic acid decarboxylase-65 autoantibodies and the *G allele among type 1 diabetes cases (OR = 1.49). Larger studies showed more conservative results (p = 0.011). After exclusion of studies with fewer than 150 subjects and studies with significant deviation from Hardy-Weinberg equilibrium in the controls, the summary odds ratio was 1.40 (95% CI: 1.28, 1.54). Available data showed no strong association for the 106-base-pair allele of the microsatellite polymorphism (OR = 0.99, 95% CI: 0.64, 1.55) or the *T allele of the C(-318)T polymorphism (OR = 0.92, 95% CI: 0.45, 1.89). This meta-analysis demonstrates that the CTLA-4*G genotype is associated with type 1 diabetes.

    View details for DOI 10.1093/aje/kwi165

    View details for Web of Science ID 000230088300002

    View details for PubMedID 15961581

  • Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power EUROPEAN JOURNAL OF HUMAN GENETICS Salanti, G., Amountza, G., Ntzani, E. E., Ioannidis, J. P. 2005; 13 (7): 840-848

    Abstract

    We evaluated the testing and reporting of Hardy-Weinberg equilibrium (HWE) in recent genetic association studies, detected how frequently HWE was violated and estimated the power for HWE testing in this literature. Genetic association studies published in 2002 in Nature Genetics, American Journal of Human Genetics, and American Journal of Medical Genetics were assessed. Data were analyzed on 239 biallelic associations using 154 distinct genotype distribution data sets where HWE could be tested. Any information on HWE was given only for 150 (62.8%) associations (92 (59.7%) data sets). Reanalysis of the data showed significant deviation from HWE in the disease-free controls of 20 associations (13 data sets), but only four of them (two data sets) were admitted in the published articles. Another four deviations (in two data sets) were observed in the combined sample of cases and controls of studies where both cases and controls were diseased, and none were reported in the papers. In all six tested multiallelic associations (six data sets), there was violation of HWE, but this was not admitted in the published articles. Power calculations showed that most studies conforming to HWE simply were largely underpowered to detect HWE deviation; for example, power to detect an inbreeding of magnitude F=0.10 exceeded 80% in only 11 (7%) of the data sets being tested. This empirical evidence suggests that, even in high profile genetics journals, testing and reporting for HWE is often neglected and deviations are rarely admitted in the published reports. Moreover, power is limited for HWE testing in most current genetic association studies.

    View details for Web of Science ID 000229977200010

    View details for PubMedID 15827565

  • International collaboration, funding and association with burden of disease in randomized controlled trials in Africa BULLETIN OF THE WORLD HEALTH ORGANIZATION Swingler, G. H., Pillay, V., Pienaar, E. D., Ioannidis, J. P. 2005; 83 (7): 511-517

    Abstract

    This study aimed to assess whether randomized controlled trials conducted in Africa with collaborators from outside Africa were more closely associated with health conditions that have a burden of disease that is of specific importance to Africa than with conditions of more general global importance or with conditions important to developed countries. We also assessed whether the source of funding influenced a study's relevance to Africa.We compared randomized controlled trials performed in Africa that looked at diseases specifically relevant to Africa (as determined by burden of disease criteria) with trials classified as looking at diseases of global importance or diseases important to developed countries in order to assess differences in collaboration and funding.Of 520 trials assessed, 347 studied diseases that are specifically important to Africa; 99 studied globally important diseases and 74 studied diseases that are important to developed countries. The strongest independent predictor of whether a study was of specifically African or global importance was the corresponding author's country of origin: African importance was negatively associated with a corresponding author being from South Africa (odds ratio (OR) = 0.04; 95% confidence interval (CI) = 0.02-0.10) but there was little difference between corresponding authors from other African countries and corresponding authors from countries outside Africa. The importance of a study to Africa was independently associated with having more non-African authors (OR per author = 1.31; 95% CI = 1.08-1.58), fewer trial sites (OR per site = 0.69; 95% CI = 0.50-0.96), and reporting of funding (OR = 2.14; 95% CI = 1.15-4.00). Similar patterns were present in the comparisons of trials studying diseases important to Africa versus those studying diseases important to developed countries with stronger associations overall. When funding was reported, private industry funding was negatively associated with African importance compared with global importance (OR = 0.31, P= 0.008 for African importance and OR = 0.51, P= 0.57 for importance for developed countries).The relevance to Africa of trials conducted in Africa was not adversely affected by collaboration with non-African researchers but funding from private industry was associated with a decreased emphasis on diseases relevant to Africa.

    View details for Web of Science ID 000230466700008

    View details for PubMedID 16175825

  • Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease - A meta-analysis CIRCULATION Katritsis, D. G., Ioannidis, J. P. 2005; 111 (22): 2906-2912

    Abstract

    Percutaneous coronary intervention (PCI) has been shown to improve symptoms compared with conservative medical treatment in patients with stable coronary artery disease (CAD); however, there is limited evidence on the effect of PCI on the risk of death, myocardial infarction, and subsequent revascularization. Therefore, we performed a meta-analysis of 11 randomized trials comparing PCI to conservative treatment in patients with stable CAD.A total of 2950 patients were included in the meta-analysis (1476 received PCI, and 1474 received conservative treatment). There was no significant difference between the 2 treatment strategies with regard to mortality, cardiac death or myocardial infarction, nonfatal myocardial infarction, CABG, or PCI during follow-up. By random effects, the risk ratios (95% CIs) for the PCI versus conservative treatment arms were 0.94 (0.72 to 1.24), 1.17 (0.88 to 1.57), 1.28 (0.94 to 1.75), 1.03 (0.80 to 1.33), and 1.23 (0.80 to 1.90) for these 5 outcomes, respectively. A possible survival benefit was seen for PCI only in trials of patients who had a relatively recent myocardial infarction (risk ratio 0.40, 95% CI 0.17 to 0.95). Except for PCI during follow-up, there was no significant between-study heterogeneity for any outcome.In patients with chronic stable CAD, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment.

    View details for DOI 10.1161/CIRCULATIONAHA.104.521864

    View details for Web of Science ID 000229600700008

    View details for PubMedID 15927966

  • Creatine kinase-MB elevation following stent implantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ioannidis, J. P., Karvouni, E., Katritsis, D. G. 2005; 45 (11): 1908-1908

    View details for DOI 10.1016/j.jacc.2005.03.006

    View details for Web of Science ID 000229593000034

    View details for PubMedID 15936632

  • Re: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis - Response JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Pavlidis, N., Ioannidis, J. P. 2005; 97 (11): 858-859
  • F-18-FDG PET for evaluation of bone marrow infiltration in staging of lymphoma: A meta-analysis JOURNAL OF NUCLEAR MEDICINE Pakos, E. E., Fotopoulos, A. D., Ioannidis, J. P. 2005; 46 (6): 958-963

    Abstract

    The ability of PET with (18)F-FDG to evaluate bone marrow infiltration in patients with lymphoma has been a matter of extensive investigation with controversial results. Therefore, we aimed to evaluate systematically, with a meta-analysis, the diagnostic performance of (18)F-FDG PET in this setting.Relevant studies were identified with MEDLINE and EMBASE searches (last update, August 2004). Data on the diagnostic performance of (18)F-FDG PET were combined quantitatively across eligible studies. We estimated weighted summary sensitivities and specificities, summary receiver-operating-characteristic (SROC) curves, and weighted summary likelihood ratios. We also conducted separate analyses according to various subgroups. Bone marrow biopsy (BMB) was used as the reference standard.Thirteen eligible nonoverlapping studies, which enrolled a total of 587 patients, were included in the meta-analysis. The independent random-effects weighted estimates of sensitivity and specificity against BMB were 51% (95% confidence interval [CI], 38%-64%) and 91% (95% CI, 85%-95%), respectively. Results were consistent in the SROC curve: a sensitivity of 51% corresponds to a specificity of 92%, whereas a specificity of 91% corresponds to a sensitivity of 55%. The weighted positive likelihood ratio (LR+) was 5.75 (95% CI, 348-9.48) and the negative likelihood ratio (LR-) was 0.67 (95% CI, 0.55-0.82). Six of 12 patients with positive (18)F-FDG PET and negative initial biopsy were found to have bone marrow involvement when biopsy was performed at the sites with positive imaging signals. Subgroup analyses showed better sensitivity in patients with Hodgkin's disease and in aggressive histologic types of non-Hodgkin's lymphoma than in patients with less aggressive histologic types and in studies using unilateral BMB compared with those using bilateral biopsy.This meta-analysis showed that (18)F-FDG PET has good, but not excellent, concordance with the results of BMB for the detection of bone marrow infiltration in the staging of patients with lymphoma. (18)F-FDG PET may complement the results of BMB and its performance may vary according to the type of lymphoma.

    View details for Web of Science ID 000229644000017

    View details for PubMedID 15937306

  • Early extreme contradictory estimates may appear in published research: The Proteus phenomenon in molecular genetics research and randomized trials JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A. 2005; 58 (6): 543-549

    Abstract

    Divergent results on the same scientific question generate controversy. We hypothesized that controversial data are attractive to investigators and editors, and thus the most extreme, opposite results would appear very early rather than late, as data accumulate, provided data can be generated rapidly.We used data from MEDLINE-indexed meta-analyses of case-control studies on genetic associations (retrospective, hypothesis-generating research with usually rapid turnaround) and meta-analyses of randomized trials of health care interventions (prospective, targeted research that usually takes longer) sampled from the Cochrane Library. Using cumulative meta-analysis, we evaluated how the between-study variance for studies on the same question changed over time and at what point the studies with the most extreme results ever observed had been published.The maximal between-study variance was more likely to be recorded early in the 44 eligible meta-analyses of genetic associations than in the 37 meta-analyses of health care interventions (P = .013). At the time of the first heterogeneity assessment, the most favorable-ever result in support of a specific association was more likely to appear than the least favorable-ever result (22 vs. 10, P = .017); the opposite was seen at the second heterogeneity assessment (15 vs. 5, P = .031). Such a sequence of extreme opposite results was not seen in the clinical trials meta-analyses. The estimated between-study variance decreased over time in genetic association studies (P = .010), but not in clinical trials (P = .30).In contrast to prospective trials, a rapid early sequence of extreme, opposite results is frequent in retrospective hypothesis-generating molecular research.

    View details for DOI 10.1016/j.jclinepi.2004.10.019

    View details for Web of Science ID 000229350000001

    View details for PubMedID 15878467

  • Relative citation impact of various study designs in the health sciences JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Analatos, A. A., Ioannidis, J. P. 2005; 293 (19): 2362-2366

    Abstract

    The relative merits of various study designs and their placement in hierarchies of evidence are often discussed. However, there is limited knowledge about the relative citation impact of articles using various study designs.To determine whether the type of study design affects the rate of citation in subsequent articles.We measured the citation impact of articles using various study designs--including meta-analyses, randomized control