DIFFERENTIAL MISCLASSIFICATION AND THE ASSESSMENT OF GENE-ENVIRONMENTINTERACTIONS IN CASE-CONTROL STUDIES

In case-control studies of interactions between genetic and environmen tal exposures, differential misclassification of the environmental exp osure with respect to disease status can introduce spurious heterogene ity of the stratum-specific odds ratios. In this paper, the authors id entify conditions under which differential misclassification does not introduce bias in the interaction parameter when no multiplicative int eraction is present, and it biases the interaction parameter toward th e null value when a multiplicative interaction is present. The conditi ons are that (i) conditional on potential confounders, the environment al exposure is independent of the genotype among the controls, and (ii ) misclassification of the environmental exposure is nondifferential w ith respect to the genotype. These conditions can be tested from the m isclassified data in the control group, since a test of the independen ce of the genotype and the misclassified environmental exposure among the controls is a test of the joint hypothesis that conditions (i) and (ii) are both true. Therefore, the authors propose a two-step test fo r interaction which first tests conditions (i) and (ii) and then goes on to test for interaction, provided the first step hypothesis is not rejected. A summary test procedure to test for gene-environment intera ctions in the presence of misclassification, based on both a conventio nal test for interaction and the two-step test, is recommended, and is illustrated with data from a case-control study of the role of diet a s a modifier of the association between a metabolic polymorphism and l ung cancer.