I am a family doctor and physician scientist interested in translational research to improve preventive health and public health strategies to improve population health. My research focuses on the integration of clinical and translational research into nicotine dependence using genomic and neuromaging investigations to identify and validate biomarkers for smoking cessation, to reduce health disparities in cardiovascular disease and cancer, and to employ community engagement and clinical implementation science approaches to fill critical gaps in preventive medicine. Recent work includes the identification of a genome-wide significant genetic marker for smoking intensity in African Americans that is associated with pharmacogenetic treatment response for smoking cessation and risk of lung cancer in African Americans. I am also an investigator in the GWAS and Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium and the Stanford Precision Health for Ethnic and Racial Equity (SPHERE) Transdisciplinary Collaborative Center. Current and future research is translating evidence in systematic reviews and meta-analyses to evidence-based guidelines, investigations of publication bias and proposed reforms to improve the fidelity of research through open science, clinical implementation sciences for precision health, and training the primary care workforce in core competencies of genetic medicine to enable precision health for all. Born and raised in Seattle, I love the west and Pac-12 football, fishing, sailing, marathon running and rowing.

Clinical Focus

  • Precision Health
  • Family Medicine
  • Pharmacogenomics
  • Tobacco Treatment

Academic Appointments

Administrative Appointments

  • Member, Stanford Cancer Institute (2016 - Present)
  • Associate Professor of Medicine, Stanford University School of Medicine (2014 - Present)
  • Member Affiliate, Meta-Research Innovation Center at Stanford (METRICS) (2014 - Present)
  • Clinical Associate Professor (secondary appointment), Stanford Prevention Research Center (2011 - Present)
  • Physician curator, PharmGKB (2010 - 2011)
  • Adjunct Associate Professor of Family Medicine, Brown Alpert Medical School (2009 - 2014)
  • Clinical Associate Professor of Family & Community Medicine, Stanford University School of Medicine (2009 - 2014)
  • Director of C. Everett Koop Health Policy Fellowship, Brown Alpert Medical School (2003 - 2009)
  • Director of Primary Care Genetics Laboratory & Translational Research Center, Memorial Hospital of Rhode Island/Brown Alpert Medical School (2002 - 2009)
  • Assistant Professor of Family Medicine, Brown Alpert Medical School (2001 - 2009)
  • Instructor of Family Medicine, Brown Alpert Medical School (1999 - 2001)

Honors & Awards

  • Family Practice Scholar Award, Glaxo-Wellcome (1997)
  • Dean’s Teaching Excellence Award, Brown Alpert Medical School (2001)
  • Advanced Research Training Award, American Academy of Family Physicians (2001-2003)
  • Profiles in Competence Teaching Award, Brown Alpert Medical School (2002)
  • Generalist Physician Faculty Scholars Award, Robert Wood Johnson Foundation (2002-2006)
  • K08 Mentored Clinical Scientist Development Award, National Institute on Drug Abuse/National Institutes of Health (2002-2008)
  • MCR President, Green College, University of Oxford (2004-2005)
  • Benjamin Meaker Visiting Professorship, University of Bristol (2010)
  • James C. Puffer, M.D./ABFM/National Academy of Medicine Anniversary Fellow, National Academies of Science, Engineering, and Medicine (2011-2013)
  • Board of US BMJ Fellows, BMJ Group (2013)
  • Fellow, American Academy of Family Physicians, American Academy of Family Physicians (2017)

Boards, Advisory Committees, Professional Organizations

  • US Board of BMJ Fellows, British Medical Journal (2013 - Present)
  • Young Leaders Advisory Group, American Board of Family Medicine (2010 - Present)
  • Smoking Cessation Guideline Panel, National Comprehensive Cancer Network (2014 - Present)
  • Scientific Advisory Committee, Tobacco-Related Disease Research Program - University of California Office of the President (2013 - 2015)
  • Committee on the Evidence Base for Genetic Testing, National Academy of Medicine (2015 - 2017)

Professional Education

  • BS, University of Washington, Zoology (1990)
  • Medical Education:University of Washington School of Medicine (1995) WA
  • Internship:NH Dartmouth Family Practice Residency (1996) NH
  • Residency:NH Dartmouth Family Practice Residency (1998) NH
  • Board Certification: Family Medicine, American Board of Family Medicine (1998)
  • SM, Harvard School of Public Health, Health & Social Behavior (1999)
  • Fellowship, Cancer Research UK GPRG, University of Oxford, Pharmacogenetics (2002)
  • Fellowship, C. Everett Koop Institute at Dartmouth, Tobacco Control (2002)
  • Fellowship, American Academy of Family Physicians, Advanced Research Training (2003)
  • Board Recertification, Family Medicine, American Board of Family Medicine (2005)
  • Fellowship, Robert Wood Johnson Foundation Generalist Physician Faculty Scholar, Pharmacogenetics of Smoking Cessation in Primary Care (2006)
  • Professional Education:University of Oxford (2006) UK
  • Fellowship, NIDA K08 Mentored Clinical Scientist, Nicotine Dependence (2007)
  • Fellowship, National Academies of Sciences, Engineering, and Medicine, Health Policy (James C. Puffer, M.D./American Board of Family Medicine/National Academy of Medicine Anniversary Fellow) (2013)
  • Board Recertification, Family Medicine, American Board of Family Medicine (2015)

Community and International Work

  • Stanford Precision Health for Ethnic and Racial Equity Center (SPHERE), Bay Area and South Dakota


    Precision health, health disparities

    Partnering Organization(s)

    National Institute on Minority Health and Health Disparities/National Institutes of Health

    Populations Served

    Asians, African-Americans, Latino/Hispanics, Native Americans



    Ongoing Project


    Opportunities for Student Involvement


  • Study of Tobacco Use in Minority Populations (STOMP) Genetics Consortium, US


    Genetics, Smoking, African Americans

    Partnering Organization(s)

    SRI International, Memorial Sloan-Kettering Cancer Center, Brown University and other institutions.

    Populations Served

    African Americans



    Ongoing Project


    Opportunities for Student Involvement


  • CYP2A6 genotype and smoking in China, Guangzhou, P.R. China


    Genetic influences on smoking

    Partnering Organization(s)

    Sun Yat-sen University; University of Toronto



    Ongoing Project


    Opportunities for Student Involvement


Research & Scholarship

Current Research and Scholarly Interests

My research encompasses a collaborative, transdisciplinary initiative to translate molecular insights to genomically-tailored and patient-centered personalized medicine. Investigations are focused on the integration of three translational streams of investigation. The first stream triangulates genome-wide association studies with preclinical research using functional neuroimaging and other modalities aimed at elucidating biobehavioural mechanisms nicotine dependence and smoking cessation. The second stream investigates moderating effects of genotype on health-related behavior and drug response (particularly in smoking cessation treatment) in multiple ancestral populations. The third stream investigates the efficacy of genomically-tailored drug and behavioural therapies in prospective first-in-human clinical trials and evidenced-based medicine and policy research (e.g., systematic review/meta-analyses, cost-effectiveness analyses, healthcare delivery systems & educating the primary care workforce).

Clinical Trials

  • Extended Treatment for Smoking Cessation Not Recruiting

    Adult smokers (21-65) and adolescent smokers (18 - 21) years of age residing in Alameda and Santa Clara counties will serve as the target population for this study. A total of 400 smokers meeting eligibility criteria will be randomized. Treatment will include both open label and extended treatment phases. Randomization. Participants will be randomized to extended therapy or control conditions at baseline (prior to open label treatment) and the analysis will be intention-to-treat (ITT) to avoid the threat of selection bias. Primary hypothesis. Smokers randomized to receive CBT during extended treatment will have a higher prolonged abstinence rate (PA) at 52 week and 104 week follow-up than participants in the Supportive therapy Control treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Erin Crew, M.P.H., (408) 415-7301.

    View full details

  • Behaviorally Enhanced Counseling on Nicotine Dependence (BEACON) Trial. Not Recruiting

    The major purpose of this exploratory developmental study will be to develop a patient-centered and feasible protocol for communicating genetic data as it relates to drug efficacy for smoking cessation inpatients receiving medication that is matched to individual genotypes associated with increased efficacy for bupropion or nicotine replacement therapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sean David, (650) 498 - 4687.

    View full details



All Publications

  • Clinical and Personal Utility of Genetic Risk Testing AMERICAN FAMILY PHYSICIAN David, S. P., Palaniappan, L. 2018; 97 (9): 600–602

    View details for Web of Science ID 000432104100008

    View details for PubMedID 29763257

  • Potential Reporting Bias in Neuroimaging Studies of Sex Differences. Scientific reports David, S. P., Naudet, F., Laude, J., Radua, J., Fusar-Poli, P., Chu, I., Stefanick, M. L., Ioannidis, J. P. 2018; 8 (1): 6082


    Numerous functional magnetic resonance imaging (fMRI) studies have reported sex differences. To empirically evaluate for evidence of excessive significance bias in this literature, we searched for published fMRI studies of human brain to evaluate sex differences, regardless of the topic investigated, in Medline and Scopus over 10 years. We analyzed the prevalence of conclusions in favor of sex differences and the correlation between study sample sizes and number of significant foci identified. In the absence of bias, larger studies (better powered) should identify a larger number of significant foci. Across 179 papers, median sample size was n = 32 (interquartile range 23-47.5). A median of 5 foci related to sex differences were reported (interquartile range, 2-9.5). Few articles (n = 2) had titles focused on no differences or on similarities (n = 3) between sexes. Overall, 158 papers (88%) reached "positive" conclusions in their abstract and presented some foci related to sex differences. There was no statistically significant relationship between sample size and the number of foci (-0.048% increase for every 10 participants, p = 0.63). The extremely high prevalence of "positive" results and the lack of the expected relationship between sample size and the number of discovered foci reflect probable reporting bias and excess significance bias in this literature.

    View details for DOI 10.1038/s41598-018-23976-1

    View details for PubMedID 29666377

  • From genes to treatments: a systematic review of the pharmacogenetics in smoking cessation. Pharmacogenomics Salloum, N. C., Buchalter, E. L., Chanani, S., Espejo, G., Ismail, M. S., Laine, R. O., Nageeb, M., Srivastava, A. B., Trapp, N., Trillo, L., Vance, E., Wenzinger, M., Hartz, S. M., David, S. P., Chen, L. S. 2018


    Smoking cessation treatment outcomes may be heavily influenced by genetic variations among smokers. Therefore, identifying specific variants that affect response to different pharmacotherapies is of major interest to the field. In the current study, we systematically review all studies published in or after the year 1990 which examined one or more gene-drug interactions for smoking cessation treatment. Out of 644 citations, 46 articles met the inclusion criteria for the systematic review. We summarize evidence on several genetic polymorphisms (CHRNA5-A3-B4, CYP2A6, DBH, CHRNA4, COMT, DRD2, DRD4 and CYP2B6) and their potential moderating pharamacotherarpy effects on patient cessation efficacy rates. These findings are promising and call for further research to demonstrate the effectiveness of genetic testing in personalizing treatment decision-making and improving outcome.

    View details for DOI 10.2217/pgs-2018-0023

    View details for PubMedID 29914292

  • Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries. Nature communications Zekavat, S. M., Ruotsalainen, S., Handsaker, R. E., Alver, M., Bloom, J., Poterba, T., Seed, C., Ernst, J., Chaffin, M., Engreitz, J., Peloso, G. M., Manichaikul, A., Yang, C., Ryan, K. A., Fu, M., Johnson, W. C., Tsai, M., Budoff, M., Ramachandran, V. S., Cupples, L. A., Rotter, J. I., Rich, S. S., Post, W., Mitchell, B. D., Correa, A., Metspalu, A., Wilson, J. G., Salomaa, V., Kellis, M., Daly, M. J., Neale, B. M., McCarroll, S., Surakka, I., Esko, T., Ganna, A., Ripatti, S., Kathiresan, S., Natarajan, P. 2018; 9 (1): 2606


    Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

    View details for DOI 10.1038/s41467-018-04668-w

    View details for PubMedID 29973585

    View details for PubMedCentralID PMC6031652

  • Whole genome sequence analyses of brain imaging measures in the Framingham Study. Neurology Sarnowski, C., Satizabal, C. L., DeCarli, C., Pitsillides, A. N., Cupples, L. A., Vasan, R. S., Wilson, J. G., Bis, J. C., Fornage, M., Beiser, A. S., DeStefano, A. L., Dupuis, J., Seshadri, S. 2018; 90 (3): e188–e196


    We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005,p= 10-8) and in 16q23 for hippocampal volume (MAF 0.05,p= 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919,p= 4.4 × 10-4) and in 17q25 for WMH (rs7214628,p= 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

    View details for DOI 10.1212/WNL.0000000000004820

    View details for PubMedID 29282330

    View details for PubMedCentralID PMC5772158

  • Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nature communications Natarajan, P., Peloso, G. M., Zekavat, S. M., Montasser, M., Ganna, A., Chaffin, M., Khera, A. V., Zhou, W., Bloom, J. M., Engreitz, J. M., Ernst, J., O'Connell, J. R., Ruotsalainen, S. E., Alver, M., Manichaikul, A., Johnson, W. C., Perry, J. A., Poterba, T., Seed, C., Surakka, I. L., Esko, T., Ripatti, S., Salomaa, V., Correa, A., Vasan, R. S., Kellis, M., Neale, B. M., Lander, E. S., Abecasis, G., Mitchell, B., Rich, S. S., Wilson, J. G., Cupples, L. A., Rotter, J. I., Willer, C. J., Kathiresan, S. 2018; 9 (1): 3391


    Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

    View details for DOI 10.1038/s41467-018-05747-8

    View details for PubMedID 30140000

  • Leveraging genomic data in smoking cessation trials in the era of Precision Medicine: Why and how. Nicotine & tobacco research Chen, L., Zawertailo, L., Piasecki, T. M., Kaprio, J., Foreman, M., Elliott, H. R., David, S. P., Bergen, A. W., Baurley, J. W., Tyndale, R. F., Baker, T. B., Bierut, L. J., Saccone, N. L. 2017


    This paper outlines a framework for the consistent integration of biological data/samples into smoking cessation pharmacotherapy trials, aligned with the objectives of the recently unveiled Precision Medicine Initiative. Our goal is to encourage and provide support for treatment researchers to consider biosample collection and genotyping their existing samples, as well as integrating genetic analyses into their study design in order to realize precision medicine in treatment of nicotine dependence.

    View details for DOI 10.1093/ntr/ntx097

    View details for PubMedID 28498934

  • The Value of Biosamples in Smoking Cessation Trials: A Review of Genetic, Metabolomic, and Epigenetic Findings. Nicotine & tobacco research Saccone, N. L., Baurley, J. W., Bergen, A. W., David, S. P., Elliott, H. R., Foreman, M. G., Kaprio, J., Piasecki, T. M., Relton, C. L., Zawertailo, L., Bierut, L. J., Tyndale, R. F., Chen, L. 2017


    Evidence is emerging that certain genotypes and biomarkers are associated with smoking cessation success and efficacy of smoking cessation treatments. We review key findings that open potential avenues for personalizing smoking cessation treatment according to an individual's genetic or metabolic profile. These results provide important incentive for smoking cessation researchers to collect biosamples and perform genotyping in research studies and clinical trials.

    View details for DOI 10.1093/ntr/ntx096

    View details for PubMedID 28472521

  • Extended treatment for cigarette smoking cessation: A randomized control trial. Addiction Laude, J. R., Bailey, S. R., Crew, E., Varady, A., Lembke, A., McFall, D., Jeon, A., Killen, D., Killen, J. D., David, S. P. 2017


    To test the potential benefit of extending cognitive-behavioral therapy (CBT) relative to not extending CBT on long-term abstinence from smoking.Two-group parallel randomised controlled trial. Patients were randomized to receive non-extended CBT (n = 111) or extended CBT (n = 112) following a 26-week open-label treatment.Community clinic in the USA.219 smokers (mean age: 43 years; mean cigarettes/day: 18).All participants received 10 weeks of combined CBT + bupropion sustained release (bupropion SR) + nicotine patch and were continued on CBT and either no medications if abstinent, continued bupropion + nicotine replacement therapy (NRT) if increased craving or depression scores, or varenicline if still smoking at 10 weeks. Half of participants were randomized at 26 weeks to extended CBT (E-CBT) through week 48 and half to non-extended CBT (no additional CBT sessions).The primary outcome was expired CO-confirmed, seven-day point-prevalence (PP) at 52-week and 104-week follow-up. Analyses were based on intention-to-treat.PP-abstinence rates at the 52-week follow-up were comparable across non-extended CBT (40%) and E-CBT (39%) groups [OR 0.99; 95% CI (0.55,1.78)]. A similar pattern was observed across non-extended CBT (39%) and E-CBT (33%) groups at the 104-week follow-up [OR 0.79; 95% CI (0.44,1.40)].Prolonging cognitive-behavioral therapy from 26 to 48 weeks does not appear to improve long-term abstinence from smoking.

    View details for DOI 10.1111/add.13806

    View details for PubMedID 28239942

  • Patient and provider perspectives on the development of personalized medicine: a mixed-methods approach. Journal of community genetics Puryear, L., Downs, N., Nevedal, A., Lewis, E. T., Ormond, K. E., Bregendahl, M., Suarez, C. J., David, S. P., Charlap, S., Chu, I., Asch, S. M., Pakdaman, N., Chang, S. I., Cullen, M. R., Palaniappan, L. 2017


    While genetic testing gains adoption in specialty services such as oncology, neurology, and cardiology, use of genetic and genomic testing has yet to be adopted as widely in primary care. The purpose of this study is to identify and compare patient and primary care provider (PCP) expectations of genetics services in primary care. Patient and PCP perspectives were assessed through a mixed-method approach combining an online survey and semi-structured interviews in a primary care department of a large academic medical institution. A convenience sample of 100 adult primary care patients and 26 PCPs was gathered. The survey and interview questions focused on perceptions of genetic testing, experience with genetic testing, and expectations of genetic services in primary care. Patients felt that their PCP was knowledgeable about genetic testing and expected their PCP to be the first to recognize a need for genetic testing based on family history. Nonetheless, patients reported that PCPs rarely used family history information to discuss genetic risks or order testing. In contrast, PCPs felt uncertain about the clinical utility and scientific value of genetic testing. PCPs were concerned that genetic testing could cause anxiety, frustration, discrimination, and reduced insurability, and that there was unequal access to testing. PCPs described themselves as being "gatekeepers" to genetic testing but did not feel confident or have the desire to become experts in genetic testing. However, PCPs were open to increasing their working knowledge of genetic testing. Within this academic medical center, there is a gap between what patients expect and what primary care providers feel they are adequately prepared to provide in terms of genetic testing services.

    View details for DOI 10.1007/s12687-017-0349-x

    View details for PubMedID 29280052

  • Novel Methodologies and the Need for Big Data in Nicotine and Tobacco Genetics Research. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco David, S. P. 2017; 19 (4): 385–86

    View details for DOI 10.1093/ntr/ntx005

    View details for PubMedID 28393169

  • Tobacco Use Disorder Integrating Psychological and Pharmacological Treatments for Addictive Disorders: An Evidence-Based Guide MacKillop, J., Gray, J. C., Owen, M. M., Laude, J., David, S. edited by MacKillop, J., Kenna, G., Leggio, L., Ray, L. A. Routledge. 2017
  • Genomic and Precision Medicine Primary Care Preface GENOMIC AND PRECISION MEDICINE: PRIMARY CARE, 3RD EDITION David, S. P., Willard, H. F., Ginsburg, G. S., David, S. P. 2017: XV-XVI
  • Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers. The Cochrane database of systematic reviews Schuit, E., Panagiotou, O. A., Munafò, M. R., Bennett, D. A., Bergen, A. W., David, S. P. 2017; 9: CD011823


    Smoking cessation therapies are not effective for all smokers, and researchers are interested in identifying those subgroups of individuals (e.g. based on genotype) who respond best to specific treatments.To assess whether quit rates vary by genetically informed biomarkers within pharmacotherapy treatment arms and as compared with placebo. To assess the effects of pharmacotherapies for smoking cessation in subgroups of smokers defined by genotype for identified genome-wide significant polymorphisms.We searched the Cochrane Tobacco Addiction Group specialised register, clinical trial registries, and genetics databases for trials of pharmacotherapies for smoking cessation from inception until 16 August 2016.We included randomised controlled trials (RCTs) that recruited adult smokers and reported pharmacogenomic analyses from trials of smoking cessation pharmacotherapies versus controls. Eligible trials included those with data on a priori genome-wide significant (P < 5 × 10(-8)) single-nucleotide polymorphisms (SNPs), replicated non-SNPs, and/or the nicotine metabolite ratio (NMR), hereafter collectively described as biomarkers.We used standard methodological procedures expected by Cochrane. The primary outcome was smoking abstinence at six months after treatment. The secondary outcome was abstinence at end of treatment (EOT). We conducted two types of meta-analyses- one in which we assessed smoking cessation of active treatment versus placebo within genotype groups, and another in which we compared smoking cessation across genotype groups within treatment arms. We carried out analyses separately in non-Hispanic whites (NHWs) and non-Hispanic blacks (NHBs). We assessed heterogeneity between genotype groups using T², I², and Cochrane Q statistics.Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms.For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotypeFor six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation armsFor those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo.We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.

    View details for DOI 10.1002/14651858.CD011823.pub2

    View details for PubMedID 28884473

  • Smoking Cessation, Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Shields, P. G., Herbst, R. S., Arenberg, D., Benowitz, N. L., Bierut, L., Luckart, J. B., Cinciripini, P., Collins, B., David, S., Davis, J., Hitsman, B., Hyland, A., Lang, M., Leischow, S., Park, E. R., Purcell, W. T., Selzle, J., Silber, A., Spencer, S., Tanvetyanon, T., Tiep, B., Tindle, H. A., Tucker-Seeley, R., Urbanic, J., Hooper, M. W., Weksler, B., Whitlock, C. W., Wood, D. E., Burns, J., Scavone, J. 2016; 14 (11): 1430-1468


    Cigarette smoking has been implicated in causing many cancers and cancer deaths. There is mounting evidence indicating that smoking negatively impacts cancer treatment efficacy and overall survival. The NCCN Guidelines for Smoking Cessation have been created to emphasize the importance of smoking cessation and establish an evidence-based standard of care in all patients with cancer. These guidelines provide recommendations to address smoking in patients and outlines behavioral and pharmacologic interventions for smoking cessation throughout the continuum of oncology care.

    View details for Web of Science ID 000386880300013

    View details for PubMedID 27799513

  • Persistent alterations of gene expression profiling of human peripheral blood mononuclear cells from smokers. Molecular carcinogenesis Weng, D. Y., Chen, J., Taslim, C., Hsu, P., Marian, C., David, S. P., Loffredo, C. A., Shields, P. G. 2016; 55 (10): 1424-1437


    The number of validated biomarkers of tobacco smoke exposure is limited, and none exist for tobacco-related cancer. Additional biomarkers for smoke, effects on cellular systems in vivo are needed to improve early detection of lung cancer, and to assist the Food and Drug Administration in regulating exposures to tobacco products. We assessed the effects of smoking on the gene expression using human cell cultures and blood from a cross-sectional study. We profiled global transcriptional changes in cultured smokers' peripheral blood mononuclear cells (PBMCs) treated with cigarette smoke condensate (CSC) in vitro (n = 7) and from well-characterized smokers' blood (n = 36). ANOVA with adjustment for covariates and Pearson correlation were used for statistical analysis in this study. CSC in vitro altered the expression of 1 178 genes (177 genes with > 1.5-fold-change) at P < 0.05. In vivo, PBMCs of heavy and light smokers differed for 614 genes (29 with > 1.5-fold-change) at P < 0.05 (309 remaining significant after adjustment for age, race, and gender). Forty-one genes were persistently altered both in vitro and in vivo, 22 having the same expression pattern reported for non-small cell lung cancer. Our data provides evidence that persistent alterations of gene expression in vitro and in vivo may relate to carcinogenic effects of cigarette smoke, and the identified genes may serve as potential biomarkers for cancer. The use of an in vitro model to corroborate results from human studies provides a novel way to understand human exposure and effect. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mc.22385

    View details for PubMedID 26294040

  • Teaching Medical Students to Help Patients Quit Smoking: Outcomes of a 10-School Randomized Controlled Trial. Journal of general internal medicine Ockene, J. K., Hayes, R. B., Churchill, L. C., Crawford, S. L., Jolicoeur, D. G., Murray, D. M., Shoben, A. B., David, S. P., Ferguson, K. J., Huggett, K. N., Adams, M., Okuliar, C. A., Gross, R. L., Bass, P. F., Greenberg, R. B., Leone, F. T., Okuyemi, K. S., Rudy, D. W., Waugh, J. B., Geller, A. C. 2016; 31 (2): 172-181


    Early in medical education, physicians must develop competencies needed for tobacco dependence treatment.To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students' counseling skills.A group-randomized controlled trial (2010-2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE).Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N = 1345) completed objective structured clinical examinations (OSCEs), and 50 % (N = 660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N = 1096) from the class of 2014 completed an OSCE and 69.7 % (N = 1047) completed pre and post surveys.The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students.The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling.Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean 8.0 [SE 0.6], p = 0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p < 0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p < 0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps ≤0.05).Inclusion of only ten schools limits generalizability.Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools. NIH Trial Registry Number: NCT01905618.

    View details for DOI 10.1007/s11606-015-3508-y

    View details for PubMedID 26391030

  • Gene by Environment Interaction Linking the Chromosome 15q25 Locus with Cigarette Consumption and Lung Cancer Susceptibility - Are African American Affected Differently? - Authors' Reply. EBioMedicine David, S. P., Amos, C. I. 2016; 4: 15-?

    View details for DOI 10.1016/j.ebiom.2016.01.006

    View details for PubMedID 26981563

  • Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans. EBioMedicine David, S. P., Wang, A., Kapphahn, K., Hedlin, H., Desai, M., Henderson, M., Yang, L., Walsh, K. M., Schwartz, A. G., Wiencke, J. K., Spitz, M. R., Wenzlaff, A. S., Wrensch, M. R., Eaton, C. B., Furberg, H., Mark Brown, W., Goldstein, B. A., Assimes, T., Tang, H., Kooperberg, C. L., Quesenberry, C. P., Tindle, H., Patel, M. I., Amos, C. I., Bergen, A. W., Swan, G. E., Stefanick, M. L. 2016; 4: 153-161


    Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(- 5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

    View details for DOI 10.1016/j.ebiom.2016.01.002

    View details for PubMedID 26981579

    View details for PubMedCentralID PMC4776066

  • Retrospective analysis of changing characteristics of treatment-seeking smokers: implications for further reducing smoking prevalence. BMJ open Leyro, T. M., Crew, E. E., Bryson, S. W., Lembke, A., Bailey, S. R., Prochaska, J. J., Henriksen, L., Fortmann, S. P., Killen, J. D., Killen, D. T., Hall, S. M., David, S. P. 2016; 6 (6)


    The goal of the current study was to empirically compare successive cohorts of treatment-seeking smokers who enrolled in randomised clinical trials in a region of the USA characterised by strong tobacco control policies and low smoking prevalence, over the past three decades.Retrospective treatment cohort comparison.Data were collected from 9 randomised clinical trials conducted at Stanford University and the University of California, San Francisco, between 1990 and 2013.Data from a total of 2083 participants were included (Stanford, n=1356; University of California San Francisco, n=727).One-way analysis of variance and covariance, χ(2) and logistic regression analyses were used to examine relations between nicotine dependence, cigarettes per day, depressive symptoms and demographic characteristics among study cohorts.Similar trends were observed at both settings. When compared to earlier trials, participants in more recent trials smoked fewer cigarettes, were less nicotine-dependent, reported more depressive symptoms, were more likely to be male and more likely to be from a minority ethnic/racial group, than those enrolled in initial trials (all p's<0.05). Analysis of covariances revealed that cigarettes per day, nicotine dependence and current depressive symptom scores were each significantly related to trial (all p's<0.001).Our findings suggest that more recent smoking cessation treatment-seeking cohorts in a low prevalence region were characterised by less smoking severity, more severe symptoms of depression and were more likely to be male and from a minority racial/ethnic group.

    View details for DOI 10.1136/bmjopen-2015-010960

    View details for PubMedID 27357195

  • Differential Efficacy of Nicotine Replacement Among Overweight and Obese Women Smokers. Nicotine & tobacco research Strong, D. R., David, S. P., Johnstone, E. C., Aveyard, P., Murphy, M. F., Munafò, M. R. 2015; 17 (7): 855-861


    Introduction Rates of obesity are higher among more dependent smokers and 37-65% of smokers seeking cessation treatment are overweight or obese. Overweight or obese smokers may possess metabolic and neurobiological features that contribute to difficulty achieving cessation using front-line nicotine replacement products. Attention to factors that facilitate effective cessation treatment in this vulnerable population is needed to significantly reduce mortality risk among overweight and obese smokers. Method This secondary analysis of two large trials of transdermal nicotine replacement in general medical practices evaluated the hypothesis that higher body mass index (BMI) would moderate the efficacy of the nicotine patch. We examined the potential for gender to further moderate the relationship between BMI and treatment efficacy. Results In the placebo controlled trial (N=1,621), 21 mg patch was no more effective than placebo for assisting biochemically verified point prevalence abstinence up to one-year after quitting for women with higher BMI, but appeared to be effective for men at normal or high BMI (gender x BMI beta = -0.22, p = 0.004). We did not find differential long-term cessation outcomes among male or female smokers in the 15mg patch trial (n=705). However, we observed significantly higher rates of early lapse among women with higher BMI treated with nicotine patch across both trials. Conclusion These results suggest that increased BMI may affect the efficacy of nicotine patch on reducing risk of early lapse in women. Additional research is needed to explore mechanisms of risk for decreased efficacy of this commonly used cessation aid.

    View details for DOI 10.1093/ntr/ntu256

    View details for PubMedID 25481918

  • Medical school curriculum characteristics associated with intentions and frequency of tobacco dependence treatment among 3rd year U.S. medical students. Preventive medicine Hayes, R. B., Geller, A. C., Crawford, S. L., Jolicoeur, D. G., Churchill, L. C., Okuyemi, K. S., David, S. P., Adams, M., Waugh, J., Allen, S. S., Leone, F. T., Fauver, R., Leung, K., Liu, Q., Ockene, J. K. 2015; 72: 56-63


    Physicians play a critical role in addressing tobacco dependence, yet report limited training. Tobacco dependence treatment curricula for medical students could improve performance in this area. This study identified student and medical school tobacco treatment curricula characteristics associated with intentions and use of the 5As for tobacco treatment among 3rd year U.S. medical students.Third year medical students (N=1065, 49.3% male) from 10 U.S. medical schools completed a survey in 2009-2010 assessing student characteristics, including demographics, tobacco treatment knowledge, and self-efficacy. Tobacco curricula characteristics assessed included amount and type of classroom instruction, frequency of tobacco treatment observation, instruction, and perception of preceptors as role models.Greater tobacco treatment knowledge, self-efficacy, and curriculum-specific variables were associated with 5A intentions, while younger age, tobacco treatment self-efficacy, intentions, and each curriculum-specific variable were associated with greater 5A behaviors. When controlling for important student variables, greater frequency of receiving 5A instruction (OR=1.07; 95%CI 1.01-1.12) and perception of preceptors as excellent role models in tobacco treatment (OR=1.35; 95%CI 1.04-1.75) were significant curriculum predictors of 5A intentions. Greater 5A instruction (B=.06 (.03); p<.05) and observation of tobacco treatment (B=.35 (.02); p<.001) were significant curriculum predictors of greater 5A behaviors.Greater exposure to tobacco treatment teaching during medical school is associated with both greater intentions to use and practice tobacco 5As. Clerkship preceptors, or those physicians who provide training to medical students, may be particularly influential when they personally model and instruct students in tobacco dependence treatment.

    View details for DOI 10.1016/j.ypmed.2014.12.035

    View details for PubMedID 25572623

  • Smoking behavior and association of melanoma and nonmelanoma skin cancer in the Women's Health Initiative. Journal of the American Academy of Dermatology Henderson, M. T., Kubo, J. T., Desai, M., David, S. P., Tindle, H., Sinha, A. A., Seiffert-Sinha, K., Hou, L., Messina, C., Saquib, N., Stefanick, M. L., Tang, J. Y. 2015; 72 (1): 190–91.e3

    View details for DOI 10.1016/j.jaad.2014.09.024

    View details for PubMedID 25497923

  • Making Personalized Health Care Even More Personalized: Insights From Activities of the IOM Genomics Roundtable. Annals of family medicine David, S. P., Johnson, S. G., Berger, A. C., Feero, W. G., Terry, S. F., Green, L. A., Phillips, R. L., Ginsburg, G. S. 2015; 13 (4): 373–80


    Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system.

    View details for DOI 10.1370/afm.1772

    View details for PubMedID 26195686

  • Smoking behavior and association of melanoma and nonmelanoma skin cancer in the Women's Health Initiative JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Henderson, M. T., Kubo, J. T., Desai, M., David, S. P., Tindle, H., Sinha, A. A., Hou, L., Messina, C., Saquib, N., Stefanick, M. L., Tang, J. Y. 2015; 72 (1): 190-191

    View details for DOI 10.1016/j.jaad.2014.09.024

    View details for Web of Science ID 000346404500053

    View details for PubMedID 25497923

  • Association of CHRNA5-A3-84 SNP rs2036527 With Smoking Cessation Therapy Response in African-American Smokers CLINICAL PHARMACOLOGY & THERAPEUTICS Zhu, A. Z., Zhou, Q., Cox, L. S., David, S. P., Ahluwalia, J. S., Benowitz, N. L., Tyndale, R. F. 2014; 96 (2): 256-265


    Associations between CHRNA5-A3-B4 variants and smoking behaviors exist, however the association with smoking abstinence is less understood, particularly among African Americans. In 1295 African Americans enrolled in two clinical trials, we investigated the association between CHRNA5-A3-B4 and smoking abstinence. Rs2056527[A] was associated with lower abstinence with active pharmacotherapy (during-treatment: OR=0.42&P<0.001; end of treatment (EOT): OR=0.55&P=0.004), or with nicotine gum alone (during-treatment: OR=0.31&P<0.001; EOT: OR=0.51&P=0.02), but not significantly with bupropion, although similar directions and magnitudes were observed (during-treatment: OR=0.54&P=0.05; EOT: OR=0.59&P=0.08). Additionally, rs588765[T] was associated with abstinence with gum during treatment (OR=2.31&P<0.01). Rs16969968 occurred at a low frequency and was not consistently associated with abstinence. CHRNA5-A3-B4 variants were not associated with tobacco consumption and adjustments for smoking behaviors did not alter the associations with smoking abstinence. Together, our data suggest that in African Americans CHRNA5-A3-B4 variants are not associated with baseline smoking, but can influence smoking abstinence during active pharmacotherapy.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 14 April 2014; doi:10.1038/clpt.2014.88.

    View details for DOI 10.1038/clpt.2014.88

    View details for Web of Science ID 000339602900037

    View details for PubMedID 24733007

  • Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human brain mapping Fusar-Poli, P., Radua, J., Frascarelli, M., Mechelli, A., Borgwardt, S., Di Fabio, F., Biondi, M., Ioannidis, J. P., David, S. P. 2014; 35 (7): 3052-3065


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

    View details for DOI 10.1002/hbm.22384

    View details for PubMedID 24123491

  • Effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype. Nicotine & tobacco research Xu, X., Clark, U. S., David, S. P., Mulligan, R. C., Knopik, V. S., McGeary, J., MacKillop, J., McCaffery, J., Niaura, R. S., Sweet, L. H. 2014; 16 (7): 939-947


    Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism, but little is known about the associated neural mechanisms.Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues, during 2 separate functional magnetic resonance imaging scans, while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥1 copy of ≥7 repeats] or short [S: 2 copies ≤6 repeats] genotype) of 6 a priori regions of interest.Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch.Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.

    View details for DOI 10.1093/ntr/ntu010

    View details for PubMedID 24659022

  • Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention TRENDS IN COGNITIVE SCIENCES Ioannidis, J. P., Munafo, M. R., Fusar-Poli, P., Nosek, B. A., David, S. P. 2014; 18 (5): 235-241


    Recent systematic reviews and empirical evaluations of the cognitive sciences literature suggest that publication and other reporting biases are prevalent across diverse domains of cognitive science. In this review, we summarize the various forms of publication and reporting biases and other questionable research practices, and overview the available methods for probing into their existence. We discuss the available empirical evidence for the presence of such biases across the neuroimaging, animal, other preclinical, psychological, clinical trials, and genetics literature in the cognitive sciences. We also highlight emerging solutions (from study design to data analyses and reporting) to prevent bias and improve the fidelity in the field of cognitive science research.

    View details for DOI 10.1016/j.tics.2014.02.010

    View details for Web of Science ID 000336113400007

    View details for PubMedID 24656991

  • No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Passarelli, M. N., Newcomb, P. A., Makar, K. W., Burnett-Hartman, A. N., Phipps, A. I., David, S. P., Hsu, L., Harrison, T. A., Hutter, C. M., Duggan, D. J., White, E., Chan, A. T., Peters, U. 2014; 21 (4): 415-420


    Sex steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase (COMT; 22q11.21) activity is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival.We identified 10 single nucleotide polymorphisms that tagged variation across two isoforms of COMT in 2,458 women with CRC from the Nurses' Health Study, Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry, VITamins And Lifestyle Study, and Women's Health Initiative. All four studies participated in the Genetics and Epidemiology of Colorectal Cancer Consortium.During a median follow-up of 7 years across all studies, there were 799 deaths, including 566 deaths from CRC. Based on multiple comparisons, no associations between single nucleotide polymorphisms and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; CRC-specific survival: hazard ratio per minor allele, 1.04; 95% CI, 0.92-1.17; overall survival: hazard ratio per minor allele, 1.01; 95% CI, 0.90-1.14).In this large study of women with CRC, we find no evidence that common inherited variation in COMT is associated with survival time after diagnosis.

    View details for DOI 10.1097/GME.0b013e31829e498d

    View details for Web of Science ID 000336214200017

    View details for PubMedID 23880798

  • Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045


    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

    View details for PubMedCentralID PMC4119063

  • Teaching tobacco dependence treatment and counseling skills during medical school: Rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial. Contemporary clinical trials Hayes, R. B., Geller, A., Churchill, L., Jolicoeur, D., Murray, D. M., Shoben, A., David, S. P., Adams, M., Okuyemi, K., Fauver, R., Gross, R., Leone, F., Xiao, R., Waugh, J., Crawford, S., Ockene, J. K. 2014; 37 (2): 284-293


    Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment is cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students.10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-facilitated training during a 3rd year clerkship rotation. The primary outcome measure is an objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE.MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students' tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians.

    View details for DOI 10.1016/j.cct.2014.01.008

    View details for PubMedID 24486635

  • Systematic review and meta-analysis of opioid antagonists for smoking cessation. BMJ open David, S. P., Chu, I. M., Lancaster, T., Stead, L. F., Evins, A. E., Prochaska, J. J. 2014; 4 (3)


    This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored.The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE.Adult smokers.We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months.Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory).8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal.The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.

    View details for DOI 10.1136/bmjopen-2013-004393

    View details for PubMedID 24633528

  • Commentary on Chen et al. (2014): Another step on the road to clinical utility of pharmacogenetics for smoking cessation? ADDICTION David, S. P. 2014; 109 (1): 138-139

    View details for DOI 10.1111/add.12390

    View details for Web of Science ID 000328157300020

    View details for PubMedID 24438115

  • Systematic review and meta-analysis of opioid antagonists for smoking cessation. BMJ open David, S. P., Chu, I. M., Lancaster, T., Stead, L. F., Evins, A. E., Prochaska, J. J. 2014; 4 (3)

    View details for DOI 10.1136/bmjopen-2013-004393

    View details for PubMedID 24633528

  • Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion. Addiction David, S. P., Strong, D. R., Leventhal, A. M., Lancaster, M. A., McGeary, J. E., Munafò, M. R., Bergen, A. W., Swan, G. E., Benowitz, N. L., Tyndale, R. F., Conti, D. V., Brown, R. A., Lerman, C., Niaura, R. 2013; 108 (12): 2202-2211


    To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies.Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2).A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment.Significant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

    View details for DOI 10.1111/add.12325

    View details for PubMedID 23941313

  • Tobacco dependence treatment teaching by medical school clerkship preceptors: Survey responses from more than 1000 US medical students PREVENTIVE MEDICINE Geller, A. C., Hayes, R. B., Leone, F., Churchill, L. C., Leung, K., Reed, G., Jolicoeur, D., Okuliar, C., Adams, M., Murray, D. M., Liu, Q., Waugh, J., David, S., Ockene, J. K. 2013; 57 (2): 81-86


    OBJECTIVE: To determine factors associated with tobacco cessation counseling in medical school clerkships. METHODS: Third-year medical students at 10 medical schools across the United States completed a 100-item survey, measuring the frequency with which they experienced their preceptors providing clinical teaching components: clear instruction, feedback, modeling behavior, setting clear objectives, and responding to questions about tobacco dependence counseling as well as frequency of use of tobacco prompts and office systems. Our primary dependent measure was student self-reported skill level for items of tobacco dependence treatment (e.g. "5As"). RESULTS: Surveys were completed by 1213 students. For both family medicine and internal medicine clerkships, modeling and providing clear instruction on ways to provide tobacco counseling were reported most commonly. In contrast, providing feedback and clear objectives for tobacco dependence treatment lagged behind. Overall, students who reported preceptors' provision of optimal clinical teaching components and office system prompts in both family medicine and internal medicine clerkships had higher self-reported skill (P<0.001) than students with no exposure or exposure during only one of the clerkships. CONCLUSIONS: Future educational interventions intended to help students adopt effective tobacco dependence treatment techniques should be engineered to facilitate these critical precepting components.

    View details for DOI 10.1016/j.ypmed.2013.04.006

    View details for Web of Science ID 000322413700003

    View details for PubMedID 23623894

  • Biomarkers for smoking cessation. Clinical pharmacology & therapeutics Bough, K. J., Lerman, C., Rose, J. E., McClernon, F. J., Kenny, P. J., Tyndale, R. F., David, S. P., Stein, E. A., Uhl, G. R., Conti, D. V., Green, C., Amur, S. 2013; 93 (6): 526-538


    One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

    View details for DOI 10.1038/clpt.2013.57

    View details for PubMedID 23588313

  • Communities of Solution: Partnerships for Population Health JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE Griswold, K. S., Lesko, S. E., Westfall, J. M. 2013; 26 (3): 232-238


    Communities of solution (COSs) are the key principle for improving population health. The 1967 Folsom Report explains that the COS concept arose from the recognition that complex political and administrative structures often hinder problem solving by creating barriers to communication and compromise. A 2012 reexamination of the Folsom Report resurrects the idea of the COS and presents 13 grand challenges that define the critical links among community, public health, and primary care and call for ongoing demonstrations of COSs grounded in patient-centered care. In this issue, examples of COSs from around the country demonstrate core principles and propose visions of the future. Essential themes of each COS are the crossing of "jurisdictional boundaries," community-led or -oriented initiatives, measurement of outcomes, and creating durable connections with public health.

    View details for DOI 10.3122/jabfm.2013.03.130102

    View details for Web of Science ID 000318768600002

    View details for PubMedID 23657688

  • Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study NICOTINE & TOBACCO RESEARCH McClure, J. B., Swan, G. E., St John, J., Fauver, R., Javitz, H. S., Bergen, A. W., Nishita, D., Niaura, R., Munafo, M. R., David, S. P. 2013; 15 (2): 518-526


    There is increasing evidence that response to pharmacological treatment for nicotine dependence may be moderated by genetic polymorphisms. However, the feasibility, acceptability, and impact of genetically tailoring treatment in real-world clinical settings are unknown.We conducted a multiphased, mixed-methods feasibility study with current smokers to develop and evaluate a patient-centered, theoretically grounded personalized medicine treatment protocol. The initial research phase included formative work to develop intervention materials. The second phase included a randomized pilot trial to evaluate the intervention. Trial participants (n = 36) were genotyped for ANKK1 rs1800497 and were randomized to receive genetic feedback (GF) plus standard behavioral counseling (BC) for smoking cessation or BC without GF. All participants received genetically tailored pharmacotherapy (nicotine patch or bupropion).The intervention was feasible to implement and was acceptable to participants based on satisfaction ratings and objective measures of participation. There was no evidence that the GF resulted in adverse psychological outcomes (e.g., depression, fatalism, reduced perceived control over quitting, differential motivation for quitting) based on quantitative or qualitative outcomes.Study results suggest that it is feasible to offer treatment within a health care setting that includes genetically tailored pharmacotherapy and doing so had no apparent adverse psychological impacts. Further evaluation of pharmacogenetically tailored smoking cessation interventions appears warranted.

    View details for DOI 10.1093/ntr/nts173

    View details for Web of Science ID 000313826600027

    View details for PubMedID 22949583

    View details for PubMedCentralID PMC3611995

  • Opioid antagonists for smoking cessation COCHRANE DATABASE OF SYSTEMATIC REVIEWS David, S. P., Lancaster, T., Stead, L. F., Evins, A. E., Prochaska, J. J. 2013


    The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies.We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model.Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes.Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.

    View details for DOI 10.1002/14651858.CD003086.pub3

    View details for Web of Science ID 000321124000022

    View details for PubMedID 23744347

  • CHRONIC STRESS & SALIVARY BIOMARKERS Western Regional Meeting of the American-Federation-for-Medical-Research Mallick, A., Bergen, A., Nishita, D., Wei, X., Michel, M., David, S. P., Swan, G. E., REID, M. W., Simons, A. D., Andrews, J. LIPPINCOTT WILLIAMS & WILKINS. 2013: 141–41
  • Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers JOURNAL OF HUMAN HYPERTENSION Liu, T., Tyndale, R. F., David, S. P., Wang, H., Yu, X., Chen, W., Wen, X., Chen, W. 2013; 27 (1): 24-30


    The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship.

    View details for DOI 10.1038/jhh.2011.111

    View details for Web of Science ID 000311994000005

    View details for PubMedID 22217675

  • Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion Addiction David, S. P., Strong, D. R., Leventhal, A. M., Lancaster, M. A., McGeary, J. E., Munafò, M. R., Bergen, A. W., Swan, G. E., Benowitz, N. L., Tyndale, R. F., Conti, D. V., Brown, R. A., Lerman, C., Niaura, R. 2013; 108 (12): 2202-11

    View details for DOI 10.1111/add.12325

  • Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human Brain Mapping Fusar-Poli, P., Joaquim, R., Marianna, F., Andrea, M., Stefan, B., Fabio, D., Massimo, B., Ioannidis, J. P., David, S. P. 2013
  • Potential reporting bias in FMRI studies of the brain. PloS one David, S. P., Ware, J. J., Chu, I. M., Loftus, P. D., Fusar-Poli, P., Radua, J., Munafò, M. R., Ioannidis, J. P. 2013; 8 (7)


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

    View details for DOI 10.1371/journal.pone.0070104

    View details for PubMedID 23936149

    View details for PubMedCentralID PMC3723634

  • PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6 PHARMACOGENETICS AND GENOMICS McDonagh, E. M., Wassenaar, C., David, S. P., Tyndale, R. F., Altman, R. B., Whirl-Carrillo, M., Klein, T. E. 2012; 22 (9): 695-708

    View details for DOI 10.1097/FPC.0b013e3283540217

    View details for Web of Science ID 000307652600006

    View details for PubMedID 22547082

    View details for PubMedCentralID PMC3413746

  • Improving America's health requires community-level solutions: Folsom revisited. American family physician 2012; 86 (4): 1-2


    Amidst sweeping changes to health care in the 1960s, the broadly influential Folsom Commission report, "Health is a Community Affair," never fully achieved its vision of galvanizing the creation of Communities of Solution, which were empowered to improve health at the local level. Passage of health care reform, and persistent concern over poor health outcomes despite runaway spending, contemporizes Folsom's call for nationally supported and evaluated, but community-driven, solutions to the nation's health care challenges.

    View details for PubMedID 23130357

  • Chronic psychosocial stressors and salivary biomarkers in emerging adults PSYCHONEUROENDOCRINOLOGY Bergen, A. W., Mallick, A., Nishita, D., Wei, X., Michel, M., Wacholder, A., David, S. P., Swan, G. E., Reid, M. W., Simons, A., Andrews, J. A. 2012; 37 (8): 1158-1170


    We investigated whole saliva as a source of biomarkers to distinguish individuals who have, and who have not, been chronically exposed to severe and threatening life difficulties. We evaluated RNA and DNA metrics, expression of 37 candidate genes, and cortisol release in response to the Trier Social Stress Test, as well as clinical characteristics, from 48 individuals stratified on chronic exposure to psychosocial stressors within the last year as measured by the Life Events and Difficulties Schedule. Candidate genes were selected based on their differential gene expression ratio in circulating monocytes from a published genome-wide analysis of adults experiencing different levels of exposure to a chronic stressor. In univariate analyses, we observed significantly decreased RNA integrity (RIN) score (P = 0.04), and reduced expression of glucocorticoid receptor-regulated genes (Ps < 0.05) in whole saliva RNA from individuals exposed to chronic stressors, as compared to those with no exposure. In those exposed, we observed significantly decreased BMI (P < 0.001), increased ever-smoking and increased lifetime alcohol abuse or dependence (P ≤ 0.03), and a reduction of cortisol release. In post hoc multivariate analyses including clinical and biospecimen-derived variables, we consistently observed significantly decreased expression of IL8 (Ps<0.05) in individuals exposed, with no significant association to RIN score. Alcohol use disorders, tobacco use, a reduced acute stress response and decreased salivary IL8 gene expression characterize emerging adults chronically exposed to severe and threatening psychosocial stressors.

    View details for DOI 10.1016/j.psyneuen.2011.11.010

    View details for Web of Science ID 000306583100003

    View details for PubMedID 22172638

  • Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry-A Meta-Analysis of Chromosome 15q25 GENETIC EPIDEMIOLOGY Chen, L., Saccone, N. L., Culverhouse, R. C., Bracci, P. M., Chen, C., Dueker, N., Han, Y., Huang, H., Jin, G., Kohno, T., Ma, J. Z., Przybeck, T. R., Sanders, A. R., Smith, J. A., Sung, Y. J., Wenzlaff, A. S., Wu, C., Yoon, D., Chen, Y., Cheng, Y., Cho, Y. S., David, S. P., Duan, J., Eaton, C. B., Furberg, H., Goate, A. M., Gu, D., Hansen, H. M., Hartz, S., Hu, Z., Kim, Y. J., Kittner, S. J., Levinson, D. F., Mosley, T. H., Payne, T. J., Rao, D. C., Rice, J. P., Rice, T. K., Schwantes-An, T., Shete, S. S., Shi, J., Spitz, M. R., Sun, Y. V., Tsai, F., Wang, J. C., Wrensch, M. R., Xian, H., Gejman, P. V., He, J., Hunt, S. C., Kardia, S. L., Li, M. D., Lin, D., Mitchell, B. D., Park, T., Schwartz, A. G., Shen, H., Wiencke, J. K., Wu, J., Yokota, J., Amos, C. I., Bierut, L. J. 2012; 36 (4): 340-351


    Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

    View details for DOI 10.1002/gepi.21627

    View details for Web of Science ID 000303319900006

    View details for PubMedID 22539395

  • Communities of Solution: The Folsom Report Revisited ANNALS OF FAMILY MEDICINE Lesko, S., Griswold, K. S., David, S. P., Bazemore, A. W., Duane, M., Morgan, T., Westfall, J. M., Koop, C. E., Garrett, B., Puffer, J. C., Green, L. A. 2012; 10 (3): 250-260


    Efforts to address the current fragmented US health care structure, including controversial federal reform, cannot succeed without a reinvigoration of community-centered health systems. A blueprint for systematic implementation of community services exists in the 1967 Folsom Report--calling for "communities of solution." We propose an updated vision of the Folsom Report for integrated and effective services, incorporating the principles of community-oriented primary care. The 21st century primary care physician must be a true public health professional, forming partnerships and assisting data sharing with community organizations to facilitate healthy changes. Current policy reform efforts should build upon Folsom Report's goal of transforming personal and population health.

    View details for DOI 10.1370/afm.1350

    View details for Web of Science ID 000304723700011

    View details for PubMedID 22585890

    View details for PubMedCentralID PMC3354975

  • Genome-wide meta-analyses of smoking behaviors in African Americans TRANSLATIONAL PSYCHIATRY David, S. P., Hamidovic, A., Chen, G. K., Bergen, A. W., Wessel, J., Kasberger, J. L., BROWN, W. M., Petruzella, S., Thacker, E. L., Kim, Y., Nalls, M. A., Tranah, G. J., Sung, Y. J., Ambrosone, C. B., Arnett, D., Bandera, E. V., Becker, D. M., BECKER, L., Berndt, S. I., Bernstein, L., Blot, W. J., Broeckel, U., Buxbaum, S. G., Caporaso, N., Casey, G., Chanock, S. J., Deming, S. L., Diver, W. R., Eaton, C. B., Evans, D. S., Evans, M. K., Fornage, M., Franceschini, N., Harris, T. B., Henderson, B. E., Hernandez, D. G., Hitsman, B., Hu, J. J., Hunt, S. C., Ingles, S. A., John, E. M., Kittles, R., Kolb, S., Kolonel, L. N., Le Marchand, L., Liu, Y., Lohman, K. K., McKnight, B., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M., Psaty, B. M., Rao, D. C., Redline, S., Rodriguez-Gil, J. L., Rybicki, B. A., Signorello, L. B., Singleton, A. B., Smoller, J., Snively, B., Spring, B., Stanford, J. L., Strom, S. S., Swan, G. E., Taylor, K. D., Thun, M. J., Wilson, A. F., Witte, J. S., Yamamura, Y., Yanek, L. R., Yu, K., Zheng, W., Ziegler, R. G., Zonderman, A. B., Jorgenson, E., Haiman, C. A., Furberg, H. 2012; 2


    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

    View details for DOI 10.1038/tp.2012.41

    View details for Web of Science ID 000312895700012

    View details for PubMedID 22832964

    View details for PubMedCentralID PMC3365260

  • The neuroeconomics of nicotine dependence: A preliminary functional magnetic resonance imaging study of delay discounting of monetary and cigarette rewards in smokers PSYCHIATRY RESEARCH-NEUROIMAGING MacKillop, J., Amlung, M. T., Wier, L. M., David, S. P., Ray, L. A., Bickel, W. K., Sweet, L. H. 2012; 202 (1): 20-29


    Neuroeconomics integrates behavioral economics and cognitive neuroscience to understand the neurobiological basis for normative and maladaptive decision making. Delay discounting is a behavioral economic index of impulsivity that reflects capacity to delay gratification and has been consistently associated with nicotine dependence. This preliminary study used functional magnetic resonance imaging to examine delay discounting for money and cigarette rewards in 13 nicotine dependent adults. Significant differences between preferences for smaller immediate rewards and larger delayed rewards were evident in a number of regions of interest (ROIs), including the medial prefrontal cortex, anterior insular cortex, middle temporal gyrus, middle frontal gyrus, and cingulate gyrus. Significant differences between money and cigarette rewards were generally lateralized, with cigarette choices associated with left hemisphere activation and money choices associated with right hemisphere activation. Specific ROI differences included the posterior parietal cortex, medial and middle frontal gyrus, ventral striatum, temporoparietal cortex, and angular gyrus. Impulsivity as measured by behavioral choices was significantly associated with both individual ROIs and a combined ROI model. These findings provide initial evidence in support of applying a neuroeconomic approach to understanding nicotine dependence.

    View details for DOI 10.1016/j.pscychresns.2011.10.003

    View details for Web of Science ID 000306622400003

    View details for PubMedID 22633679

  • Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers ANNALS OF BEHAVIORAL MEDICINE Liu, T., David, S. P., Tyndale, R. F., Wang, H., Yu, X., Chen, W., Zhou, Q., Chen, W. 2012; 43 (2): 253-261


    Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established.This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes.Nine hundred fifty-four male current smokers were selected. A venous specimen was collected to test serum cotinine and CYP2A6 genotype, and all smokers were divided into heavy (>15 cigarettes/day) and light smokers (≤15 cigarettes/day).Heavy smoking increased the risk of abdominal obesity (odds ratio (OR) = 1.57; 95% CI, 1.13-2.19) compared with light smoking. Furthermore, heavy smoking had a positive interactive effect with CYP2A6 poor metabolizer genotype on abdominal obesity (OR = 3.90; 95% CI, 1.25-12.18). Moreover, CYP2A6 poor metabolizer genotypes were associated with slower nicotine metabolism.Heavy smoking may increase the risk of abdominal obesity-particularly in smokers with CYP2A6 poor metabolizer genotypes.

    View details for DOI 10.1007/s12160-011-9318-5

    View details for Web of Science ID 000301460500015

    View details for PubMedID 22160797

  • Dopamine D4 receptor gene variation moderates the efficacy of bupropion for smoking cessation PHARMACOGENOMICS JOURNAL Leventhal, A. M., David, S. P., Brightman, M., Strong, D., McGeary, J. E., Brown, R. A., Lloyd-Richardson, E. E., Munafo, M., Uhl, G. R., Niaura, R. 2012; 12 (1): 86-92


    Smokers (≥10 cigarettes per day, N=331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of tandem repeats polymorphism in exon III of the dopamine D4 receptor gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6 and 12 months after the end of treatment indicated that bupropion (vs placebo) predicted increased odds of abstinence. The main effect of Genotype was not significant. A Genotype × Treatment interaction (P=0.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (odds ratios (OR)=1.31, P<0.0001), whereas bupropion was not associated with abstinence among short-allele homozygotes (OR=1.06, P=0.23). The Genotype × Treatment interaction remained when controlling for demographic and clinical covariates (P=0.01) and in analyses predicting continuous abstinence (P's≤0.054). Bupropion may be more efficacious for smokers who carry the long allele, which is relevant to personalized pharmacogenetic treatment approaches.

    View details for DOI 10.1038/tpj.2010.64

    View details for Web of Science ID 000299719200010

    View details for PubMedID 20661272

    View details for PubMedCentralID PMC2981689

  • Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women DRUG AND ALCOHOL DEPENDENCE Janes, A. C., Smoller, J. W., David, S. P., Frederick, B. d., Haddad, S., Basu, A., Fava, M., Evins, A. E., Kaufman, M. J. 2012; 120 (1-3): 7-13


    Tobacco smoking is the leading preventable cause of death in the developed world. Identifying risk factors for smoking may lead to more effective treatments. Genome wide association studies revealed a relationship between development of nicotine dependence and a single-nucleotide polymorphism (SNP, rs16969968) of the nicotine acetylcholine receptor (nAChR) alpha-5 subunit gene (CHRNA5). The relationship between this SNP and other factors contributing to smoking behavior such as smoking cue reactivity is unclear.We assessed the role of rs16969968 on brain functional MRI (fMRI) reactivity to smoking cues by studying nicotine dependent women with the nicotine dependence 'risk' allele (A allele, N=14) and without the 'risk' allele (G/G smokers, N=10). Nicotine dependence severity, as assessed with the Fagerstrom test for nicotine dependence, smoking pack-years, and expired carbon monoxide levels, were equivalent in these groups.We observed a group difference in fMRI reactivity; women without the A allele (G/G smokers) showed greater fMRI reactivity to smoking images in brain areas related to memory and habitual behavior such as the hippocampus and dorsal striatum.Our finding suggests that nicotine-dependent smokers lacking the rs16969968 A allele are more likely to recall smoking-related memories and engage in habitual responding to smoking cues than A allele smokers. Although more studies are necessary to determine the mechanism underlying and significance of this cue reactivity difference, these data suggest that smokers may develop and remain nicotine dependent due to different factors including genetics and cue reactivity. This finding may have implications for personalizing smoking treatment.

    View details for DOI 10.1016/j.drugalcdep.2011.06.009

    View details for Web of Science ID 000299499800002

    View details for PubMedID 21764527

  • Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways EUROPEAN JOURNAL OF ENDOCRINOLOGY Liu, T., Chen, W., David, S. P., Tyndale, R. F., Wang, H., Chen, Y., Yu, X., Chen, W., Zhou, Q., Ling, W. 2011; 165 (6): 961-967


    To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM.Cross-sectional study.A total of 1344 smokers with complete data from a community-based T2DM survey in Guangzhou and Zhuhai of China from July 2006 to June 2007 were interviewed with a structured questionnaire about socio-demographic status and daily cigarette consumption. Serum glucose, insulin, and cotinine were measured after an overnight fast. Subjects were genotyped for CYP2A6 and classified, according to genotype, into normal, intermediate, slow, or poor nicotine metabolizers based on prior knowledge of CYP2A6 allele associations with nicotine C-oxidation rate. Abdominal obesity was defined as a waist-to-hip ratio ≥0.90 for males or ≥0.85 for females. Type 2 diabetic patients (n=154) were diagnosed according to WHO 1999 criteria. Chi-square tests, multivariate logistic regression models, and a structural equation model were used in this study.Multivariate analysis indicated that, compared with light smoking, heavy smoking significantly increased the risk of T2DM (odds ratio (OR)=1.75, 95% CI=1.01-3.05). There were significant interactions between heavy smoking and slow CYP2A6 (OR=5.12, 95% CI=1.08-24.23) and poor CYP2A6 metabolizer genotypes (OR=8.54, 95% CI=1.28-57.02) on T2DM. Structural equation modeling indicated that CYP2A6 moderation of smoking quantity risk on T2DM was mediated by the effects on serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.Heavy smoking was significantly associated with T2DM, and this association was moderated by CYP2A6 genotype and mediated by serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.

    View details for DOI 10.1530/EJE-11-0596

    View details for Web of Science ID 000297687900015

    View details for PubMedID 21964962

  • Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)


    Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

    View details for DOI 10.1371/journal.pgen.1002280

    View details for Web of Science ID 000295419100031

    View details for PubMedID 21935354

    View details for PubMedCentralID PMC3174201

  • Associations of CYP2A6 genotype with smoking behaviors in southern China ADDICTION Liu, T., David, S. P., Tyndale, R. F., Wang, H., Zhou, Q., Ding, P., He, Y., Yu, X., Chen, W., Crump, C., Wen, X., Chen, W. 2011; 106 (5): 985-994


    To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers.Case-only genetic association study.Southern China.A total of 1328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007.All participants answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles were genotyped for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6*4,*5,*7,*9 and *10).The frequencies of CYP2A6*4, *5, *7, *9 and *10 alleles were 8.5, 1.2, 6.3, 13.5 and 2.4%, which corresponded to 48.9, 15.4, 24.2 and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses in male smokers demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day [adjusted odds ratio (OR) = 0.49; 95% confidence interval (CI): 0.32-0.76], started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06-2.26) and, among former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12-0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (adjusted OR = 0.54; 95% CI: 0.34-0.86). Conclusions: Reduced metabolism function of cytochrome P450 2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.

    View details for DOI 10.1111/j.1360-0443.2010.03353.x

    View details for Web of Science ID 000289296900035

    View details for PubMedID 21205058

    View details for PubMedCentralID PMC3074015

  • Pharmacogenetics of Smoking Cessation in General Practice: Results From the Patch II and Patch in Practice Trials NICOTINE & TOBACCO RESEARCH David, S. P., Johnstone, E. C., Churchman, M., Aveyard, P., Murphy, M. F., Munafo, M. R. 2011; 13 (3): 157-?


    Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that 'one size fits all' smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice.New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach.By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed.The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.

    View details for DOI 10.1093/ntr/ntq246

    View details for Web of Science ID 000287747600001

    View details for PubMedID 21330274

  • Application of Functional Neuroimaging Methods to Nicotine Dependence. Chapter 9 in: Brain Imaging in Behavioral Medicine and Neuropsychology. Edited by Cohen R. Springer, New York, NY, USA David, S. P., Sweet, L. H., Cohen, R. A., Mulligan, R. C. 2011
  • Effects of nicotine withdrawal on verbal working memory and associated brain response PSYCHIATRY RESEARCH-NEUROIMAGING Sweet, L. H., Mulligan, R. C., Finnerty, C. E., Jerskey, B. A., David, S. P., Cohen, R. A., Niaura, R. S. 2010; 183 (1): 69-74


    Previous literature has reported effects of nicotine withdrawal on brain function during cognitive tasks such as verbal working memory (VWM). Mechanisms of these withdrawal effects have not been clearly identified. Functional neuroimaging offers an objective method to examine brain mechanisms associated with observable behavior and subjective reports. To investigate these mechanisms, 12 smokers were administered a 2-Back VWM challenge during two functional magnetic resonance imaging sessions. Participants abstained from smoking prior to both sessions; however, they applied a nicotine patch before one session and a placebo patch prior to the other. Among regions that exhibited a significant response to the 2-Back during either session, withdrawal was associated with significantly greater deactivation in left and right temporal poles and left medial frontal gyrus. The magnitude of task-related activation showed a significant inverse relationship to craving in the majority of regions during placebo administration. Also, individual brain responses varied more during placebo, suggesting inefficient neural processing. Results suggest that differences in brain response to a VWM challenge during abstinence may be attributed to increased craving. Further deactivation of regions associated with the default network (medial frontal and anterior temporal clusters) during the placebo condition suggests further suspension of default activity, possibly to compensate for inefficient neural processing.

    View details for DOI 10.1016/j.pscychresns.2010.04.014

    View details for Web of Science ID 000280033600008

    View details for PubMedID 20570495

  • Genome-wide association for smoking cessation success: participants in the Patch in Practice trial of nicotine replacement PHARMACOGENOMICS Uhl, G. R., Drgon, T., Johnson, C., Walther, D., Aveyard, P., Murphy, M., Johnstone, E. C., Munafo, M. R. 2010; 11 (3): 357-367


    To confirm and extend to primary care settings prior genome-wide association results that distinguish smokers who successfully quit from individuals who were not able to quit smoking in clinical trials.Affymetrix 6.0 Arrays were used to study DNA from successful quitters and matched individuals who did not quit from the Patch in Practice study of 925 smokers in 26 UK general practices who were provided with 15 mg/16 h nicotine-replacement therapy and varying degrees of behavioral support.Only a few SNPs provided results near 'genome-wide' levels of significance. Nominally significant (p < 0.01) SNP results identify the same chromosomal regions identified by prior genome-wide association studies to a much greater extent than expected by chance.Ability to change smoking behavior in a general practice setting appears to share substantial underlying genetics with the ability to change this behavior in clinical trials, though the modest sample sizes available for these studies provides some caution to these conclusions.

    View details for DOI 10.2217/PGS.09.156

    View details for Web of Science ID 000276291100016

    View details for PubMedID 20235792

  • Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans NICOTINE & TOBACCO RESEARCH David, S. P., Mezuk, B., Zandi, P. P., Strong, D., Anthony, J. C., Niaura, R., Uhl, G. R., Eaton, W. W. 2010; 12 (3): 251-262


    The 11q23.1 genomic region has been associated with nicotine dependence in Black and White Americans.By conducting linkage disequilibrium analyses of 7 informative single nucleotide polymorphisms (SNPs) within the tetratricopeptide repeat domain 12 (TTC12)/ankyrin repeat and kinase containing 1 (ANKK1)/dopamine (D2) receptor gene cluster, we identified haplotype block structures in 270 Black and 368 White (n = 638) participants, from the Baltimore Epidemiologic Catchment Area cohort study, spanning the TTC12 and ANKK1 genes consisting of three SNPs (rs2303380-rs4938015-rs11604671). Informative haplotypes were examined for sex-specific associations with daily tobacco smoking initiation and cessation using longitudinal data from 1993-1994 and 2004-2005 interviews.There was a Haplotype x Sex interaction such that Black men possessing the GTG haplotype who were smokers in 1993-2004 were more likely to have stopped smoking by 2004-2005 (55.6% GTG vs. 22.0% other haplotypes), while Black women were less likely to have quit smoking if they possessed the GTG (20.8%) versus other haplotypes (24.0%; p = .028). In Whites, the GTG haplotype (vs. other haplotypes) was associated with lifetime history of daily smoking (smoking initiation; odds ratio = 1.6; 95% CI = 1.1-2.4; p = .013). Moreover, there was a Haplotype x Sex interaction such that there was higher prevalence of smoking initiation with GTG (77.6%) versus other haplotypes (57.0%; p = .043).In 2 different ethnic American populations, we observed man-woman variation in the influence of the rs2303380-rs4938015-rs11604671 GTG haplotype on smoking initiation and cessation. These results should be replicated in larger cohorts to establish the relationship among the rs2303380-rs4938015-rs11604671 haplotype block, sex, and smoking behavior.

    View details for DOI 10.1093/ntr/ntp201

    View details for Web of Science ID 000274778400009

    View details for PubMedID 20133381

    View details for PubMedCentralID PMC2825103

  • Dopamine Transporters: Chemistry, Biology, and Pharmacology. Clin Pharmacol Ther. David SP. 2009; 85 (1): 16-17.
  • Lifestyle Medicine by Gary Egger, Andrew Binns, and Stephen Rossner. Am J Lifestyle Med. David, S. P. 2009; 3 (5): 409
  • Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data NICOTINE & TOBACCO RESEARCH Munafo, M. R., Timpson, N. J., David, S. P., Ebrahim, S., Lawlor, D. A. 2009; 11 (1): 64-76


    Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies.We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study.Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.

    View details for DOI 10.1093/ntr/ntn012

    View details for Web of Science ID 000264188900009

    View details for PubMedID 19246443

  • [Smoking cessation]. Praxis Koplan, K. E., David, S. P., Rigotti, N. A. 2008; 97 (22): 1185-1186

    View details for DOI 10.1024/1661-8157.97.22.1185

    View details for PubMedID 18979437

  • Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses DRUG AND ALCOHOL DEPENDENCE David, S. P., Johnstone, E. C., Murphy, M. F., Aveyardd, P., Guo, B., Lerman, C., Munafo, M. R. 2008; 98 (1-2): 77-85


    The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A45-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p=0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p=0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p=0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p=0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p=0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p=0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N=1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR)=1.25, 95% CI 0.89, 1.74, p=0.19; SS: OR=1.31, 95% CI 0.86, 1.98, p=0.21) or 26-week follow-up (Reference LL; SL: OR=0.93, 95% CI 0.64, 1.33, p=0.68; SS: OR=1.00, 95% CI 0.63, 1.58, p=1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.

    View details for DOI 10.1016/j.drugalcdep.2008.04.013

    View details for Web of Science ID 000259768500010

    View details for PubMedID 18562131

  • Genetic variation in the dopamine pathway and smoking cessation PHARMACOGENOMICS David, S. P., Munafo, M. R. 2008; 9 (9): 1307-1321


    Twin and family studies have established that genetic factors account for much of the variation in tobacco dependence. Therefore, identification of genetic variants predictive of successful smoking cessation has implications for the future prospect of personalized smoking cessation therapies. Converging data implicate the dopamine pathway as an important neural substrate for tobacco dependence. Several candidate genes within the dopamine pathway (e.g., DRD2 and COMT) have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy, and others (e.g., SLC6A3 and DRD4) have been reported to be associated with smoking cessation independent of pharmacotherapy. However, few of these candidate genes are present within regions of suggestive or significant linkage or overlap with genome-wide linkage or association studies of tobacco dependence or smoking cessation. Future studies should seek to replicate genome-wide association analyses with individual-level genotyping, and use better-defined smoking cessation phenotypes. Once robust evidence for association is established, which may take several more years, further research into the likely cost-effectiveness, feasibility and acceptability of personalized medicine for smoking cessation will be necessary before it can be translated into practice.

    View details for DOI 10.2217/14622416.9.9.1307

    View details for Web of Science ID 000259533200017

    View details for PubMedID 18781857

  • Molecular genetics of successful smoking cessation - Convergent genome-wide association study results ARCHIVES OF GENERAL PSYCHIATRY Uhl, G. R., Liu, Q., Drgon, T., Johnson, C., Walther, D., David, S. P., Niaura, R., Lerman, C., Rose, E. 2008; 65 (6): 683-693


    Smoking remains a major public health problem. Twin studies indicate that the ability to quit smoking is substantially heritable, with genetics that overlap modestly with the genetics of vulnerability to dependence on addictive substances.To identify replicated genes that facilitate smokers' abilities to achieve and sustain abstinence from smoking (herein after referred to as quit-success genes) found in more than 2 genome-wide association (GWA) studies of successful vs unsuccessful abstainers, and, secondarily, to nominate genes for selective involvement in smoking cessation success with bupropion hydrochloride vs nicotine replacement therapy (NRT).The GWA results in subjects from 3 centers, with secondary analyses of NRT vs bupropion responders.Outpatient smoking cessation trial participants from 3 centers.European American smokers who successfully vs unsuccessfully abstain from smoking with biochemical confirmation in a smoking cessation trial using NRT, bupropion, or placebo (N = 550).Quit-success genes, reproducibly identified by clustered nominally positive single-nucleotide polymorphisms (SNPs) in more than 2 independent samples with significant P values based on Monte Carlo simulation trials. The NRT-selective genes were nominated by clustered SNPs that display much larger t values for NRT vs placebo comparisons. The bupropion-selective genes were nominated by bupropion-selective results.Variants in quit-success genes are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, and/or protein-handling functions. Quit-success genes are identified by clustered nominally positive SNPs from more than 2 samples and are unlikely to represent chance observations (Monte Carlo P< .0003). These genes display modest overlap with genes identified in GWA studies of dependence on addictive substances and memory.These results support polygenic genetics for success in abstaining from smoking, overlap with genetics of substance dependence and memory, and nominate gene variants for selective influences on therapeutic responses to bupropion vs NRT. Molecular genetics should help match the types and/or intensity of antismoking treatments with the smokers most likely to benefit from them.

    View details for Web of Science ID 000256403600009

    View details for PubMedID 18519826

  • Smoking cessation in primary care BRITISH MEDICAL JOURNAL David, S. P., Munafo, M. R. 2008; 336 (7655): 1200-1201

    View details for DOI 10.1136/bmj.39546.520694.80

    View details for Web of Science ID 000256612700002

    View details for PubMedID 18441374

  • Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch PHARMACOGENOMICS JOURNAL David, S. P., Munafo, M. R., Murphy, M. F., Proctor, M., Walton, R. T., Johnstone, E. C. 2008; 8 (2): 122-128


    Smokers of European ancestry (n=720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position -521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P=0.001) and 26-week (P=0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P=0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.

    View details for DOI 10.1038/sj.tpj.6500447

    View details for Web of Science ID 000254123900006

    View details for PubMedID 17387332

  • Smoking cessation. BMJ (Clinical research ed.) Koplan, K. E., David, S. P., Rigotti, N. A. 2008; 336 (7637): 217-?

    View details for DOI 10.1136/bmj.39248.531748.47

    View details for PubMedID 18219045

  • A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation NICOTINE & TOBACCO RESEARCH Welton, N. J., Johnstone, E. C., David, S. P., Munafo, M. R. 2008; 10 (1): 231-240


    We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current "one-size-fits-all" model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.

    View details for DOI 10.1080/14622200701767761

    View details for Web of Science ID 000252342800025

    View details for PubMedID 18188764

  • Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: A diffusion tensor imaging study NICOTINE & TOBACCO RESEARCH Paul, R. H., Grieve, S. M., Niaura, R., David, S. P., Laidlaw, D. H., Cohen, R., Sweet, L., Taylor, G., Clark, C. R., Pogun, S., Gordon, E. 2008; 10 (1): 137-147


    Results from recent studies suggest that chronic cigarette smoking is associated with increased white matter volume in the brain as determined by in vivo neuroimaging. We used diffusion tensor imaging to examine the microstructural integrity of the white matter in 10 chronic smokers and 10 nonsmokers. All individuals were healthy, without histories of medical or psychiatric illness. Fractional anisotropy (FA) and trace were measured in the genu, body, and splenium of the corpus callosum. FA provides a measure of directional versus nondirectional water diffusion, whereas trace provides a measure of nondirectional water diffusion. Lower FA and higher trace values are considered to reflect less brain integrity. Voxel-based morphometry was used to define volumes in each of these regions of the corpus callosum. Chronic smokers exhibited significantly higher FA in the body and whole corpus callosum and a strong trend for higher FA in the splenium compared with nonsmokers. FA did not differ between groups in the genu, and neither trace nor white matter volumes differed between groups in any of the regions of interest. When subdivided by Fagerström score (low vs. high), the low Fagerström group exhibited significantly higher FA in the body of the corpus callosum compared with the high Fagerström group and the nonsmokers. These results suggest that, among healthy adults, lower exposure to cigarette smoking is associated with increased microstructural integrity of the white matter compared with either no exposure or higher exposure. Additional studies are needed to further explore differences in white matter integrity between smokers and nonsmokers.

    View details for DOI 10.1080/14622200701767829

    View details for Web of Science ID 000252342800015

    View details for PubMedID 18188754

  • Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study BRAIN IMAGING AND BEHAVIOR David, S. P., Munafo, M. R., Johansen-Berg, H., MacKillop, J., Sweet, L. H., Cohen, R. A., Niaura, R., Rogers, R. D., Matthews, P. M., Walton, R. T. 2007; 1 (3-4): 43-57
  • Successful Latino community partnership program for smoking cessation AMERICAN JOURNAL OF PUBLIC HEALTH David, S. P., Smith, M., Lee, C. S., Sullivan, G. 2007; 97 (8): 1348-1349

    View details for DOI 10.2105/AJPH.2007.111237

    View details for Web of Science ID 000255648000001

    View details for PubMedID 17600240

  • Association of COMT Val(108/158) met genotype with smoking cessation in a nicotine replacement therapy randomized trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Johnstone, E. C., Elliot, K. M., David, S. P., Murphy, M. F., Walton, R. T., Munafo, M. R. 2007; 16 (6): 1065-1069


    We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype x treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.

    View details for DOI 10.1158/1055-9965.EPI-06-0936

    View details for Web of Science ID 000247163100004

    View details for PubMedID 17548664

  • The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial NICOTINE & TOBACCO RESEARCH David, S. P., Munafo, M. R., Murphy, M. F., Walton, R. T., Johnstone, E. C. 2007; 9 (2): 225-231


    In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotypextreatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care-based trial.

    View details for DOI 10.1080/14622200601078566

    View details for Web of Science ID 000244927500007

    View details for PubMedID 17365753

  • Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation NICOTINE & TOBACCO RESEARCH David, S. P., Brown, R. A., Papandonatos, G. D., Kahler, C. W., Lloyd-Richardson, E. E., Munafo, M. R., Shields, P. G., Lerman, C., Strong, D., McCaffery, J., Niaura, R. 2007; 9 (8): 821-833


    This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N = 291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3' VNTR), and cytochrome P450 2B6 (CYP2B6 1459 CT) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 x bupropion interaction (B = 1.49, SE = 0.59, p = .012) [corrected] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes (B = -0.45, SE = 0.22, p = .038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 x CYP2B6 interaction (B = 1.43, SE = 0.56, p = .01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene x gene and gene x craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.

    View details for DOI 10.1080/14622200701382033

    View details for Web of Science ID 000248725500005

    View details for PubMedID 17654295

  • Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study. Brain imaging and behavior David, S. P., Munafò, M. R., Johansen-Berg, H., Mackillop, J., Sweet, L. H., Cohen, R. A., Niaura, R., Rogers, R. D., Matthews, P. M., Walton, R. T. 2007; 1 (3-4): 43–57


    To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs-suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.

    View details for DOI 10.1007/s11682-007-9004-1

    View details for PubMedID 18458752

    View details for PubMedCentralID PMC2367252

  • Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials NICOTINE & TOBACCO RESEARCH David, S. P., Strong, D. R., Munafo, M. R., Brown, R. A., Lloyd-Richardson, E. E., Wileyto, P. E., Evins, E. A., Shields, P. G., Lerman, C., Niaura, R. 2007; 9 (12): 1251-1257


    We analyzed pooled data from two comparable randomized placebo-controlled clinical trials of bupropion pharmacotherapy for smoking cessation for which data on DRD2 Taq1A genotype were available. A total of 722 smokers across the two trials were randomized to 10 weeks of sustained-release bupropion hydrochloride or placebo. General estimating equation analysis demonstrated a significant gene x drug interaction (B = 0.87, SE = 0.34, p = .009). Smokers with the A2/A2 genotype using bupropion were more than three times as likely, relative to placebo, to be abstinent at end of treatment (35.2% vs. 15.1%; OR = 3.25, 95% CI 2.00-5.28) and at 6 months of follow-up (26.7% vs. 12.2%; OR = 2.81, 95% CI 1.66-4.77), which was attenuated by 12 months (16.3% vs. 10.7%; OR = 1.70, 95% CI 0.95-3.05). We found no significant benefit of bupropion relative to placebo on smoking cessation outcomes at any time point in participants with A1/A1 or A1/A2 genotypes. These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype.

    View details for DOI 10.1080/14622200701705027

    View details for Web of Science ID 000251966100002

    View details for PubMedID 18058343

  • Building a successful research enterprise in family medicine: the Brown experience. Medicine and health, Rhode Island David, S. P., Eaton, C. B., Culpepper, L., Goldman, R. E., Lavallee, L. K., Simmons, E. M. 2006; 89 (8): 281-284

    View details for PubMedID 16967659

  • Fellowship training in family medicine at Brown: adding depth to breadth. Medicine and health, Rhode Island Long, R., David, S. P., Monroe, A., Shaw, J. 2006; 89 (8): 274-275


    The Brown Family Medicine fellowship programs share a common goal of nurturing the future leaders of our specialty. In a complex and demanding practice environment our fellowships have contributed to the development and propagation of an adept Family Medicine specialist. These fellowships endorse our specialty's broad approach to healthcare through addressing primary care and prevention, but also enhance the future of our field through melding the breadth of our discipline with the depth of expertise and the stewardship of responsible leadership.

    View details for PubMedID 16967657

  • Opioid antagonists for smoking cessation COCHRANE DATABASE OF SYSTEMATIC REVIEWS David, S., Lancaster, T., Stead, L. F., Evins, A. E. 2006


    The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. Smokers report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.We searched the Cochrane Tobacco Addiction Group specialized register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in March 2006. We also contacted investigators, when possible, for information on unpublished studies.We considered randomized controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was cotinine- or carbon monoxide-verified abstinence from smoking after at least six months follow up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed-effect model (Mantel-Haenszel odds ratios).Four trials of naltrexone met inclusion criteria for meta-analyses for long-term cessation. All four trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on long-term abstinence, and confidence intervals were wide (odds ratio 1.26, 95% confidence interval 0.80 to 2.01). No trials of naloxone or buprenorphine reported long-term follow up.Based on limited data from four trials it is not possible to confirm or refute whether naltrexone helps smokers quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

    View details for DOI 10.1002/14651858.CD003086.pub2

    View details for Web of Science ID 000241386000138

    View details for PubMedID 17054160

  • The Pharmacogenetics of Nicotine Addiction and Smoking Cessation. Chapter 21 in: Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine. Edited by Wong SHY, Linder MW, Valdes, Jr. R. AACC Press, Washington, DC. David SP., Munaf_ M, Walton RT. 2006; 1: 203-212.
  • Studies of Genetic Influences on Nicotine Dependence Utilising Functional Neuroimaging. Doctoral thesis: University of Oxford, Bodleian Library, Oxford, UK. David SP. 2006
  • Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: A functional magnetic resonance imaging study BIOLOGICAL PSYCHIATRY David, S. P., Munafo, M. R., Johansen-Berg, H., Smith, S. M., Rogers, R. D., Matthews, P. M., Walton, R. T. 2005; 58 (6): 488-494


    Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity.Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues.Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls.This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.

    View details for DOI 10.1016/j.biopsych.2005.04.028

    View details for Web of Science ID 000232296000009

    View details for PubMedID 16023086

  • A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans JOURNAL OF NEUROSCIENCE David, S. P., Murthy, N. V., Rabiner, E. A., Munafo, M. R., Johnstone, E. C., Jacob, R., Walton, R. T., Grasby, P. M. 2005; 25 (10): 2586-2590


    In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

    View details for DOI 10.1523/JNEUROSCI.3769-04.2005

    View details for Web of Science ID 000227528600017

    View details for PubMedID 15758168

  • Envisaging and applying a unifying three-dimensional theoretical framework for generalist physicians. Medicine and health, Rhode Island David, S. P., Eaton, C. B., Taylor, J. S., Stamp, M. J., Cyr, M., Siegel, B., Gramling, R., Walton, R. 2004; 87 (11): 336-340

    View details for PubMedID 15631301

  • Does providing hereditary breast cancer risk assessment support to practicing physicians decrease the likelihood of them discussing such risk with their patients? GENETICS IN MEDICINE Gramling, R., Duffy, C., David, S. 2004; 6 (6): 542-542

    View details for Web of Science ID 000225180000014

    View details for PubMedID 15545753

  • Investigating subgroups in smoking cessation treatment response: Response to Perkins NICOTINE & TOBACCO RESEARCH Munafo, M. R., Bradburn, M., Bowes, L., David, S. 2004; 6 (5): 865-867
  • Are there sex differences in transdermal nicotine replacement therapy patch efficacy? A meta-analysis NICOTINE & TOBACCO RESEARCH Munafo, M., Bradburn, M., Bowes, L., David, S. 2004; 6 (5): 769-776


    Smoking-related death and disability rates for women have risen sharply recently. Despite lower smoking cessation success rates for women using behavioral therapies, data are limited on whether specific pharmacological therapies are equally efficacious in men and women. Using meta-analytic techniques, we examined whether significant differences in therapeutic efficacy of nicotine replacement therapy (NRT) for smoking cessation exist by sex. Out of the 31 randomized clinical trials of NRT that met inclusion criteria, 11 contributed to the analysis. The odds ratios for NRT vs. placebo were derived from each trial separately by sex for males and females, and these ratios were combined to give a pooled estimate of the effect of sex in response to NRT. NRT was effective at all time points in men (< 6 months: OR = 2.05, 95% CI= 1.61-2.60; 6 months: OR = 1.98, 95% CI = 1.51-2.60; 12 months: OR = 1.86, 95% CI = 1.39-2.50) and women (< 6 months: OR = 2.09, 95% CI = 1.65-2.65; 6 months, OR = 1.52, 95% CI = 1.17-1.98; 12 months: OR = 1.63, 95% CI = 1.22-2.18). At all time points, no significant difference was observed between sexes (< 6 months: OR = .97, 95% CI = .69-1.36; 6 months: OR = 1.33, 95% CI = .91-1.95; 12 months: OR = 1.21, 95% CI = .79-1.84). The results of this meta-analysis do not support the hypothesis that NRT has higher therapeutic efficacy for men than women.

    View details for DOI 10.1080/1462200410001696556

    View details for Web of Science ID 000225135700004

    View details for PubMedID 15700912

  • Pharmacogenetics PRIMARY CARE David, S. P. 2004; 31 (3): 543-?


    This article provides an introduction to the discipline of pharmacogenetics and discusses the implications of pharmacogenetics research for primary care practice. Examples are given of how genetic information can predict and inform; drug interactions influencing drug efficacy, metabolism, dosing, and toxicity. Caveats on the need for vigilance in the interpretation of pharmacogenetics studies are discussed briefly, together with the need for a convergence of biomolecular research, translational research, education,and policy to promote evidence-based genetic medicine.

    View details for DOI 10.1016/j.pop.2004.04.009

    View details for Web of Science ID 000224051500008

    View details for PubMedID 15331247

  • Evaluation of an educational intervention for medical students to promote competency in social and community determinants of health. ABSAME David SP., Taylor JS, Monroe A, Goldman R, Green AR, Boss JD, Sagaties D. 2004; 10 (2): 68-73.
  • Investigating subgroups in smoking cessation treatment response: Response to Perkins. Nicotine Tob Res Munaf_ M, Bradburn M, Bowes L, David S. 2004; 6 (5): 865-867
  • Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? NICOTINE & TOBACCO RESEARCH David, S. P., Niaura, R., Papandonatos, G. D., Shadel, W. G., Burkholder, G. J., Britt, D. M., Day, A., Stumpff, J., Hutchison, K., Murphy, M., Johnstone, E., Griffiths, S. E., Walton, R. T. 2003; 5 (6): 935-942


    Bupropion hydrochloride is effective in promoting long-term abstinence from smoking and may reduce risk for relapse through attenuation of withdrawal symptoms and craving. Bupropion is a weak dopamine reuptake inhibitor, and individual genetic variation in the dopamine D2 receptor has been associated with nicotine dependence in case-control studies. Thirty smokers were randomly assigned to bupropion or placebo and interviewed using the Minnesota Nicotine Withdrawal Scale on two occasions: prior to starting medication and after 14 days on bupropion or placebo. The individual symptoms of craving, irritability, and anxiety were significantly reduced in the bupropion group, whereas no withdrawal symptoms were diminished in the placebo group. Within the bupropion group, subgroup analyses with stratification by genotype demonstrated that craving, irritability, and anxiety were significantly attenuated only among subjects with DRD2-Taq1 A2/A2 genotypes. In the DRD2-Taq1 A1/A1 and A1/A2 groups, no significant reduction was seen in any individual symptom of the nicotine withdrawal syndrome. These data suggest that bupropion attenuates specific symptoms of the nicotine withdrawal syndrome and that this effect may be modified by genotype for the dopamine D2 receptor.

    View details for DOI 10.1080/14622200310001615295

    View details for Web of Science ID 000188241000016

    View details for PubMedID 14668077

  • Should we offer routine breast cancer screening with mammography? AMERICAN FAMILY PHYSICIAN David, S. P. 2003; 68 (2): 260-262

    View details for Web of Science ID 000184320500006

    View details for PubMedID 12892345

  • Genetic susceptibility to breast cancer: Teaching points FAMILY MEDICINE Gramling, R., David, S. 2003; 35 (7): 466-468

    View details for Web of Science ID 000184126400005

    View details for PubMedID 12861454

  • Comment on "The public health implications of smoking-induced decreased serum and red blood cell folate levels" NICOTINE & TOBACCO RESEARCH David, S. P., Eaton, C. B. 2003; 5 (3): 397-399

    View details for DOI 10.1080/1462220031000094123

    View details for Web of Science ID 000185022100013

    View details for PubMedID 12791535

  • Are family physicians willing to use pharmacogenetics for smoking cessation therapy? FAMILY MEDICINE Stamp, M. J., David, S. P. 2003; 35 (2): 83-83

    View details for Web of Science ID 000180976200002

    View details for PubMedID 12607800

  • Should we prescribe antibiotics for acute conjunctivitis? American family physician David, S. P. 2002; 66 (9): 1649-1650

    View details for PubMedID 12449262

  • Should we use multiple risk factor interventions for the primary prevention of coronary heart disease? AMERICAN FAMILY PHYSICIAN David, S. P. 2002; 66 (2): 245-246

    View details for Web of Science ID 000177110500006

    View details for PubMedID 12152959

  • No association between functional catechol O-methyl transferase 1947A > G polymorphism and smoking initiation, persistent smoking or smoking cessation PHARMACOGENETICS David, S. P., Johnstone, E., Griffiths, S. E., Murphy, M., Yudkin, P., Mant, D., Walton, R. 2002; 12 (3): 265-268


    Nicotine stimulates dopamine release and activates dopaminergic reward neurones in central pathways giving rise to dependence. Catechol O-methyl transferase (COMT) inactivates extraneuronally released dopamine and is present in dopaminergic brain regions. A functional polymorphism (COMT 1947A>G) resulting in increased enzyme activity has been associated with alcoholism and polysubstance abuse. We examined the relationship between the COMT 1947A>G polymorphism and smoking initiation, smoking persistence and smoking cessation. We genotyped 266 current smokers, 270 ex-smokers and 265 lifetime non-smokers (never smokers), matched for age and gender, for the COMT 1947A>G polymorphism. Smoking status was ascertained by self-report. There was no difference in genotype frequencies between never smokers and ever smokers (current + ex-smokers); between non-smokers (never + ex-smokers) and current smokers; or between current smokers and ex-smokers. These data suggest that the COMT 1947A>G polymorphism is not associated with smoking initiation, smoking persistence or smoking cessation.

    View details for Web of Science ID 000175057600011

    View details for PubMedID 11927842

  • Should we recommend nicotine replacement therapy? AMERICAN FAMILY PHYSICIAN David, S. P. 2001; 63 (11): 2245-2247

    View details for Web of Science ID 000169272700019

    View details for PubMedID 11417777

  • A civic role for physicians in the promotion of global tobacco control FAMILY PRACTICE David, S. P. 2001; 18 (1): 107-107

    View details for Web of Science ID 000167146700020

    View details for PubMedID 11145639

  • Social marketing: Application to medical education ANNALS OF INTERNAL MEDICINE David, S. P., Greer, D. S. 2001; 134 (2): 125-127


    Medical education is often a frustrating endeavor, particularly when it attempts to change practice behavior. Traditional lecture-based educational methods are limited in their ability to sustain concentration and interest and to promote learner adherence to best-practice guidelines. Marketing techniques have been very effective in changing consumer behavior and physician behavior. However, the techniques of social marketing-goal identification, audience segmentation, and market research-have not been harnessed and applied to medical education. Social marketing can be applied to medical education in the effort to go beyond inoculation of learners with information and actually change behaviors. The tremendous potential of social marketing for medical education should be pilot-tested and systematically evaluated.

    View details for Web of Science ID 000166356000006

    View details for PubMedID 11177316

  • Opioid antagonists for smoking cessation. Cochrane database of systematic reviews David, S., Lancaster, T., Stead, L. F. 2001: CD003086-?


    The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. Smokers report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.We searched the Cochrane Tobacco Addiction Group trials register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of Medline using '"Narcotic antagonists" and smoking terms in March 2001. We also contacted, when possible, investigators for information on unpublished studies.We considered randomized controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included only trials reporting data on abstinence of a minimum of 6 months in the meta-analyses. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psychobiological mediating variables associated with nicotine dependence.We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was cotinine or carbon monoxide verified abstinence from smoking after at least six months follow-up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed effects model (Peto method).Two trials of naltrexone met inclusion criteria for meta-analyses for long term cessation. Both trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on long-term abstinence, and confidence intervals were wide (OR 1.34, 95% CI 0.49,3.63). No trials of naloxone or buprenorphine reported long term follow-upBased on limited data from two trials it is not possible to confirm or refute whether naltrexone helps smokers quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

    View details for PubMedID 11687036

  • Smoking cessation for the primary care physician. Prim Care Rep. David SP. 2001; 7 (24): 211-221.
  • International tobacco control: A focus group study of US anti-tobacco activists JOURNAL OF PUBLIC HEALTH POLICY David, S., DeJong, W., Resnick, N. 2001; 22 (4): 415-428


    Massachusetts tobacco control activists participated in focus groups to explore their knowledge, beliefs, and attitudes regarding international tobacco control. Initially, each of three focus groups ranked this issue at or near the bottom of important tobacco control issues. Participants ranked ten message concepts for their ability to motivate politically active Americans to contact a government representative about international tobacco issues. The top four message concepts dealt with deliberate marketing of cigarettes to children, dramatic increases in global mortality due to smoking, American hypocrisy in being the world's largest tobacco exporter, and use of overseas profits to finance youth-oriented marketing in the U.S. The rankings revealed little initial concern about U.S. diplomatic pressure to force foreign nations to open up their markets to American tobacco products. Yet during the subsequent discussion this was among the message concepts the generated the most outrage. This suggests that international tobacco control issues would resonate among U.S. opinion leaders once the facts were presented to them through a media advocacy campaign.

    View details for Web of Science ID 000172987300003

    View details for PubMedID 11787307

  • Media advocacy for the office-based teacher of family medicine FAMILY MEDICINE David, S. P. 2001; 33 (1): 16-18

    View details for Web of Science ID 000166289600007

    View details for PubMedID 11199903

  • Reflections from a rotation in Cambridge, England FAMILY MEDICINE David, S. P. 2000; 32 (5): 310-312

    View details for Web of Science ID 000086882900009

    View details for PubMedID 10820671

  • The Transatlantic Conference on Tobacco (TACT): a model for international tobacco policy activism. Journal of cancer education David, S. P. 1998; 13 (4): 253-254


    Smoking prevalence rates are alarmingly high in developing countries at a time when the United States and the United Kingdom are mobilizing domestic anti-smoking forces. A resident at Dartmouth-Hitchcock Medical Center established an American-British partnership to promote international tobacco policy activism.The program assembled a coalition of physicians and public health experts from the two countries and provided them with an Internet-based chat resource.The coalition utilized Internet resources to follow international trends in tobacco use policies and agreed to meet bimonthly through the site to promote anti-smoking activism.This report introduces a novel approach to international anti-tobacco policy activism. It provides a model that is transportable to other institutions and other public health measures.

    View details for PubMedID 9883786