Breath test apparatus and methods

• US 6,656,127 B1
• Filed: 04/04/2000
• Issued: 12/02/2003
• Est. Priority Date: 06/08/1999
• Status: Expired due to Term

• Current Assignee: BREATHID (2006)
• Original Assignee: Oridion BreathID Ltd.
• Inventors: Katzman, Daniel, Ben-Oren, Ilan, Carlebach, Ephraim, Daich, Julian, Levitsky, Gershon, Colman, Lewis, Givron, Boaz
• Primary Examiner(s): Hindenburg, Max F.
• Assistant Examiner(s): Natnithithadha, Navin
• Application Number:
  US09/542,768
• Time in Patent Office: 1,337 Days
• Field of Search: 600/529, 600/531, 600/532, 600/533, 600/538, 600/543, 73/233, 128/920, 128/923, 128/924, 128/925
• US Class Current: 600/532
• CPC Class Codes: A61B 2560/0223 of calibration, e.g. protocols for calibrating sensors
• CPC Class Codes: A61B 5/083 Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: A61B 5/097 Devices for facilitating collection of breath or for directing breath into or through measuring devices
• CPC Class Codes: G01N 33/0006 Calibrating gas analysers
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath
• CPC Class Codes: H01J 61/14 having one or more carbon compounds as the principal constituents
• CPC Class Codes: H01J 61/35 provided with coatings on the walls thereof; Selection of materials for the coatings using coloured coatings H01J61/40; using luminescent coatings H01J61/42
• CPC Class Codes: H01J 65/042 by an external electromagnetic field
• CPC Class Codes: H01J 9/247 specially adapted for gas-discharge lamps

Abstract

Breath test methods and apparatus for increasing accuracy and reducing the time taken to achieve diagnostically useful results. In order to determine when an increase in isotopic ratio of the exhaled breath is clinically significant, methods are described for the use of a variable and multiple threshold level; for reducing the time taken to determine an accurate baseline level; and for avoiding the effects of oral activity when making measurements. To increase measurement accuracy, methods are described, using the results of the breath tests themselves, of continuous and automatic self-calibration to correct for drifts in the gas spectrometer absorption curves. A method for increasing the spectral stability of cold cathode discharge infra-red light sources for use in breath test instrumentation is described. Calibration checking devices and methods of mandating their use at regular time intervals are described, to ensure maintenance of the accuracy of breath tests.

Claims

1. A method of performing a breath test, comprising the steps of:

using a predetermined criterion for determining when a change in a measurement of an isotopic ratio of at least one breath sample of a subject is clinically significant; and

allowing said criterion to change during said breath test.

2. The method according to claim 1 and wherein said change in said measurement comprises the deviation of said isotopic ratio from a measurement of at least one previous sample of said subject.

3. The method according to claim 2 and wherein said measurement of at least one previous sample of said subject is a baseline measurement.

4. The method according to claim 1 and wherein said change in said measurement comprises the rate of change of said isotopic ratio.

5. The method according to claim 1 and wherein said criterion is a function of the elapsed time of the test.

6. The method according to claim 1 and wherein said criterion is a function of the noise level of the instrument performing said test.

7. The method according to claim 1 and wherein said criterion is a function of the physiological results of said test.

8. A breath test method, comprising the steps of:

performing a first measurement of the isotopic ratio of at least a first breath sample of a subject;

performing a second measurement of the isotopic ratio of at least a second breath sample of said subject; and

determining when said second measurement shows sufficient deviation from said first measurement that a clinically significant result of the breath test may be concluded;

wherein the level of said sufficient deviation is allowed to undergo variation during said breath test.

9. The method according to claim 8 and wherein said first measurement of the isotopic ratio of at least a first breath sample of said subject is a baseline measurement.

10. The method according to claim 8 and wherein said level of sufficient deviation is at least a function of the elapsed time from ingestion of an identifying substrate by a subject.

11. The method according to claim 8 and wherein said level of sufficient deviation is at least a function of the physiological results of the analysis of at least one of said samples.

12. The method according to claim 8 and wherein said level of sufficient deviation is at least a function of the nature of the results obtained in said breath test.

13. The method according to claim 12 and wherein said nature of the results is at least a function of the standard deviation of the spread of results in said breath test.

14. The method according to claim 12 and wherein said nature of the results is at least a function of the noise level present in said results.

15. The method according to claim 12 and wherein said nature of the results is at least a function of the instrumental drift present in said results.

16. The method according to claim 8 and wherein said level of sufficient deviation covers a range of values between an upper threshold and a lower threshold.

17. The method according to claim 16 and wherein said upper threshold and said lower threshold converge as the test proceeds.

18. The method according to claim 8 and wherein said first measurement of the isotopic ratio of at least a first breath sample of a subject is performed only after significant subsidence of oral activity.

19. The method according to claim 16 and wherein the presence of at least two measurements above said upper threshold within a predetermined time is indicative of a positive result of said breath test.

20. The method according to claim 16 and wherein the presence of at least two successive measurements above said upper threshold is indicative of a positive result of said breath test.

21. The method according to claim 16 and wherein the presence of at least two measurements above said upper threshold in combination with the absence of measurements below said lower threshold is indicative of a positive result of said breath test.

22. The method according to claim 16 and wherein the presence of at least two measurements below said lower threshold within a predetermined time is indicative of a negative result of said breath test.

23. The method according to claim 16 and wherein the presence of at least two successive measurements below said lower threshold is indicative of a negative result of said breath test.

24. The method according to claim 16 and wherein the presence of at least two measurements below said lower threshold in combination with the absence of any measurements above said upper threshold is indicative of a negative result of said breath test.

25. The method according to claim 16 and wherein the presence of at least two successive measurements falling below the upper threshold, with less than a predetermined difference in the value of delta between said three measurements, and with less than a predetermined average slope between them, is indicative of a negative result of said breath test.

26. The method according to claim 16 and wherein the presence of at least two successive measurements falling below the lower threshold, with less than a predetermined average slope between them, is indicative of a negative result of said breath test.

27. A breath test method for determining the presence of a clinically significant state in a subject, comprising the steps of:

performing measurements of the changes from a baseline of an isotopic ratio in a plurality of samples of exhaled breath of said subject, following the effective cessation of oral activity;

determining a polynomial which approximates the functional plot of said measurements with time;

calculating a weighted standard deviation of said measurements from said polynomial, wherein for measurements over said baseline by more than a predetermined amount, a predefined fractional part of the measurement is taken, while for measurements not over said baseline by more than said predetermined amount, the measurement is taken in its entirety; and

determining whether said weighted standard deviation exceeds a predetermined level.

28. A breath test method comprising the steps of:

performing a measurement of the isotopic ratio of at least a first breath sample of a subject; and

determining when said measurement shows sufficient deviation from a baseline measurement that a clinically significant result of the breath test may be concluded;

wherein said deviation comprises an upper and a lower threshold band of uncertainty, and wherein the extent of this band is dependent on at least one of the parameters selected from the group consisting of the elapsed time of said breath test, the standard deviation of the physiological spread of results, the dynamics of the physiological change in isotopic ratio, the number of points measured in the breath test, the environmental conditions present during the breath test, and the noise and/or drift levels of the instrument executing the breath test.

29. A method for determining the reliability of a breath test, comprising the steps of:

obtaining results from said breath test;

defining a reliability parameter by combining at least one of the criteria selected from the group consisting of the instrument noise and/or drift level, the standard deviation of the physiological spread of results, the dynamics of the physiological change in isotopic ratio, and the time elapsed since ingestion of a labeled substrate; and

using said reliability parameter to assess the results of said breath test according to a predetermined reliability criterion.

30. The method according to claim 29 and wherein said reliability parameter is taken into account in determining when a clinically significant result has been obtained in said breath test, in order to terminate said test.

31. The method according to claim 29 and wherein said reliability parameter is output with the result of the breath test.

32. A breath test instrument comprising:

tubing for collecting breath from a subject; and

a gas analyzer for determining isotopic ratio in said gas;

wherein said gas analyzer monitors changes in an isotopic ratio of a gas in exhaled breath samples of said subject virtually continuously, and determines that said test has a clinically significant outcome in accordance with the ongoing results of said test.

33. A breath test instrument according to claim 32, further comprising a signal for indication that a clinically significant outcome of a breath test has been determined.

34. A breath test instrument according to claim 33, and wherein said signal is a visible signal.

35. A breath rest instrument according to claim 33, and wherein said signal is an audible signal.

36. A breath test instrument according to claim 35, and wherein said signal also indicates the nature of the clinically significant outcome of said breath test.

37. A breath test instrument according to claim 32, such that the outcome of said test is substantially independent of dynamic physiological effects occurring in said subject as a result of background conditions.

38. A breath test instrument according to claim 37, and wherein said background conditions are the result of treatment with a drug therapy.

39. A breath test instrument according to claim 37, and wherein said background conditions are the result of food intake in a period prior to the performance of the breath test.

40. A breath instrument according to claim 39, and wherein the need for a pre-test fast by the subject is obviated.

41. A breath test instrument according to claim 32, and wherein the outcome of said test on said subject undergoing treatment with a gastro-intestinal drug therapy, is obtained more reliably than using corresponding breath tests which do not monitor said changes in an isotopic ratio substantially continuously.

42. A breath test instrument according to claim 32, and wherein the outcome of said test is obtained more reliably than would be obtained by corresponding breath test instruments which do not monitor said changes in an isotopic ratio substantially continuously.

43. A breath test instrument according to claim 32, and in which said outcome of said test is obtained sooner than would be obtained by corresponding breath test instruments which do not monitor said changes in an isotopic ratio substantially continuously.

44. A breath test instrument according to claim 32, and in which said ongoing results of said test enable a positive result to be determined even when said isotopic ratio does not clearly exceed a predetermined threshold level.

45. A breath test instrument according to claim 32, and in which said ongoing results of said test enable a negative result to be determined even when said isotopic ratio exceeds a predetermined threshold level.

46. A breath test instrument according to claim 45, and in which said negative result is determined even when said isotopic ratio exceeds said predetermined threshold level because of instrumental drift.

47. A breath test instrument according to claim 32, and in which said ongoing results of said test enable a negative result to be determine by the detection of correlation between said isotopic ratio and instrumental drift.