Method and apparatus for predicting the presence of haemostatic dysfunction in a patient sample

• US 6,898,532 B1
• Filed: 02/28/2003
• Issued: 05/24/2005
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Biomerieux Incorporated (Compagnie Merieux Alliance SAS)
• Original Assignee: Biomerieux Incorporated (Compagnie Merieux Alliance SAS)
• Inventors: Fischer, Timothy J., Downey, Colin, Toh, Cheng Hock
• Primary Examiner(s): WACHSMAN, HAL D
• Application Number:
  US10/377,228
• Time in Patent Office: 816 Days
• Field of Search: 702/19, 702/22, 702/23, 702/21, 702 27- 32, 702/128, 702/131, 702/179, 702/139, 702/180, 702/183, 702/FOR.171, 702/FOR.170, 702/FOR.131, 702FOR 115-119, 700/266, 700/268, 73/644.3, 703/6, 703/9, 703/11, 703/12, 422/73, 422/68.1, 422/50, 422 61- 67, 422/82.05, 382/133.134, 382158-159, 356/39, 356/49, 356/42, 706/924, 706/21, 706/20, 435/13, 377/10, 377/11, 436/69, 436/66, 436/43, 436 47- 50, 436/54, 436/55, 436/174, 436/164, 436/171, 436/180, 436/805
• US Class Current: 702/22
• 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 10/40 for data related to laboratory analysis, e.g. patient specimen analysis
• CPC Class Codes: G16H 15/00 ICT specially adapted for medical reports, e.g. generation or transmission thereof
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• 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

A method is disclosed for predicting the presence of haemostatic dysfunction. At least one time-dependent measurement on an unknown sample is performed and a respective property of the sample is measured over time so as to derive a time-dependent measurement profile. One or more predictor variables, including initial slope, 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 haemostatic dysfunction, such as septicemia or disseminated intravascular coagulation (DIC).

Claims

1. A method for predicting the presence of haemostatic dysfunction in a patient from at least one time-dependent measurement profile, comprising:

a) performing at least one time-dependent measurement on an unknown sample and measuring a respective property over time so as to derive a time-dependent measurement profile;

b) defining one or more predictor variables based on the data of the time-dependent measurement profile, said one or more predictor variables including the slope of the time-dependent measurement profile prior to clot formation;

c) deriving a model that represents the relationship between the haemostatic dysfunction and the one or more predictor variables; and

d) utilizing the derived model to predict the existence of haemostatic dysfunction in the patient.

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

3. A method according to claim 2 wherein said at least one optical profile is provided by an automated analyzer for thrombosis and hemostasis testing.

4. A method according to claim 3, wherein in step a) said at least one optical profile is provided automatically by said automated analyzer, 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 changes in said respective property within said unknown sample, and the development of said respective property over time is automatically optically monitored so as to derive said at least one optical profile.

5. A method according to claim 4, wherein after step d), a predicted congenital or acquired imbalance or therapeutic condition is automatically stored in a memory of said automated analyzer and/or displayed on said automated analyzer.

6. A method according to claim 4, wherein in step d), one or more assays for confirming the existence of said haemostatic dysfunction is automatically performed.

7. A method according to claim 6, wherein said one or more confirming assays are automatically ordered and performed on said automated analyzer, with results of said one or more confirming assays being stored in a memory of said automated analyzer and/or displayed on said automated analyzer.

8. A method according to claim 2, 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 transmission through the unknown sample.

9. A method according to claim 2, 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.

10. A method according to claim 1, further comprising:

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

11. A method according to claim 10, wherein said set of data from known samples is provided by performing a plurality of assays on said known samples.

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

13. A method according to claim 12, wherein said plurality of time dependent measurement profiles includes at least two profiles from assays initiated with prothrombin time (PT) reagents, activated partial thromboplastin time (APTT) reagents, fibrinogen reagents and thrombin time (TT) reagents.

14. A 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 said haemostatic dysfunction.

15. A method according to claim 14, wherein said additional patient medical data includes one or more of Fibrinogen, D-dimer or platelet count information.

16. A method according to claim 1, wherein step (d), the prediction of haemostatic dysfunction is performed a plurality of times so as to monitor disease progression or regression in the patient.

17. A method according to claim 1, wherein the prediction of haemostatic dysfunction is a prediction of Disseminated Intravascular Coagulation.

18. A method according to claim 17, wherein said prediction of Disseminated Intravascular Coagulation is correct in at least 75% of predicted cases.

19. A method according to claim 1, wherein said time-dependent measurement profile is an optical transmission through a sample during an activated partial thromboplastin time (APTT) assay.

20. A method according to claim 1, wherein said time-dependent measurement profile is an optical transmission through a sample during a prothrombin time (PT) assay.

21. A method according to claim 1, wherein in step (b), the slope of the time-dependent measurement profile is taken from an end of blank time up to immediately before the initiation of clot formation or a predetermined time period.

22. A method according to claim 1, wherein said time-dependent measurement profile is an optical transmission profile and said one or more predictor variables include minimum transmittance and/or clot time.

23. A method according to claim 1, wherein said predicted haemostatic dysfunction is due to one or more conditions associated with disseminated intravascular coagulation, including trauma, malignancy, surgery, aortic aneurysm rupture, and systemic inflammatory response syndrome.

24. A method according to claim 1, wherein said prediction of the existence of haemostatic dysfunction includes flagging an existence or likelihood of the haemostatic dysfunction.

25. A method according to claim 24, wherein method steps (a) to (d) are performed on an automated or semi-automated analyzer, and said flagging is an alert to an individual operating said automated or semi-automated analyzer or an individual reading or evaluating the results of a test run on said automated or semi-automated analyzer, that there is a possibility or probability of haemostatic dysfunction of a patient whose test sample has been run on the automated or semi-automated analyzer and flagged.

26. A method according to claim 25, wherein said alter is an alert on a paper printout or on a monitor.

27. A method according to claim 1, wherein the only predictor variable is said slope of the time-dependent measurement profile prior to clot formation.

28. A method according to claim 1, wherein the predictor variable of slope of the time-dependent measurement profile prior to clot formation is a slope which is less than about −

0.0003.

29. A method according to claim 28, wherein said slope less than −

0.0003 corresponds to activation of coagulation prior to initiation of clot formation.

30. A method according to claim 29, wherein a slope of less than −

0.0003 causes flagging of the unknown sample, and wherein an increase in steepness of the slope from test to test corresponds to disease progression.

31. A method according to claim 1, wherein the predicted haemostatic dysfunction is due to one or more of infection, trauma, major surgery, malignancy, hepatic disease, pregnancy and/or child birth, hypoxia, acidosis, lithium overdose, and graft rejection.

32. A method according to claim 1, wherein said unknown sample is whole blood or a portion thereof.

33. A method according to claim 32, wherein said unknown sample is a plasma sample.

34. A method according to claim 1, wherein said haemostatic dysfunction is disseminated intravascular coagulation.

35. A method according to claim 34, wherein said prediction of disseminated intravascular coagulation in the patient has a specificity or sensitivity greater than one or more of platelet count, determination of D-dimer level, and determination of fibrinogen level.

36. A method according to claim 1, wherein said haemostatic dysfunction predicted is disseminated intravascular coagulation, and wherein said method further comprises running platelet count, D-dimer level and/or fibrinogen level assays.

37. A method according to claim 1, wherein said slope is determined from an end of blank time to initiation of clot formation or from blank time to a predetermined time period less than the time of initiation of clot formation, whichever is less.

38. A method according to claim 1, wherein the predictor variable of slope of the time-dependent measurement profile prior to clot formation is a slope less than about −

0.0005.

39. A method according to claim 1, wherein said one or more predictor variables are a plurality of predictor variables further comprising one or more of a minimum of the first derivative of the profile, a time index of the minimum of the first derivative, a minimum of the second derivative of the profile, a time index of the minimum of the second derivative, a time index of the maximum of the second derivative, an overall change in a coagulation parameter during the at least one time-dependent measurement on the unknown sample, a clotting time, a slope of the profile prior to clot formation, and a slope of the profile after clot formation.