title: Identification of pharmacogenetic markers in smoking cessation therapy.
abstract: Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773-795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. dheitjan@mail.med.upenn.edu
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.forename: Mengye
authors.initials: M
authors.lastname: Guo
authors.forename: Riju
authors.initials: R
authors.lastname: Ray
authors.forename: E Paul
authors.initials: EP
authors.lastname: Wileyto
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Epstein
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis; D016642:Bupropion / Q000627:therapeutic use*; D002795:Choline O-Acetyltransferase / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers / Q000502:physiology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D010597:Pharmacogenetics; D010919:Placebos; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011978:Receptors, Nicotinic / Q000235:genetics; D012907:Smoking / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D016540:Smoking Cessation / Q000379:methods*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000235:genetics; D017211:Treatment Failure
chemical_list: D018687:Antidepressive Agents, Second-Generation; D054316:Biomarkers, Pharmacological; C436489:CHRNA2 protein, human; C447158:CHRNA5 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D010919:Placebos; D011978:Receptors, Nicotinic; D016642:Bupropion; D002795:Choline O-Acetyltransferase