Computer systems and methods for selecting subjects for clinical trials

• US 20080033658A1
• Filed: 07/16/2007
• Published: 02/07/2008
• Est. Priority Date: 07/17/2006
• Status: Active Grant

• Current Assignee: H Lee Moffitt Cancer Center & Research Institute (State University System of Florida), University of South Florida (State University System of Florida)
• Original Assignee: H Lee Moffitt Cancer Center & Research Institute (State University System of Florida)
• Inventors: Yeatman, Timothy, Dalton, William
• Granted Patent: US 8,095,389 B2
• Time in Patent Office: Days
• US Class Current: 702/19
• CPC Class Codes: G16H 10/20 for electronic clinical trials or questionnaires
• CPC Class Codes: G16H 10/60 for patient-specific data, e.g. for electronic patient records
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: G16H 20/40 relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture

Abstract

Computers, computer program products, and methods for identifying a plurality of subjects for a clinical trial are provided. A candidate set of molecular profiles in a stored plurality of molecular profiles are identified. Each such profile has measurements for a discriminating set of cellular constituents that match the measurements of corresponding cellular constituents in a responder set of biological samples, thereby identifying the plurality of subjects for the trial from those subjects from which the candidate set of molecular profiles were derived. Each respective molecular profile in the stored plurality of profiles has measurements of a plurality of cellular constituents from a respective biological sample in a plurality of samples obtained from a first plurality of subjects. The discriminating set of cellular constituents is identified from those cellular constituents in the plurality of cellular constituents whose measurement values discriminates between the responder and nonresponder sets of biological samples.

Claims

1. A method of identifying a plurality of subjects for a clinical trial for a therapy of interest, the method comprising:

identifying a candidate set of molecular profiles in a stored first plurality of molecular profiles, wherein each molecular profile in said candidate set of molecular profiles has measurements for a discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in a responder set of biological samples, said responder set being responsive to said therapy of interest, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived;

wherein

each respective molecular profile in said stored first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in a first plurality of biological samples obtained from a first plurality of subjects; and

said discriminating set of cellular constituents is identified from those cellular constituents in said first plurality of cellular constituents whose measurement values taken prior to exposure to said therapy of interest discriminates between said responder set of biological samples and a nonresponder set of biological samples, said nonresponder set being nonresponsive to said therapy of interest.

2. The method of claim 1, the method further comprising, prior to said identifying step, a step of measuring a molecular profile for each biological sample in said first plurality of biological samples thereby obtaining said first plurality of molecular profiles.

3. The method of claim 2, the method further comprising storing said first plurality of molecular profiles.

4. The method of claim 1, the method further comprising, prior to said identifying step, a step of:

measuring a molecular profile for each biological sample in a second plurality of biological samples prior to exposure to said therapy of interest, thereby obtaining a second plurality of molecular profiles, wherein each biological sample in said second plurality of biological samples is from a subject having a disease of interest or is a model for said disease of interest and each respective molecular profile in said second plurality of molecular profiles comprises measurements of two or more of said first plurality of cellular constituents from a respective biological sample in said second plurality of biological samples; and

identifying said responder set of biological samples that are responders to said therapy of interest for said disease of interest in said second plurality of biological samples and a nonresponder set of biological samples that are nonresponders to said therapy of interest for said disease of interest in said second plurality of biological samples.

5. The method of claim 4, wherein each biological sample in said second plurality of biological samples is a cell line.

6. The method of claim 4, wherein each biological sample in said second plurality of biological samples is obtained from a subject in a second plurality of subjects.

7. The method of claim 6, wherein each biological sample in said second plurality of biological samples is a portion of a tumor.

8. The method of claim 1, the method further comprising, prior to said identifying step, a step of determining:

said responder set of biological samples that are responders to said therapy of interest for said disease of interest in said first plurality of biological samples, and

said nonresponder set of biological samples that are nonresponders to said therapy of interest for said disease of interest in said first plurality of biological samples.

9. The method of claim 1, the method further comprising steps of:

making a first observation of a clinical feature, other than a cellular constituent, in a subject in said plurality of subjects at a first time point; and

storing said first observation of said clinical feature with the molecular profile for said subject.

10. The method of claim 9, wherein the molecular profile for the subject is in the candidate set of molecular profiles and wherein the first observation is absence or presence of said clinical feature in the subject, the method further comprising:

removing the molecular profile from the candidate set when the clinical feature is absent from the subject; and

retaining the molecular profile in the candidate set when the clinical feature is present in the subject.

11. The method of claim 9, the method further comprising

making a second observation of said clinical feature in said subject at a second time point;

and

storing said second observation of said clinical feature with the molecular profile for said subject.

12. The method of claim 11, wherein the second time point is at least one day after said first time point.

13. The method of claim 11, wherein the second time point is at least one week after said first time point.

14. The method of claim 11, wherein the second time point is at least one month after said first time point.

15. The method of claim 11, wherein the second time point is at least one year after said first time point.

16. The method of claim 9, wherein the clinical feature is absence or presence of a disease in said subject.

17. The method of claim 16, wherein the disease is arthritis, asthma, an allergy, cancer, chronic fatigue syndrome, diabetes, epilepsy, heart disease, hemochromatosis, hepatitis B, hepatitis C, or osteoporosis.

18. The method of claim 16, wherein the disease is breast cancer, cervical cancer, colorectal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, skin cancer, or testicular cancer.

19. The method of claim 9, wherein the clinical feature is ankle swelling, anorexia, dyspnoea, fatigue, high blood pressure, hypoxemia, lethargy, lymphopenia, nocturnal cough, nocturnal dyspnoea, obesity, orthopnoea, paroxysmal, a viral infection, reduced exercise tolerance, tachycardia, tachypnea, or wheeze.

20. The method of claim 1, wherein said first plurality of cellular constituents comprises more than five thousand cellular constituents.

21. The method of claim 1, wherein said method comprises obtaining each molecular profile for each biological sample in said first plurality of biological samples using a microarray that comprises oligonucleotides representing more than five thousand cellular constituents.

22. The method of claim 1, wherein a cellular constituent in said discriminating set of cellular constituents is a nucleic acid or a protein.

23. The method of claim 1, wherein measurements for a cellular constituent in said set of discriminating set of cellular constituents discriminates with a p value of less than 0.05 as determined by a parametric or nonparametric test using measurements for said cellular constituent in the responder set of biological samples and measurements for said cellular constituent in the nonresponder set of biological samples.

24. The method of claim 23, wherein said parametric test or nonparametric test is a nonparametric test.

25. The method of claim 24, wherein the nonparametric test is a Chi-square test, a Phi coefficient, a Fisher exact test, or a Wilcoxon rank sum test.

26. The method of claim 23, wherein the parametric test or nonparametric test is a parametric test.

27. The method of claim 26, wherein the parametric test is analysis of variance or a t-test.

28. The method of claim 1, wherein said therapy of interest is exposure to a drug, exposure to radiation, exposure to radio-frequency ablation, or exposure to an siRNA.

29. The method of claim 1, wherein said first plurality of subjects are human, bovine, porcine, canine, feline, ovine, equine, lapine, hamster, chicken, rat, mouse, chimpanzee, or baboon.

30. The method of claim 1, the method further comprising prior to said identifying step:

obtaining patient information about a subject in said plurality of subjects; and

storing said patient information about said subject with the molecular profile for said subject.

31. The method of claim 30, wherein the patient information is an address where the subject lives, next of kin contact information, a telephone number for the subject, an age of the subject, an allergy of the subject, a height of the subject, a weight of the subject, a race of the subject, insurance information for the subject, subject treatment history, a diagnosis of the subject, or family medical history for the subject.

32. The method of claim 31, wherein the patient information is entered directly onto a web-based questionnaire and wherein said storing step comprises completing said web-based questionnaire.

33. The method of claim 30, wherein the molecular profile for the subject is in the candidate set of molecular profiles identified in said identifying step, and wherein the method further comprises:

removing the molecular profile from the candidate set when the patient information does not satisfy a selection criterion; and

retaining the molecular profile in the candidate set when the patient information satisfies the selection criterion.

34. The method of claim 33 wherein the selection criterion is a minimum age, a maximum age, a minimum weight, or a maximum weight.

35. The method of claim 1, the method further comprising:

subjecting said plurality of subjects to said therapy of interest;

identifying a first set of subjects in said plurality of subjects that are responders to said therapy of interest and a second set of subjects in said plurality of subjects that are not responders to said therapy of interest;

identifying a revised set of discriminating cellular constituents whose measurement values taken from said plurality of subjects prior to exposure to said therapy of interest discriminates between said first set of subjects in said plurality of subjects that are responders to said therapy of interest and said second set of subjects in said plurality of subjects that are not responders to said therapy of interest; and

identifying a new plurality of subjects for said clinical trial for said therapy of interest based on matches between cellular constituent values for said revised set of discriminating cellular constituents in (i) the molecular profiles of the first set of subjects in the plurality of subjects that are responders to the therapy of interest and (ii) the molecular profiles of the first plurality of subjects.

36. The method of claim 1, the method further comprising:

observing a progression of a disease in each subject in said first plurality of subjects; and

storing said progression of said disease in each subject in said first plurality of subjects.

37. The method of claim 36, wherein the method further comprises:

removing the molecular profile of a subject from the candidate set when the progression of the disease in the subject does not satisfy a selection criterion; and

retaining the molecular profile of a subject in the candidate set when the progression of the disease in the subject satisfies the selection criterion.

38. The method of claim 37, wherein the selection criterion is a failure to respond to a therapy other than the therapy of interest.

39. The method of claim 37, wherein the selection criterion is responsiveness to a therapy other than the therapy of interest.

40. The method of claim 36, wherein the observing the progression of the disease comprises completing a web-based questionnaire.

41. The method of claim 1, the method further comprising:

administering to a subject in said plurality of subjects said therapy of interest; and

storing a record of the therapy of interest in a record associated with the subject.

42. The method of claim 41, wherein the storing step comprises completing a web-based questionnaire.

43. The method of claim 1, the method further comprising:

obtaining a biological sample in said plurality of biological samples from a remote location.

44. The method of claim 1, wherein said obtaining step comprises entering patient data or clinical data associated with the biological sample, at said remote location, into a web-based questionnaire.

60. A computer program product for use in conjunction with a computer system, wherein the computer program product comprises a computer readable storage medium and a computer program mechanism embedded therein, the computer program mechanism comprising instructions for carrying out the method of claim 1.

61. A computer comprising:

a central processing unit; and

a memory coupled to the central processing unit, the memory storing a module that comprises instructions for carrying out the method of claim 1.

62. The method of claim 6 wherein the subject is a mammal, human, or non-human mammal.

63. The method of claim 1, wherein each measurement of a cellular constituent in the discriminating set of cellular constituents in a molecular profile in the candidate set of molecular profiles is an indication of the presence or absence of one or more genetic markers.

64. The method of claim 63 wherein the cellular constituent is a nucleic acid and the one or more genetic markers are within the nucleic acid.

65. The method of claim 1, wherein each measurement of a respective cellular constituent in the discriminating set of cellular constituents in a molecular profile in the candidate set of molecular profiles is an abundance of the cellular constituent in a respective biological sample.

66. The method of claim 65 wherein the cellular constituent is nucleic acid or protein.

45. A computer program product for use in conjunction with a computer system, wherein the computer program product comprises a computer readable storage medium and a computer program mechanism embedded therein, the computer program mechanism for identifying a plurality of subjects for a clinical trial for a therapy of interest, the computer program mechanism comprising instructions for:

identifying a candidate set of molecular profiles in a stored first plurality of molecular profiles, wherein each molecular profile in said candidate set of molecular profiles has measurements for a discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in a responder set of biological samples, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived;

wherein

each respective molecular profile in said stored first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in a first plurality of biological samples obtained from a first plurality of subjects; and

said discriminating set of cellular constituents is identified from those cellular constituents in said first plurality of cellular constituents whose measurement values taken prior to exposure to said therapy of interest discriminates between said responder set of biological samples and a nonresponder set of biological samples.

46. A computer comprising:

a central processing unit; and

a memory coupled to the central processing unit, the memory storing a module for identifying a plurality of subjects for a clinical trial for a therapy of interest, the module comprising instructions for;

identifying a candidate set of molecular profiles in a stored first plurality of molecular profiles, wherein each molecular profile in said candidate set of molecular profiles has measurements for a discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in a responder set of biological samples, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived;

wherein

each respective molecular profile in said stored first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in a first plurality of biological samples obtained from a first plurality of subjects; and

said discriminating set of cellular constituents is identified from those cellular constituents in said first plurality of cellular constituents whose measurement values taken prior to exposure to said therapy of interest discriminates between said responder set of biological samples and a nonresponder set of biological samples.

47. A method of identifying a plurality of subjects for a clinical trial for a therapy of interest, the method comprising:

(a) measuring a molecular profile for each biological sample in a first plurality of biological samples thereby obtaining a first plurality of molecular profiles, wherein said first plurality of biological samples are obtained from a first plurality of subjects and each respective molecular profile in said first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in said first plurality of biological samples;

(b) storing said first plurality of molecular profiles;

(c) measuring a molecular profile for each biological sample in a second plurality of biological samples prior to exposure to said therapy of interest, thereby obtaining a second plurality of molecular profiles, wherein each biological sample in said second plurality of biological samples is from a subject having a disease of interest or is a model for said disease of interest and each respective molecular profile in said second plurality of molecular profiles comprises measurements of two or more of said first plurality of cellular constituents from a respective biological sample in said second plurality of biological samples;

(d) determining a responder set of biological samples that are responders to said therapy of interest for said disease of interest in said second plurality of biological samples and a nonresponder set of biological samples that are nonresponders to said therapy of interest for said disease of interest in said second plurality of biological samples;

(e) finding a discriminating set of cellular constituents in said first plurality of cellular constituents, wherein the measurements in said second plurality of molecular profiles for each respective cellular constituent in said discriminating set of cellular constituents discriminates between the responder set of biological samples and the nonresponder set of biological samples; and

(f) identifying a candidate set of molecular profiles in said stored first plurality of molecular profiles that have measurements for the discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in the responder set of biological samples, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived.

48. The method of claim 47, wherein said first plurality of cellular constituents comprises more than five thousand cellular constituents.

49. The method of claim 47, wherein said molecular profile for each biological sample in said first plurality of biological samples is obtained using a microarray that comprises oligonucleotides representing more than five thousand cellular constituents.

50. The method of claim 47, wherein a cellular constituent in said discriminating set of cellular constituents is a nucleic acid or a protein and the measurements in said second plurality of molecular profiles for each respective cellular constituent in said discriminating set of cellular constituents are abundance levels.

51. The method of claim 47, wherein each biological sample in said second plurality of biological samples is a cell line.

52. The method of claim 47, wherein each biological sample in said second plurality of biological samples is obtained from a subject in a second plurality of subjects.

53. The method of claim 52, wherein each biological sample in said second plurality of biological samples is a portion of a tumor.

54. The method of claim 47, wherein said second plurality of molecular profiles consists of less than one hundred molecular profiles and said first plurality of molecular profiles comprises more than five hundred molecular profiles.

55. The method of claim 47, wherein measurements for a cellular constituent in said discriminating set of cellular constituents discriminates with a p value of less than 0.05 as determined by a parametric or nonparametric test using measurements for said cellular constituent in the molecular profiles of the responder set of biological samples and measurements for said cellular constituent in the molecular profiles of the nonresponder set of biological samples.

56. The method of claim 47, wherein said therapy of interest is exposure to a drug, exposure to radiation, exposure to radio-frequency ablation, or exposure to an siRNA.

57. The method of claim 47, wherein said first plurality of subjects are human, bovine, porcine, canine, feline, ovine, equine, lapine, hamster, chicken, rat, mouse, chimpanzee, or baboon.

67. The method of claim 47, wherein each measurement of a cellular constituent in the discriminating set of cellular constituents in a molecular profile in the candidate set of molecular profiles is an indication of the presence or absence of one or more genetic markers.

68. The method of claim 67 wherein the cellular constituent is a nucleic acid and the one or more genetic markers are within the nucleic acid.

58. A computer program product for use in conjunction with a computer system, wherein the computer program product comprises a computer readable storage medium and a computer program mechanism embedded therein, the computer program mechanism for identifying a plurality of subjects for a clinical trial for a therapy of interest, the computer program mechanism comprising instructions for:

(a) receiving a molecular profile for each biological sample in a first plurality of biological samples thereby obtaining a first plurality of molecular profiles, wherein said first plurality of biological samples are obtained from a first plurality of subjects and each respective molecular profile in said first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in said first plurality of biological samples;

(b) storing said first plurality of molecular profiles;

(c) receiving a molecular profile for each biological sample in a second plurality of biological samples prior to exposure to said therapy of interest, thereby obtaining a second plurality of molecular profiles, wherein each biological sample in said second plurality of biological samples is from a subject having a disease of interest or is a model for said disease of interest and each respective molecular profile in said second plurality of molecular profiles comprises measurements of two or more of said first plurality of cellular constituents from a respective biological sample in said second plurality of biological samples;

(d) determining a responder set of biological samples that are responders to said therapy of interest for said disease of interest in said second plurality of biological samples and a nonresponder set of biological samples that are nonresponders to said therapy of interest for said disease of interest in said second plurality of biological samples;

(e) finding a discriminating set of cellular constituents in said first plurality of cellular constituents, wherein the measurements in said second plurality of molecular profiles for each respective cellular constituent in said discriminating set of cellular constituents discriminates between the responder set of biological samples and the nonresponder set of biological samples; and

(f) identifying a candidate set of molecular profiles in said stored first plurality of molecular profiles that have measurements for the discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in the responder set of biological samples, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived.

59. A computer comprising:

a central processing unit; and

a memory coupled to the central processing unit, the memory storing a module for identifying a plurality of subjects for a clinical trial for a therapy of interest, the module comprising instructions for;

(a) receiving a molecular profile for each biological sample in a first plurality of biological samples thereby obtaining a first plurality of molecular profiles, wherein said first plurality of biological samples are obtained from a first plurality of subjects and each respective molecular profile in said first plurality of molecular profiles comprises measurements of a first plurality of cellular constituents from a respective biological sample in said first plurality of biological samples;

(b) storing said first plurality of molecular profiles;

(c) receiving a molecular profile for each biological sample in a second plurality of biological samples prior to exposure to said therapy of interest, thereby obtaining a second plurality of molecular profiles, wherein each biological sample in said second plurality of biological samples is from a subject having a disease of interest or is a model for said disease of interest and each respective molecular profile in said second plurality of molecular profiles comprises measurements of two or more of said first plurality of cellular constituents from a respective biological sample in said second plurality of biological samples;

(d) determining a responder set of biological samples that are responders to said therapy of interest for said disease of interest in said second plurality of biological samples and a nonresponder set of biological samples that are nonresponders to said therapy of interest for said disease of interest in said second plurality of biological samples;

(e) finding a discriminating set of cellular constituents in said first plurality of cellular constituents, wherein the measurements in said second plurality of molecular profiles for each respective cellular constituent in said discriminating set of cellular constituents discriminates between the responder set of biological samples and the nonresponder set of biological samples; and

(f) identifying a candidate set of molecular profiles in said stored first plurality of molecular profiles that have measurements for the discriminating set of cellular constituents that match the measurements of said discriminating set of cellular constituents in the responder set of biological samples, thereby identifying said plurality of subjects for said clinical trial from those subjects from which said candidate set of molecular profiles were derived.