ABSTRACT
The main objective in pharmacogenomics is to study variation in genetic characteristics or gene expression and determine whether the variation is related to drug response. Genetic variations can inuence all aspects of
CONTENTS
9.1 Introduction ................................................................................................ 265 9.1.1 Pharmacogenomics and Drug Development ............................. 265 9.1.2 Multiplicity Issues in Pharmacogenomics Research ................ 267
9.2 Overview of Multiple Testing Procedures ............................................. 268 9.2.1 Denitions of Type I and II Errors .............................................. 268
9.2.1.1 Type I Error Rates Based on the Distribution of the Number of Type I Errors ..................................... 269
9.2.1.2 Type I Error Rates Based on the Distribution of the Proportion of Type I Errors among the Rejected Hypotheses ...................................................... 270
9.2.2 Multiple Testing Procedures for Controlling FWER ................ 271 9.2.2.1 Single-Step Multiple Testing Procedures for
Controlling FWER ........................................................... 272 9.2.3 Multiple Testing Procedures for Controlling gFWER .............. 275 9.2.4 Multiple Testing Procedures for Controlling FDR .................... 276 9.2.5 Multiple Testing Procedures for Controlling FDP .................... 278
9.3 Addressing the Impact of Multiplicity in Pharmacogenomics ...........280 9.4 Discussion and Recommendations ......................................................... 282 Acknowledgments .............................................................................................. 282 Appendix Software Implementation ................................................................ 282
A. R Implementation ................................................................................. 282 B. SAS Implementation ............................................................................. 286 C. Power Analysis Using Multiple Comparison Procedures in East® ... 291
References ............................................................................................................. 295
disease and the potential treatment of the disease. Genomic differences that are of most relevance to drug development fall into the following four categories: (1) pharmacokinetic (PK) markers: genes relevant to drug PK characteristics such as absorption, distribution, metabolism and formation of active metabolites, and excretion, (2) pharmacodynamic (PD) markers: genes that affect intended and unintended responses to a drug, (3) prognostic markers: genes that predict the course of disease development (e.g., genes that predict the likelihood of tumor development or metastasis), either without treatment or with standard-of-care treatment, and (4) predictive markers: genes that predict the course of disease development when the patient is treated with a particular drug.
