Locally-efficient robust estimation of haplotype-disease association in family-based studies
Modelling human genetic variation is critical to understanding the genetic basis of complex disease. The Human Genome Project has discovered millions of binary DNA sequence variants, called single nucleotide polymorphisms, and millions more may exist. As coding for proteins takes place along chromosomes, organisation of polymorphisms along each chromosome, the haplotype phase structure, may prove to be most important in discovering genetic variants associated with disease. As haplotype phase is often uncertain, procedures that model the distribution of parental haplotypes can, if this distribution is misspecified, lead to substantial bias in parameter estimates even when complete genotype information is available. Using a geometric approach to estimation in the presence of nuisance parameters, we address this problem and develop locally-efficient estimators of the effect of haplotypes on disease that are robust to incorrect estimates of haplotype frequencies. The methods are demonstrated with a simulation study of a case-parent design. © 2005 Biometrika Trust.
Allen, AS; Satten, GA; Tsiatis, AA
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