Methods for high throughput genotyping

A method for genotyping a polymorphism in a test individual comprising:

• (a) obtaining allele specific intensity measurements for a first allele of the polymorphism and for a second allele of the polymorphism in a training set comprising a plurality of individuals of known genotype for said polymorphism;
• (b) grouping the individuals in the training set into groups according to genotype, wherein each individual is assigned to one of the following groups:
• homozygous for the first allele, homozygous for the second allele or heterozygous;
• (c) calculating a summary ratio of the intensity measurements for said first allele to the intensity measurements for said second allele for each group to obtain a first summary ratio for the group that are homozygous for said first allele, a second summary ratio for the group that are homozygous for said second allele and a third summary ratio for the group that are heterozygous;
• (d) obtaining an allele specific intensity for said first allele and for said second allele in said test individual and calculating a test ratio for said test individual;
• (e) adjusting the allele specific intensity value for said first allele according to the third summary ratio obtained in (c) if said test ratio is closer to the third summary ratio than to the first or second summary ratios;
• and
• (e) making a genotype call for said polymorphism using the adjusted value obtained in (e) for said first allele and the intensity value obtained in (d) for the second allele.

A method for calling the genotype of a sample at a selected polymorphism in a sample using a genotyping array, comprising:

• (a) obtaining hybridization intensity values for said genotyping array for each of a set of training samples comprising a plurality of training samples of known genotype;
• (b) making a genotype call for each of a plurality of SNPs in the each of the training samples using the hybridization intensity values from individual probe quartets;
• (c) comparing the genotype call with the known genotype for each probe quartet to identify a plurality of K best probe quartets for each SNP, where K is at least 1, wherein probe quartets are selected as best probe quartets if the genotype call made using said quartet has high concordance with the known genotype for that SNP;
• (d) calculating a distribution of (intensity A)/(intensity B) distribution for the training samples for each sub-group of AA, AB and BB to obtain an AA reference distribution, an AB reference distribution and a BB reference distribution;
• (e) hybridizing a test sample to the genotyping array to obtain hybridization intensity values for said K best probe quartets;
• (f) calculate (intensity A)/(intensity B) for each quartet and compare with the reference distributions for AA, AB and BB to determine the likelihood that the polymorphism is AB;
• (g) if the likelihood that the polymorphism is greater than a selected threshold adjust the intensity of intensity B by the (intensity A)/(intensity B) ratio from the AB group from the reference set to obtain an adjusted allele B intensity;
• and
• (h) use the adjusted intensity B value to generate a genotype call using a selected algorithm.