In this paper we consider test statistics based on individual genotyping. For sibships without parents, but with unaffected as well as affected sibs, we introduce a new test statistic (referred to asTDS), which contrasts the allele frequency in affected sibs versus that estimated for the parents from the entire sibship. For sibships without parents, this test is analogous to the TDT and is completely robust to nonrandom mating patterns. The efficiency of the TDS test is comparable to that of the THS test (which compares affected vs. unaffected sibs and was based on DNA pooling), for sibships with one affected child. However, as the number of affected sibs in the sibship grows, the relative efficiency of the TDS test versus theTHS test also increases. For example, for sibships with three affected, one-third fewer families are required; for families with four affected, nearly half as many are required. Thus, when sibships contain multiple affected individuals, theTDS test provides both an increase in power and robustness to nonrandom mating.
Family-Based versus Unrelated Case-Control Designs for Genetic Associations