Method for cohort selection

• US 20040175700A1
• Filed: 03/03/2003
• Published: 09/09/2004
• Est. Priority Date: 05/15/2002
• Status: Abandoned Application

• Current Assignee: Elixir Pharmaceuticals, Inc.
• Original Assignee: Elixir Pharmaceuticals, Inc.
• Inventors: Geesaman, Bard J.
• Application Number:
  US10/378,397
• Publication Number:
  US 20040175700A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 Haplotypes
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/502 for testing non-proliferative effects

Abstract

Information for each individual of a first group of individuals and each individual of a second group of individuals is used to select a subset of individuals from the second group. The information can be about a plurality of different biological features. The selection can use a comparison between information for members of the first group and information for members of the subset. It is also possible to compare members of the first group to members of the selected subset with respect to at least one factor. The method can be used to reduce stratification, for example, in the analysis of genetic associations.

Claims

1. A method comprising:

receiving information for each individual of a first group of individuals and each individual of a second group of individuals, wherein the information for each individual comprises indications about a plurality of different biological features;

selecting a subset of individuals from the second group using a comparison between information for members of the first group and information for members of the subset; and

evaluating the relationship of at least one factor to members of the first group relative to members of the selected subset.

2. The method of claim 1, wherein the different biological features comprises a property of a biomolecule.

3. The method of claim 2 wherein the biomolecule is a protein, nucleic acid, lipid, or carbohydrate.

4. The method of claim 3 wherein the different biological features comprise polymorphisms of genomic DNA.

5. The method of claim 1 wherein the different biological features comprises a property of a cell.

6. The method of claim 1 wherein the plurality of different biological features comprises at least ten features.

7. The method of claim 1 wherein the comparison comprises representing the information for each member as a multi-dimensional vector or matrix.

8. The method of claim 1 wherein the comparison is weighted by covariance of at least two different features.

9. The method of claim 7 wherein the comparison is weighted by a covariance matrix for the plurality of different features.

10. The method of claim 4, wherein the individuals are humans, the first group of individuals is associated with a particular phenotypic trait, and the evaluating comprises evaluating association of a genetic marker with individuals of the first group relative to individuals of the select subset.

11. The method of claim 10 wherein the plurality of different biological features comprises genetic polymorphisms located on at least four different chromosomes.

12. The method of claim 10 wherein the comparison comprises assessing a multivariate distance.

13. The method of claim 11 wherein the evaluating association of the genetic marker comprises evaluating a LOD score.

14. A method of evaluating the relationship between a genetic polymorphism and a trait, the method comprising:

obtaining nucleic acid from each individual of a plurality of individuals, wherein a first group of the individuals are associated with a trait and a second group of individuals are not associated with the trait;

analyzing the nucleic acid to determine genetic information about a plurality of genetic loci for each individual of the plurality;

selecting a subset of individuals from the second group based on a comparison between the genetic information for members of the first group and the genetic information for members of the subset; and

evaluating association of a genetic locus of interest and individuals of the first group relative to association of the genetic locus of interest and individuals of the selected subset.

15. The method of claim 14 wherein the genetic information comprises indications of presence or absence of single nucleotide polymorphisms at least some genetic loci.

16. The method of claim 14 wherein the selecting comprises selecting a subset that compares to the first group more favorably than at least another subset.

17. The method of claim 14 wherein the selecting comprises incrementally adding members of the second group to the subset.

18. The method of claim 17 wherein the incremental adding comprises selecting one or more members of the second group based on how a group that includes the one or more members compares to the first group.

19. The method of claim 18 wherein the incremental adding comprises selecting a single member of the second group that minimizes a comparative function for a comparison between a group that includes the single member and the first group.

20. The method of claim 14 wherein the comparison comprises a comparative function that returns a scalar value.

21. The method of claim 20 wherein the selecting comprises minimizing the comparative function.

22. The method of claim 20 wherein the comparative function is a function of distance.

23. The method of claim 22 wherein the distance is weighted for allele variability.

24. The method of claim 22 wherein the distance is weighted for allele co-variance.

25. The method of claim 22 wherein the distance is a Mahalanobis distance.

26. The method of claim 14 wherein the selecting comprises pairing each member of the first group to a unique member of the second group.

27. The method of claim 14 wherein the evaluating of the association comprises evaluating a LOD score for the marker of interest.

28. The method of claim 14 wherein the plurality of genetic markers excludes the marker of interest.

29. The method of claim 14 wherein the plurality of genetic markers contains between 10 and 100 markers.

30. The method of claim 25 wherein the selecting comprises a filter that requires that the mean chi-square of the G-test is less than 1.5.

31. A system comprising:

a memory that stores information for each individual of a first group of individuals and each individual of a second group of individuals, wherein the information for each individual comprises indications about a plurality of different biological features;

a communications interface;

and a processor configured to

select a subset of individuals from the second group using a comparison between information for members of the first group and information for members of the subset;

evaluate the relationship of at least one factor to members of the first group relative to members of the selected subset; and

communicate results of the evaluation using the interface.

32. A method comprising:

obtaining nucleic acid samples from each individual of a first group of individuals and each individual of a second group of individuals;

analyzing the nucleic acid samples to determine information about a plurality of genetic markers for each individual of the first and second groups;

selecting a subset of individuals from the second group using a comparison between the information for members of the first group and the information for members of the subset; and

comparing members of the first group to members of the selected subset with respect to at least one factor.

33. The method of claim 32 wherein the comparing comprise subjecting members of the first group, but not the second group to a condition and evaluating members of the first group and members the second group.

34. The method of claim 33 wherein the condition is a medical procedure.

35. The method of claim 32 wherein the comparison comprises a distance function that returns a scalar value.

36. The method of claim 35 wherein the distance function is weighted for marker co-variance.

37. A method comprising:

obtaining DNA samples from and information about each individual of a first group of the individuals are associated with a trait;

analyzing the DNA samples to determine genetic information about a plurality of genetic loci for each individual of the plurality;

sending the allelic information to a server that stores genetic information for each individual of a second group of individuals; and

receiving information about a subset of individuals selected from the second group of individuals, wherein the subset of individuals is selected using a comparison between the genetic information for members of the first group and genetic information for members of the selected subset.

38. A server comprising

a memory that stores allelic information for a plurality of genetic markers for each individual of a first group of individuals;

and

software configured to;

receive genetic information about a plurality of genetic loci for each individual of a plurality of individuals;

select a subset of individuals from the second group using a comparison between genetic information for members of the plurality of individuals and genetic information for members of the selected subset; and

communicate information about individuals of the subset to a user.

39. A method of comparing a first and second population of individuals, the method comprising:

receiving genetic information for the first and second populations of individuals, the genetic information including information about a plurality of genetic markers for each of the individuals, the plurality including markers located on at least four different chromosomes and at least twenty different markers; and

returning a scalar value that is a function of the marker distribution for the first and second population and the degree of covariance among the genetic markers.

40. The method of claim 39 wherein the function further weights each marker by the degree of variability of the respective marker.

41. The method of claim 40 wherein the function is a function of the Mahalanobis distance between the genetic information for the first and second populations.

42. The method of claim 39 wherein each allele is weighted by its allele frequency in a third population.

43. A method of performing a controlled study, the method comprising:

identifying a first and second subset of individuals from the plurality of individuals by comparing occurrences of a plurality of genetic markers among individuals of the first and second subsets; and

subjecting the first subset of individuals to a first condition and the second subset of individuals to a second condition.

44. The method of claim 43 wherein the plurality of genetic markers includes markers located on at least four different chromosomes and at least twenty different markers.

45. The method of claim 44 wherein the first conditions comprises administering a test treatment, and the second condition comprises administering a control/placebo treatment.

46. The method of claim 43 wherein the comparing comprises evaluating a function that returns a scalar value and depends on of the marker distribution for the first and second subset and the degree of covariance among the genetic markers in the respective subsets.

47. The method of claim 44 where the subsets are complementary.

49. The medium of claim 47 wherein the relationship is a function of distance.

48. A machine readable medium having encoded thereon information comprising:

a first list of records;

a second list of records, wherein each record of the first and second list corresponds to a genome and comprises genetic information about each of a plurality of genetic markers in the genome; and

information describing a relationship between records of the first list and records of the second list, wherein the relationship is a function of the genetic information for at least a subset of the genetic markers, the markers of the subset including markers on at least two different chromosomes, and covariance of genetic markers of the subset between records of each list.

50. The medium of claim 48 wherein the distance is a Mahalanobis distance.