P. Holmans, Likelihood-ratio affected sib-pair tests applied to multiply affected sibships: Issues of power and type I error rate, GENET EPID, 20(1), 2001, pp. 44-56
"All-pairs" Likelihood-ratio analyses, such as those performed by MAPMAKER/
SIBS [Kruglyak and Lander, 1995], require that a sibship containing N affe
cted siblings be split into N(N - 1)/2 sibships, each containing a differen
t pair of affected sibs, before analysis. Each of these N(N - 1)/2 sibships
may also contain the other affected sibs from the original sibship, coded
as unaffected, to infer missing parental genotypes, as is done automaticall
y in MAPMAKER/SIBS. Then, the use of the same individuals bath as affecteds
to test for linkage and, elsewhere, as unaffecteds to infer missing parent
al genotypes leads to negative correlations in the estimated identity by de
scent sharing among affected pairs from the same original multiplex sibship
. This gives a conservative test of linkage, even when no downweighting is
applied. Conversely if the other affected sibs from the original sibship ar
e omitted, the correlations are positive and the linkage test is anticonser
vative in the absence of weighting. True type I error probability also depe
nds on marker informativity, typed parents, number of affected sibs include
d in the analysis, and the weighting scheme. This suggests the use of simul
ation, rather than asymptotic theory, to assess significance levels. The po
wer of multiplex sibships relative to affected pairs increases with increas
ing phenocopy percentage, but the presence of typed unaffected sibs improve
s the relative power of multiplex sibships greatly only when penetrance is
high. It was found that the 2/N weighting proposed by Suarez and Hodge [197
9] increased power over an unweighted analysis in many situations, provided
significance levels were adjusted appropriately by simulation, Genet. Epid
emiol. 20:44-56, 2001. (C) 2001 Wiley-Liss, Inc.