Indirect Estimation of the Comparative Treatment Effect in Pharmacogenomic Subgroups
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Date
2013-08
Authors
Sorich, Michael J
Coory, M
Pekarsky, B
Journal Title
Journal ISSN
Volume Title
Publisher
PLOS
Rights
Copyright © 2013 Sorich et al. 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.
Rights Holder
Sorich et al.
Abstract
Evidence of clinical utility is a key issue in translating pharmacogenomics into clinical practice. Appropriately designed
randomized controlled trials generally provide the most robust evidence of the clinical utility, but often only data from a
pharmacogenomic association study are available. This paper details a method for reframing the results of
pharmacogenomic association studies in terms of the comparative treatment effect for a pharmacogenomic subgroup
to provide greater insight into the likely clinical utility of a pharmacogenomic marker, its’ likely cost effectiveness, and the
value of undertaking the further (often expensive) research required for translation into clinical practice. The method is
based on the law of total probability, which relates marginal and conditional probability. It takes as inputs: the prevalence of
the pharmacogenomic marker in the patient group of interest, prognostic effect of the pharmacogenomic marker based on
observational association studies, and the unstratified comparative treatment effect based on one or more conventional
randomized controlled trials. The critical assumption is that of exchangeability across the included studies. The method is
demonstrated using a case study of cytochrome P450 (CYP) 2C19 genotype and the anti-platelet agent clopidogrel. Indirect
subgroup analysis provided insight into relationship between the clinical utility of genotyping CYP2C19 and the risk ratio of
cardiovascular outcomes between CYP2C19 genotypes for individuals using clopidogrel. In this case study the indirect and
direct estimates of the treatment effect for the cytochrome P450 2C19 subgroups were similar. In general, however, indirect
estimates are likely to have substantially greater risk of bias than an equivalent direct estimate.
Description
2013 Sorich et al. 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.
Keywords
Pharmacogenomics, Drug therapy, Meta-analysis
Citation
Sorich MJ, Coory M, Pekarsky BAK (2013) Indirect Estimation of the Comparative Treatment Effect in Pharmacogenomic Subgroups. PLoS ONE 8(8): e72256.