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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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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. |
format | Online Article Text |
id | pubmed-4807465 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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