Mathematical assumptions versus biological reality: myths in affected sib pair linkage analysis.
Affected sib pair (ASP) analysis has become common ever since it was shown that, under very specific assumptions, ASPs afford a powerful design for linkage analysis. In 2003, Vieland and Huang, on the basis of a "fundamental heterogeneity equation," proved that heterogeneity and epistasis are confounded in ASP linkage analysis. A much more serious limitation of ASP linkage analysis is the implicit assumption that randomly sampled sib pairs share half their alleles identical by descent at any locus, whereas a critical assumption underlying Vieland and Huang's proof is that of joint Hardy-Weinberg equilibrium proportions at two trait loci. These are considered as examples of mathematical assumptions that may not always reflect biological reality. More-robust sib-pair designs and appropriate methods for their analysis have long been available.
Elston
Robert C
RC
Department of Epidemiology and Biostatistics, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106-7281, USA. rce@darwin.case.edu
Song
Danhong
D
Iyengar
Sudha K
SK
D002874:Chromosome Mapping / Q000379:methods*; D004843:Epistasis, Genetic; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006801:Humans; D015233:Models, Statistical; D035781:Siblings