title: Effectiveness of computational methods in haplotype prediction.
abstract: Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.
authors.affiliation: Discovery Genetics, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. cfx74267@gsk.com
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Karen
authors.initials: K
authors.lastname: Lewis
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Cantone
authors.forename: Parveen
authors.initials: P
authors.lastname: Khan
authors.forename: Christine
authors.initials: C
authors.lastname: Donnelly
authors.forename: Nicola
authors.initials: N
authors.lastname: White
authors.forename: Nikki
authors.initials: N
authors.lastname: Crocker
authors.forename: Pete R
authors.initials: PR
authors.lastname: Boyd
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Purvis
mesh_terms: D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D004247:DNA / Q000097:blood / Q000235:genetics; D017931:DNA Primers; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009657:North Carolina; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012495:San Francisco; D044465:White People; D014960:X Chromosome
chemical_list: D017931:DNA Primers; D004247:DNA; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human