Trick or treat: the effect of placebo on the power of pharmacogenetic association studies

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Title
Trick or treat: the effect of placebo on the power of pharmacogenetic association studies
Journal
Human Genomics
Author(s)
Singer  C., Grossman  I., Avidan  N., Beckmann  J. S., Pe'er  I.
ISSN
1479-7364 (Electronic)
Publication state
Published
Issued date
03/2005
Volume
2
Number
1
Pages
28-38
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Mar
Abstract
The genetic mapping of drug-response traits is often characterised by a poor signal-to-noise ratio that is placebo related and which distinguishes pharmacogenetic association studies from classical case-control studies for disease susceptibility. The goal of this study was to evaluate the statistical power of candidate gene association studies under different pharmacogenetic scenarios, with special emphasis on the placebo effect. Genotype/phenotype data were simulated, mimicking samples from clinical trials, and response to the drug was modelled as a binary trait. Association was evaluated by a logistic regression model. Statistical power was estimated as a function of the number of single nucleotide polymorphisms (SNPs) genotyped, the frequency of the placebo 'response', the genotype relative risk (GRR) of the response polymorphism, the strategy for selecting SNPs for genotyping, the number of individuals in the trial and the ratio of placebo-treated to drug-treated patients. We show that: (i) the placebo 'response' strongly affects the statistical power of association studies--even a highly penetrant drug-response allele requires at least a 500-patient trial in order to reach 80 per cent power, several-fold more than the value estimated by standard tools that are not calibrated to pharmacogenetics; (ii) the power of a pharmacogenetic association study depends primarily on the penetrance of the response genotype and, when this penetrance is fixed, power decreases for larger placebo effects; (iii) power is dramatically increased when adding markers; (iv) an optimal study design includes a similar number of placebo- and drug-treated patients; and (v) in this setting, straightforward haplotype analysis does not seem to have an advantage over single marker analysis.
Keywords
Clinical Trials Computer Simulation Genetic Markers Genotype Haplotypes Humans Models, Genetic Pharmacogenetics/*methods Phenotype *Placebo Effect Polymorphism, Single Nucleotide
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25/01/2008 16:18
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20/08/2019 12:42
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