Epidemiological studies on genetic polymorphism: study design issues and measures of occurrence and association

As with other epidemiological studies, the design and analysis of a study including genetic polymorphisms generally involve relating a particular disease or health outcome to a particular exposure or genetic trait, while assessing the presence of systematic error, controlling random error and assessing effect modification (interaction) with other exposures or traits. In studies of determinants and mechanisms of disease, markers of genetic polymorphism are generally treated either as exposure variables or as effect modifiers. In epidemiological studies the study base can be completely enumerated, and the cases can be identified as either incident or prevalent cases (incidence and prevalence studies). Alternatively, the study may involve cases of the disease (or condition) under investigation and a control group sampled from the study base that generated the cases (incidence and prevalence case-control studies). Most available studies on metabolic polymorphism and cancer risk are incidence case-control studies. Their major methodological problem is the selection of controls, which may be an important source of bias. Another important limitation of many available studies is the small sample size, which may be inadequate for assessing statistical interaction when the metabolic polymorphism is treated as an effect modifier.