Bio

Academic Appointments


Administrative Appointments


  • Senator At-large, Stanford University School of Medicine (2013 - 2015)
  • Senator, Academic Council of Stanford University (2008 - 2010)

Honors & Awards


  • 6/6 - The genetics of endophenotypes and schizophrenia, NIH-NIMH R01 MH086135 (2010-2014)
  • Associate Editor, Biometrics (2003-2005)
  • Associate Editor, Statistical Applications in Genetics and Molecular Biology (2002-present)
  • Complex trait mapping - models and semiparametric methods, NIH-NIGMS R01 GM062628 (2000-2007)
  • Statistical Methods for Gene Mapping, NIH-NIGMS R01 GM053275, Stanford subcontract (1995-2003)
  • Exact confidence intervals for multidmensional contingency tables, NSF-DMS 95105161 (1995-1997)
  • Exact Estimation of Genetic Equilibrium, Stanford University Research Incentive Fund Award (1995-1996)

Professional Education


  • PhD, UCLA, Biostatistics (1994)

Teaching

2013-14 Courses


Publications

Journal Articles


  • Evaluating the evidence of replication for genetic associations with schizophrenia. JAMA psychiatry Lazzeroni, L. C. 2014; 71 (1): 94-5

    View details for DOI 10.1001/jamapsychiatry.2013.2987

    View details for PubMedID 24382567

  • P-values in genomics: Apparent precision masks high uncertainty. Molecular psychiatry Lazzeroni, L. C., Lu, Y., Belitskaya-Lévy, I. 2014

    Abstract

    Scientists often interpret P-values as measures of the relative strength of statistical findings. This is common practice in large-scale genomic studies where P-values are used to choose which of numerous hypothesis test results should be pursued in subsequent research. In this study, we examine P-value variability to assess the degree of certainty P-values provide. We develop prediction intervals for the P-value in a replication study given the P-value observed in an initial study. The intervals depend on the initial value of P and the ratio of sample sizes between the initial and replication studies, but not on the underlying effect size or initial sample size. The intervals are valid for most large-sample statistical tests in any context, and can be used in the presence of single or multiple tests. While P-values are highly variable, future P-value variability can be explicitly predicted based on a P-value from an initial study. The relative size of the replication and initial study is an important predictor of the P-value in a subsequent replication study. We provide a handy calculator implementing these results and apply them to a study of Alzheimer's disease and recent findings of the Cross-Disorder Group of the Psychiatric Genomics Consortium. This study suggests that overinterpretation of very significant, but highly variable, P-values is an important factor contributing to the unexpectedly high incidence of non-replication. Formal prediction intervals can also provide realistic interpretations and comparisons of P-values associated with different estimated effect sizes and sample sizes.Molecular Psychiatry advance online publication, 14 January 2014; doi:10.1038/mp.2013.184.

    View details for DOI 10.1038/mp.2013.184

    View details for PubMedID 24419042

  • BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenetics and genomics Murphy, G. M., Sarginson, J. E., Ryan, H. S., O'Hara, R., Schatzberg, A. F., Lazzeroni, L. C. 2013; 23 (6): 301-313

    Abstract

    Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.

    View details for DOI 10.1097/FPC.0b013e328360b175

    View details for PubMedID 23619509

  • Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008 JOURNAL OF ALZHEIMERS DISEASE Lazzeroni, L. C., Halbauer, J. D., Ashford, J. W., Noda, A., Hernandez, B., Azor, V., Hozack, N., Hasson, N., Henderson, V. W., Yesavage, J. A., Tinklenberg, J. R. 2013; 36 (4): 791-798

    Abstract

    Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

    View details for DOI 10.3233/JAD-130662

    View details for Web of Science ID 000322738000016

    View details for PubMedID 23703151

  • A Generalized Defries-Fulker Regression Framework for the Analysis of Twin Data BEHAVIOR GENETICS Lazzeroni, L. C., Ray, A. 2013; 43 (1): 85-96

    Abstract

    Twin studies compare the similarity between monozygotic twins to that between dizygotic twins in order to investigate the relative contributions of latent genetic and environmental factors influencing a phenotype. Statistical methods for twin data include likelihood estimation and Defries-Fulker regression. We propose a new generalization of the Defries-Fulker model that fully incorporates the effects of observed covariates on both members of a twin pair and is robust to violations of the Normality assumption. A simulation study demonstrates that the method is competitive with likelihood analysis. The Defries-Fulker strategy yields new insight into the parameter space of the twin model and provides a novel, prediction-based interpretation of twin study results that unifies continuous and binary traits. Due to the simplicity of its structure, extensions of the model have the potential to encompass generalized linear models, censored and truncated data; and gene by environment interactions.

    View details for DOI 10.1007/s10519-012-9573-7

    View details for Web of Science ID 000313804300008

    View details for PubMedID 23264207

  • The cost of large numbers of hypothesis tests on power, effect size and sample size MOLECULAR PSYCHIATRY Lazzeroni, L. C., Ray, A. 2012; 17 (1): 108-114

    Abstract

    Advances in high-throughput biology and computer science are driving an exponential increase in the number of hypothesis tests in genomics and other scientific disciplines. Studies using current genotyping platforms frequently include a million or more tests. In addition to the monetary cost, this increase imposes a statistical cost owing to the multiple testing corrections needed to avoid large numbers of false-positive results. To safeguard against the resulting loss of power, some have suggested sample sizes on the order of tens of thousands that can be impractical for many diseases or may lower the quality of phenotypic measurements. This study examines the relationship between the number of tests on the one hand and power, detectable effect size or required sample size on the other. We show that once the number of tests is large, power can be maintained at a constant level, with comparatively small increases in the effect size or sample size. For example at the 0.05 significance level, a 13% increase in sample size is needed to maintain 80% power for ten million tests compared with one million tests, whereas a 70% increase in sample size is needed for 10 tests compared with a single test. Relative costs are less when measured by increases in the detectable effect size. We provide an interactive Excel calculator to compute power, effect size or sample size when comparing study designs or genome platforms involving different numbers of hypothesis tests. The results are reassuring in an era of extreme multiple testing.

    View details for DOI 10.1038/mp.2010.117

    View details for Web of Science ID 000299014000015

    View details for PubMedID 21060308

  • Serotonin transporter polymorphism is associated with increased apnea-hypopnea index in older adults. International journal of geriatric psychiatry Schröder, C. M., Primeau, M. M., Hallmayer, J. F., Lazzeroni, L. C., Hubbard, J. T., O'Hara, R. 2014; 29 (3): 227-235

    Abstract

    RATIONALE: A functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. OBJECTIVES: We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5-HTTLPR in older adults. METHODS: DNA samples from 94 community-dwelling older adults (57% female, mean age 72?±?8) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. RESULTS: The 5-HTT l allele was significantly associated with AHI (p?=?0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5-HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p?=?0.014). CONCLUSIONS: The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. Copyright © 2013 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/gps.3994

    View details for PubMedID 23754303

  • HPA axis genetic variation, cortisol and psychosis in major depression. Molecular psychiatry Schatzberg, A. F., Keller, J., Tennakoon, L., Lembke, A., Williams, G., Kraemer, F. B., Sarginson, J. E., Lazzeroni, L. C., Murphy, G. M. 2014; 19 (2): 220-227

    Abstract

    Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900?h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100?h (r(2)=0.288) and from 0100 to 0900?h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.Molecular Psychiatry advance online publication, 29 October 2013; doi:10.1038/mp.2013.129.

    View details for DOI 10.1038/mp.2013.129

    View details for PubMedID 24166410

  • Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS SCHIZOPHRENIA RESEARCH Swerdlow, N. R., Light, G. A., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Ray, A., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2014; 152 (2-3): 503-512

    Abstract

    Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data.Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures.884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures.The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

    View details for DOI 10.1016/j.schres.2013.12.004

    View details for Web of Science ID 000330188500026

    View details for PubMedID 24405980

  • Effects of body mass index related disorders on cognition. Diabetes, Metabolic Syndrome and Obesisty: Targets and Therapy Yesavage, J. A., Kinoshita, L., Noda, A., Lazzeroni, L. C., Fairchild, J. K., Taylor, J., Kulick, D., Friedman, L., Cheng, J., Zeitzer, J., O'Hara, R. 2014; in press
  • Is There an Association between Advanced Paternal Age and Endophenotype Deficit Levels in Schizophrenia? PloS one Tsuang, D., Esterberg, M., Braff, D., Calkins, M., Cadenhead, K., Dobie, D., Freedman, R., Green, M. F., Greenwood, T., Gur, R., Gur, R., Horan, W., Lazzeroni, L. C., Light, G. A., Millard, S. P., Olincy, A., Nuechterlein, K., Seidman, L., Siever, L., Silverman, J., Stone, W., Sprock, J., Sugar, C., Swerdlow, N., Tsuang, M., Turetsky, B., Radant, A. 2014; 9 (2)

    Abstract

    The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n?=?293) or were unaffected first-degree siblings of those probands (n?=?382). Paternal age at the time of subjects' birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age-endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.

    View details for DOI 10.1371/journal.pone.0088379

    View details for PubMedID 24523888

  • Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Nimgaonkar, V. L., Go, R. C., Savage, R. M., Swerdlow, N. R., Gur, R. E., Braff, D. L., King, M., McClellan, J. M. 2013; 154 (3): 518-529

    Abstract

    Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.

    View details for DOI 10.1016/j.cell.2013.06.049

    View details for PubMedID 23911319

  • A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

    Abstract

    Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

    View details for DOI 10.1542/peds.2013-0533

    View details for PubMedID 23897914

  • Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS) INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Beaudreau, S. A., Fairchild, J. K., Spira, A. P., Lazzeroni, L. C., O'Hara, R. 2013; 28 (7): 672-680

    Abstract

    OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) ?4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n?=?856) 71?years and older (mean age?=?79.15?years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE ?4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48?months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE ?4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. Copyright © 2012 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/gps.3868

    View details for Web of Science ID 000319944200002

  • Intraindividual variability in basic reaction time predicts middle-aged and older pilots' flight simulator performance. journals of gerontology. Series B, Psychological sciences and social sciences Kennedy, Q., Taylor, J., Heraldez, D., Noda, A., Lazzeroni, L. C., Yesavage, J. 2013; 68 (4): 487-494

    Abstract

    ObjectivesIntraindividual variability (IIV) is negatively associated with cognitive test performance and is positively associated with age and some neurological disorders. We aimed to extend these findings to a real-world task, flight simulator performance. We hypothesized that IIV predicts poorer initial flight performance and increased rate of decline in performance among middle-aged and older pilots.MethodTwo-hundred and thirty-six pilots (40-69 years) completed annual assessments comprising a cognitive battery and two 75-min simulated flights in a flight simulator. Basic and complex IIV composite variables were created from measures of basic reaction time and shifting and divided attention tasks. Flight simulator performance was characterized by an overall summary score and scores on communication, emergencies, approach, and traffic avoidance components. RESULTS: Although basic IIV did not predict rate of decline in flight performance, it had a negative association with initial performance for most flight measures. After taking into account processing speed, basic IIV explained an additional 8%-12% of the negative age effect on initial flight performance.DiscussionIIV plays an important role in real-world tasks and is another aspect of cognition that underlies age-related differences in cognitive performance.

    View details for DOI 10.1093/geronb/gbs090

    View details for PubMedID 23052365

  • Sex differences in familiality effects on neurocognitive performance in schizophrenia. Biological psychiatry Calkins, M. E., Ray, A., Gur, R. C., Freedman, R., Green, M. F., Greenwood, T. A., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L., Lazzeroni, L. C., Gur, R. E. 2013; 73 (10): 976-984

    Abstract

    Numerous studies have documented that patients with schizophrenia show neurocognitive impairments, which are also heritable in schizophrenia families. In view of these findings, the current investigation tested the hypothesis that neurocognitive performance of schizophrenia probands can predict the neurocognitive performance of their unaffected family members.Participants (n=1967; schizophrenia=369; first-degree relatives=1072; community comparison subjects=526) in the Consortium on the Genetics of Schizophrenia were administered the Penn Computerized Neurocognitive Battery.Consistent with prior work, probands showed significant neurocognitive impairment, and neurocognitive ability was significantly heritable across domains. On average, unaffected relatives did not differ from community comparison subjects in their neurocognitive performance. However, in six of seven domains, proband scores predicted the performance of their unaffected siblings. Male, but not female, proband performance was predictive of their unaffected relatives' (siblings and mothers) performance, most consistently in face memory and spatial processing.Using a novel approach in which individual probands are paired with their respective unaffected relatives within each family, we found that male proband performance predicted both sister and brother performance, an effect that was most powerfully observed for face memory and spatial processing. Results suggest that the familial transmission of sexually dimorphic neurocognitive domains, in which a particular sex tends to show a performance advantage over the other, may not itself be sex specific in schizophrenia families.

    View details for DOI 10.1016/j.biopsych.2012.12.021

    View details for PubMedID 23395246

  • Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia. American journal of psychiatry Greenwood, T. A., Swerdlow, N. R., Gur, R. E., Cadenhead, K. S., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M. F., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Olincy, A., Radant, A. D., Ray, A., Schork, N. J., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Light, G. A., Braff, D. L. 2013; 170 (5): 521-532

    Abstract

    The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated.Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods.Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23).Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

    View details for DOI 10.1176/appi.ajp.2012.12020186

    View details for PubMedID 23511790

  • Predischarge Screening for Severe Neonatal Hyperbilirubinemia Identifies Infants Who Need Phototherapy JOURNAL OF PEDIATRICS Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-?

    Abstract

    To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ?35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

    View details for DOI 10.1016/j.jpeds.2012.08.022

    View details for Web of Science ID 000315790100010

    View details for PubMedID 23043681

  • Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients. PloS one Kushner, L. E., Wendelboe, A. M., Lazzeroni, L. C., Chary, A., Winters, M. A., Osinusi, A., Kottilil, S., Polis, M. A., Holodniy, M. 2013; 8 (4)

    Abstract

    Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.Fifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.

    View details for DOI 10.1371/journal.pone.0060387

    View details for PubMedID 23593207

  • High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PLoS One St Julien KR, Jelliffe-Pawlowski LL, Shaw GM, Stevenson DK, O'Brodovich HM, Krasnow MA, Stanford BPD Study Group (Gould JB, Oehlert JW, Quaintance C, Wang H, Lazzeroni L, Hoffman T, Witte J, Lorey F) 2013; 8 (5): e4710

    View details for PubMedID 23737996

  • Combinatorial Pharmacogenetic Interactions of Bucindolol and beta(1), alpha(2C) Adrenergic Receptor Polymorphisms PLOS ONE O'Connor, C. M., Fiuzat, M., Carson, P. E., Anand, I. S., Plehn, J. F., Gottlieb, S. S., Silver, M. A., Lindenfeld, J., Miller, A. B., White, M., Walsh, R., Nelson, P., Medway, A., Davis, G., Robertson, A. D., Port, J. D., Carr, J., Murphy, G. A., Lazzeroni, L. C., Abraham, W. T., Liggett, S. B., Bristow, M. R. 2012; 7 (10)

    Abstract

    Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a ?-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (?(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (?(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of ?(1)389 and ?(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for ?(1)389 AR variants was measured in human explanted left ventricles.The combination of ?(1)389 Arg+?(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in ?(1)389 Arg homozygotes+?(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P?=?0.009) of high-affinity NE binding sites in ?(1)389 Arg vs. Gly ARs, which converts ?(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit.On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (?(1)389 Arg homozygotes), intermediate (?(1)389 Gly carriers+?(2C)322-325 Wt homozygotes), and no (?(1)389 Gly carriers+?(2C)322-325 Del carriers) efficacy.

    View details for DOI 10.1371/journal.pone.0044324

    View details for Web of Science ID 000312385200002

    View details for PubMedID 23071495

  • Aversive and Reinforcing Opioid Effects A Pharmacogenomic Twin Study ANESTHESIOLOGY Angst, M. S., Lazzeroni, L. C., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Clark, J. D. 2012; 117 (1): 22-37

    Abstract

    The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk.A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The ?-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.

    View details for Web of Science ID 000305672800007

    View details for PubMedID 22713632

  • Pain sensitivity and opioid analgesia: A pharmacogenomic twin study PAIN Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2012; 153 (7): 1397-1409

    Abstract

    Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the ?-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

    View details for DOI 10.1016/j.pain.2012.02.022

    View details for Web of Science ID 000305423700014

    View details for PubMedID 22444188

  • Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases PLOS COMPUTATIONAL BIOLOGY Ruau, D., Dudley, J. T., Chen, R., Phillips, N. G., Swan, G. E., Lazzeroni, L. C., Clark, J. D., Butte, A. J., Angst, M. S. 2012; 8 (6)

    Abstract

    Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P?=?1.3×10?¹?) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P?=?1.7×10??, 1.8×10??, and 2.2×10?? respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.

    View details for DOI 10.1371/journal.pcbi.1002538

    View details for Web of Science ID 000305965300012

    View details for PubMedID 22685391

  • Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development PSYCHOPHARMACOLOGY Casper, R. C., Gilles, A. A., Fleisher, B. E., Baran, J., Enns, G., Lazzeroni, L. C. 2011; 217 (2): 211-219

    Abstract

    This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants might affect neonatal outcome and psychomotor development in infancy.Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies. At an average age of 14 months, children underwent a pediatric examination and an evaluation with the Bayley Scales of Infant Development (BSID-II).Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score (<2) on this scale were 3.8 and 6.0 at 1 and 5 min, respectively. Newborns with longer exposure were more often admitted to the Neonatal Intensive Care Unit (p?

    View details for DOI 10.1007/s00213-011-2270-z

    View details for Web of Science ID 000294224800006

    View details for PubMedID 21499702

  • Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Greenwood, T. A., Lazzeroni, L. C., Murray, S. S., Cadenhead, K. S., Calkins, M. E., Dobie, D. J., Green, M. F., Gur, R. E., Gur, R. C., Hardiman, G., Kelsoe, J. R., Leonard, S., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Schork, N. J., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Freedman, R., Braff, D. L. 2011; 168 (9): 930-946

    Abstract

    The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

    View details for DOI 10.1176/appi.ajp.2011.10050723

    View details for Web of Science ID 000294484100013

    View details for PubMedID 21498463

  • Influences of APOE epsilon 4 and Expertise on Performance of Older Pilots PSYCHOLOGY AND AGING Taylor, J. L., Kennedy, Q., Adamson, M. M., Lazzeroni, L. C., Noda, A., Murphy, G. M., Yesavage, J. A. 2011; 26 (2): 480-487

    Abstract

    Little is known about how APOE ?4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ?4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE ?4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ?4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ?4 carriers.

    View details for DOI 10.1037/a0021697

    View details for Web of Science ID 000291668800026

    View details for PubMedID 21668123

  • Markers in the 15q24 Nicotinic Receptor Subunit Gene Cluster (CHRNA5-A3-B4) Predict Severity of Nicotine Addiction and Response to Smoking Cessation Therapy AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Killen, J. D., Lazzeroni, L. C., Fortmann, S. P., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2011; 156B (3): 275-284

    Abstract

    Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.

    View details for DOI 10.1002/ajmg.b.31155

    View details for Web of Science ID 000288332600003

    View details for PubMedID 21268243

  • Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability TWIN RESEARCH AND HUMAN GENETICS Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Galinkin, J. L., Christians, U., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2010; 13 (5): 412-425

    Abstract

    Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

    View details for Web of Science ID 000283001300002

    View details for PubMedID 20874462

  • Keratin Variants Predispose to Acute Liver Failure and Adverse Outcome: Race and Ethnic Associations GASTROENTEROLOGY Strnad, P., Zhou, Q., Hanada, S., Lazzeroni, L. C., Zhong, B. H., So, P., Davern, T. J., Lee, W. M., Omary, M. B. 2010; 139 (3): 828-U175

    Abstract

    Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans.We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects).Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008).KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

    View details for DOI 10.1053/j.gastro.2010.06.007

    View details for Web of Science ID 000281365500025

    View details for PubMedID 20538000

  • ABCB1 ( MDR1) polymorphisms and antidepressant response in geriatric depression PHARMACOGENETICS AND GENOMICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Ershoff, B. D., Schatzberg, A. F., Murphy, G. M. 2010; 20 (8): 467-475

    Abstract

    Variation in the ATP-binding cassette, subfamily B, member 1 transporter (ABCB1) (multidrug-resistance gene 1) gene has been investigated as a predictor of response to treatment with a variety of medications such as antiarrhythmics, chemotherapeutic agents, anti-HIV medications, and some psychotropics. The ABCB1 gene product, P-glycoprotein, affects the transport of drugs out of many cell types, including endothelial cells at the blood-brain barrier. We sought to determine if ABCB1 polymorphisms predict response to antidepressant treatment in geriatric patients.We compared the effects of ABCB1 genetic variation on the therapeutic response to paroxetine, a P-glycoprotein substrate, and to mirtazapine, which is not thought to be transported by ABCB1, in a sample of 246 elderly patients with major depression treated in a clinical trial setting. A total of 15 single nucleotide polymorphisms in the ABCB1 gene were assessed in each patient. Two of these ABCB1 single nucleotide polymorphisms were earlier reported to predict treatment response in patients prescribed with P-glycoprotein substrate antidepressants.The two earlier identified ABCB1 markers for antidepressant response predicted time to remission in our paroxetine-treated patients, but not in the mirtazapine-treated patients. These results replicate the published findings of others. If a Bonferroni correction for type I error is made, our results do not reach the criteria for statistical significance. However, the Bonferroni correction may be too conservative given the strong linkage disequilibrium among some of the markers and our aim to replicate the earlier published findings.Our study provides confirmation that certain ABCB1 polymorphisms predict response to substrate medications in geriatric patients.

    View details for DOI 10.1097/FPC.0b013e32833b593a

    View details for Web of Science ID 000279865400001

    View details for PubMedID 20555295

  • FKBP5 Polymorphisms and Antidepressant Response in Geriatric Depression AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2010; 153B (2): 554-560

    Abstract

    Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

    View details for DOI 10.1002/ajmg.b.31019

    View details for Web of Science ID 000275377900023

    View details for PubMedID 19676097

  • An alpha(2C)-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the beta-Blocker Bucindolol in Chronic Heart Failure CIRCULATION-HEART FAILURE Bristow, M. R., Murphy, G. A., Krause-Steinrauf, H., Anderson, J. L., Carlquist, J. F., Thaneemit-Chen, S., Krishnan, V., Abraham, W. T., Lowes, B. D., Port, J. D., Davis, G. W., Lazzeroni, L. C., Robertson, A. D., Lavori, P. W., Liggett, S. B. 2010; 3 (1): 21-28

    Abstract

    Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional alpha(2C)-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel beta-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether alpha(2C)-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.In the beta-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and alpha(2C)-AR gene polymorphisms (alpha(2C) Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were alpha(2C) Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153+/-57 pg/mL, P=0.012 compared with placebo versus decrease of 50+/-13 pg/mL in alpha(2C) wild type, P=0.0005 versus placebo; P=0.010 by interaction test). alpha(2C) Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the alpha(2C)-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025).In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by alpha(2C) receptor genotype.

    View details for DOI 10.1161/CIRCHEARTFAILURE.109.885962

    View details for Web of Science ID 000273735100005

    View details for PubMedID 19880803

  • A randomized trial of computer-based reminders and audit and feedback to improve HIV screening in a primary care setting INTERNATIONAL JOURNAL OF STD & AIDS Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Sanders, G. D., Tempio, P., Owens, D. K. 2009; 20 (8): 527-533

    Abstract

    Despite recommendations for voluntary HIV screening, few medical centres have implemented screening programmes. The objective of the study was to determine whether an intervention with computer-based reminders and feedback would increase screening for HIV in a Department of Veterans Affairs (VA) health-care system. The design of the study was a randomized controlled trial at five primary care clinics at the VA Palo Alto Health Care System. All primary care providers were eligible to participate in the study. The study intervention was computer-based reminders to either assess HIV risk behaviours or to offer HIV testing; feedback on adherence to reminders was provided. The main outcome measure was the difference in HIV testing rates between intervention and control group providers. The control group providers tested 1.0% (n = 67) and 1.4% (n = 106) of patients in the preintervention and intervention period, respectively; intervention providers tested 1.8% (n = 98) and 1.9% (n = 114), respectively (P = 0.75). In our random sample of 753 untested patients, 204 (27%) had documented risk behaviours. Providers were more likely to adhere to reminders to test rather than with reminders to perform risk assessment (11% versus 5%, P < 0.01). Sixty-one percent of providers felt that lack of time prevented risk assessment. In conclusion, in primary care clinics in our setting, HIV testing rates were low. Providers were unaware of the high rates of risky behaviour in their patient population and perceived important barriers to testing. Low-intensity clinical reminders and feedback did not increase rates of screening.

    View details for DOI 10.1258/ijsa.2008.008423

    View details for Web of Science ID 000269809200003

    View details for PubMedID 19625582

  • Identification of a Major Susceptibility Locus for Lethal Graft-versus-Host Disease in MHC-Matched Mice JOURNAL OF IMMUNOLOGY Cao, T. M., Lazzeroni, L. C., Tsai, S., Pang, W. W., Kao, A., Camp, N. J., Thomas, A., Shizuru, J. A. 2009; 183 (1): 462-469

    Abstract

    Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F(1) mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F(1) x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.

    View details for DOI 10.4049/jimmunol.0900454

    View details for Web of Science ID 000275119400051

    View details for PubMedID 19525392

  • Trends in US Autism Research Funding JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Singh, J., Illes, J., Lazzeroni, L., Hallmayer, J. 2009; 39 (5): 788-795

    Abstract

    This study shows that the number of autism research grants funded in the US from 1997 to 2006 significantly increased 15% per year. Although the majority of projects were concentrated in basic science (65%) compared to clinical (15%) and translational research (20%), there is a significant decrease in the proportion of basic research grants per year and a significant increase in the proportion of translational projects per year. The number of translational projects funded by the National Alliance for Autism Research and Cure Autism Now increased significantly, whereas the number of clinical projects significantly increased for the National Institutes of Health. In conclusion, this study demonstrates the shifting landscape of autism research from basic science to clinical and translational research.

    View details for DOI 10.1007/s10803-008-0685-0

    View details for Web of Science ID 000265820500009

    View details for PubMedID 19148735

  • Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E NEUROBIOLOGY OF AGING Selwood, S. P., Parvathy, S., Cordell, B., Ryan, H. S., Oshidari, F., Vincent, V., Yesavage, J., Lazzeroni, L. C., Murphy, G. M. 2009; 30 (4): 574-590

    Abstract

    The APOE epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP(V717)) mice modeling AD that show extensive amyloid beta (A beta) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of A beta deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of A beta deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Abeta deposition, and the effects of APOE deletion on this process.

    View details for DOI 10.1016/j.neurobiolaging.2007.08.006

    View details for Web of Science ID 000264579500013

    View details for PubMedID 17904698

  • Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tsao, G. J., Allen, J. A., Logronio, K. A., Lazzeroni, L. C., Shizuru, J. A. 2009; 106 (9): 3288-3293

    Abstract

    Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lympho-depleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.

    View details for DOI 10.1073/pnas.0813335106

    View details for Web of Science ID 000263844100057

    View details for PubMedID 19223585

  • Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study ACTA NEUROLOGICA SCANDINAVICA Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Lazzeroni, L., Rasgon, N. L. 2009; 119 (3): 172-179

    Abstract

    To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status).A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD.ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance.Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

    View details for DOI 10.1111/j.1600-0404.2008.01084.x

    View details for Web of Science ID 000262949100005

    View details for PubMedID 18705678

  • Physiological Correlates of Social Avoidance Behavior in Children and Adolescents With Fragile X Syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hall, S. S., Lightbody, A. A., Huffman, L. C., Lazzeroni, L. C., Reiss, A. L. 2009; 48 (3): 320-329

    Abstract

    To investigate whether eye-gaze avoidance, a striking phenotypic feature in fragile X syndrome (FXS), is associated with high levels of "hyperarousal" during social interactions with others. To date, almost all studies in this area have been confounded by inclusion of task demands in addition to social demands.We monitored the cardiovascular activity and eye-gaze avoidance of 50 boys and girls with FXS aged 5 to 20 years during a 25-minute intensive social interaction session with an unfamiliar experimenter. To control for possible family and genetic factors in cardiovascular activity, we compared each child with FXS with their same-sex typically developing biological sibling.Participants with FXS obtained significantly higher heart rates, lower vagal tone, and lower heart rate variability estimates both at baseline and during the social interaction session compared with their typically developing siblings. Although eye-gaze avoidance occurred at significantly higher levels in the children with FXS, this behavior decreased slightly over the course of the session (a "warm-up" effect) and did not seem to be associated with cardiovascular activity. In the girls with FXS, higher levels of the fragile X mental retardation protein were associated with higher (and more typical) heart rate variability.These data suggest that both sympathetic and parasympathetic nervous systems are dysregulated in FXS. However, given that prolonged exposure to social demands does not inevitably lead to increased anxiety or "hyperarousal," professionals should not be deterred from providing much needed social skills interventions for individuals with FXS.

    View details for DOI 10.1097/CHI.0b013e318195bd15

    View details for Web of Science ID 000263742100011

    View details for PubMedID 19182690

  • Pharmacogenetic effect of an endothelin-1 haplotype on response to bucindolol therapy in chronic heart failure PHARMACOGENETICS AND GENOMICS Taylor, M. R., Slavov, D., Humphrey, K., Zhao, L., Cockroft, J., Zhu, X., Lavori, P., Bristow, M. R., Mestroni, L., Lazzeroni, L. C. 2009; 19 (1): 35-43

    Abstract

    Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to beta-blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to beta-blockers in heart failure.Single nucleotide polymorphisms (SNPs) in six endothelin system genes were genotyped in 309 heart failure patients in a randomized trial of bucindolol versus placebo therapy. We adjusted for multiple comparisons and tested for association between genotype and time to two prospective endpoints.Nine SNPs were sufficiently common to undergo statistical analysis. The SNPs had no significant effect on prospective outcomes in the placebo group, or on the primary endpoint of time to death in either arm. Two SNPs (IVS-4 G/A and Lys198Asn) in the endothelin-1 gene, however, predicted time to the combined endpoint of heart failure hospitalization or all-cause death in bucindolol-treated patients. The alleles at these SNPs were in tight linkage disequilibrium appearing on either of two complementary haplotypes. A 'dose-response' trend was observed, with participants carrying the rarer haplotype having the highest hazard ratios as compared to the relative 'protective' effect of the common haplotype.A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients. The existence of a less common 'high-risk' haplotype could identify a subpopulation of heart failure patients destined to respond poorly to beta-blocker therapies.

    View details for DOI 10.1097/FPC.0b013e328317cc57

    View details for Web of Science ID 000262342500004

    View details for PubMedID 18953265

  • Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD: a prospective study. Am J Kidney Dis. Jamison, R. L., Shih, M. C., Humphries, D. E., Guarino, P. D., Kaufman, J. S., Goldfarb, D. S., Warren, S. R., Gaziano, J. M., Lavori, P., BEST DNA Bank 2009; 53 (5): 779-789
  • Prevalence of HIV infection among inpatients and outpatients in department of veterans affairs health care systems: Implications for screening programs for HIV AMERICAN JOURNAL OF PUBLIC HEALTH Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Sanders, G. D., Taylor, K., VanGroningen, R., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Nyland, J., Tempio, P., Khayr, W., Dietzen, D. J., Jensen, P., Simberkoff, M. S., Bozzette, S. A., Holodniy, M. 2007; 97 (12): 2173-2178

    Abstract

    We sought to determine the prevalence of HIV in both inpatient and outpatient settings in 6 Department of Veterans Affairs (VA) health care sites.We collected demographic data and data on comorbid conditions and then conducted blinded, anonymous HIV testing. We conducted a multivariate analysis to determine predictors of HIV infection.We tested 4500 outpatient blood specimens and 4205 inpatient blood specimens; 326 (3.7%) patients tested positive for HIV. Inpatient HIV prevalence ranged from 1.2% to 6.9%; outpatient HIV prevalence ranged from 0.9% to 8.9%. Having a history of hepatitis B or C infection, a sexually transmitted disease, or pneumonia also predicted HIV infection. The prevalence of previously undocumented HIV infection varied from 0.1% to 2.8% among outpatients and from 0.0% to 1.7% among inpatients.The prevalence of undocumented HIV infection was sufficiently high for routine voluntary screening to be cost effective in each of the 6 sites we evaluated. Many VA health care systems should consider expanded routine voluntary HIV screening.

    View details for DOI 10.2105/AJPH.2007.110700

    View details for Web of Science ID 000251395900022

    View details for PubMedID 17971545

  • Prevalence of desmin mutations in dilated cardiomyopathy CIRCULATION Taylor, M. R., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., Haubold, K., Boucek, M. M., Ferguson, D., Graw, S. L., Zhu, X., Cavanaugh, J., Sucharov, C. C., Long, C. S., Bristow, M. R., Lavori, P., Mestroni, L. 2007; 115 (10): 1244-1251

    Abstract

    Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects.The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

    View details for DOI 10.1161/CIRCULATIONAHA.106.646778

    View details for Web of Science ID 000244864100013

    View details for PubMedID 17325244

  • HIV testing of at risk patients in a large integrated health care system JOURNAL OF GENERAL INTERNAL MEDICINE Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Tempio, P., Holodniy, M., Sanders, G. D., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Chavis, D., Borowsky, L. H., Yano, E. M., Jensen, P., Simberkoff, M. S., Bozzette, S. A. 2007; 22 (3): 315-320

    Abstract

    Early identification of HIV infection is critical for patients to receive life-prolonging treatment and risk-reduction counseling. Understanding HIV screening practices and barriers to HIV testing is an important prelude to designing successful HIV screening programs. Our objective was to evaluate current practice patterns for identification of HIV.We used a retrospective cohort analysis of 13,991 at-risk patients seen at 4 large Department of Veterans Affairs (VA) health-care systems. We also reviewed 1,100 medical records of tested patients. We assessed HIV testing rates among at-risk patients, the rationale for HIV testing, and predictors of HIV testing and of HIV infection.Of the 13,991 patients at risk for HIV, only 36% had been HIV-tested. The prevalence of HIV ranged from 1% to 20% among tested patients at the 4 sites. Approximately 90% of patients who were tested had a documented reason for testing.One-half to two-thirds of patients at risk for HIV had not been tested within our selected VA sites. Among tested patients, the rationale for HIV testing was well documented. Further testing of at-risk patients could clearly benefit patients who have unidentified HIV infection by providing earlier access to life-prolonging therapy.

    View details for DOI 10.1007/s11606-006-0028-9

    View details for Web of Science ID 000244718600005

    View details for PubMedID 17356961

  • Prevalence of desmin mutations in dilated cardiomyopathy. Circulation Taylor, M. R., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., Haubold, K., Boucek, M. M., Ferguson, D., Graw, S. L., Zhu, X., Cavanaugh, J., Sucharov, C. C., Long, C. S., Bristow, M. R., Lavori, P., Mestroni, L., BEST DNA Bank 2007; 115 (10): 1244-51
  • A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., Weber, S. A., Greene, S. M., Hodne, D., Nelson, B., Morrison, J., Domanski, M. J., Wagoner, L. E., Abraham, W. T., Anderson, J. L., Carlquist, J. F., Krause-Steinrauf, H. J., Lazzeroni, L. C., Port, J. D., Lavori, P. W., Bristow, M. R. 2006; 103 (30): 11288-11293

    Abstract

    Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

    View details for DOI 10.1073/pnas.0509937103

    View details for Web of Science ID 000239353900034

    View details for PubMedID 16844790

  • Keratin variants associate with progression of fibrosis during chronic hepatitis C infection HEPATOLOGY Strnad, P., Lienau, T. C., Tao, G., Lazzeroni, L. C., Stickel, F., Schuppan, D., Omary, M. B. 2006; 43 (6): 1354-1363

    Abstract

    Keratins 8 and 18 (K8/K18) protect the liver from various forms of injury. Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown. We tested the hypothesis that K8/K18 variants are associated with chronic hepatitis C (CHC) and that their presence correlates with progression of fibrosis. Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Our findings showed: (1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients (7.3%) and non-coding heterozygous variants in 26 patients (7.8%), and (2) 3 new exonic K8 variants (T26R/G55A/A359T); 6 novel non-coding variants and one K18 coding variant (K18 S230T; 2 patients). The most common variants were K8 R341H (10 patients), K8 G62C (6 patients) and K8 I63V (4 patients). A novel and exclusive association of an intronic KRT8 IVS7+10delC deletion in all 10 patients with K8 R341H was observed. Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis. In conclusion, previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection. The unique 100% segregation of the most common K8 variant, R341H, with an intronic deletion suggests that one of these two genetic changes might lead to the other.

    View details for DOI 10.1002/hep.21211

    View details for Web of Science ID 000237984500022

    View details for PubMedID 16729313

  • The effect of diagnosis with HIV infection on health-related quality of life QUALITY OF LIFE RESEARCH Honiden, S., Sundaram, V., Nease, R. F., Holodniy, M., Lazzeroni, L. C., Zolopa, A., Owens, D. K. 2006; 15 (1): 69-82

    Abstract

    We sought to understand how diagnosis with HIV affects health-related quality of life. We assessed health-related quality of life using utility-based measures in a Department of Veterans Affairs (VA) clinic and a University-based clinic. Respondents assessed health-related quality of life regarding their current health, and retrospectively assessed their health 1 month prior to and 2 months after diagnosis with HIV infection. Sixty-six patients completed the study. The overall mean utilities for health 1 month before and 2 months after diagnosis were 0.87 (standard error 0.037), and 0.80 (0.043) (p<0.005 by rank sign test), but the effect of diagnosis differed between the two clinics, with a substantial decrease in the university clinic and a small non-significant decrease in the VA clinic. The overall mean utility for current health was 0.85 (0.034), assessed on average 7.5 years after diagnosis. When asked directly whether diagnosis of HIV decreased health-related quality of life, 47% agreed, but 35% stated that HIV diagnosis positively affected health-related quality of life. Diagnosis with HIV decreased health-related quality of life at 2 months on average, but this effect diminished over time, and differed among patient populations. Years after diagnosis, although half of the patients believed that diagnosis reduced health-related quality of life, one-third reported improved health-related quality of life.

    View details for DOI 10.1007/s11136-005-8485-x

    View details for Web of Science ID 000234601400007

    View details for PubMedID 16411032

  • The role of a common adenosine monophosphate deaminase (AMPD)-1 polymorphism in outcomes of ischemic and nonischemic heart failure JOURNAL OF CARDIAC FAILURE Kolek, M. J., Carlquist, J. F., Thaneemit-Chen, S., Lazzeroni, L. C., Whiting, B. M., Horne, B. D., Muhlestein, J. B., Lavori, P., Anderson, J. L. 2005; 11 (9): 677-683

    Abstract

    A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning.We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P < .001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality.Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.

    View details for DOI 10.1016/j.cardfail.2005.06.437

    View details for Web of Science ID 000234655900005

    View details for PubMedID 16360962

  • Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: An international comparison (The GUESS Study) CLINICAL INFECTIOUS DISEASES Zolopa, A. R., Lazzeroni, L. C., Rinehart, A., Vezinet, F. B., Clavel, F., Collier, A., Conway, B., Gulick, R. M., Holodniy, M., Perno, C. F., Shafer, R. W., Richman, D. D., Wainberg, M. A., Kuritzkes, D. R. 2005; 41 (1): 92-99

    Abstract

    Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

    View details for Web of Science ID 000229530400015

    View details for PubMedID 15937768

  • Cost-effectiveness of screening for HIV in the era of highly active antiretroviral therapy NEW ENGLAND JOURNAL OF MEDICINE Sanders, G. D., Bayoumi, A. M., Sundaram, V., Bilir, S. P., Neukermans, C. P., Rydzak, C. E., Douglass, L. R., Lazzeroni, L. C., Holodniy, M., Owens, D. K. 2005; 352 (6): 570-585

    Abstract

    The costs, benefits, and cost-effectiveness of screening for human immunodeficiency virus (HIV) in health care settings during the era of highly active antiretroviral therapy (HAART) have not been determined.We developed a Markov model of costs, quality of life, and survival associated with an HIV-screening program as compared with current practice. In both strategies, symptomatic patients were identified through symptom-based case finding. Identified patients started treatment when their CD4 count dropped to 350 cells per cubic millimeter. Disease progression was defined on the basis of CD4 levels and viral load. The likelihood of sexual transmission was based on viral load, knowledge of HIV status, and efficacy of counseling.Given a 1 percent prevalence of unidentified HIV infection, screening increased life expectancy by 5.48 days, or 4.70 quality-adjusted days, at an estimated cost of 194 dollars per screened patient, for a cost-effectiveness ratio of 15,078 dollars per quality-adjusted life-year. Screening cost less than 50,000 dollars per quality-adjusted life-year if the prevalence of unidentified HIV infection exceeded 0.05 percent. Excluding HIV transmission, the cost-effectiveness of screening was 41,736 dollars per quality-adjusted life-year. Screening every five years, as compared with a one-time screening program, cost 57,138 dollars per quality-adjusted life-year, but was more attractive in settings with a high incidence of infection. Our results were sensitive to the efficacy of behavior modification, the benefit of early identification and therapy, and the prevalence and incidence of HIV infection.The cost-effectiveness of routine HIV screening in health care settings, even in relatively low-prevalence populations, is similar to that of commonly accepted interventions, and such programs should be expanded.

    View details for Web of Science ID 000226862100007

    View details for PubMedID 15703422

  • Genome-wide identification of genes conferring resistance to the anticancer agents cisplatin, oxaliplatin, and mitomycin C CANCER RESEARCH Wu, H. I., BROWN, J. A., Dorie, M. J., Lazzeroni, L., Brown, J. M. 2004; 64 (11): 3940-3948

    Abstract

    Cisplatin is a crucial agent in the treatment of many solid tumors, yet many tumors have either acquired or intrinsic resistance to the drug. We have used the homozygous diploid deletion pool of Saccharomyces cerevisiae, containing 4728 strains with individual deletion of all nonessential genes, to systematically identify genes that when deleted confer sensitivity to the anticancer agents cisplatin, oxaliplatin, and mitomycin C. We found that deletions of genes involved in nucleotide excision repair, recombinational repair, postreplication repair including translesional synthesis, and DNA interstrand cross-link repair resulted in sensitivity to all three of the agents, although with some differences between the platinum drugs and mitomycin C in the spectrum of required translesional polymerases. Putative defective repair of oxidative damage (imp2'Delta strain) also resulted in sensitivity to platinum and oxaliplatin, but not to mitomycin C. Surprisingly in light of their different profiles of clinical activity, cisplatin and oxaliplatin have very similar sensitivity profiles. Finally, we identified three novel genes (PSY1-3, "platinum sensitivity") that, when deleted, demonstrate sensitivity to cisplatin and oxaliplatin, but not to mitomycin C. Our results emphasize the importance of multiple DNA repair pathways responsible for normal cellular resistance to all three of the agents. Also, the similarity of the sensitivity profiles of the platinum agents with that of the known DNA interstrand cross-linking agent mitomycin C, and the importance of the gene PSO2 known to be involved in DNA interstrand cross-link repair strongly suggests that interstrand cross-links are important toxic lesions for cisplatin and oxaliplatin, at least in yeast.

    View details for Web of Science ID 000221727300033

    View details for PubMedID 15173006

  • A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes DIABETES Noble, J. A., White, A. M., Lazzeroni, L. C., Valdes, A. M., Mirel, D. B., Reynolds, R., Grupe, A., Aud, D., Peltz, G., Erlich, H. A. 2003; 52 (6): 1579-1582

    Abstract

    Type 1 diabetes is an autoimmune disease with a Th1 phenotype in which insulin-producing beta-cells in the pancreas are destroyed. The T-cell-specific transcription factor TCF7 activates genes involved in immune regulation and is a candidate locus for genetic susceptibility to type 1 diabetes. A nonsynonymous single nucleotide polymorphism (SNP) (Pro to Thr) in the TCF7 gene, C883A, was examined in samples from 282 Caucasian multiplex type 1 diabetic families. HLA-DRB1 and -DQB1 genotypes were previously determined for these samples, allowing data stratification based on HLA-associated risk. The transmission disequilibrium test showed significant overtransmission of the A allele from fathers (64.1%, P < 0.007) and nonsignificant overtransmission (57.4%, P < 0.06) of the A allele to patients who do not carry the highest-risk HLA-DR3/DR4 genotype. Elliptical sib pair analysis showed significant associations of the A allele with type 1 diabetes in paternal transmissions (P < 0.03), transmissions to male children (P < 0.04), and in the non-DR3/DR4 group (P < 0.04). These data also suggest that TCF7 C883A may affect age of disease onset. Analysis of genotype data from surrounding SNPs suggests that this TCF7 polymorphism may itself represent a risk factor for type 1 diabetes.

    View details for Web of Science ID 000183167600037

    View details for PubMedID 12765974

  • Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations. BMC medical genetics Traynor, J., Agarwal, P., Lazzeroni, L., Francke, U. 2002; 3: 12-?

    Abstract

    Females with the neurological disorder Rett syndrome are heterozygous for mutations in X-linked MECP2 that encodes methyl-CpG binding protein 2 (MeCP2) thought to act as a transcriptional repressor. To identify target genes for MeCP2 modulation, we studied global gene expression in single cell-derived wild-type and mutant MECP2 expressing fibroblast clones with four common mutations (R106W, R306C, 705delG, 1155del32) and in lymphoblastoid cell lines (LCLs) that included four mutant MeCP2 (T158M, 803delG, R168X and 1159del28) expressing, and five (1159del28, R106W, R255X, 803delG, 803delG) wild-type MeCP2 expressing lines.Clonality and mutation status were verified by androgen receptor methylation assays for X-inactivation and by sequencing MECP2 transcripts. Expression studies were done with oligonucleotide microarrays (Affymetrix U95) and verified with real-time quantitative RT-PCR using Sybr Green.Expression of 49 transcripts was increased, and expression of 21 transcripts was decreased, in at least 3 of 4 mutant/wild-type fibroblast comparisons. Transcript levels of 11 genes, determined by quantitative RT-PCR, were highly correlated with the microarray data. Therefore, multiple additional clones from two Rett individuals were tested by RT-PCR only. Striking expression differences were found in both mutant and wildtype MeCP2 expressing clones. Comparing expression profiles of lymphoblastoid cell lines yielded 16 differentially expressed genes.MeCP2 deficiency does not lead to global deregulation of gene expression. Either MeCP2's in vivo function does not involve widespread transcriptional repression, or its function is redundant in cell types that also express other methyl-CpG binding proteins. Our data suggest that clonal fibroblast strains may show substantial inter-strain variation, making them a difficult and unstable resource for genome-wide expression profiling studies.

    View details for PubMedID 12418965

  • Association of IL4R haplotypes with type 1 diabetes DIABETES Mirel, D. B., Valdes, A. M., Lazzeroni, L. C., Reynolds, R. L., Erlich, H. A., Noble, J. A. 2002; 51 (11): 3336-3341

    Abstract

    We have investigated, in 282 multiplex Caucasian families (the Human Biological Data Interchange Repository), the association of type 1 diabetes with polymorphisms in the IL4R gene. IL4R encodes a subunit of the interleukin-4 receptor, a molecule critical to T-helper cell development. By genotyping eight different IL4R single-nucleotide polymorphisms (SNPs) and identifying haplotypes (complex alleles) in the multiplex type 1 diabetic families who were stratified for HLA genotype, we have observed significant evidence of linkage and association of the IL4R gene to type 1 diabetes. In particular, we have identified a specific haplotype that appears to be protective and observed that this protective effect is strongest among individuals not carrying the HLA DR3/DR4 genotype (which confers the strongest genetic risk for type 1 diabetes). These findings suggest an important role for the IL4R gene in immune-related disease susceptibility and illustrate the value of using multi-SNP haplotype information in association studies.

    View details for Web of Science ID 000178914900025

    View details for PubMedID 12401728

  • Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV-infected patients - Natural history and clinical predictors RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Lin, D. Y., Warren, J. F., Lazzeroni, L. C., Wolitz, R. A., Mansour, S. E. 2002; 22 (3): 268-277

    Abstract

    To characterize the natural course and clinical predictors of cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients after initiation of highly active antiretroviral therapy (HAART).Retrospective analysis of 53 HIV-positive patients (73 eyes with CMV retinitis) treated with and without HAART. All participants continued to take anti-CMV therapy. Survival analysis was used to characterize the natural course of CMV retinitis. Proportional hazards analysis was performed to assess the correlation of the nine potential clinical predictors (baseline CD4 count, post-HAART CD4 count, post-HAART rise in CD4 count, baseline weight, post-HAART rise in weight, post-HAART percentage rise in weight, log of baseline HIV viral load, log of minimum post-HAART HIV viral load, and post-HAART log unit reduction in HIV viral load) with the duration of CMV retinitis remission.Patients receiving HAART had a median CMV retinitis remission duration of 574 days (95% confidence interval, 336-NA) whereas those not receiving HAART had a median remission duration of 80.5 days (95% confidence interval, 28-NA; P < 0.001). Within the HAART-treated population, the minimal viral load reached after HAART was the only clinical predictor to demonstrate significance (P = 0.0075). Several other clinical predictors demonstrated borderline significance; however, this was most likely due to the high correlation of these variables with the minimum post-HAART viral load. A potential secondary clinical predictor identified was the post-HAART rise in CD4 count (P = 0.085).With the introduction of HAART, HIV-infected patients have much longer remission durations from recurrent CMV retinitis. The minimum HIV viral load level reached after the initiation of HAART treatment appears to be more important than other clinical variables in the prediction of favorable CMV retinitis remission status. Furthermore, a rise in CD4 T-lymphocyte count by itself appears to be a less significant clinical predictor but may be useful in combination with the HIV viral load data. Selective discontinuation of anti-CMV therapy may be considered in patients with a favorable set of clinical predictors.

    View details for Web of Science ID 000176594200003

    View details for PubMedID 12055458

  • Allele sharing and allelic association I: Sib pair tests with increased power GENETIC EPIDEMIOLOGY Lazzeroni, L. C. 2002; 22 (4): 328-344

    Abstract

    Affected sib pair data contain information about allele sharing and allelic association. Either of these features can point to the presence of a risk-related gene. This study introduces the elliptical sib pair test, a generalization of traditional sib pair tests. The proposed test can be implemented using any of three strategies, the choice of which depends on the anticipated combination of sharing and association. The elliptical sib pair test can achieve substantial gains in power relative to traditional tests for likely alternative hypotheses at little or no cost for other alternatives. The proposed test is valid under most models of genetic risk, disease etiology, and genotype-haplotype distributions. This study also provides new insight into the trade-off between tests of allelic association and tests of allele sharing.

    View details for DOI 10.1002/gepi.0185

    View details for Web of Science ID 000175413700005

    View details for PubMedID 11984865

  • Plaid models for gene expression data STATISTICA SINICA Lazzeroni, L., Owen, A. 2002; 12 (1): 61-86
  • A high-resolution radiation hybrid map of the human genome draft sequence SCIENCE Olivier, M., Aggarwal, A., Allen, J., Almendras, A. A., Bajorek, E. S., Beasley, E. M., Brady, S. D., Bushard, J. M., Bustos, V. I., Chu, A., Chung, T. R., de Witte, A., Denys, M. E., Dominguez, R., Fang, N. Y., Foster, B. D., Freudenberg, R. W., Hadley, D., Hamilton, L. R., Jeffrey, T. J., Kelly, L., Lazzeroni, L., Levy, M. R., Lewis, S. C., Liu, X., Lopez, F. J., Louie, B., Marquis, J. P., Martinez, R. A., Matsuura, M. K., Misherghi, N. S., NORTON, J. A., Olshen, A., Perkins, S. M., Perou, A. J., Piercy, C., Piercy, M., Qin, F., Reif, T., Sheppard, K., Shokoohi, V., Smick, G. A., Sun, W. L., Stewart, E. A., Tejeda, J. F., Tran, N. M., Trejo, T., Vo, N. T., Yan, S. C., Zierten, D. L., Zhao, S. Y., Sachidanandam, R., Trask, B. J., Myers, R. M., Cox, D. R. 2001; 291 (5507): 1298-?

    Abstract

    We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

    View details for Web of Science ID 000166993400040

    View details for PubMedID 11181994

  • A chronology of fine-scale gene mapping by linkage disequilibrium STATISTICAL METHODS IN MEDICAL RESEARCH Lazzeroni, L. C. 2001; 10 (1): 57-76

    Abstract

    The past decade produced several proposals for fine-scale gene mapping using linkage disequilibrium data. The suggested methods fall into two main groups, those that rely on pairwise statistics and those that rely on haplotypes. This paper reviews each strategy's development from a chronological perspective.

    View details for Web of Science ID 000168123300004

    View details for PubMedID 11329692

  • Statistical refinement of primer design parameters. PCR Applications: Protocols for Functional Genomics Beasley EM, Myers RM, Cox DR, Lazzeroni LC 1999
  • A conditional inference framework for extending the transmission/disequilibrium test HUMAN HEREDITY Lazzeroni, L. C., Lange, K. 1998; 48 (2): 67-81

    Abstract

    The transmission/disequilibrium test (TDT) of Terwilliger and Ott [Hum Hered 1992;42:337-346] and Spielman et al. [Am J Hum Genet 1993;52:506-516] is widely used to detect linkage and/or association between a genetically influenced disease and the alleles of a codominant marker locus. The TDT was specifically designed to avoid the spurious population associations produced by ethnic stratification of a sample of affected people. In this paper, we describe permutation extensions of the TDT that share this advantage. Our conditional inference framework permits extensions to multiple alleles, multiple loci, unaffected siblings, and genotypic rather than allelic associations. In the case of multiple loci, the conditional perspective provides a straightforward correction for multiple tests that can be substantially more powerful than the standard Bonferroni correction.

    View details for Web of Science ID 000072240900002

    View details for PubMedID 9526165

  • Random-effects models for smoothing post-stratification weights Journal of Official Statistics Lazzeroni LC, Little RJA 1998; 14: 61-78
  • Linkage disequilibrium and gene mapping: An empirical least-squares approach AMERICAN JOURNAL OF HUMAN GENETICS Lazzeroni, L. C. 1998; 62 (1): 159-170

    Abstract

    This paper proposes a novel approach for fine-scale mapping of disease genes that is based on the well-known linkage-disequilibrium parameter delta. Using a very simple, very general model, I show how delta can be interpreted in terms of identity-by-descent probabilities. The value of delta follows a piecewise curve along the chromosome, with the maximum occurring at the disease locus where the two pieces intersect. A semiparametric, multilocus approach is used to fit this nonlinear regression curve in order to estimate the gene location. Using the bootstrap to empirically estimate much of the probability model from the data avoids the need for many detailed population assumptions. One advantage of the approach is its use of the observed covariance structure of the data, which can be highly informative as to the gene location. I illustrate the method on the cystic fibrosis data of Kerem et al.

    View details for Web of Science ID 000072127900021

    View details for PubMedID 9490574

  • Markov chains for Monte Carlo tests of genetic equilibrium in multidimensional contingency tables ANNALS OF STATISTICS Lazzeroni, L. C., Lange, K. 1997; 25 (1): 138-168
  • Individual variation in recombination among human males AMERICAN JOURNAL OF HUMAN GENETICS Yu, J., Lazzeroni, L., Qin, J., Huang, M. M., Navidi, W., Erlich, H., Arnheim, N. 1996; 59 (6): 1186-1192

    Abstract

    Studies of recombination between the markers D6S291 and D6S109 in individuals by sperm typing provide direct evidence for significant variation in recombination among humans. A statistically significant difference in the recombination fraction (range 5.1%-11.2%) was detected among five donors. This variation could reflect polymorphisms in genes affecting recombination or in chromosome structure. Ignoring this variability in studies designed to examine the relationship between physical and genetic distances could lead to incorrect inferences. Individual variation in recombination makes it difficult to predict the recombination fraction for an interval in any particular individual. This could be important in certain genetic counseling situations.

    View details for Web of Science ID A1996VV31500004

    View details for PubMedID 8940263

  • In vivo sequence diversity of the protease of human immunodeficiency virus type 1: Presence of protease inhibitor-resistant variants in untreated subjects JOURNAL OF VIROLOGY Lech, W. J., Wang, G., Yang, Y. L., Chee, Y., Dorman, K., McCrae, D., Lazzeroni, L. C., Erickson, J. W., Sinsheimer, J. S., Kaplan, A. H. 1996; 70 (3): 2038-2043

    Abstract

    We have evaluated the sequence diversity of the protease human immunodeficiency virus type 1 in vivo. Our analysis of 246 protease coding domain sequences obtained from 12 subjects indicates that amino acid substitutions predicted to give rise to protease inhibitor resistance may be present in patients who have not received protease inhibitors. In addition, we demonstrated that amino acid residues directly involved in enzyme-substrate interactions may be varied in infected individuals. Several of these substitutions occurred in combination either more or less frequently than would be expected if their appearance was independent, suggesting that one substitution may compensate for the effects of another. Taken together, our analysis indicates that the human immunodeficiency virus type 1 protease has flexibility sufficient to vary critical subsites in vivo, thereby retaining enzyme function and viral pathogenicity.

    View details for Web of Science ID A1996TV69600086

    View details for PubMedID 8627733

  • MULTIPOINT LINKAGE MAP OF THE HUMAN PSEUDOAUTOSOMAL REGION, BASED ON SINGLE-SPERM TYPING - DO DOUBLE CROSSOVERS OCCUR DURING MALE MEIOSIS AMERICAN JOURNAL OF HUMAN GENETICS Schmitt, K., Lazzeroni, L. C., Foote, S., Vollrath, D., Fisher, E. M., Goradia, T. M., Lange, K., Page, D. C., Arnheim, N. 1994; 55 (3): 423-430

    Abstract

    Sperm typing was used to measure recombination fractions among pseudoautosomal markers and the beginning of the X/Y-specific sequences located at the pseudoautosomal boundary. These experiments included primer-extension preamplification and PCR followed by allele typing using gel electrophoresis. A newly developed data-analysis program allowed the construction of the first multipoint-linkage sperm-typing map, using results obtained on seven loci from three individuals. The large sample size not only confirmed the increased recombination activity of the pseudoautosomal region but allowed an estimate of interference of recombination to be made. The coefficient of coincidence was calculated to be .26 over a physical distance of only approximately 1,800 kb. The observation of a few sperm presumably resulting from double recombination argues that more than one crossover event can occur in this region during male meiosis.

    View details for Web of Science ID A1994PF50900002

    View details for PubMedID 8079986

  • MULTIPOINT MAPPING CALCULATIONS FOR SPERM-TYPING DATA AMERICAN JOURNAL OF HUMAN GENETICS Lazzeroni, L. C., Arnheim, N., Schmitt, K., Lange, K. 1994; 55 (3): 431-436

    Abstract

    This paper explains how multipoint likelihoods can be computed for sperm-typing data. Experimental errors such as multiple sperm per tube, inadequate amplification, and contamination by exogenous DNA are explicitly taken into account. By limiting the number of sperm theoretically possible per tube to a predetermined maximum and by assuming no chiasma interference, maximum-likelihood estimation can be carried out rapidly using the theory of hidden Markov chains.

    View details for Web of Science ID A1994PF50900003

    View details for PubMedID 8079987

  • Models for smoothing post-stratification weights Proceedings of the Survey Research Methods Section, ASA Lazzeroni LC, Little RJA 1993: 764-769
  • Robustness of multiple-imputation techniques to model misspecification Proc. Survey Research Methods Section, ASA Lazzeroni LC, Schenker N, Taylor JMG 1990: 260-265

Conference Proceedings


  • Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study Light, G., Greenwood, T. A., Swerdlow, N. R., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2014
  • Pure hematopoietic stem cells reconstitute immunity in allogeneic hosts superior to bone marrow: Immunosuppression by subclinical graft-versus-host disease Tsao, G. J., Allen, J. A., Logronio, K., Lazzeroni, L. C., Shizuru, J. A. AMER SOC HEMATOLOGY. 2007: 292B-292B
  • Genotype to phenotype: associations, errors and complexity. Lazzeroni, L. C., Karlovich, C. A. 2002: 283-284

    Abstract

    The Keystone Symposium on Genotype to Phenotype: Focus on Disease was held in Santa Fe, New Mexico, USA, from 19 to 24 February 2002.

    View details for PubMedID 12044349

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