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Collection of a single affected individual can take place in the context of the traditional epidemiologic cross‐sectional, case‐control, and cohort designs, as well as the case‐parent trio design. The case‐parent trio design is primarily used in family‐based association analysis and includes collection of a case and both their parents. An alternative to the case‐control and trio designs is the case‐only design (Khoury and Flanders 1996). Similar to the trio design, the case‐only approach arose from concerns regarding selection of appropriate controls for the study of genetic factors in the more traditional case‐control approach. The case‐only approach has been promoted as a particularly useful approach in the examination of gene–environment interactions (Piegorsch et al. 1994). From the ascertainment perspective, collection of single affected individuals is more feasible because in complex disorders, large families with multiple affected individuals are often difficult to identify. A disadvantage of this approach is that it limits the statistical genetic analyses to specific types of association methods (discussed in more detail in Chapter 8). Traditional linkage analysis (described in more detail in Chapter 6) usually cannot be performed on a case‐control or trio data set because the necessary family structure is not available for most genetic models.