Analysis of case-control/family sampling design

A commonly adopted design in genetic epidemiologic studies is the so-called case-control/family sampling design. Here, cases and controls are sampled and response variables, either quantitative or qualitative, for relatives of cases are contrasted with those of control relatives. This design can be used to examine familial aggregation, contribute to identification of genetic subtypes, and test the discrete versus continuous spectrum hypothesis for disorders of unknown etiology. However, the statistical independence assumption required by conventional case-control studies is violated for observations from related individuals who share the same genetic/environmental conditions. Consequently, ignoring dependence among related subjects will lead to incorrect sample size calculations and potentially erratic scientific conclusions. In this paper, we discuss several statistical issues that are relevant to the case-control/family sampling design with a focus on the use of this design in psychiatric research. Specifically, we 1) discuss the relative merit of matched versus unmatched designs; 2) present statistical methods that are useful for analyzing family data and 3) present sample size formulas for studies of quantitative and qualitative traits. A genetic epidemiologic study of schizophrenia is used for illustrative purposes.