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The authors consider issues that should be weighed when designing a retrospective study in which a focus of interest is the joint role of genetic and environmental factors in causing a disease. In place of the classical case-control design, in which controls are sampled from the same population that gives rise to the cases, one could study cases only. The case-only approach can be usefully extended by genotyping the two biologic parents of each case and in effect letting the parental genotype data provide the genetic control. Alternatively, one could carry out a case-control study in which the controls are siblings or cousins of the cases and inference is based on within-family parameters. The authors compare and contrast the parameters that can be estimated and the assumptions that must be made when each of these designs is used. The investigator must also consider certain practical issues, such as the availability of parents or sibling controls.

Choosing a Retrospective Design to Assess Joint Genetic and Environmental Contributions to Risk