Method and apparatus for predicting the presence of an abnormal level of one or more proteins in the clotting cascade

• US 6,321,164 B1
• Filed: 12/31/1997
• Issued: 11/20/2001
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Biomerieux B.V. (Compagnie Merieux Alliance SAS)
• Original Assignee: Akzo Nobel N.V. (Nouryon BV)
• Inventors: Fischer, Timothy J., Braun, Paul, Givens, Thomas B.
• Primary Examiner(s): WACHSMAN, HAL D
• Application Number:
  US09/001,647
• Time in Patent Office: 1,420 Days
• Field of Search: 702/22, 702/23, 702/27-32, 702/128, 702/131, 702/139, 702/179, 702/180, 702/183, 702/FOR 115-FOR 119, 702/FOR 131, 702/FOR 170, 702/FOR 171, 700/266, 700/268, 73/64.43, 703/6, 703/9, 703/11, 703/12, 436/69, 436/66, 436/43, 436/47-50, 436/54, 436/55, 436/174, 436/164, 436/171, 436/180, 436/805, 422/73, 422/68.1, 422/50, 422/61-67, 422/82.05, 382/133, 382/134, 382/156-159, 356/39, 356/40, 356/42, 706/924, 706/21, 706/20, 435/13, 377/10, 377/11
• US Class Current: 702/22
• CPC Class Codes: G01N 2800/226 Thrombotic disorders, i.e. thrombo-embolism irrespective of location/organ involved, e.g. renal vein thrombosis, venous thrombosis
• CPC Class Codes: G01N 2800/385 Congenital anomalies
• CPC Class Codes: G01N 33/4905 Determining clotting time of blood by chemical methods G01N33/86, C12Q1/56
• CPC Class Codes: G01N 33/86 involving blood coagulating time or factors, or their receptors
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems

Abstract

A method is disclosed for predicting the presence of an abnormal level of one or more proteins in the clotting cascade from at least one time-dependent measurement profile. At least one time-dependent measurement on an unknown sample is performed and a respective property of said sample is measured over time so as to derive a time-dependent measurement profile. A set of a plurality of predictor variables are defined which sufficiently define the data of the time-dependent measurement profile. A model is then derived that represents the relationship between the abnormality and the set of predictor variables. Subsequently, the model is utilized to predict which protein or proteins in the clotting cascade are at an abnormal level, with the prediction being a more informative prediction than clot time alone.

Claims

1. A method for predicting the presence of an abnormal level of one or more proteins of a coagulation cascade from at least one time-dependent measurement profile, comprising,

a) performing at least one time-dependent measurement on an unknown sample of a property over time, which property changes when said sample undergoes coagulation, so as to derive at least one time-dependent measurement profile;

b) defining a set of a plurality of predictor variables which sufficiently define at least one time-dependent measurement profile;

c) deriving a model that represents the relationship between the abnormal level of said one or more proteins in the clotting cascade and the set of a plurality of predictor variables; and

d) utilizing the model of step c) to predict the existence of an abnormal level of said one or more proteins in said coagulation cascade and to predict which protein or proteins in said coagulation cascade are said one or more proteins which are at an abnormal level as compared to a known sample.

2. The method of claim 1, where in the prediction of the one or more proteins at an abnormal level, the specificity is equal to or greater than 0.85.

3. The method of claim 2, where in the prediction of the one or more proteins at an abnormal level, the sensitivity is greater than 0.6.

4. The method of claim 3, where the one or more proteins predicted to be at an abnormal level, is one or more of Factors II, X, XI or XII.

5. The method of claim 2, where the one or more proteins predicted to be at an abnormal level, is one or more of Factors II, V, VII, VIII, IX, X, XI or XII.

6. The method of claim 2, where in the prediction of the one or more proteins at an abnormal level, the sensitivity is between 0.3 and 0.8.

7. The method of claim 6, where the one or more proteins predicted to be at an abnormal level is one or more of Factors VIII through XII.

8. The method of claim 2, wherein samples with a measured concentration of less than about 30% of normal for a specific factor are defined as being at an abnormal level.

9. The method according to claim 1, wherein said at least one time-dependent measurement profile is at least one optical profile.

10. The method according to claim 9, wherein said at least one optical profile is provided by an automated analyzer for thrombosis and hemostasis testing.

11. The method according to claim 10, wherein in step a) said at least one optical profile is provided automatically by said analyzer, and wherein said unknown sample is automatically removed by an automated probe from a sample container to a test well, one or more reagents are automatically added to said test well so as to initiate said property changes within said unknown sample, and the development of said property over time is automatically optically monitored so as to derive said optical profile.

12. The method according to claim 11, wherein after step d), a predicted abnormal level of one or more proteins of the coagulation cascade is automatically stored in a memory of said automated analyzer and/or displayed on said automated analyzer.

13. The method according to claim 11, wherein in step d), one or more assays for confirming the existence of said abnormal level of one or more proteins in the coagulation cascade is automatically performed.

14. The method according to claim 13, wherein said one or more confirming assays are automatically ordered and performed on said automated analyzer, with results of said one or more assays being stored in a memory of said automated analyzer and/or displayed on said automated analyzer.

15. The method according to claim 9, wherein a plurality of optical measurements at one or more wavelengths are taken over time so as to derive said at least one optical profile, said plurality of optical measurements corresponding to changes in light scattering and/or light absorption in the unknown sample.

16. The method according to claim 9, wherein a plurality of optical measurements are taken over time so as to derive said at least one optical profile, and wherein said plurality of optical measurements are each normalized to a first optical measurement.

17. The method according to claim 1, further comprising:

before step a), providing a set of data from known samples, which set of data is used in step c) for deriving said model.

18. The method according to claim 17, wherein said set of data from known samples is provided by performing a plurality of assays on said known samples.

19. The method according to claim 1, wherein in step a), a plurality of time-dependent measurement profiles are derived for use in step b).

20. The method according to claim 19, wherein said plurality of time dependent measurement profiles includes at least two profiles from assays initiated with PT reagents, APTT reagents, fibrinogen reagents and TT reagents.

21. The method according to claim 1, wherein said unknown sample is a sample from a medical patient, and wherein in step d), both said model and additional patient medical data are utilized for predicting the existence of a congenital or acquired imbalance or therapeutic condition.