Commentary: The affected sib‐pair method in the context of an epidemiologic study design

Abstract

The purpose of this commentary is to provide a framework for using the well-known sib-pair methodology in the context of epidemiologic study designs. Using examples from the Pittsburgh family studies of insulin-dependent diabetes mellitus, we illustrate that the sib-pair method can be used in family-based epidemiologic studies. In a cohort study, unaffected relatives of probands ascertained from well-defined populations are followed for disease development. Disease risks are then stratified according to the number of alleles at one or more loci (0, 1, 2) that are identical by descent (ibd) with the proband. In the absence of linkage between the marker locus and the disease locus, disease risks are expected to be identical in the three groups. Measures of relative risk can be computed (with share-0 as baseline group). In a case-control study, relatives of probands that become affected (cases) are compared to a sample of relatives of probands that stay unaffected (controls) with respect to the number of alleles ibd with the proband. Measures of odds ratio can be computed (with share-0 as baseline group). In both cohort and case-control approaches, covariates including other genetic markers and environmental exposures can be evaluated in relation to disease risk and also for evidence of interaction with the specific marker of interest using stratified and multivariate analyses. Family-based epidemiologic studies allow investigators to study, in a single design, the role of environmental factors and specific gene loci in the etiology of diseases.

Extensions to methods of sib‐pair linkage analyses

“…This approach has several strengths, only a few of which are shared by other Khoury et al [1991]. Additionally, many selection schemes can be used without need for modifying the analyses.…”

Evolving Methods in Genetic Epidemiology. III. Gene-Environment Interaction in Epidemiologic Research

“…The sib-pair methods can be incorporated into family-based epidemiologic studies (cohort and case-control designs); such incorporation allows investigators to control for suspected nongenetic risk factors and to test for gene-environment interaction in searching for genetic linkage (85,86). To look for gene-environment interaction using this method, investigators can stratify affected individuals by their exposure status or incorporate the geneenvironment interaction term in a multivariate analysis.…”

Epidemiologic and Genetic Approaches in the Study of Gene-Environment Interaction: an Overview of Available Methods

“…The use of unaffected siblings has also been proposed in an extension of the sib-pair methodology (described in the case-only study section above) to study the role of environmental factors and specific gene loci, and to provide evidence of geneenvironment interaction (35). Cases are affected siblings of the proband (case who led to family selection) and controls are randomly chosen from unaffected siblings of the proband.…”