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Journal articles
Some alternatives to asymptotic tests for the analysis of pharmacogenetic data using nonlinear mixed effects models.: Alternatives to Asymptotic Tests in NLMEM: an Application to Pharmacogenetics
Abstract : Nonlinear mixed effects models allow investigating individual differences in drug concentration profiles (pharmacokinetics) and responses. Pharmacogenetics focuses on the genetic component of this variability. Two tests often used to detect a gene effect on a pharmacokinetic parameter are (1) the Wald test, assessing whether estimates for the gene effect are significantly different from 0 and (2) the likelihood ratio test comparing models with and without the genetic effect. Because those asymptotic tests show inflated type I error on small sample size and/or with unevenly distributed genotypes, we develop two alternatives and evaluate them by means of a simulation study. First, we assess the performance of the permutation test using the Wald and the likelihood ratio statistics. Second, for the Wald test we propose the use of the F-distribution with four different values for the denominator degrees of freedom. We also explore the influence of the estimation algorithm using both the first-order conditional estimation with interaction linearization-based algorithm and the stochastic approximation expectation maximization algorithm. We apply these methods to the analysis of the pharmacogenetics of indinavir in HIV patients recruited in the COPHAR2-ANRS 111 trial. Results of the simulation study show that the permutation test seems appropriate but at the cost of an additional computational burden. One of the four F-distribution-based approaches provides a correct type I error estimate for the Wald test and should be further investigated.
Cited literature [25 references]
https://www.hal.inserm.fr/inserm-00709820
Contributor : Emmanuelle Comets Connect in order to contact the contributor
Submitted on : Tuesday, June 19, 2012 - 3:01:52 PM
Last modification on : Thursday, May 14, 2020 - 2:48:10 PM
Long-term archiving on: : Thursday, September 20, 2012 - 2:35:36 AM
Contributor : Emmanuelle Comets Connect in order to contact the contributor
Submitted on : Tuesday, June 19, 2012 - 3:01:52 PM
Last modification on : Thursday, May 14, 2020 - 2:48:10 PM
Long-term archiving on: : Thursday, September 20, 2012 - 2:35:36 AM
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