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Identification of pharmacogenetic markers in smoking cessation therapy
Author(s) -
Heitjan Daniel F.,
Guo Mengye,
Ray Riju,
Wileyto E. Paul,
Epstein Leonard H.,
Lerman Caryn
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30669
Subject(s) - frequentist inference , pharmacogenetics , bayesian probability , sample size determination , multiple comparisons problem , bayes' theorem , single nucleotide polymorphism , statistical hypothesis testing , bayes factor , medicine , bioinformatics , statistics , bayesian inference , computer science , biology , artificial intelligence , genetics , genotype , mathematics , gene
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. © 2007 Wiley‐Liss, Inc.