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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Gang Liu
  • Bhramar Mukherjee
  • Seunggeun Lee
  • Alice W Lee
  • Anna H Wu
  • Elisa V Bandera
  • Allan Jensen
  • Mary Anne Rossing
  • Kirsten B Moysich
  • Jenny Chang-Claude
  • Jennifer A Doherty
  • Aleksandra Gentry-Maharaj
  • Lambertus Kiemeney
  • Simon A Gayther
  • Francesmary Modugno
  • Leon Massuger
  • Ellen L Goode
  • Brooke L Fridley
  • Kathryn L Terry
  • Daniel W Cramer
  • Susan J Ramus
  • Hoda Anton-Culver
  • Argyrios Ziogas
  • Jonathan P Tyrer
  • Joellen M Schildkraut
  • Kjær, Susanne Krüger
  • Penelope M Webb
  • Roberta B Ness
  • Usha Menon
  • Andrew Berchuck
  • Paul D Pharoah
  • Harvey Risch
  • Celeste Leigh Pearce
  • Ovarian Cancer Association Consortium

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.

Original languageEnglish
JournalAmerican Journal of Epidemiology
Volume187
Issue number2
Pages (from-to)366-377
Number of pages12
ISSN0002-9262
DOIs
Publication statusPublished - 2018

ID: 215459019