title: Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests.
abstract: We show through a simulation study how the joint analysis of data from phase I and phase II studies enhances the power of pharmacogenetic tests in pharmacokinetic (PK) studies. PK profiles were simulated under different designs along with 176 genetic markers. The null scenarios assumed no genetic effect, while under the alternative scenarios, drug clearance was associated with six genetic markers randomly sampled in each simulated dataset. We compared penalized regression Lasso and stepwise procedures to detect the associations between empirical Bayes estimates of clearance, estimated by nonlinear mixed effects models, and genetic variants. Combining data from phase I and phase II studies, even if sparse, increases the power to identify the associations between genetics and PK due to the larger sample size. Design optimization brings a further improvement, and we highlight a direct relationship between η-shrinkage and loss of genetic signal.
authors.affiliation: INSERM IAME UMR 1137 Paris France; Université Paris Diderot, IAME UMR 1137, Sorbonne Paris Cité Paris France; Division of Clinical Pharmacokinetics and Pharmacometrics Institut de Recherches Internationales Servier Suresnes France.
authors.forename: A
authors.initials: A
authors.lastname: Tessier
authors.affiliation: University College London, Genetics Institute London UK.
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
authors.affiliation: Division of Clinical Pharmacokinetics and Pharmacometrics Institut de Recherches Internationales Servier Suresnes France.
authors.forename: M
authors.initials: M
authors.lastname: Chenel
authors.affiliation: INSERM IAME UMR 1137 Paris France; Université Paris Diderot, IAME UMR 1137, Sorbonne Paris Cité Paris France; INSERM CIC 1414, Université Rennes 1 Rennes France.
authors.forename: E
authors.initials: E
authors.lastname: Comets
mesh_terms: D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D014644:Genetic Variation; D006801:Humans; D008657:Metabolic Clearance Rate; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics / Q000379:methods*; D018401:Sample Size