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Robust Tests for Additive Gene-Environment Interaction in Case-Control Studies Using Gene-Environment Independence

Accepted version
Peer-reviewed

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Type

Article

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Authors

Liu, Gang 
Mukherjee, Bhramar 
Lee, Seunggeun 
Lee, Alice W 
Wu, Anna H 

Abstract

There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case-control data. Our simulation studies suggest that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium.

Description

Keywords

bias-variance tradeoff, effect modification, empirical Bayes estimation, genetic risk score, relative excess risk, shrinkage

Journal Title

American Journal of Epidemiology

Conference Name

Journal ISSN

0002-9262
1476-6256

Volume Title

187

Publisher

Oxford University Press
Sponsorship
Cancer Research Uk (None)
Cancer Research Uk (None)
Multiple funders listed on paper.