Effects of stratification in the analysis of affected-sib-pair data: Benefits and costs

The benefits and costs of stratification of affected-sib-pair (ASP) data we re examined in three situations: (1) when there is no difference in identit y-by-descent (IBD) allele sharing between stratified and unstratified ASP d ata sets; (2) when there is an increase in IBD allele sharing in one of the stratified groups; and (3) when the data are stratified on the basis of IB D allele-sharing status at one locus, and the stratified ASPs are then anal yzed for linkage at a second locus. When there is no difference in IBD shar ing between strata, a penalty is always paid for stratifying the data. The loss of power to detect linkage in the stratified ASP data sets is the resu lt of multiple testing and the smaller sample size within individual strata . In the case in which etiologic heterogeneity (i.e., severity of phenotype , age at onset) represents genetic heterogeneity, the power to detect linka ge can be increased by stratifying the ASP data. This benefit is obtained w hen there is sufficient IBD allele sharing and sample sizes. Once linkage h as been established for a given locus, data can be stratified on the basis of IBD status at this locus and can be tested for linkage at a second locus . When the relative risk is in the vicinity of 1, the power to detect linka ge at the second locus is always greater for the unstratified ASP data set. Even for values of the relative risk that diverge sufficiently from 1, wit h adequate sample sizes and IBD allele sharing, the benefits of stratifying ASP data are minimal.