Designing studies to estimate the penetrance of an identified autosomal dominant mutation: Cohort, case-control, and genotyped-proband designs

One can obtain population-based estimates of the penetrance of a measurable mutation from cohort studies, from population-based case-control studies, and from genotyped-proband designs (GPD). In a GPD, we assume that represen tative individuals (probands) agree to be genotyped, and one then obtains i nformation on the phenotypes of first-degree relatives. We also consider an extension of the GPD in which a relative is genotyped (GPDR design). In th is paper, we give methods and tables for determining sample sizes needed to achieve desired precision for penetrance estimates from such studies. We e mphasize dichotomous phenotypes, but methods for survival data are also giv en. In an example based on the BRCA1 gene and parameters given by Claus et al. [(1991) Am J Hum Genet 48:232-242], we find that similar large numbers of families need to be studied using the cohort, case-control, and GPD desi gns if the allele frequency is known, though the GPDR design requires fewer families, and, if one can study mainly probands with disease, the GPD desi gn also requires fewer families. If the allele frequency is not known, some what larger sample sizes are required. Surprisingly, studies with mixtures of families of affected and non-affected probands can sometimes be more eff icient than studies based exclusively on affected probands when the allele frequency is unknown. We discuss the feasibility and validity of these desi gns and point out that GPD and GPDR designs are more susceptible to a bias that results when the tendency for an individual to volunteer to be a proba nd or to be a subject in a cohort or case-control study depends on the phen otypes of his or her relatives. Published 1999 by Wiley-Liss.