System, method, and computer software product for genotype determination using probe array data

Abstract

An embodiment of a method of analyzing data from processed images of biological probe arrays is described that comprises receiving a plurality of files comprising a plurality of intensity values associated with a probe on a biological probe array; normalizing the intensity values in each of the data files; determining an initial assignment for a plurality of genotypes using one or more of the intensity values from each file for each assignment; estimating a distribution of cluster centers using the plurality of initial assignments; combining the normalized intensity values with the cluster centers to determine a posterior estimate for each cluster center; and assigning a plurality of genotype calls using a distance of the one or more intensity values from the posterior estimate.

What is claimed is: 
     
         1 . A method for calling genotypes from a probe array experiment, comprising:
 contacting a genotyping probe array with a DNA sample to obtain a hybridized sample;   obtaining hybridization intensity information from the hybridized sample;   normalizing probe intensity data;   transforming the data by clustering the data for each genetic loci of interest to obtain transformed data;   dividing the transformed data into trial genotypes by generating genotyping calls;   calculating the highest log-likelihood of data; and   assigning a genotype to the data.   
     
     
         2 . The method of  claim 1  wherein the array comprises more than 1 million different sequence probes and wherein each probe is perfectly complementary to an allele of a SNP that has a minor allele frequency of at least 2% in a population. 
     
     
         3 . A method for determining the genotype of a nucleic acid sample at a plurality of SNPs, comprising: (a) hybridizing said nucleic acid sample to an array of allele specific probes to obtain raw probe intensity measurements; (b) normalizing said raw probe intensity measurements to obtain normalized probe intensities; performing an allele summarization to obtain allele signal estimates; (c) transforming said allele signal estimates in clustering space to obtain transformed allele signal estimates; (d) generating seed genotypes from said raw probe intensity measurements to obtain initial genotype estimates; (e) fit prior across multiple SNPs using initial genotype estimates and transformed allele signal estimates to obtain prior for cluster characteristics; and (f) update the cluster characteristics using a Bayesian update to obtain posterior for cluster characteristics; and make genotype calls to obtain the genotype of the nucleic acid sample at a plurality of SNPs. 
     
     
         4 . The method of  claim 3  further comprising obtaining confidence values for each of the genotype calls.