Computer systems and methods for selecting subjects for clinical trials

• US 8,095,389 B2
• Filed: 07/16/2007
• Issued: 01/10/2012
• 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), University of South Florida (State University System of Florida)
• Inventors: Dalton, William S., Yeatman, Timothy
• Primary Examiner(s): Sereboff, Neal
• Application Number:
  US11/879,387
• Publication Number:
  US 20080033658A1
• Time in Patent Office: 1,639 Days
• Field of Search: 705 2- 4
• US Class Current: 705/3
• 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:

providing and storing a plurality of molecular profiles where each molecular profile is associated with a subject having a particular condition and is developed from a biological sample taken prior to treatment of any of the subjects using a therapy of interest;

providing and storing results of treating one or more of the subjects using the therapy of interest;

determining, after treatment of the one or more subjects, one or more responders of the one or more subjects to the therapy of interest where a responder is a subject that has a change in progression of the particular condition;

evaluating the molecular profiles of the one or more responders to determine a discriminating set of cellular constituents from among the cellular constituents in a respective molecular profile, wherein the discriminating set of cellular constituents distinguishes the molecular profiles of responders from the molecular profiles of subjects who were non-responders to the therapy of interest; and

determining, by one or more processors, a candidate set of molecular profiles from the plurality of molecular profiles that were previously stored and not including the one or more subjects that were treated with the therapy of interest comprising,

matching the discriminating set of cellular constituents against the molecular profiles of one or more non-treated subjects; and

identifying a candidate set of subjects for a clinical trial whose molecular profiles match the discriminating set of cellular constituents without ex-vivo testing of each of the molecular profiles of respective subjects with the therapy of interest.

2. The method of claim 1, the method further comprising, prior to said determining a candidate set step, a step of measuring a molecular profile for each biological sample thereby obtaining the set of molecular profiles.

3. The method of claim 2, the method further comprising storing the set of molecular profiles.

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

measuring a molecular profile for each biological sample in a plurality of biological samples prior to exposure to said therapy of interest, thereby obtaining the set of molecular profiles, wherein each biological sample in the 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 the plurality of molecular profiles comprises measurements of two or more of a plurality of cellular constituents from a respective biological sample in the plurality of biological samples; and

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

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

6. The method of claim 4, wherein each biological sample in the 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 the plurality of biological samples is a portion of a tumor.

8. 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 a plurality of subjects at a first time point; and

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

9. The method of claim 8, 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 the 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.

10. The method of claim 8, the method further comprising

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

and

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

11. The method of claim 10, wherein the second time point is at least one day after the first time point.

12. The method of claim 10, wherein the second time point is at least one week after the first time point.

13. The method of claim 10, wherein the second time point is at least one month after the first time point.

14. The method of claim 10, wherein the second time point is at least one year after the first time point.

15. The method of claim 8, wherein the clinical feature is absence or presence of a disease in the subject.

16. The method of claim 15, wherein the disease is arthritis, asthma, an allergy, cancer, chronic fatigue syndrome, diabetes, epilepsy, heart disease, hemochromatosis, hepatitis B, hepatitis C, or osteoporosis.

17. The method of claim 15, wherein the disease is breast cancer, cervical cancer, colorectal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, skin cancer, or testicular cancer.

18. The method of claim 8, 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.

19. The method of claim 1, wherein the method comprises obtaining each molecular profile for each biological sample using a microarray that comprises oligonucleotides representing more than five thousand cellular constituents.

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

21. The method of claim 1, wherein measurements for a cellular constituent in the 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 a cellular constituent in a responder set of biological samples and measurements for the cellular constituent in a nonresponder set of biological samples.

22. The method of claim 21, wherein measurements are taken using a nonparametric test.

23. The method of claim 22, wherein the nonparametric test is a Chi-square test, a Phi coefficient, a Fisher exact test, or a Wilcoxon rank sum test.

24. The method of claim 21, wherein measurements are taken using a parametric test.

25. The method of claim 24, wherein the parametric test is analysis of variance or a t-test.

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

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

28. The method of claim 1, the method further comprising prior to the providing step:

obtaining patient information about a subject; and

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

29. The method of claim 28, 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.

30. The method of claim 29, wherein the patient information is entered directly onto a web-based questionnaire and wherein the storing step comprises completing the web-based questionnaire.

31. The method of claim 28, wherein the method further comprises:

removing a 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.

32. The method of claim 31 wherein the selection criterion is a minimum age, a maximum age, a minimum weight, or a maximum weight.

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

identifying a revised set of discriminating cellular constituents whose measurement values taken from a plurality of subjects prior to exposure to the therapy of interest discriminates between responders to said therapy of interest and non-responders to said therapy of interest; and

identifying a new plurality of subjects for the clinical trial for the therapy of interest based on matches between cellular constituent values for the revised set of discriminating cellular constituents in the stored set of the molecular profiles.

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

observing a progression of a disease in each subject in the subjects; and

storing said progression of said disease for each subject.

35. The method of claim 34, 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.

36. The method of claim 35, wherein the selection criterion is a failure to respond to a therapy other than the therapy of interest.

37. The method of claim 35, wherein the selection criterion is responsiveness to a therapy other than the therapy of interest.

38. The method of claim 34, wherein the observing the progression of the disease comprises completing a web-based questionnaire.

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

administering to a subject the therapy of interest; and

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

40. The method of claim 39, wherein the storing step comprises completing a web-based questionnaire.

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

obtaining a biological sample from a remote location.

42. The method of claim 41, wherein the obtaining step comprises entering patient data or clinical data associated with the biological sample, at the remote location, into a web-based questionnaire.

43. 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 a presence or absence of one or more genetic markers.

44. The method of claim 43 wherein the cellular constituent is a nucleic acid and the one or more genetic markers are within the nucleic acid.

45. 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.

46. The method of claim 45 wherein the cellular constituent is nucleic acid or protein.

47. 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:

providing and storing a plurality of molecular profiles where each molecular profile is associated with a subject having a particular condition and is developed from a sample taken prior to treatment of any of the subjects using a therapy of interest and providing and storing results of using the therapy of interest on one or more of the subjects;

determining, after treatment of the one or more subjects, one or more responders to the therapy of interest where a responder is a subject that has a change in progression of the particular condition;

evaluating the molecular profiles of the one or more responders to determine a discriminating set of cellular constituents from among cellular constituents in a respective molecular profile, wherein the discriminating set of cellular constituents distinguishes the molecular profiles of responders from the molecular profiles of subjects who were non-responders to the therapy of interest; and

determining a candidate set of molecular profiles from the plurality of molecular profiles that were previously stored and not including the molecular profiles of the one more subjects with the therapy of interest comprising,

matching the discriminating set of cellular constituents against the molecular profiles of one or more non-treated subjects; and

identifying a candidate set of subjects for a clinical trial whose molecular profiles match the discriminating set of cellular constituents without ex-vivo testing of each of the molecular profiles of the subjects with the therapy of interest.

48. 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;

providing and storing in the memory a plurality of molecular profiles where each molecular profile is associated with a subject having a particular condition and is developed from a sample taken prior to any of the subjects treatment using a therapy of interest and providing results of using the therapy of interest on one or more of the subjects;

determining, after treatment of the one or more subjects, one or more responders to the therapy of interest where a responder is a subject that has a change in progression of the particular condition;

evaluating the molecular profiles of the one or more responders to determine a discriminating set of cellular constituents from among cellular constituents in a respective molecular profile, wherein the discriminating set of cellular constituents distinguishes the molecular profiles of responders from the molecular profiles of subjects who were non-responders to the therapy of interest; and

determining a candidate set of molecular profiles in the plurality of molecular profiles and not including the one or more subjects that were treated with the therapy of interest comprising

matching the discriminating set of cellular constituents against the molecular profiles of one or more non-treated subjects; and

identifying a candidate set of subjects for a clinical trial whose molecular profiles match the discriminating set of cellular constituents without ex-vivo testing of each of the molecular profiles of respective subjects with the therapy of interest.