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Statistical tests for detection of misspecified relationships by use of genome-screen data - PubMed

Statistical tests for detection of misspecified relationships by use of genome-screen data

M S McPeek et al. Am J Hum Genet. 2000 Mar.

Abstract

Misspecified relationships can have serious consequences for linkage studies, resulting in either reduced power or false-positive evidence for linkage. If some individuals in the pedigree are untyped, then Mendelian errors may not be observed. Previous approaches to detection of misspecified relationships by use of genotype data were developed for sib and half-sib pairs. We extend the likelihood calculations of Göring and Ott and Boehnke and Cox to more-general relative pairs, for which identity-by-descent (IBD) status is no longer a Markov chain, and we propose a likelihood-ratio test. We also extend the identity-by-state (IBS)-based test of Ehm and Wagner to nonsib relative pairs. The likelihood-ratio test has high power, but its drawbacks include the need to construct and apply a separate Markov chain for each possible alternative relationship and the need for simulation to assess significance. The IBS-based test is simpler but has lower power. We propose two new test statistics-conditional expected IBD (EIBD) and adjusted IBS (AIBS)-designed to retain the simplicity of IBS while increasing power by taking into account chance sharing. In simulations, the power of EIBD is generally close to that of the likelihood-ratio test. The power of AIBS is higher than that of IBS, in all cases considered. We suggest a strategy of initial screening by use of EIBD and AIBS, followed by application of the likelihood-ratio test to only a subset of relative pairs, identified by use of EIBD and AIBS. We apply the methods to a Genetic Analysis Workshop 11 data set from the Collaborative Study on the Genetics of Alcoholism.

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Figures

Figure 1
Figure 1

A, Pedigree for avuncular pair. B, Pedigree for first-cousin pair.

Figure 2
Figure 2

Power versus genome-screen resolution for the four test statistics with 1 million replications, microsatellite marker frequencies .40, .20, .20, .05, .05, .05, and .05. A, Null relationship half-sib, alternative relationship first-cousin, significance level .01. B, Null relationship half-sib, alternative relationship first-cousin, significance level .001.

Figure 3
Figure 3

Half-sib plus first-cousin pedigree: individuals 1 and 2 are half-sibs through their father and first cousins through their mother.

Figure 4
Figure 4

A pedigree from the GAW 11 COGA data set, with some extraneous individuals removed and sexes of some individuals changed. The starred individuals are untyped, and all other individuals are typed for ⩾250 markers. Arrows indicate individuals discussed in the text.

Figure C1
Figure C1

Graphic representation of the nine IBD states of Jacquard (1974). An edge is present between a given pair of nodes if and only if they are identical by descent.

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