This is manifestly not the case with environmental, behavioral, and social exposures, wherein one exposure is likely to affect many others downstream. 2 While a particular variant may serve as a proxy for the true effect of another, it is the case that once the genome is fixed, each variant is acting on the outcome, possibly in conjunction with, but not by altering the value of, any other variant. In a genome-wide association study, although hundreds of thousands of variants are examined, it is often thought to be the case that, subject to control for population stratification (often done say by principal components analysis adjustment strategies), the association between the variant and the outcome is roughly unconfounded. The difference between genetic exposures and almost all others, and the difference that arguably creates problems for an exposure-wide epidemiology, lies in the nature of confounding. 3, 4 Could we not then pursue something similar within epidemiology more broadly using environmental, social, and behavioral exposures as well? This approach has effectively been what has been used in genome-wide association studies, 1, 2 and these have now yielded thousands of replicated associations between genetic variants and various diseases. The notion of an exposure-wide epidemiologic study is that a researcher could select a specific outcome, regress it upon a wide range of different exposures, assess which relationships are most substantial, and for which there is the strongest statistical evidence of an association, and, provided appropriate control is made for multiple testing, thereby potentially gain insight into the underlying causes of the disease or outcome under study. Moreover, outcome-wide approaches will generally be more useful than exposure-wide approaches in shaping public health recommendations. These problems simplify considerably in an outcome-wide approach when a single exposure is being considered. Such exposure-wide studies are likely to be subject to numerous biases because of the inability to make simultaneous confounding control and because exposures are likely to affect, and mediate the effects of, other exposures. Methodologically, the conduct of outcome-wide epidemiology will generally be more straightforward than recent proposals for exposure-wide epidemiologic studies, in which the associations between a single outcome and many exposures are assessed simultaneously. ![]() Outcome-wide epidemiology may also be helpful in prioritizing public health recommendations. Such “outcome-wide epidemiology” will be especially important for exposures that may be beneficial for some outcomes but harmful for others. The author proposes that epidemiologic studies should more often assess the associations of a single exposure with multiple outcomes simultaneously.
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