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A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change.

ABSTRACT: In pharmacogenetic (PGx) studies, drug response phenotypes are often measured in the form of change in a quantitative trait before and after treatment. There is some debate in recent literature regarding baseline adjustment, or inclusion of pre-treatment or baseline value as a covariate, in PGx genome-wide association studies (GWAS) analysis. Here, we provide a clear statistical perspective on this baseline adjustment issue by running extensive simulations based on nine statistical models to evaluate the influence of baseline adjustment on type I error and power. We then apply these nine models to analyzing the change in low-density lipoprotein cholesterol (LDL-C) levels with ezetimibe + simvastatin combination therapy compared with simvastatin monotherapy therapy in the 5661 participants of the IMPROVE-IT (IMProved Reduction of Outcomes: Vytroin Efficacy International Trial) PGx GWAS, supporting the conclusions drawn from our simulations. Both simulations and GWAS analyses consistently show that baseline-unadjusted models inflate type I error for the variants associated with baseline value if the baseline value is also associated with change from baseline (e.g., when baseline value is a mediator between a variant and change from baseline), while baseline-adjusted models can control type I error in various scenarios. We thus recommend performing baseline-adjusted analyses in PGx GWASs of quantitative change.

SUBMITTER: Zhang H

PROVIDER: S-EPMC9184591 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change.

Zhang Hong H Chhibber Aparna A Shaw Peter M PM Mehrotra Devan V DV Shen Judong J

NPJ genomic medicine 20220609 1

In pharmacogenetic (PGx) studies, drug response phenotypes are often measured in the form of change in a quantitative trait before and after treatment. There is some debate in recent literature regarding baseline adjustment, or inclusion of pre-treatment or baseline value as a covariate, in PGx genome-wide association studies (GWAS) analysis. Here, we provide a clear statistical perspective on this baseline adjustment issue by running extensive simulations based on nine statistical models to eva ...[more]

PMID: 35680959

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Dataset Information

A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change.

Publications

A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change.

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