Sample size calculations for classical association and TDT-type methods using family data

Transmission Disequilibrium Test (TDT)-based methods have been advocated by several authors for testing that a marker-phenotype association is actuall y due to linkage and not to uncontrolled stratification. As a pre-requisite of TDT-type methods is the presence of an association between marker and p henotype, one may wish to first investigate the association using a classic al association study, and then to check by a TDT approach whether this asso ciation is actually due to linkage. We propose an estimating equation (EE) procedure, to compute analytically the minimum sample size of sibship data required to detect the association between a marker and a quantitative phen otype, and that required to confirm it by two TDT methods. We show that, wh en the marker allele frequency is low or high, the number of informative si bs needed in TDT-type methods can be lower than the number required in an a ssociation analysis, and even more so when the familial clustering is stron g. However, in all cases, the number of sibs that need to be sampled to get the appropriate number of informative sibs for analysis is always larger f or TDT methods than for an association study. In a phenotype-first strategy , this number may be critical when investigating costly phenotypes.