Signal processing for measurement of physiological analysis

• US 6,233,471 B1
• Filed: 05/11/1999
• Issued: 05/15/2001
• Est. Priority Date: 05/13/1998
• Status: Expired due to Term

• Current Assignee: LifeScan IP Holdings, LLC
• Original Assignee: Cygnus, Inc. (Johnson & Johnson)
• Inventors: Berner, Bret, Kurnik, Ronald T., Potts, Russell O., Tamada, Janet A., Tierney, Michael J., Garrison, Michael D., Dunn, Timothy C., Lesho, Matthew J., Farinas, Kathleen C.
• Primary Examiner(s): O'Connor, Cary
• Assistant Examiner(s): Natnithithadha, Navin
• Application Number:
  US09/309,728
• Time in Patent Office: 735 Days
• Field of Search: 600/345, 600/309, 600/346, 600/347, 600/365
• US Class Current: 600/345
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14542 for measuring blood gases A61B5/14551 takes precedence
• CPC Class Codes: A61B 5/1477 non-invasive
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase

Abstract

A method is provided for continually or continuously measuring the concentration of target chemical analytes present in a biological system, and processing analyte-specific signals to obtain a measurement value that is closely correlated with the concentration of the target chemical analyte in the biological system. One important application of the invention involves a method for signal processing in a system for monitoring blood glucose values.

Claims

1. A method for measuring an analyte present in a biological system, said method comprising:

(a) transdermally extracting the analyte from the biological system using a sampling system that is in operative contact with a skin or mucosal surface of said biological system;

(b) obtaining a raw signal from the extracted analyte, wherein said raw signal is related to analyte concentration;

(c) subjecting the raw signal obtained in step (b) to a conversion step in order to convert said raw signal to an initial signal output which is indicative of the amount of analyte extracted by the sampling system;

(d) performing a calibration step which converts the initial signal output obtained in step (c) to a measurement value indicative of the concentration of analyte present in the biological system at the time of extraction; and

(e) repeating steps (a)-(c) at least once to obtain a plurality of measurement values, wherein the sampling system is maintained in operative contact with the skin or mucosal surface of said biological system to provide for analyte measurement.

2. The method of claim 1, wherein the analyte is extracted from the biological system into a first collection reservoir to obtain a concentration of the analyte in said reservoir.

3. The method of claim 2, wherein the first collection reservoir is in contact with the skin or mucosal surface of the biological system and the analyte is extracted using an iontophoretic current applied to said skin or mucosal surface.

4. The method of claim 2, wherein the first collection reservoir contains an enzyme that reacts with the extracted analyte to produce an electrochemically detectable signal.

5. The method of claim 4, wherein the analyte is glucose and the enzyme is glucose oxidase.

6. The method of claim 1, wherein the raw signal obtained in step (b) is subjected to a data screen which invalidates or corrects poor or incorrect signals based on a detected parameter indicative of a poor or incorrect signal.

7. The method of claim 6, wherein the data screen applies a set of selection criteria to the raw signal, wherein each selection criterium is based on a different detected parameter indicative of a poor or incorrect signal.

8. The method of claim 6, wherein the data screen entails monitoring changes in temperature over time during steps (a) and (b), and a maximum temperature change over time (d(temp)/d(time)) value is used to invalidate or correct measurements taken during a measurement period during which the maximum d(temp)/d(time) value was exceeded.

9. The method of claim 6, wherein the data screen entails monitoring perspiration levels in the biological system at selected time points, and a maximum perspiration level threshold is used to invalidate or correct measurements taken during a measurement period during which the maximum perspiration level threshold was exceeded.

10. The method of claim 3, wherein the raw data obtained in step (b) is subjected to a data screen which entails monitoring iontophoretic voltage during steps (a) and (b), and uses a maximum iontophoretic voltage value to invalidate or correct measurements taken during a measurement period during which said maximum voltage value was exceeded.

11. The method of claim 1, wherein the conversion step entails a baseline background subtraction method to remove background noise from the raw signal.

12. The method of claim 11, wherein the baseline background subtraction method uses a temperature-corrected baseline value.

13. The method of claim 11, wherein the baseline background subtraction method uses a skin conductivity-corrected baseline value.

14. The method of claim 2, wherein the sampling system further comprises a second collection reservoir which does not contain the enzyme, and step (b) further entails obtaining a blank signal from said second collection reservoir, which blank signal is used in step (c) as a blank correction value to remove background information from the initial signal output.

15. The method of claim 2, wherein the sampling system further comprises a second collection reservoir containing an enzyme that reacts with the extracted analyte to produce an electrochemically detectable signal, and step (b) further entails obtaining signals from said first and second collection reservoirs.

16. The method of claim 1, wherein the conversion step integrates the initial signal output over a sensing time period.

17. The method of claim 14, wherein the conversion step uses a mathematical transformation to individually smooth the signals obtained from the first and second collection reservoirs.

18. The method of claim 15, wherein the conversion step uses a mathematical transformation to individually smooth the signals obtained from the first and second collection reservoirs.

19. The method of claim 17, wherein the difference between signals obtained from the first and second collection reservoirs are smoothed.

20. The method of claim 1, wherein the calibration step entails a single-point calibration against a calibration reference value.

21. The method of claim 1, wherein the calibration step entails the use of a neural network algorithm that correlates the initial signal output obtained in step (c) with a measurement value indicative of the concentration of analyte present in the biological system at the time of extraction.

22. The method of claim 1, wherein the sampling system is programmed to begin obtaining raw signal at a designated time.

23. The method of claim 22, wherein the designated time precedes step (d).

24. The method of claim 1, wherein the calibration step entails the use of a linear correlation to correlate the initial signal output obtained in step (c) with a measurement value indicative of the concentration of analyte present in the biological system at the time of extraction.

25. The method of claim 1, wherein the calibration step further entails compensating for time-dependent behavior between signal measurements obtained in step (b).

26. The method of claim 25, wherein the time-dependent behavior comprises signal decline between said measurements.

27. The method of claim 25, wherein the compensating is carried out using the following function:

${\mathrm{EG}}_t=\left(\left[\frac{{\mathrm{BG}}_{\mathrm{cal}}-\mathrm{\alpha <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t_{\mathrm{cal}}}{E_{\mathrm{cal}}+\mathrm{OS}}-\mathrm{\gamma <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t_{\mathrm{cal}}\right]+\mathrm{\gamma <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t\right)*\left(E_t+\mathrm{OS}\right)+\mathrm{\alpha <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t$$\mathrm{where}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{BGAIN}=\left[\frac{{\mathrm{BG}}_{\mathrm{cal}}-\mathrm{\alpha <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t_{\mathrm{cal}}}{E_{\mathrm{cal}}+\mathrm{OS}}-\mathrm{\gamma <br><br>}<br><br>\text{\hspace{1em}<br><br>}<br><br>t_{\mathrm{cal}}\right]$

wherein;

BG_cal is the true blood glucose at the calibration point;

E_cal is the analyte signal at calibration;

(t_cal) is the elapsed time of the calibration point;

(EG_t) is the estimated blood glucose concentration at time t;

(E_t) is the analyte signal at time t;

(OS) is the constant offset term which accounts for a non-zero signal at an estimated zero blood glucose concentration;

(γ

) is a time-dependent correction term for signal decline;

(α

) is a time-dependent correction term for signal decline; and

(t) is the elapsed time.

28. The method of claim 27, wherein a time segmentation is performed as follows:

${\mathrm{BGAIN}}_1=\left[\frac{{\mathrm{BG}}_{\mathrm{cal}}-{\mathrm{\alpha <br><br>}}_1<br><br>t_{\mathrm{cal}}}{E_{\mathrm{cal}}+\mathrm{OS}}-{\mathrm{\gamma <br><br>}}_1<br><br>t_{\mathrm{cal}}\right]<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{if}<br><br>\text{\hspace{1em}<br><br>}<br><br>t<<br><br>t_{12}$${\mathrm{BGAIN}}_2=\left[\frac{{\mathrm{BG}}_{\mathrm{cal}}-{\mathrm{\alpha <br><br>}}_1<br><br>t_{12}-{\mathrm{\alpha <br><br>}}_2<br><br>\left(t_{\mathrm{cal}}-t_{12}\right)}{E_{\mathrm{cal}}+\mathrm{OS}}-{\mathrm{\gamma <br><br>}}_1<br><br>t_{12}-{\mathrm{\gamma <br><br>}}_2<br><br>\left(t_{\mathrm{cal}}-t_{12}\right)\right]$$\mathrm{if}<br><br>\text{\hspace{1em}<br><br>}<br><br>t_{12}<<br><br>t_{\mathrm{cal}}<<br><br>t_{23}$${\mathrm{BGAIN}}_3=\left[\frac{{\mathrm{BG}}_{\mathrm{cal}}-{\mathrm{\alpha <br><br>}}_1<br><br>t_{12}-\mathrm{\alpha <br><br>}<br><br>2\left(t_{\mathrm{cal}}-t_{12}\right)-\mathrm{\alpha <br><br>}<br><br>3<br><br>\left(t_{\mathrm{cal}}-t_{23}\right)}{E_{\mathrm{cal}}+\mathrm{OS}}-{\mathrm{\gamma <br><br>}}_1<br><br>t_{12}-{\mathrm{\gamma <br><br>}}_2<br><br>\left(t_{\mathrm{cal}}-t_{12}\right)-{\mathrm{\gamma <br><br>}}_3<br><br>\left(t_{\mathrm{cal}}-t_{23}\right)\right]$

if t₂₃<

t_cal

29. The method of claim 1, wherein the conversion step further entails using a temperature correction function to correct for changes in the biological system and/or changes in the sensing device.

30. The method of claim 29, wherein the changes in the biological system comprise a change in temperature.

31. The method of claim 29, wherein the conversion step entails correcting for temperature changes occurring between a measurement of background signal in the sensing device and measurement of a raw signal in step (b), and during the measurement of the raw signal.

32. The method of claim 31, wherein the temperature correction uses an Arrhenius correction function.

33. The method of claim 31, wherein the temperature correction uses an integral average temperature correction function obtained from a measurement cycle to correct for temperature at subsequent time points.

34. The method of claim 29, wherein the conversion step entails correcting for temperature differences between multiple signals obtained from the sensing device.

35. The method of claim 2, wherein said biological system includes skin, and said extracting of analyte from the biological system into a reservoir further comprises enhancement of skin permeability by pricking the skin with micro-needles.

44. The method of claim 25, wherein the compensating is carried out using the following function:

36. A monitoring system for measuring an analyte present in a biological system, said system comprising, in operative combination:

(a) sampling means for extracting the analyte from the biological system, wherein said sampling means is adapted for extracting the analyte across a skin or mucosal surface of said biological system;

(b) sensing means in operative contact with the analyte extracted by the sampling means, wherein said sensing means obtains a raw signal from the extracted analyte and said raw signal is specifically related to the analyte; and

(c) microprocessor means in operative communication with the sensing means, wherein said microprocessor means (i) subjects the raw signal to a conversion step to convert said raw signal to an initial signal output which is indicative of the amount of analyte extracted by the sampling means, and (ii) performs a calibration step which correlates said initial signal output with a measurement value indicative of the concentration of analyte present in the biological system at the time of extraction.

37. The monitoring system of claim 36, wherein the sampling means includes one or more collection reservoirs for containing the extracted analyte.

38. The monitoring system of claim 37, wherein the sampling means uses an iontophoretic current to extract the analyte from the biological system.

39. The monitoring system of claim 38, wherein the collection reservoir contains an enzyme that reacts with the extracted analyte to produce an electrochemically detectable signal.

40. The monitoring system of claim 39, wherein the analyte is glucose and the enzyme is glucose oxidase.

41. The monitoring system of claim 36 further comprising temperature sensing means and skin conductance sensing means for monitoring temperature and skin conductance in the monitoring system or biological system.

42. The monitoring system of claim 36, wherein the microprocessor is programed to begin execution of sampling and sensing at a defined time.

43. A monitoring system for measuring an analyte present in a biological system, said system comprising,

one or more microprocessors capable of (i) subjecting a raw signal, obtained from an extracted analyte, to a conversion step to convert said raw signal to an initial signal output which is indicative of an amount or concentration of the extracted analyte, and (ii) performing a calibration step which correlates said initial signal output with a measurement value indicative of the amount or concentration of analyte present in the biological system at the time of analyte extraction.