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Developing your study design and delineating the phenotype are not independent steps. Review of the available data may indicate that a trait as originally defined has little or no evidence of a genetic component. However, there may be strong evidence that a subset of the trait is strongly genetic. For example, there had for many years been debate about the role of genetics in Alzheimer’s disease. Over time it became increasingly clear that a subset of individuals with the onset of Alzheimer’s disease before age 65 existed and strongly clustered in families with apparent autosomal dominant inheritance. Within each of these families, Alzheimer’s disease appeared to be caused by a single gene. By restricting sample collection and genetic analysis to these types of families, three genes (APP, PSEN1, and PSEN2) were identified with mutations causing early‐onset Alzheimer’s disease (Goate et al. 1991; Levy‐Lahad et al. 1995; Rogaev et al. 1995; Sherrington et al. 1995).

The exact approach to the disease gene discovery process should be outlined as completely as possible before the project gets underway. With the clinical phenotype in hand, it is possible to determine the best strategy for defining what type of dataset to collect. Participant recruitment is perhaps the longest and most labor‐intensive step in the entire process. It is imperative that the enrollment of participants (particularly if studying multiple members of the same family) proceeds with careful consideration of the wishes and norms of the participating individuals, families, and communities. The rights of individuals to participate or refuse participation should receive careful consideration, and the informed consent process should provide adequate explanation of the study and answer any questions, and, critically, confidentiality must be carefully protected. These issues are outlined in detail in Chapter 5.

Determination of the study design (case–control, cohort, case series, family‐based) is based on the characteristics of the phenotype, the estimated genetic model, and the research objective. For example, the existence of large families with apparent Mendelian segregation suggests that a single major gene could be detected, and a family‐based study would be appropriate. A phenotype with weaker estimated heritability, a pattern of recurrence risks suggesting many genes of small effect, and little familial aggregation would suggest that a case–control study design is most feasible. The process of selecting a study design to answer a research question is reviewed in Chapter 4.

It is also important to have some sense of the sample size required to identify the genes being sought. When pedigree structures are already available in family‐based studies of single‐gene disorders, power is easily calculated with high confidence for specific genetic models using computer simulation programs. For complex traits, however, genetic models are not as easily specified in advance, and computer simulations often must consider a range of parameter values for the genetic model to describe the power across several competing alternatives. Chapter 12 provides an overview of the available approaches and tools for sample size, power estimation, and genetic simulations.