Methods of dna marker-based genetic analysis using estimated haplotype frequencies and uses thereof

A system for determining the statistical significance of the difference between haplotype frequency profiles of at least two groups of individuals, comprising:

• a) first instructions for determining the combined likelihood that said at least two groups of individuals are derived from the same distribution of haplotypes;
• b) second instructions for determining the sum of the separate likelihoods that each of said at least two groups of individuals are derived from the same distribution of haplotypes;
• c) third instructions for determining the difference of said sum and said combined likelihood;
• and
• d) fourth instructions for determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes.

A method of estimating haplotype frequencies for single nucleotide polymorphisms in groups of individuals comprising:

• a) estimating all haplotype and diplotype probabilities for said groups of individuals using an estimation-maximization process;
• b) storing said probabilities;
• and
• c) repeating said estimation-maximization process using random starting values.

A computer system for estimating haplotype frequencies for single nucleotide polymorphisms in groups of individuals comprising:

• a) first instructions that when executed perform a method of estimating all haplotype and diplotype probabilities using an estimation-maximization process;
• b) second instructions that when executed perform a method of storing said haplotype and diplotype probabilities;
• and
• c) third instructions that when executed perform said estimation-maximization process that is automatically repeated using random starting values.

A method of determining the statistical significance of the difference between haplotype frequency profiles of at least two groups of individuals, comprising:

• a) estimating haplotype frequencies using single nucleotide polymorphism data for each group individually and for each group in combination with another group, wherein all haplotype and diplotype probabilities are calculated once and then stored, and wherein a maximization process is automatically repeated for each group using random starting values in order to determine final likelihoods;
• b) comparing the final likelihood that all groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately to determine their difference;
• and
• c) determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes.

A system for determining the statistical significance of the difference between haplotype frequency profiles of at least two groups of individuals, comprising:

• a) a first module configured to estimate haplotype frequencies using single nucleotide polymorphism data for each group individually and for each group in combination with another group, wherein all haplotype and diplotype probabilities are calculated once and then stored, and wherein the maximization process is automatically repeated for each group using random starting values, to determine final likelihoods;
• b) a second module configured to compare the final likelihood that all groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately to determine their difference;
• and
• c) a third module configured to determine the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes.

A programmed storage device comprising instructions that when executed perform a method of determining the statistical significance of the difference between haplotype frequency profiles of at least two groups of individuals, comprising

• a) a first module adapted to perform a method of estimating haplotype frequencies using single nucleotide polymorphism data for each group individually and for each group in combination with the other group, wherein all haplotype and diplotype probabilities are calculated once and then stored, and wherein the maximization process is automatically repeated for each group using random starting values to determine final likelihoods;
• b) a second module adapted to compare the final likelihood that all groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately to determine their difference;
• and
• c) a third module adapted to determine the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes.

A method of determining an association between a haplotype and a phenotype, comprising:

• a) estimating haplotype frequencies using single nucleotide polymorphism data for an affected group and an unaffected group individually and in combination with another group, wherein all haplotype and diplotype probabilities are calculated once and then stored, and wherein a maximization process is automatically repeated for each group using random starting values to determine final likelihoods;
• b) comparing the final likelihood that both groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately to determine their difference;
• and
• c) determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes and determine whether a statistically significant association exists between said haplotype and said phenotype.

A method of determining an association between a haplotype and a phenotype, comprising:

• a) estimating haplotype frequencies using single nucleotide polymorphism data for an affected group and an unaffected group individually and in combination with another group, wherein all haplotype and diplotype probabilities are calculated once;
• b) storing said probabilities;
• and
• c) repeating a maximization process for each group using random starting values to determine whether a statistically significant association exists between said haplotype and said phenotype.

A system for detecting an association between a haplotype and a phenotype, comprising:

• a) first instructions for estimating haplotype frequencies using single nucleotide polymorphism data for an affected group and an unaffected group individually and in combination, wherein all haplotype and diplotype probabilities are calculated once, and wherein the maximization process is automatically repeated using random starting values to determine final likelihoods;
• b) second instructions for comparing the final likelihood that both groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately;
• and
• c) third instructions for determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes and determine whether a statistically significant association exists between said haplotype and said phenotype.

A programmed storage device comprising instructions that when executed perform a method of detecting an association between a haplotype and a phenotype, comprising:

• a) estimating haplotype frequencies using single nucleotide polymorphism data for an affected and an unaffected group individually and in combination, wherein all haplotype and diplotype probabilities are calculated once and are stored, and wherein the maximization process is automatically repeated using random starting values to determine final likelihoods;
• b) comparing the final likelihood that both groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately;
• and
• c) determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes and determine whether a statistically significant association exists between said haplotype and said phenotype.

A programmed storage device comprising instructions that when executed perform a method of detecting an association between a haplotype and a phenotype, comprising:

• a) comparing a likelihood that members of an affected group and an unaffected group come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately;
• b) determining the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes;
• and
• c) determining whether a statistically significant association exists between said haplotype and said phenotype.

A computer-readable data signal embedded in a transmission medium that when interpreted performs a method determining the statistical significance of the difference between haplotype frequency profiles of at least two groups of individuals, comprising:

• a) first signals adapted to perform a method of estimating haplotype frequencies using single nucleotide polymorphism data for each group individually and in combination with the other group, wherein all haplotype and diplotype probabilities are calculated once and are stored, and wherein a maximization process is automatically repeated using random starting values, to determine final likelihoods;
• b) second signals adapted to compare the final likelihood that all groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately;
• and
• c) third signals adapted to determine the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes.

A computer system for detecting an association between a haplotype and a phenotype, comprising:

• a) a first code segment configured to estimate haplotype frequencies using single nucleotide polymorphism data for an affected and an unaffected group individually and in combination, wherein all haplotype and diplotype probabilities are calculated once and are stored, and wherein a maximization process is automatically repeated using random starting values to determine final likelihoods;
• b) a second code segment configured to compare the final likelihood that both groups come from the same distribution of haplotypes with the sum of the final likelihoods for each group separately;
• and
• c) a third code segment configured to determine the significance of this difference by simulating hypothetical groups by randomly permuting the haplotypes between groups to determine the probability that the groups do not come from the same distribution of haplotypes and determine whether a statistically significant association exists between said haplotype and said phenotype.