Trick or treat: the effect of placebo on the power of pharmacogenetic association studies.
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.
Singer
Clara
C
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Grossman
Iris
I
Avidan
Nili
N
Beckmann
Jacques S
JS
Pe'er
Itsik
I
D002986:Clinical Trials as Topic; D003198:Computer Simulation; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D015990:Placebo Effect; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers