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When drug treatments bias genetic studies: Mediation and interaction

Schmidt, AF; Heerspink, HJL; Denig, P; Finan, C; Groenwold, RHH; (2019) When drug treatments bias genetic studies: Mediation and interaction. PLoS One , 14 (8) , Article e0221209. 10.1371/journal.pone.0221209. Green open access

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Abstract

Background Increasingly, genetic analyses are conducted using information from subjects with established disease, who often receive concomitant treatment. We determined when treatment may bias genetic associations with a quantitative trait. Methods Graph theory and simulated data were used to explore the impact of drug prescriptions on (longitudinal) genetic effect estimates. Analytic derivations of longitudinal genetic effects are presented, accounting for the following scenarios: 1) treatment allocated independently of a genetic variant, 2) treatment that mediates the genetic effect, 3) treatment that modifies the genetic effect. We additionally evaluate treatment modelling strategies on bias, the root mean squared error (RMSE), coverage, and rejection rate. Results We show that in the absence of treatment by gene effect modification or mediation, genetic effect estimates will be unbiased. In simulated data we found that conditional models accounting for treatment, confounding, and effect modification were generally unbiased with appropriate levels of confidence interval coverage. Ignoring the longitudinal nature of treatment prescription, however (e.g. because of incomplete records in longitudinal data), biased these conditional models to a similar degree (or worse) as simply ignoring treatment. Conclusion The mere presence of (drug) treatment affecting a GWAS phenotype is insufficient to bias genetic associations with quantitative traits. While treatment may bias associations through effect modification and mediation, this might not occur frequently enough to warrant general concern at the presence of treated subjects in GWAS. Should treatment by gene effect modification or mediation be present however, current GWAS approaches attempting to adjust for treatment insufficiently account for the multivariable and longitudinal nature of treatment trajectories and hence genetic estimates may still be biased.

Type: Article
Title: When drug treatments bias genetic studies: Mediation and interaction
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0221209
Publisher version: https://doi.org/10.1371/journal.pone.0221209
Language: English
Additional information: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10080880
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