Computer systems and methods for selecting subjects for clinical trials

• US 8,175,896 B2
• Filed: 08/08/2011
• Issued: 05/08/2012
• 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:
  US13/205,536
• Publication Number:
  US 20110288890A1
• Time in Patent Office: 274 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 pre-treatment molecular profiles where each pre-treatment 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;

providing and storing post-treatment molecular profiles for the responders, where each post-treatment molecular profile is associated with a subject having a particular condition and is developed from a biological sample taken after treatment using the therapy of interest;

evaluating the pre-treatment and post-treatment molecular profiles of the one or more responders to determine a discriminating set of cellular constituents from among the cellular constituents in respective molecular profiles, 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 pre-treatment molecular profiles including matching the discriminating set of cellular constituents against the pre-treatment 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 based on the determining.

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

identifying a revised set of discriminating cellular constituents whose measurement values taken from a the 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.

3. 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.

4. The method of claim 3, 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.

5. The method of claim 4, wherein the selection criterion is a failure to respond to a therapy other than the therapy of interest.

6. The method of claim 4, wherein the selection criterion is responsiveness to a therapy other than the therapy of interest.

7. The method of claim 1 where evaluating the pre-treatment and post-treatment molecular profiles of the one or more responders to determine a discriminating set of cellular constituents includes developing a signature for the responders and using the signature to determine candidates for the clinical trial.

8. A computer-implemented 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, wherein

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, and wherein

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 8, the method further comprising steps of:

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

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

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

12. The method of claim 11, wherein the disease is arthritis, asthma, an allergy, cancer, chronic fatigue syndrome, diabetes, epilepsy, heart disease, hemochromatosis, hepatitis B, hepatitis C5 or osteoporosis.

13. The method of claim 11, wherein the disease is breast cancer, cervical cancer, colorectal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, skin cancer, or testicular cancer.

14. 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.

15. The method of claim 8, wherein a cellular constituent in said discriminating set of cellular constituents is a nucleic acid or a protein.

16. The method of claim 8, wherein said therapy of interest is exposure to a drug, exposure to radiation, exposure to radio-frequency ablation, or exposure to an siRNA.

17. The method of claim 8, 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.

18. The method of claim 17, 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.

19. The method of claim 18, wherein the selection criterion is a failure to respond to a therapy other than the therapy of interest.

20. The method of claim 18, wherein the selection criterion is responsiveness to a therapy other than the therapy of interest.

21. A computer-implemented 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) identifying 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.

22. The method of claim 21, wherein said first plurality of cellular constituents comprises more than five thousand cellular constituents.

23. The method of claim 21, 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.

24. The method of claim 21, 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.

25. The method of claim 21, wherein said therapy of interest is exposure to a drug, exposure to radiation, exposure to radio-frequency ablation, or exposure to an siRNA.

26. The method of claim 21, wherein said first plurality of subjects are human, bovine, porcine, canine, feline, ovine, equine, lapine, hamster, chicken, rat, mouse, chimpanzee, or baboon.

27. 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 is determined based on a presence of a mutation in DNA associated with the biological sample; 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.

28. The method of claim 27, where the mutation is a determined based on a presence of a genetic marker including presence of random amplified polymorphic DNA.