Method and system for determining haplotypes from a collection of polymorphisms

• US 20030211501A1
• Filed: 10/18/2002
• Published: 11/13/2003
• Est. Priority Date: 04/18/2001
• Status: Abandoned Application

• Current Assignee: Genaissance Pharmaceuticals Incorporated (Abbvie Incorporated)
• Original Assignee: Genaissance Pharmaceuticals Incorporated (Abbvie Incorporated)
• Inventors: Windemuth, Andreas, Stephens, J. Claiborne
• Application Number:
  US10/258,155
• Publication Number:
  US 20030211501A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/20 Sequence assembly
• CPC Class Codes: G16H 50/70 for mining of medical data, e.g. analysing previous cases of other patients
• 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 programs and databases for determining haplotypes from a collection of polymorphisms are provided. These include methods, programs, and databases to find and measure the frequency of haplotypes in the general population; and methods, programs, and databases for predicting an individual'"'"'s haplotypes from the individual'"'"'s genotype for a gene.

Claims

1. A method for assigning haplotype pairs for a polymorphic genomic region to a plurality of individuals, comprising:

(a) obtaining a genotype for the polymorphic genomic region from each of the individuals;

(b) enumerating all possible haplotypes h_i that are consistent with each genotype;

(c) assigning an evidence score s_i to each of the enumerated haplotypes h_i;

(d) calculating an initial haplotype frequency f_i for each haplotype among the possible haplotypes, wherein the initial haplotype frequency f_i is a function of the evidence score s_i;

(e) determining for each genotype obtained in step (a) a pair score F_k for each pair of haplotypes that is consistent with that genotype, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(f) calculating, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct;

(g) generating a revised haplotype frequency f_i for each haplotype, wherein the revised haplotype frequency f_i is a function of the probability p_k for each consistent haplotype pair which contains the haplotype; and

(h) repeating steps (e) through (g) until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (e) is replaced by the revised frequency f_i determined in step (g).

2. The method of claim 1, wherein the evidence score s_i obeys a formula selected from the group consisting of:

0≦

s_i≦

2 and $\underset{i=1}{\overset{n}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>s_i=2,$

where n is the number of ambiguous positions in said genotype, wherein an ambiguous polymorphic site is either a heterozygous site or is a site for which nucleotide sequence information is lacking.

3. The method of claim 2 wherein the evidence score s_i is 2/2ⁿ, wherein n is the number of ambiguous positions in said genotype, with the proviso that if the polymorphic genomic region is haploid or hemizygous in the individual, an evidence score of 1 is assigned.

4. The method of claim 1 wherein the initial frequency f_i is calculated from the sum of the evidence scores across all the different individuals, for each of the possible haplotypes h_i.

5. The method of claim 1 wherein the enumerating step is applied only to each genotype that meets an ambiguity criterion.

6. The method of claim 5, wherein the ambiguity criterion is a function of the number of ambiguous polymorphic sites in the genotype, wherein an ambiguous polymorphic site is either a heterozygous site or is a site for which information is lacking.

7. The method of claim 1 wherein the pair score criterion is chosen from the group consisting of (a) a specific numerical cutoff;

(b) a function of the values of the pair scores; and

(c) a function of the rankings of the pair scores.

8. The method of claim 1, wherein the pair score F_k=2f_if_j, if i≢

j, and otherwise F_k=f_i², with the proviso that the pair score F_k=f_i when the polymorphic genomic region is haploid or hemizygous, where f_i and f_j are the haplotype frequencies for the haplotypes h_i and h_j in the pair.

9. The method of claim 7, wherein the pair score criterion is a function of the rankings of the pair scores, and wherein the probability p_k is calculated by:

(a) ranking each of the pair scores F_k by score, with the highest score first;

(b) disregarding all but the N_rank highest ranking assignments; and

(c) defining the probability p_k as;

$p_k=\frac{F_k}{\underset{l=0}{\overset{N_{\mathrm{rank}}}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>F_l};<br><br>$

10. The method of claim 1, wherein the end condition is selected from the group consisting of:

(i) steps (e) through (g) have been repeated a preset number of times;

(ii) one or more of the parameters f_i, F_k, and p_k has stabilized; and

(iii) the operator choosses to stop.

11. The method of claim 1, wherein the plurality of individuals includes at least one multi-generation family and the probability p_k is reduced for each pair assignment for each genotype in the family that does not obey Mendelian inheritance.

12. The method of claim 11, wherein the reduced probability is reduced to 0 or is reduced by the formula p_k(1−

p_k′

), where p_k′

is the probability calculated for a pair assignment of a related genotype.

13. The method of claim 1, wherein the plurality of individuals comprises at least one population group and the probability p_k is reduced for each pair assignment for each genotype in the population group that does not obey Hardy-Weinberg Equilibrium.

14. The method of claim 13, wherein the probability p_k is reduced by the formula

15. The method of claim 1, wherein steps (a), (b) and (c) are performed for one individual at a time.

16. The method of claim 1, wherein steps (a), (b) and (c) are performed for each of the individuals in parallel.

17. The method of claim 1, wherein one or both of steps (e) and (f) are performed for one genotype at a time.

18. The method of claim 1, wherein one or both of steps (e) and (f) are performed for each genotype in parallel.

19. A method for predicting an individual'"'"'s haplotype pair for a polymorphic genomic region, comprising:

(a) obtaining the genotype for the polymorphic genomic region from the individual;

(b) enumerating all possible haplotypes h_i for the genotype;

(c) providing a frequency f_i for each of the possible haplotypes, where f_i is determined by the method of claim 1,

(d) determining a pair score F_k for each pair of possible haplotypes h_i that are consistent with the genotype, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair; and

(e) assigning to the genotype the haplotype pair having the highest pair score F_k.

20. The method of claim 1, further including generating an error estimate.

21. A method of constructing a haplotype database for a population, comprising:

(a) determining haplotype data for a plurality of individuals from genotype information using the method of claim 1;

(c) organizing the haplotype data for the plurality of individuals into fields; and

(d) storing the haplotype data for the plurality of individuals according to the fields.

22. The method of claim 21, wherein the haplotype data comprises haplotype frequencies and haplotype pair scores for a polymorphic genomic region.

23. The method of claim 22, wherein the probabilities are reduced for haplotype pairs that do not meet the requirements of the Hardy-Weinberg equilibrium.

24. The method of claim 22 wherein the haplotype data further comprises probabilities that pair assignments are correct.

25. The method of claim 24, wherein the validating comprises correcting an observed distribution of haplotypes or haplotype pairs for effects imposed by a limited number of individuals in the population.

26. The method of claim 25, wherein the validating further comprises analyzing compliance of the observed distribution with Mendelian inheritance principles.

27. The method of claim 21, wherein the population is selected from the group consisting of a reference population, a clinical population, a disease population, an ethnic population, a family population and a same-sex population.

38. The method of any one of claims 1-27, wherein all of the individuals in the plurality of individuals meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.

28. A method for predicting an individual'"'"'s haplotype pair for a polymorphic genomic region, comprising

(a) identifying a genotype for the individual;

(b) enumerating all possible haplotype pairs which are consistent with the genotype;

(c) determining a probability for each possible haplotype pair that the individual has that possible haplotype pair by accessing a database containing frequency data for reference haplotype pairs; and

(d) analyzing the determined probabilities to predict an individual'"'"'s haplotype pair.

29. The method of claim 28, further comprising storing the haplotype pair.

30. The method of claim 29, further comprising generating an error estimate.

31. A computer implemented method for generating haplotype pair and haplotype frequency screens for display on a display device, comprising the steps of:

(a) displaying in a first area a plurality of selectable items each corresponding to a polymorphic site for a predetermined gene;

(b) selecting one or more of said selectable items;

(c) displaying in a second area the haplotype pairs occurring in a reference population for the selected polymorphic sites;

(d) displaying in a third area data indicative of haplotype frequencies for a plurality of member groupings within the population.

32. A computer system for assigning haplotype pairs for a polymorphic genomic region to a plurality of individuals, comprising:

a database for storing genotyping information;

a processor connected to the database;

a computer program for controlling the processor connected to said database comprising instruction code to;

(a) accept input of a genotype for the polymorphic genomic region from each of the individuals and store said genotype within said database;

(b) enumerate all possible haplotypes h_i consistent with each genotype and store said haplotypes h_i within said database;

(c) calculate an evidence score s_i for each of said possible haplotypes h_i and store said evidence score s_i within said database;

(d) calculate an initial haplotype frequency f_i for each haplotype h_i among the possible haplotypes, and store the haplotype frequency f_i in said database, wherein the haplotype frequency f_i is a function of the evidence score s_i;

(e) calculate for each genotype received in step (a) a pair score F_k for each pair of haplotypes that are consistent with that genotype, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(f) calculate, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct and store the probability p_k in said database;

(g) calculate a revised haplotype frequency f_i for each of the haplotypes, wherein the revised haplotype frequency f_i is a function of the probability p_k for each consistent haplotype pair which contains the haplotype and storing the revised frequency f_i in said database; and

(h) repeat steps e through g until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (e) is replaced by the revised frequency f_i determined in step (g) and stored in the database.

33. The computer system of claim 32 wherein the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user and stored in said database.

34. The computer system of claim 33 wherein the computer system is connected to the internet and the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user through the internet.

35. The computer system of claim 33 wherein the computer system is connected to the internet and the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user through electronic mail.

36. The computer system of claim 33 wherein the genotype for the polymorphic genomic region from each of the individuals is obtained from a database of one or more known genotypes.

39. The computer system of any one of claims 32-36, wherein all of the individuals in the plurality of individuals meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.

37. A computer readable medium comprising instruction code to:

(a) accept input of a genotype for the polymorphic genomic region from each of the individuals and store said genotype within said database;

(b) enumerate all possible haplotypes h_i consistent with each genotype and store said haplotypes h_i within said database;

(c) calculate an evidence score s_i for each of said possible haplotypes h_i and store said evidence score s_i within said database;

(d) calculate an initial haplotype frequency f_i for each haplotype h_i among the possible haplotypes, and store the haplotype frequency f_i in said database, wherein the haplotype frequency f_i is a function of the evidence score s_i;

(e) calculate for each genotype received in step (a) a pair score F_k for each pair of haplotypes that are consistent with that genotype, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(f) calculate, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct and store the probability p_k in said database;

(g) calculate a revised haplotype frequency f_i for each of the haplotypes, wherein the revised haplotype frequency f_i is a function of the probability p_k for each consistent haplotype pair which contains the haplotype and storing the revised frequency f_i in said database; and

(h) repeat steps e through g until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (e) is replaced by the revised frequency f_i determined in step (g).

40. The computer-readable medium of claim 37, wherein all of the individuals in the plurality of individuals meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.

41. A method for assigning haplotype pairs for a polymorphic genomic region to a plurality of individuals, comprising:

(a) obtaining a genotype for the polymorphic genomic region from each of the individuals;

(b) grouping the genotypes obtained in step (a) into groups, wherein in each group g there are n_g identical genotypes, and wherein any unique genotypes are regarded as groups having n_g=1;

(c) enumerating all possible haplotypes h_i that are consistent with each distinct genotype;

(d) assigning an evidence score s_i to each of the enumerated possible haplotypes h_i;

(e) for each group g, calculating an initial haplotype frequency (f_i) for each haplotype among the possible haplotypes, wherein the initial haplotype frequency f_i is a function of the product (s_i)(n_g);

(f) determining for each group g, a pair score F_k for each pair of haplotypes that is consistent with the genotype of that group, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(g) calculating, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct;

(h) generating a revised haplotype frequency f_i for each haplotype, wherein the revised haplotype frequency f_i is a function of the product (n_g)(p_k) for each consistent haplotype pair which contains the haplotype; and

(i) repeating steps (f) through (h) until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (f) is replaced by the revised frequency f_i determined in step (h).

42. The method of claim 41, wherein the evidence score s_i obeys a formula selected from the group consisting of:

0≦

s_i≦

2 and

43. The method of claim 42 wherein the evidence score s_i is 2/2ⁿ, wherein n is the number of ambiguous positions in said genotype, with the proviso that if the polymorphic genomic region is haploid or hemizygous in the individual, an evidence score of 1 is assigned.

44. The method of claim 41 wherein the initial frequency f_i is calculated from the sum of the products (n_g)(s_i) across all the different genotypes, for all genotypes consistent with the haplotype f_i.

45. The method of claim 41 wherein the enumerating step is applied only to each genotype that meets an ambiguity criterion.

46. The method of claim 45, wherein the ambiguity criterion is a function of the number of ambiguous polymorphic sites in the genotype, wherein an ambiguous polymorphic site is either a heterozygous site or is a site for which information is lacking.

47. The method of claim 41 wherein the pair score criterion is chosen from the group consisting of (a) a specific numerical cutoff;

(b) a function of the values of the pair scores; and

(c) a function of the rankings of the pair scores.

48. The method of claim 41, wherein the pair score F_k=2f_if_j, if i≢

j, and otherwise F_k=f_i², with the proviso that the pair score F_k=f_i when the polymorphic genomic region is haploid or hemizygous, where f_i and f_j are the haplotype frequencies for the haplotypes h_i and h_j in the pair.

49. The method of claim 47, wherein the pair score criterion is a function of the rankings of the pair scores, and wherein the probability p_k is calculated by:

(a) ranking each of the pair scores F_k by score, with the highest score first;

(b) disregarding all but the N_rank highest ranking assignments; and

(c) defining the probability p_k as;

$p_k=\frac{F_k}{\underset{l=0}{\overset{N_{\mathrm{rank}}}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>F_l};<br><br>$

50. The method of claim 41, wherein the end condition is selected from the group consisting of:

(i) steps (e) through (g) have been repeated a preset number of times;

(ii) one or more of the parameters f_i, F_k, and p_k has stabilized; and

(iii) the operator choosses to stop.

51. The method of claim 41, wherein the plurality of individuals includes at least one multi-generation family and the probability p_k is reduced for each pair assignment for each genotype in the family that does not obey Mendelian inheritance.

52. The method of claim 51, wherein the reduced probability is reduced to 0 or is reduced by the formula p_k(1−

p_k′

), where p_k′

is the probability calculated for a pair assignment of a related genotype.

53. The method of claim 41, wherein the plurality of individuals comprises at least one population group and the probability p_k is reduced for each pair assignment for each genotype in the population group that does not obey Hardy-Weinberg Equilibrium.

54. The method of claim 53, wherein the probability p_k is reduced by the formula

55. The method of claim 41, wherein steps (c), (d) and (e), are performed for one group at a time.

56. The method of claim 41, wherein steps (c), (d) and (e), are performed for each of the groups in parallel.

57. The method of claim 41, wherein one or both of steps (f) and (g) are performed for one genotype at a time.

58. The method of claim 42, wherein one or both of steps (f) and (g) are performed for each genotype in parallel.

59. A method for predicting an individual'"'"'s haplotype pair for a polymorphic genomic region, comprising:

(a) obtaining the genotype for the polymorphic genomic region from the individual;

(b) enumerating all possible haplotypes h_i for the genotype;

(c) providing a frequency f_i for each of the possible haplotypes, where f_i is determined by the method of claim 41,

(d) determining a pair score F_k for each pair of possible haplotypes h_i that are consistent with the genotype, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair; and

(e) assigning to the genotype the haplotype pair having the highest pair score F_k.

60. The method of claim 41, further including generating an error estimate.

61. A method of constructing a haplotype database for a population, comprising:

(a) determining haplotype data for a plurality of individuals from genotype information using the method of claim 41;

(c) organizing the haplotype data for the plurality of individuals into fields; and

(d) storing the haplotype data for the plurality of individuals according to the fields.

62. The method of claim 61, wherein the haplotype data comprises haplotype frequencies and haplotype pair scores for a polymorphic genomic region.

63. The method of claim 61, wherein the probabilities are reduced for haplotype pairs that do not meet the requirements of the Hardy-Weinberg equilibrium.

64. The method of claim 61 wherein the haplotype data further comprises probabilities that pair assignments are correct.

65. The method of claim 61, wherein the validating comprises correcting an observed distribution of haplotypes or haplotype pairs for effects imposed by a limited number of individuals in the population.

66. The method of claim 65, wherein the validating further comprises analyzing compliance of the observed distribution with Mendelian inheritance principles.

67. The method of claim 61, wherein the population is selected from the group consisting of a reference population, a clinical population, a disease population, an ethnic population, a family population and a same-sex population.

68. A method for predicting an individual'"'"'s haplotype pair for a polymorphic genomic region, comprising

(a) identifying a genotype for the individual;

(b) enumerating all possible haplotype pairs which are consistent with the genotype;

(c) determining a probability for each possible haplotype pair that the individual has that possible haplotype pair by accessing a database prepared by the method of claim 61 and containing frequency data for reference haplotype pairs; and

(d) analyzing the determined probabilities to predict an individual'"'"'s haplotype pair.

69. The method of claim 68, further comprising storing the haplotype pair.

70. The method of claim 69, further comprising generating an error estimate.

71. A computer implemented method for generating haplotype pair and haplotype frequency screens for display on a display device, comprising the steps of:

(a) displaying in a first area a plurality of selectable items each corresponding to a polymorphic site for a predetermined gene;

(b) selecting one or more of said selectable items;

(c) displaying in a second area the haplotype pairs occurring in a reference population for the selected polymorphic sites;

(d) displaying in a third area data indicative of haplotype frequencies for a plurality of member groupings within the population;

wherein the data indicative of haplotype frequencies is retrieved from a database prepared by the method of claim 61.

78. The method of any one of claims 41-71, wherein the groups are further characterized in that all the individuals, from whom the genotypes in the group are derived, meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.

72. A computer system for assigning haplotype pairs for a polymorphic genomic region to a plurality of individuals, comprising:

a database for storing genotyping information;

a processor connected to the database; and

a computer program for controlling the processor connected to said database, comprising instruction code to;

(a) accept input of a genotype for the polymorphic genomic region from each of the individuals and store said genotype within said database;

(b) group the genotypes input in step (a) into groups, wherein in each group g there are n_g identical genotypes, and wherein any unique genotypes are regarded as groups having n_g=1;

(c) enumerate all possible haplotypes h_i consistent with the genotype of each group g, and store said haplotypes h_i within said database;

(d) calculate an evidence score s_i for each of said possible haplotypes h_i and store said evidence score s_i within said database;

(e) for each group g, calculate an initial haplotype frequency f_i for each haplotype h_i among the possible haplotypes, and store the haplotype frequency f_i in said database, wherein the initial haplotype frequency f_i is a function of the product (s_i)(n_g);

(f) calculate for each group obtained in step (b) a pair score F_k for each pair of haplotypes that are consistent with that group, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(g) calculate, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct and store the probability p_k in said database;

(h) calculate a revised haplotype frequency f_i for each of the haplotypes, wherein the revised haplotype frequency f_i is a function of the product (n_g)(p_k) for each consistent haplotype pair which contains the haplotype and storing the revised frequency f_i in said database; and

(i) repeat steps (f) through (h) until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (f) is replaced by the revised frequency f_i determined in step (h) and stored in the database.

73. The computer system of claim 72 wherein the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user and stored in said database.

74. The computer system of claim 73 wherein the computer system is connected to the internet and the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user through the internet.

75. The computer system of claim 73 wherein the computer system is connected to the internet and the genotype for the polymorphic genomic region from each of the individuals is obtained electronically from a remote user through electronic mail.

76. The computer system of claim 73 wherein the genotype for the polymorphic genomic region from each of the individuals is obtained from a database of one or more known genotypes.

79. The computer system of any one of claims 72-76, wherein the groups are further characterized in that all the individuals, from whom the genotypes in the group are derived, meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.

77. A computer readable medium comprising instruction code to:

(a) accept input of a genotype for the polymorphic genomic region from each of the individuals and store said genotype within said database;

(b) group the genotypes input in step (a) into groups, wherein in each group g there are n_g identical genotypes, and wherein any unique genotypes are regarded as groups having n_g=1;

(c) enumerate all possible haplotypes h_i consistent with the genotype of each group g, and store said haplotypes h_i within said database;

(d) calculate an evidence score s_i for each of said possible haplotypes h_i and store said evidence score s_i within said database;

(e) for each group g, calculate an initial haplotype frequency f_i for each haplotype h_i among the possible haplotypes, and store the haplotype frequency f_i in said database, wherein the initial haplotype frequency f_i is a function of the product (s_i)(n_g);

(f) calculate for each group obtained in step (b) a pair score p_k for each pair of haplotypes that are consistent with that group, wherein F_k is a function of the frequency f_i for each of the haplotypes in the pair;

(g) calculate, for each genotype and consistent haplotype pair whose pair score F_k meets a pair score criterion, a probability p_k that assignment of that haplotype pair to the genotype would be correct and store the probability p_k in said database;

(h) calculate a revised haplotype frequency f_i for each of the haplotypes, wherein the revised haplotype frequency f_i is a function of the product (n_g)(p_k) for each consistent haplotype pair which contains the haplotype and storing the revised frequency f_i in said database; and

(i) repeat steps (f) through (h) until an end condition is reached, with the proviso that for each repetition the frequency f_i employed in step (f) is replaced by the revised frequency f_i determined in step (h) and stored in the database.

80. The computer-readable medium of claim 77, wherein the groups are further characterized in that all the individuals, from whom the genotypes in the group are derived, meet one or more criteria selected from the group consisting of:

(a) having the same gender;

(b) belonging to the same population group;

(c) belonging to the same clinical or disease population;

(d) exhibiting a particular response to a stimulus;

(e) having in common a particular genotype at a different polymorphic region; and

(f) having in common a particular haplotype at a different polymorphic region.