Correcting for ascertainment bias of relative-risk estimates obtained using affected-sib-pair linkage data

Abstract

Locus-specific sibling relative risk is often estimated using affected-sib-pair lod score analysis of affected sibships and may be used to decide whether to continue or discontinue the search for additional susceptibility genes. We showed that relative-risk estimates obtained using affected-sib-pair data are asymptotically unbiased when each pair is given a weight inversely proportional to the sibship ascertainment probability. Here we show by simulation that the extent of the bias of relative risks estimated using the incorrect ascertainment weights is small for dominant models, but large for single-locus recessive models and some two-locus heterogeneity models. Since in practice the ascertainment scheme is often unknown, we investigate methods for jointly estimating ascertainment and relative risks from affected-sibship data. Given a sufficient sample size, a reasonable estimate of relative risk may always be obtained using only affected pairs from sibships with two affected and no unaffected siblings. This estimate, which has a large variance, may then be used in a three-stage procedure (which we call the alpha method) to estimate consistently both the ascertainment probabilities and the relative risks with greater precision. We additionally propose correction factors to eliminate small-sample bias of relative risks and investigate the bias due to error in the estimate of disease locus location.