Methods for obtaining and using haplotype data

• US 6,931,326 B1
• Filed: 12/21/2001
• Issued: 08/16/2005
• Est. Priority Date: 06/26/2000
• Status: Expired due to Fees

• Current Assignee: PGxHealth LLC (Abbvie Incorporated)
• Original Assignee: Genaissance Pharmaceuticals Incorporated (Abbvie Incorporated)
• Inventors: Judson, Richard S., Stephens, J. Claiborne, Windemuth, Andreas K.
• Primary Examiner(s): Allen, Marianne P.
• Application Number:
  US10/019,342
• Time in Patent Office: 1,334 Days
• Field of Search: 702/19, 702/20, 435/6
• US Class Current: 702/20
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/30 Data warehousing; Computing architectures
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods, computer program(s) and database(s) to analyze and make use of gene haplotype information. These include methods, program, and database to find and measure the frequency of haplotypes in the general population; methods, program, and database to find correlation'"'"'s between an individual'"'"'s haplotypes or genotypes and a clinical outcome; methods, program, and database to predict an individual'"'"'s haplotypes from the individual'"'"'s genotype for a gene; and methods, program, and database to predict an individual'"'"'s clinical response to a treatment based on the individual'"'"'s genotype or haplotype.

Claims

1. A method of determining polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, comprising:

(a) providing a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each individual polymorphism in the haplotypes for the degree to which it correlates with the outcome of interest and calculating a numerical measure of the degree of correlation;

(c) saving each individual polymorphism whose numerical measure of the degree of correlation meets a first cut-off criterion and its numerical measure of the degree of correlation;

(d) generating all possible pair-wise combinations of the saved individual polymorphisms so as to provide a set of n-site sub-haplotypes where n=2;

(e) statistically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the numerical measure of the degree of correlation;

(f) saving each n-site sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion and its numerical measure of the degree of correlation;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new sub-haplotypes with increased values of n; and

(h) repeating steps (e) trough (g) until either (i) no new sub-haplotypes can be generated, or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

2. The method of claim 1, further comprising the step of displaying the saved individual polymorphisms and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut-off criterion.

3. The method of claim 1, wherein the numerical measure of the degree of correlation is a p-value, and the first cut-off criterion is that the p-value is less than or equal to a first cut-off value.

4. The method of claim 3, further comprising the stop of displaying the saved individual polymorphisms and sub-haplotypes whose p-value is less than or equal to a second cut-off value, wherein the second cut-off value is less than the first cut-off value.

5. The method of any one of claims 1-4, further comprising the step of eliminating a complex redundant sub-haplotype generated from smaller saved, sub-haplotypes, wherein the numerical measure of the degree of correlation of each of the smaller saved sub-haplotypes is at least as significant as that of the complex redundant sub-haplotype.

6. The method of claim 2, further comprising displaying the numerical measure of the degree of correlation of each displayed individual polymorphism or sub-haplotype.

7. The method of claim 1, wherein providing comprises determining the haplotype for each allele of the locus for each subject and acquiring the outcome value for the outcome of interest for each subject.

8. A method of determining polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, comprising:

(a) providing a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort, the locus comprising at least two polymorphic sites;

(b) statically analyzing each haplotype for the degree to which it correlates with the outcome of interest, and calculating a numerical measure of the degree of correlation;

(c) saving each haplotype whose numerical measure of the degree of correlation meets a first cut-off criterion and its numerical measure of the degree of correlation;

(d) from each haplotype composed of m polymorphic sites, generating all possible sub-haplotypes having a single site masked, so as to provide a set of sub-haplotypes having (m-n) sites, where n=1;

(e) statistically analyzing each newly generated sub-haplotype for the degree to which it correlates with the outcome of interest, and calculating the numerical measure of the degree of correlation;

(f) saving each sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion and its numerical measure of the degree of correlation;

(g) from the saved sub-haplotypes, generating all possible sub-haplotypes having one additional site masked; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes or (ii) no further sub-haplotypes having more unmasked sites than a pre-selected limit can be generated.

9. The method of claim 8, further comprising the step of displaying those saved haplotypes and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut off criterion.

10. The method of claim 8, wherein the numerical measure of the degree of correlation is a p-value and the first cut-off criterion is that the p-value is less than or equal to a first selected value.

11. The method of claim 10, further comprising the step of displaying those saved haplotypes and sub-haplotypes whose p-value is less than or equal to a second selected value, wherein the second selected value is less than the first selected value.

12. The method of any one of claims 8-11, further comprising the step of discarding a complex redundant sub-haplotype which is constructed from smaller saved sub-haplotypes, wherein the numerical measure of the degree of correlation of each of the smaller saved sub-haplotypes is at least as significant as that of the complex redundant sub-haplotype.

13. The method of claim 9, further comprising displaying the numerical measure of the degree of correlation of each displayed haplotype or sub-haplotype.

14. The method of claim 8, wherein providing comprises determining the haplotype for each allele of the locus for each subject and acquiring the outcome value for the outcome of interest for each subject.

15. A computer-usable medium having computer-readable program code stored thereon, for causing a computer to execute a method to determine polymorphisms or sub-haplotypes for a locus that correlate with an outcome of interest, the method comprising:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects, and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statically analyzing each individual polymorphism in the haplotypes for the degree to which it correlates with the outcome of interest and calculating a numerical measure of the degree of correlation;

(c) storing each individual polymorphism whose numerical measure of the degree of correlation meets a first cut-off criterion and its numerical measure of the degree of correlation;

(d) generating all possible pair-wise combinations of the saved individual polymorphisms so as to provide a set of n-site sub-haplotypes where n=2;

(e) statistically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the numerical measure of the degree of correlation;

(f) storing each n-site sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion and its numerical measure of the degree of correlation;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new sub-haplotypes with increased values of n; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes can be generated, or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

16. The computer-usable medium of claim 15, wherein the method further comprises displaying those saved individual polymorphisms and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut-off criterion.

17. The computer-usable medium of claim 15, wherein the method further comprises displaying the saved individual polymorphisms and sub-haplotypes whose p-value does not exceed a second cut-off value, wherein the second cut-off value is less than the it cut-off value.

18. The computer-useable medium of claim 15, wherein the method further comprises eliminating a complex redundant subhaplotype generated from smaller saved sub-haplotypes, wherein the numerical measure of the degree of correlation of each of the smaller saved sub-haplotypes is at least as significant as that of the complex redundant sub-haplotype.

19. A computer-usable medium having computer-readable program code stored thereon, for causing a computer to execute a method to determine polymorphic sits or sub-haplotypes for a locus that correlate with an outcome of interest, the method comprising:

(a) accessing a database comprising a haplotype from each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each individual polymorphism in the haplotypes for the degree to which it correlates with the outcome of interest and calculating the p-value for the correlation;

(c) storing each individual polymorphism whose p-value does not exceed a first cut-off value and its p-value;

(d) generating all possible pair-wise combinations of the saved individual polymorphisms so as to provide a set of n-site sub-haplotypes where n=2;

(e) statistically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the p-value for the correlation;

(f) storing each n-site sub haplotype whose p-value does not exceed the first cut-off value and its p-value;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new subhaplotypes with increased values of n; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes can be generated, or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

20. A computer-usable medium having computer-readable program code stored thereon, for causing a computer to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, the method comprising:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each haplotype for the degree to which it correlates with the outcome of interest, and calculating a numerical measure of the degree of correlation;

(c) storing each haplotype whose numerical measure of the degree of correlation meets a first cut-off value criterion and its numerical measure of the degree of correlation;

(d) generating, from each haplotype composed of m polymorphic sites, all possible sub-haplotypes having a single site masked, so as to provide a set of m-n site sub-haplotypes where n=1;

(e) statistically analysing each newly generated sub-haplotype for the degree to which it correlates with the outcome of interest, and calculating the numerical measure of the degree of correlation;

(f) storing each sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion and its numerical measure of the degree of correlation;

(g) generating, from the stored sub-haplotypes, all possible sub-haplotypes having one additional site masked; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes, or (ii) no further sub-haplotypes having more unmasked sites than a pre-selected limit can be generated.

21. The computer-usable medium of claim 20, wherein the method further comprises displaying those stored haplotypes and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut-off criterion.

22. A computer-usable medium having computer-readable program code stored thereon, for causing a computer to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, the method comprising:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each haplotype for the degree to which it correlates with the outcome of interest, and calculating the p-value for the correlation;

(c) storing each haplotype whose p-value does not exceed a first cut-off value and its p-value;

(d) generating, for each haplotype composed of m polymorphic sites, all possible sub-haplotypes having a single site masked, so as to provide a set of m-n site sub-haplotypes where n=1;

(e) statistically analyzing each newly generated sub-haplotype for the degree to which it correlates with the outcome of interest, and calculating the p-value for the correlation;

(f) storing those sub-haplotypes whose p-value does not exceed the first out-off value and its p-value;

(g) generating, from the stored sub-haplotypes, all possible sub-haplotypes having one additional site masked; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes, or (ii) no further sub-haplotypes having more unmasked sites than a pre selected limit can be generated.

23. The computer-usable medium of claim 22, wherein the method further comprises displaying those stored haplotypes and sub-haplotypes whose p-value does not exceed a second cut-off value, wherein the second cut-off value is less than the first cut-off value.

24. The computer-usable medium of claim 22, wherein the method further comprises discarding a complex redundant sub-haplotype which is constructed from smaller stored sub-haplotypes, wherein the p-value of each of the smaller sub-haplotypes is at least as significant at that of the complex redundant sub-haplotype.

25. A computer programmed to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlates with an outcome of interest, the computer comprising a memory having at least one region for storing computer executable program code and a processor for executing the program code stored in memory wherein the method comprises:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each individual polymorphism in the haplotype for the degree to which it correlates with the outcome of interest and calculating a numerical measure of the degree of correlation;

(c) saving each individual polymorphism whose numerical measure of the degree of correlation meets a first cut-off criterion and its numerical measure of the degree of correlation;

(d) generating all possible pair-wise combinations of the saved individual polymorphism so as to provide a set of n-site sub-haplotypes where n=2;

(e) statistically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the numerical measure of the degree of correlation;

(f) saving each n-site sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion ad its numerical measure of the degree of correlation;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new sub-haplotypes with increased values of n; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes can be generated, or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

26. The computer of claim 25, wherein the method further comprises displaying those saved individual polymorphisms and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut-off criterion.

27. The computer of claim 25, wherein the method further comprises displaying those saved individual polymorphisms and sub-haplotypes whose p-value does not exceed a second cut-off value, wherein the second cut-off value is less than the first cut-off value.

28. The computer of any one of claims 25-26, wherein the method further comprises discarding a complex redundant sub-haplotype which is generated from smaller saved sub-haplotypes, wherein the numerical measure of the degree of correlation of each of the smaller saved sub-haplotypes is at least as significant as that of the complex redundant sub-haplotype.

29. A computer programmed to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, the computer comprising a memory having at least one region for storing computer executable program code and a processor for executing the program code stored in memory, wherein the method comprises:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymeric sites;

(b) statistically analyzing each individual polymorphism in the haplotype for the degree to which it correlates with the outcome of interest and calculating a p-value for the correlation;

(c) saving each individual polymorphism whose p-value does not exceed a first cut-off value and its p-value;

(d) generating all possible pair-wise combinations of the saved individual polymorphisms so as to provide a set of n-site sub-haplotypes where n=2;

(e) statistically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the p-value for the correlation;

(f) saving each n-site sub-haplotype whose p-value does not exceed the first cut-off value and its p-value;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new sub-haplotypes with increased values of n; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes can be generated, or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

30. A computer programmed to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, the computer comprising a memory having at least one region for storing computer executable program code and a processor for executing the program code stored in memory, wherein the method comprises:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each haplotype for the degree to which it correlates with the outcome of interest, and calculating a numerical measure of the degree of correlation;

(c) saving each haplotype whose numerical measure of the degree of correlation meets a first cut-off criterion and its numerical measure of the degree of correlation;

(d) generating, from each haplotype composed of m polymorphic sites, all possible sub-haplotypes having a single site masked, so as to provide a set of m-n site sub-haplotypes where n=1;

(e) statistically analyzing each newly generated sub-haplotype for the degree to which it correlates with the outcome of interest, and calculating the numerical measure of the degree of correlation;

(f) saving each sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion and its numerical measure of the degree of correlation;

(g) generating, form the saved sub-haplotypes, all possible sub-haplotypes having one additional site masked; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes, or (ii) no further sub-haplotypes having more unmasked sites than a pre-selected limit can be generated.

31. The computer of claim 30, wherein the method further comprises displaying those saved haplotypes and sub-haplotypes whose numerical measure of the degree of correlation meets a second cut-off criterion, wherein the second cut-off criterion is more stringent than the first cut-off criterion.

34. The computer of any one of claims 30-31, wherein the method further comprises discarding a complex redundant sub-haplotype which is constructed from smaller saved sub-haplotypes, wherein the numerical measure of the degree of correlation of each of the smaller saved sub-haplotypes is at least as significant as that of the complex redundant sub-haplotype.

32. A computer programmed to execute a method to determine polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, the computer comprising a memory having at least one region for storing computer executable program code and a processor for executing the program code stored in memory, wherein the method comprises:

(a) accessing a database comprising a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each haplotype for the degree to which it correlates with to outcome of interest, and calculating a p-value for the correlation;

(c) saving each haplotype whose p-value does not exceed a first cut-off value and its p-value;

(d) generating, from each haplotype composed of m polymorphic sites, all possible sub-haplotypes having a single site masked, so as to provide a set of m-n site sub-haplotypes where n=1;

(e) statistically analyzing each newly generated sub-haplotype for the degree to which it correlates with the outcome of interest, and calculating the p-value for the correlation;

(f) saving each sub-haplotype whose p-value does not exceed the first cut-off value and its p-value;

(g) generating, from the saved sub-haplotypes, all possible sub-haplotypes having one additional site masked; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes or (ii) no further sub-haplotypes having more unmasked sites than a pre-selected limit can be generated.

33. The computer of claim 32, wherein the method further comprises displaying those saved haplotypes and sub-haplotypes whose p-value des not exceed a second cut-off value, wherein the second cut-off value is less than the first cut-off value.

35. A method of determining polymorphic sites or sub-haplotypes for a locus that correlate with an outcome of interest, comprising:

(a) providing a haplotype for each allele of the locus for each subject in a cohort of subjects and an outcome value for the outcome of interest for each subject in the cohort of subjects, the locus comprising at least two polymorphic sites;

(b) statistically analyzing each individual polymorphism in the haplotypes for the degree to which it correlates with the outcome of interest and calculating a numerical measure of the degree of correlation;

(c) saving each individual polymorphism whose numerical measure of the degree of correlation meets a first cut-off criterion for statistical significance;

(d) generating all possible pair-wise combinations of the saved individual polymorphisms so as to provide a set of n-site sub-haplotypes where n=2;

(e) statically analyzing each newly generated n-site sub-haplotype for the degree to which it correlates with the outcome of interest and calculating the numerical measure of the degree of correlation;

(f) saving each n-site sub-haplotype whose numerical measure of the degree of correlation meets the first cut-off criterion;

(g) generating all possible pair-wise combinations among and between the saved individual polymorphisms and saved sub-haplotypes, to produce new sub-haplotypes with increased values of n; and

(h) repeating steps (e) through (g) until either (i) no new sub-haplotypes or (ii) no new sub-haplotypes having n less than a pre-selected limit can be generated.

36. The method of claim 35, wherein providing comprises determining the haplotype for each allele of the locus for each subject and acquiring the outcome value for the outcome of interest for each subject.

37. The method of claim 35, further comprising saving the numerical measure of the degree of correlation of each saved individual polymorphism or sub-haplotype.