The virtues of a deliberately mis-specified disease model in demonstrating a gene-environment interaction.
OBJECTIVE
This study seeks to assess the impact of measurement errors in cumulative exposure on estimates of a gene-environment interaction in a nested case-control study in occupational epidemiology. In the approach considered here, exposure intensity is assessed at the group level and the exposure duration individually (both with error). Genetic susceptibility is assumed to be known exactly. Differences in "gene" are assumed to affect disease risk only in exposed subjects.


METHODS
Three data analysis strategies were considered: one using a correctly specified disease model (exposure and exposure-gene interaction), and two using mis-specified disease models, one with "gene" as the only risk factor ("gene-only" model) and the other with main effects of both gene and exposure along with their interaction ("full" model).


RESULTS
In simulations, estimates of the gene-environment interaction based on the correctly specified disease model were greatly attenuated and power was diminished appreciably even when errors in exposure were modest. Significant associations were detected more frequently in the gene-only model when errors in exposure were large. When the "full" mis-specified model was fitted to the simulated data, it yielded erratic estimates. This is illustrated in an analysis of the interaction of cumulative exposure to organophosphate pesticides and paraoxonase gene on the risk of chronic neuropsychological effects among farmers who dip sheep.


CONCLUSIONS
If "gene" contributes to disease risk only in the presence of exposure, the existence of the gene-environment interaction can be efficiently inferred from a deliberately mis-specified "gene-only" disease model in nested case-control studies.
Burstyn
I
I
Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. iburstyn@ualberta.ca
Kim
H-M
HM
Yasui
Y
Y
Cherry
N M
NM
D000382:Agricultural Workers' Diseases / Q000139:chemically induced; D016022:Case-Control Studies; D003625:Data Collection / Q000592:standards*; D004781:Environmental Exposure / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D009784:Occupational Diseases / Q000235:genetics*; D010755:Organophosphates / Q000633:toxicity; D010575:Pesticides / Q000633:toxicity
D010755:Organophosphates; D010575:Pesticides