Genetics. Published Articles Ahead of Print: March 31, 2005, Copyright © 2005
doi:10.1534/genetics.104.039958


A more recent version of this article appeared on June 1, 2005.

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Theoretical Basis for the Identification of Allelic Variants that Encode Drug Efficacy and Toxicity

Min Lin 1 and Rongling Wu 1*

1 University of Florida

* To whom correspondence should be addressed. E-mail: rwu{at}stat.ufl.edu.

Submitted on December 15, 2004
Revised on February 7, 2005
Accepted on 18 February 2005


Abstract

Almost all drugs that produce a favorable response (efficacy) may also produce adverse effects (toxicity). The relative strengths of drug efficacy and toxicity that vary in human populations are controlled by the combined influences of multiple genes and environmental influences. In this article, we present a novel statistical model for sequence mapping of these two different but related drug responses. This model is incorporated by mathematical functions of drug response to varying doses and the statistical approaches for structuring the residual covariance matrix. We implement a closed-form solution for the EM algorithm to estimate the population genetic parameters of SNPs and the simplex algorithm to estimate the curve parameters that define the pharmacodynamic changes of different genetic variants and the antedependence parameters that model the covariance structure. Monte Carlo simulations were performed to investigate the statistical properties of our model. We discuss the implications of the model in pharmacogenetic and pharmacogenomic research.

Key Words: Drug response, EM algorithm, Emax model, HapMap, Sequence mapping