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Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests

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 ef...

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Detalles Bibliográficos
Autores principales: Tessier, A, Bertrand, J, Chenel, M, Comets, E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807465/
https://www.ncbi.nlm.nih.gov/pubmed/27069775
http://dx.doi.org/10.1002/psp4.12054
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author Tessier, A
Bertrand, J
Chenel, M
Comets, E
author_facet Tessier, A
Bertrand, J
Chenel, M
Comets, E
author_sort Tessier, A
collection PubMed
description 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.
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spelling pubmed-48074652016-04-11 Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests Tessier, A Bertrand, J Chenel, M Comets, E CPT Pharmacometrics Syst Pharmacol Original Articles 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. John Wiley and Sons Inc. 2016-03-14 2016-03 /pmc/articles/PMC4807465/ /pubmed/27069775 http://dx.doi.org/10.1002/psp4.12054 Text en © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Tessier, A
Bertrand, J
Chenel, M
Comets, E
Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title_full Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title_fullStr Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title_full_unstemmed Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title_short Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests
title_sort combined analysis of phase i and phase ii data to enhance the power of pharmacogenetic tests
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807465/
https://www.ncbi.nlm.nih.gov/pubmed/27069775
http://dx.doi.org/10.1002/psp4.12054
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