Bias in association studies resulting from gene-environment interactions and competing risks

The etiology, particularly the genetic basis, of multifactorial late-onset diseases is the subject of many genetic epidemiologic studies. The authors' aim in this paper was to investigate the circumstances under which competing risks can lead to bias in studies of genetic susceptibility to late-onset diseases. The authors used a model built in an epidemiologic framework to show that when a genetic risk factor and an environmental risk factor interact to cause a frequent competing risk of death, the measure of the association between the disease under investigation and the genetic risk factor will be biased if the environmental risk factor is also associated with the latter disease and is omitted from the analysis. This is an example of confounding bias, and it is the consequence of an association between the genetic risk factor and the environmental risk factor that appears over time. Numerical examples show that under certain conditions this bias can be substantial. The authors present several patterns of association in favor of such a bias. Because competing risks of death are likely to be present in older subjects, researchers studying the etiology of late-onset diseases should be aware of the possibility of this bias.