Identification, monitoring and treatment of disease and characterization of biological condition using gene expression profiles

• US 20030219771A1
• Filed: 11/08/2002
• Published: 11/27/2003
• Est. Priority Date: 11/09/2001
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Source Precision Medicine Inc.
• Inventors: Cheronis, John C., Tryon, Victor, Bevilacqua, Michael
• Granted Patent: US 6,964,850 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: G01N 2800/042 Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 33/57415 of breast
• CPC Class Codes: G01N 33/6803 General methods of protein analysis not limited to specific proteins or families of proteins
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/6869 Interleukin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 25/10 Gene or protein expression profiling; Expression-ratio estimation or normalisation
• CPC Class Codes: G16Z 99/00 Subject matter not provided for in other main groups of this subclass
• 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

Gene expression data, in particular gene expression profiles, are created and used in the identification, monitoring and treatment of disease and characterization of biological conditions. Profile data sets are derived from subject samples and include quantitative substantially repeatable measures of a distinct amount of RNA or protein constituent in a panel selected to enable evaluation of a biological condition. Such profile data sets may be used to provide an index indicative of the biological state of a subject, which may be compared to a normative value of the index determined with respect to a relevant population of subjects.

Claims

1. A method, for evaluating a biological condition of a subject, based on a sample from the subject, comprising:

deriving from the sample a profile data set, the profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables evaluation of the biological condition; and

in deriving the profile data set, achieving such measure for each constituent under measurement conditions that are substantially repeatable.

3. A method according to claim 1, further comprising in deriving the profile data set, achieving such measure for each constituent under measurement conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar.

11. A method according to any of claims 1 through 10, wherein efficiencies of amplification, expressed as a percent, for all constituents lie within a range of approximately 2 percent.

12. A method according to any of claims 1 through 10, wherein efficiencies of amplification, expressed as a percent, for all constituents lie within a range of approximately 1 percent.

13. A method according to any of claims 1 through 10, wherein measurement conditions are repeatable so that such measure for each constituent has a coefficient of variation, on repeated derivation of such measure from the sample, that is less than approximately 3 percent.

14. A method according to claim 11, wherein measurement conditions are repeatable so that such measure for each constituent has a coefficient of variation, on repeated derivation of such measure from the sample, that is less than approximately 3 percent.

15. A method according to claim 12, wherein measurement conditions are repeatable so that such measure for each constituent has a coefficient of variation, on repeated derivation of such measure from the sample, that is less than approximately 3 percent.

16. A method according to any of claims 1 through 10, wherein the panel includes at least three constituents.

17. A method according to any of claims 1 through 10, wherein the panel has fewer than approximately 500 constituents.

18. A method according to claim 1 through 10, wherein the biological condition being evaluated is with respect to a localized tissue of the subject and the sample is derived from tissue or fluid of a type distinct from that of the localized tissue.

19. A method according to any of claims 1 through 10, wherein the biological condition is inflammation and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Inflammation Gene Expression Panel of Table 1.

20. A method according to any of claims 1 through 10, wherein the biological condition is diabetes and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Diabetes Gene Expression Panel of Table 2.

21. A method according to any of claims 1 through 10, wherein the biological condition is prostate health or disease and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Prostate Gene Expression Panel of Table 3.

22. A method according to any of claims 1 through 10, wherein the biological condition is manifested in skin and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Skin Response Gene Expression Panel of Table 4.

23. A method according to any of claims 1 through 10, wherein the biological condition is liver metabolism and disease and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Liver Metabolism and Disease Gene Expression Panel of Table 5.

24. A method according to any of claims 1 through 10, wherein the biological condition is vascular and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Endothelial Gene Expression Panel of Table 6.

25. A method according to any of claims 1 through 10, wherein the biological condition is abnormal cell development and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Cell Health and Apoptosis Gene Expression Panel of Table 7.

26. A method according to any of claims 1 through 10, wherein the biological condition is inflammation and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Cytokine Gene Expression Panel of Table 8.

27. A method according to any of claims 1 through 10, wherein the biological condition is inflammation and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the TNF/IL1 Inhibition Gene Expression Panel of Table 9.

28. A method according to any of claims 1 through 10, wherein the biological condition is inflammation and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Chemokine Gene Expression Panel of Table 10.

29. A method according to any of claims 1 through 10, wherein the biological condition is cancer and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Breast Cancer Gene Expression Panel of Table 11.

30. A method according to any of claims 1 through 10, wherein the biological condition is infectious disease and the panel of constituents includes at least two, and optionally at least three, four, five, six, seven, eight, nine or ten, of the constituents of the Infectious Disease Gene Expression Panel of Table 12.

2. A method of providing an index that is indicative of the state of a subject, as to a biological condition, based on a sample from the subject, the method comprising:

deriving from the sample a profile data set, the profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables evaluation of the biological condition; and

in deriving the profile data set, achieving such measure for each constituent under measurement conditions that are substantially repeatable; and

applying values from the profile data set to an index function that provides a mapping from an instance of a profile data set into a single-valued measure of biological condition, so as to produce an index pertinent to the biological condition of the subject.

4. A method according to claim 2, further comprising in deriving the profile data set, achieving such measure for each constituent under measurement conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar.

5. A method according to claims 2, further comprising providing with the index a normative value of the index function, determined with respect to a relevant population, so that the index may be interpreted in relation to the normative value.

6. A method according to claim 4, further comprising providing with the index a normative value of the index function, determined with respect to a relevant population, so that the index may be interpreted in relation to the normative value.

7. A method according to claim 5, wherein providing the normative value includes constructing the index function so that the normative value is approximately 1.

8. A method according to claim 6, wherein providing the normative value includes constructing the index function so that the normative value is approximately 0 and deviations in the index function from 0 are expressed in standard deviation units.

9. A method according to claim 5, wherein the relevant population has in common a property that is at least one of age group, gender, ethnicity, geographic location, diet, medical disorder, clinical indicator, medication, physical activity, body mass, and environmental exposure.

10. A method according to claim 6, wherein the relevant population is has in common a property that is at least one of age group, gender, ethnicity, geographic location, diet, medical disorder, clinical indicator, medication, physical activity, body mass, and environmental exposure.

31. A method of providing an index that is indicative of the biological state of a subject based on a sample from the subject, the method comprising:

deriving from the sample a first profile data set, the first profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents, the panel including at least two of the constituents of the Inflammation Gene Expression Panel of Table 1;

wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions; and

applying values from the first profile data set to an index function that provides a mapping from an instance of a profile data set into a single-valued measure of biological condition, so as to produce an index pertinent to the biological condition of the sample or the subject.

32. A method according to claim 31, wherein the panel includes at least three of the constituents in the Inflammation Gene Expression Panel.

33. A method according to claim 31, wherein the panel includes at least four of the constituents in the Inflammation Gene Expression Panel.

34. A method according to claim 31, wherein the panel includes at least five of the constituents in the Inflammation Gene Expression Panel.

35. A method according to claim 31, wherein the panel includes at least six of the constituents in the Inflammation Gene Expression Panel.

36. A method according to claim 31, wherein the panel includes at least 10 of the constituents in the Inflammation Gene Expression Panel.

37. A method according to claim 31, wherein the biological condition is an inflammatory condition.

38. A method according to claim 31, wherein

(i) the mapping by the index function is further based on an instance of a relevant baseline profile data set;

and

(ii) applying values from the first profile data set further includes applying values from a corresponding baseline profile data set from the same subject or from a population of subjects or samples with a similar or different biological condition.

39. A method according to claim 31, wherein the index function is constructed to deviate from a normative value generally upwardly in an instance of an increase in expression of a constituent whose increase is associated with an increase of inflammation and also in an instance of a decrease in expression of a constituent whose decrease is associated with an increase of inflammation.

40. A method according to claim 39, wherein the index function is constructed to weigh the expression value of a constituent in the panel generally in accordance with the extent to which its expression level is determined to be correlated with extent of inflammation.

41. A method according to claim 39, wherein the index function is constructed to take into account clinical insight into inflammation biology.

42. A method according to claim 39, wherein the index function is constructed to take into account experimentally derived data.

43. A method according to claim 39, wherein the index function is constructed to take into account relationships derived from computer analysis of profile data sets in a data base associating profile data sets with clinical and demographic data.

44. A method according to claim 31, wherein the panel includes at least one constituent that is associated with a specific inflammatory disease.

45. A method according to claim 31, wherein (i) the mapping by the index function is also based on an instance of at least one of demographic data and clinical data and (ii) applying values from the first profile data set also includes applying a set of values associated with at least one of demographic data and clinical data.

46. A method according to claim 31, wherein a portion of deriving the first profile data set is performed at a first location and applying the values from the first profile data set is performed at a second location, and data associated with performing the portion of deriving the first profile data set are communicated to the second location over a network to enable, at the second location, applying the values from the first profile data set.

47. A method according to claim 31, wherein the index function is a linear sum of terms, each term being a contribution function of a member of the profile data set.

48. A method according to claim 47, wherein the contribution function is a weighted power of the member.

49. A method according to claim 48, wherein the power is integral, so that the index function is a linear polynomial.

50. A method according to claim 49, wherein the profile data set includes at least three members corresponding to constituents selected from the group consisting of IL1A, IL1B, TNF, IFNG and IL10.

51. A method according to claim 49, wherein the profile data set includes at least four members corresponding to constituents selected from the group consisting of IL1A, IL1B, TNF, IFNG and IL10.

52. A method according to claim 51, wherein the index function is approximately proportional to ¼

(IL1A}+¼

{IL1B}+¼

{TNF}+¼

{INFG}−

1/{IL10}and braces around a constituent designate measurement of such constituent.

53. A method of analyzing complex data associated with a sample from a subject for information pertinent to inflammation, the method comprising:

deriving a Gene Expression Profile for the sample, the Gene Expression Profile being based on a Signature Panel for Inflammation; and

using the Gene Expression Profile to determine a Gene Expression Profile Inflammatory Index for the sample.

54. A method of monitoring the biological condition of a subject, the method comprising:

deriving a Gene Expression Profile for each of a series of samples over time from the subject, the Gene Expression Profile being based on a Signature Panel for Inflammation; and

for each of the series of samples, using the corresponding Gene Expression Profile to determine a Gene Expression Profile Inflammatory Index.

55. A method of determining at least one of (i) an effective dose of an agent to be administered to a subject and (ii) a schedule for administration of an agent to a subject, the method comprising:

deriving a Gene Expression Profile for a sample from the subject, the Gene Expression Profile being based on a Signature Panel for Inflammation;

using the Gene Expression Profile to determine a Gene Expression Profile Inflammatory Index for the sample; and

using the Gene Expression Profile Inflammatory Index as an indicator in establishing at least one of the effective dose and the schedule.

56. A method of guiding a decision to continue or modify therapy for a biological condition of a subject, the method comprising:

deriving a Gene Expression Profile for a sample from the subject, the Gene Expression Profile being based on a Signature Panel for Inflammation; and

using the Gene Expression Profile to determine a Gene Expression Profile Inflammatory Index for the sample.

57. A method of predicting change in biological condition of a subject as a result of exposure to an agent, the method comprising:

deriving a first Gene Expression Profile for a first sample from the subject in the absence of the agent, the first Gene Expression Profile being based on a Signature Panel for Inflammation;

deriving a second Gene Expression Profile for a second sample from the subject in the presence of the agent, the second Gene Expression Profile being based on the same Signature Panel; and

using the first and second Gene Expression Profiles to determine correspondingly a first Gene Expression Profile Inflammatory Index and a second Gene Expression Profile Inflammatory Index.

58. A method according to claim 57, wherein the agent is a compound.

59. A method according to claim 58, wherein the compound is therapeutic.

60. A method of evaluating a property of an agent, the property being at least one of purity, potency, quality, efficacy or safety, the method comprising:

deriving a first Gene Expression Profile from a sample reflecting exposure to the agent of (i) the sample, or (ii) a population of cells from which the sample is derived, or (iii) a subject from which the sample is derived;

using the Gene Expression Profile to determine a Gene Expression Profile Inflammatory Index; and

using the Gene Expression Profile Inflammatory Index in determining the property.

61. A method, for evaluating a biological condition of a subject, based on a sample from the subject, comprising:

deriving from the sample a first profile data set, the first profile dataset including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables measurement of the biological condition; and

producing a calibrated profile data set for the panel, wherein each member of the calibrated profile data set is a function of a corresponding member of the first profile data set and a corresponding member of a baseline profile data set for the panel, wherein each member of the baseline data set is a normative measure, determined with respect to a relevant population of subjects, of the amount of one of the constituents in the panel, the calibrated profile data set providing a measure of the biological condition of the subject.

64. A method according to any of claims 61 through 63, wherein the relevant population is a population of healthy subjects.

65. A method according to any of claims 61 through 63, wherein the relevant population is has in common a property that is at least one of age group, gender, ethnicity, geographic location, diet, medical disorder, clinical indicator, medication, physical activity, body mass, and environmental exposure.

68. A method according to any of claims 61 through 63, the panel including at least two of the constituents of the Inflammation Gene Expression Panel of Table 1 and wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

69. A method according to any of claims 61 through 63, the panel including at least three of the constituents of the Inflammation Gene Expression Panel of Table 1 and wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

70. A method according to any of claims 61 through 63, the panel including at least four of the constituents of the Inflammation Gene Expression Panel of Table 1 and wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

71. A method according to any of claims 61 through 63, the panel including at least five of the constituents of the Inflammation Gene Expression Panel of Table 1 and wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

72. A method according to any of claims 61 through 63, the panel including at least six of the constituents of the Inflammation Gene Expression Panel of Table 1 and wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

62. A method, for evaluating a biological condition of a subject, based on a sample from the subject, comprising:

applying the first sample or a portion thereof to a defined population of indicator cells;

obtaining from the indicator cells a second sample containing at least one of RNAs or proteins;

deriving from the second sample a first profile data set, the first profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables measurement of the biological condition; and

producing a calibrated profile data set for the panel, wherein each member of the calibrated profile data set is a function of a corresponding member of the first profile data set and a corresponding member of a baseline profile data set for the panel, wherein each member of the baseline data set is a normative measure, determined with respect to a relevant population of subjects, of the amount of one of the constituents in the panel, the calibrated profile data set providing a measure of the biological condition of the subject.

63. A method, for evaluating a biological condition affected by an agent, the method comprising:

obtaining, from a target population of cells to which the agent has been administered, a sample having at least one of RNAs and proteins;

deriving from the sample a first profile data set, the first profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables measurement of the biological condition; and

producing a calibrated profile data set for the panel, wherein each member of the calibrated profile data set is a function of a corresponding member of the first profile data set and a corresponding member of a baseline profile data set for the panel, wherein each member of the baseline data set is a normative measure, determined with respect to a relevant population of subjects, of the amount of one of the constituents in the panel, the calibrated profile data set providing a measure of the biological condition as affected by the agent.

66. A method, for evaluating a biological condition of a subject, based on a sample from the subject, comprising:

deriving from the sample a first profile data set, the first profile dataset including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables measurement of the biological condition;

wherein, in deriving the first profile data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

67. A method according to claim 66, wherein the panel includes at least two, and optionally, at least three, at least four, at least five, or at least six of the constituents of the Inflammation Gene Expression Panel of Table 1.

73. A method, for evaluating the effect on a biological condition by a first agent in relation to the effect by a second agent, the method comprising:

obtaining, from first and second target populations of cells to which the first and second agents have been respectively administered, first and second samples respectively, each sample having at least one of RNAs and proteins;

deriving from the first sample a first profile data set and from the second sample a second profile data set, the profile data sets each including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents selected so that measurement of the constituents enables measurement of the biological condition; and

producing for the panel a first calibrated profile data set and a second profile data set, wherein (i) each member of the first calibrated profile data set is a function of a corresponding member of the first profile data set and a corresponding member of a baseline profile data set for the panel, wherein each member of the baseline data set is a normative measure, determined with respect to a relevant population of subjects, of the amount of one of the constituents in the panel, and (ii) each member of the second calibrated profile data set is a function of a corresponding member of the second profile data set and a corresponding member of the baseline profile data set, the calibrated profile data sets providing a measure of the effect by the first agent on the biological condition in relation to the effect by the second agent

wherein, in deriving the first and second profile data sets, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.

74. A method according to claim 73, wherein the first agent is a first drug and the second agent is a second drug.

75. A method according to claim 73, wherein the first agent is a drug and the second agent is a complex mixture.

76. A method according to claim 74, wherein the first agent is a drug and the second agent is a nutriceutical.

77. A method of providing an index that is indicative of the inflammatory state of a subject based on a sample from the subject, the method comprising:

deriving from the sample a first profile data set, the first profile data set including a plurality of members, each member being a quantitative measure of the amount of a distinct RNA or protein constituent in a panel of constituents, the panel including at least two of the constituents of the Inflammation Gene Expression Panel of Table 1; and

applying values from the first profile data set to an index function that provides a mapping from an instance of a profile data set into a single-valued measure of biological condition, so as to produce an index pertinent to the biological condition of the sample or the subject;

wherein the index function also uses data from a baseline profile data set for the panel, wherein each member of the baseline data set is a normative measure, determined with respect to a relevant population of subjects, of the amount of one of the constituents in the panel; and

wherein, in deriving the first profile data set and the baseline data set, such measure is performed for each constituent both under conditions wherein specificity and efficiencies of amplification for all constituents are substantially similar and under substantially repeatable conditions.