the original association was due to confounding. Although a disease-genotype association may sometimes validate the idea that an environmental exposure raises disease risk, other design and analysis issues, such as population stratification, complicate studies aimed at detecting the genotype association. Also, the genotype might influence phenotypic traits other than the one being studied, thus its association with disease might not validate the relationship that it is intended to validate.

Human Laboratory Research

Human laboratory designs, in which interventions are tested in human subjects in a highly controlled laboratory setting, also can be utilized effectively to investigate the interacting effects of social, behavioral, and genetic factors on health. Such designs afford an opportunity for greater experimental control over environmental exposures and the use of interventions (within-subject designs) for exposure testing that increase statistical power. A hypothetical example would be an investigation of the effects of genetic variation in alcohol metabolizing enzymes (between subject factor) and exposure to a stress paradigm (e.g., public speaking or interpersonal stress compared to a low-stress task) (within subject factor) on alcohol sensitivity and ad lib alcohol intake. One recent human laboratory study conducted by Lerman et al. (2004) involved 71 smokers enrolled in a randomized controlled trial of buproprion treatment versus placebo for smoking cessation. The goal was to examine the degree to which abstinent smokers experience increased reward from food (possibly related to weight gain following smoking cessation), and the moderating effects of buproprion treatment and the Taq 1 polymorphism of the dopamine D2 receptor gene (DRD2). At two time points (before and after smoking cessation), subjects participated in a taste test to measure palatability of various foods followed by a behavioral economics evaluation of food reward. Carriers of the minor allele (A1) of the DRD2 polymorphism had significant increases in the rewarding value of food following smoking cessation that were not observed in noncarriers. Moreover, these effects were attenuated by buproprion treatment and predicted subsequent weight gain. Similar paradigms can be tested in animal and human laboratory models providing cross-species validation (Blendy et al., 2005). However, this approach generally is not feasible on a population basis.

Evaluation of Gene-Environment Interactions for Nonbinary Outcome Variables

In most classical epidemiologic designs, the outcome variable is binary. Other types of health outcomes include a continuous quantity (e.g., hyper-



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