A comparison of several methods for haplotype frequency estimation and haplotype reconstruction for tightly linked markers from general pedigrees

Abstract

Haplotype inference for tightly linked markers from general pedigrees remains a challenging problem. Only a few methods are available to efficiently and accurately estimate haplotype frequencies and reconstruct haplotypes for a large number of tightly linked markers from general pedigrees in the presence of missing data, and their performance has not been carefully and extensively evaluated. In this paper, we compare four published methods for haplotype reconstruction and frequency estimation for tightly linked markers from general pedigrees, including HAPLORE, GENEHUNTER, PedPhase, and MERLIN. We review these methods and discuss the differences between them in terms of the models and computational strategies employed. We assess their performance based on simulations using pedigrees and haplotypes on tightly linked single nucleotide polymorphisms from real studies. We investigate the effect of several factors, including the missing rate, the departure from Hardy-Weinberg Equilibrium, and the sample size, on the accuracy for haplotype inference. We also compare these methods with a widely used method for haplotype inference from unrelated individuals, PHASE, by treating individuals within a pedigree as unrelated samples. This comparison allows us to investigate the relative efficiency in haplotype inference using pedigree data. Our results indicate that incorporation of pedigree information can improve the precision for haplotype frequency estimation and the accuracy for haplotype reconstruction. Among four haplotyping methods capable of analyzing general pedigrees, HAPLORE and MERLIN have comparable performance and outperform the other two methods in almost all situations.