Calibration method for the prospective calibration of measuring equipment

• US 10,289,652 B2
• Filed: 11/18/2015
• Issued: 05/14/2019
• Est. Priority Date: 08/27/2009
• Status: Active Grant

• Current Assignee: Roche Diabetes Care Inc. (Roche Holding AG)
• Original Assignee: Roche Diabetes Care Inc. (Roche Holding AG)
• Inventors: Schmitt, Nikolaus, Frisch, Gerhard
• Primary Examiner(s): Weston, Tiffany
• Application Number:
  US14/944,981
• Publication Number:
  US 20160070675A1
• Time in Patent Office: 1,273 Days
• CPC Class Codes: A61B 2560/0223 of calibration, e.g. protocols for calibrating sensors
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: A61B 5/7207 of noise induced by motion artifacts
• CPC Class Codes: A61B 5/7232 involving compression of the physiological signal, e.g. to extend the signal recording period
• CPC Class Codes: G01N 2035/00702 Curve-fitting; Parameter matching; Calibration constants
• CPC Class Codes: G01N 27/3271 Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood amperometry per se G01N27/49; aspects concerning the enzyme reagent C12Q1/001
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: G01N 35/00693 Calibration
• CPC Class Codes: G06F 17/18 for evaluating statistical data , e.g. average values, frequency distributions, probability functions, regression analysis forecasting specially adapted for a specific administrative, business or logistic context G06Q10/04

Abstract

A method for operating measuring equipment for detecting at least one analyte in a bodily fluid by means of at least one continuously measuring blood glucose sensor. At least one calibration method is carried out for the prospective calibration of the measuring equipment. At least three calibration points are detected in the calibration method, wherein each calibration point comprises at least one measurement signal from the measuring equipment and at least one reference value of an associated reference measurement. A plurality of possible slopes are established between the calibration points. At least one robust estimation method, more particularly using a formation of at least one median, is used to determine at least one probable slope from the plurality of possible slopes. Furthermore, at least one measurement is carried out. During the measurement and using the probable slope, a concentration of the analyte in the bodily fluid is deduced from at least one measurement signal from the measuring equipment and the probable slope.

Claims

1. A method for operating measuring equipment for detecting at least one analyte in a bodily fluid, the measuring equipment including a continuously monitoring sensor and a reference measurement sensor, the method comprising:

implanting the continuously monitoring sensor into the skin of a patient;

detecting at least three calibration points, each calibration point comprising (i) a measurement signal obtained from the implanted sensor and corresponding to the concentration of the analyte in the bodily fluid and (ii) a reference value obtained using the reference measurement sensor, wherein the reference value corresponds to an actual present value of concentration of the analyte in the bodily fluid;

establishing a plurality of possible slopes between the calibration points;

using a robust estimation method to determine a probable slope from the plurality of possible slopes, the robust estimation method comprising a statistical estimation method which supplies stable statistical estimators even if outliers occur or if distribution assumptions are only approximately valid, the robust estimation being based on one or more permutation algorithms and/or on one or more sorting algorithms;

determining through a plurality of the calibration points a plurality of straight lines having the probable slope; and

using the continuously monitoring sensor to perform at least one measurement in which the probable slope is used with the measurement equipment to determine a concentration of the analyte in the bodily fluid.

2. The method of claim 1, further comprising:

determining the axis intercepts of the straight lines;

forming a median to determine a probable axis intercept from the axis intercepts; and

using the probable axis intercept during the measurement.

3. The method of claim 2, wherein the calibration method is carried out repeatedly at different times, the method further comprising determining a new probable slope and a new probable axis intercept after the calibration method has been repeated and then using the new probable slope and the new probable axis intercept in at least one subsequent measurement.

4. The method of claim 1, further comprising preforming plausibility analysis during the calibration and using the plausibility analysis to discard unrealistic calibration points and/or unrealistic slopes and/or unrealistic axis intercepts.

5. The method of claim 1, further comprising using a sorting algorithm and/or a permutation algorithm during the robust estimation to form a median.

6. The method of claim 1, further comprising determining at least one current calibration quality having at least one confidence interval.

7. The method of claim 1, further comprising automatically inviting a user to carry out the calibration method.

8. The method of claim 1, wherein a user is invited to carry out the calibration method if at least one current measurement signal lies in a region in which the calibration method was not yet carried out with sufficient calibration quality.

9. The method of claim 1, further comprising informing a user if a current measurement signal lies in a region of insufficient calibration quality.

10. The method of claim 1, further comprising discarding at regular or irregular intervals calibration points that are older than a predetermined time threshold.

11. The method of claim 1, wherein the calibration points and/or the measurement signals are subjected to at least one smoothing method, using an exponential filter.

12. The method of claim 1, wherein the calibration points and/or the measurement signals are subjected to at least one linearization step, wherein the linearization step produces an approximately linear relationship between the measurement signals and the reference values.

13. The method of claim 1, further comprising detecting a plurality of the measurement signals from the measuring equipment over a measurement time period and applying a first data reduction method, comprising:

combining the measurement signals with associated measurement times to form measurement value pairs, wherein a plurality of possible slopes are established between the measurement value pairs;

using a median to establish a probable slope from the plurality of possible slopes, wherein a plurality of straight lines with the probable slope through the measurement value pairs are formed;

selecting a representative time for the measurement time period and establishing functional values of the straight lines for the representative time;

establishing a probable functional value from the functional values; and

using the at least one probable functional value and the at least one representative time to replace the plurality of the measurement value pairs with a representative measurement value pair;

the method further comprising applying a second data reduction method, comprising;

forming a median and using the median to determine at least one probable measurement signal for the measurement time from the plurality of measurement signals, wherein the plurality of measurement signals are replaced by the probable measurement signal.

14. The method of claim 13, further comprising determining a standard deviation and/or a measure of the quantile.

15. The method of claim 13, further comprising comparing robust estimators of the measurement signals and parametric estimators of the measurement signals.

16. The method of claim 13, further comprising determining a trend from the plurality of measurement signals.

17. The method of claim 1, wherein, during the calibration method, a calibration of measurement signals from the measuring equipment is carried out against reference values of associated reference measurements and the calibration strategy comprises one or more of the following steps:

a region of measurement signals from the measuring equipment that can be used for a measurement is restricted depending on a current calibration quality, wherein information is provided to a user when detecting measurement signals outside of the region that is usable or covered by calibration values or outside of a tolerance region based on the calibration values;

a user is invited to carry out the calibration method again;

a user is informed that now is a good time for carrying out the calibration method; and

a user is invited to carry out the calibration method again at regular or irregular intervals or at predetermined times.

18. Measuring equipment for detecting at least one analyte in a bodily fluid, comprising:

a continuously measuring bodily fluid analyte sensor adapted for implanting into the skin of a patient;

a processor having a program stored in memory and configured for execution by the processor, the program including instructions for;

detecting at least three calibration points, each calibration point comprising (i) a measurement signal obtained from the continuously measuring sensor implanted in a patient, the measurement signal corresponding to the concentration of the analyte in the bodily fluid and (ii) a reference value obtained using a reference measurement sensor, wherein the reference value corresponds to an actual present value of concentration of the analyte in the bodily fluid;

establishing a plurality of possible slopes between the calibration points;

using a robust estimation method to determine a probable slope from the plurality of possible slopes, the robust estimation method comprising a statistical estimation method which supplies stable statistical estimators even if outliers occur or if distribution assumptions are only approximately valid, the robust estimation being based on one or more permutation algorithms and/or on one or more sorting algorithms;

determining through a plurality of the calibration points a plurality of straight lines having the probable slope; and

using the implanted sensor to perform at least one measurement in which the probable slope is used with the measurement equipment to determine a concentration of the analyte in the bodily fluid.

19. The measuring equipment of claim 18, wherein the bodily fluid analyte sensor comprises a glucose sensor.

20. A method for operating measuring equipment for measuring concentration of an analyte in a bodily fluid, the measuring equipment including a continuously monitoring sensor, a reference measurement sensor, and a user interface, the method comprising:

implanting the continuously monitoring sensor into the skin of a patient;

initially calibrating the continuously monitoring sensor using measurement signals obtained from the implanted sensor that are matched to respective reference values obtained with the reference measurement sensor;

using the calibrated sensor to continuously monitor the concentration of the analyte in the patient'"'"'s bodily fluid;

when a signal monitored from the calibrated sensor falls within a region that has less than a minimum number of calibration points, the user interface generates a visual, audible or haptic signal to the patient to recalibrate the continuously monitoring sensor; and

recalibrating the sensor based on the visual, audible or haptic signal.

21. The method of claim 20, wherein the user interface invites the patient to recalibrate when the continuously monitoring sensor records a value that exceeds or falls below all previously recorded values.

22. The method of claim 20, wherein the user interface informs the patient that analyte measurement is terminated or interrupted and the continuously monitoring sensor suspends operation.

23. The method of claim 20, wherein the step of the user interface inviting the patient to recalibrate comprises producing a “

must calibrate”

signal.

24. The method of claim 20, wherein the step of the user interface inviting the patient to recalibrate comprises producing a “

calibration recommended”

signal.

25. The method of claim 20, wherein the step of the user interface inviting the patient to recalibrate comprises producing a “

may calibrate”

or “

ready to calibrate”

signal.

26. The method of claim 20, wherein:

the measuring equipment distinguishes between and selects one of the following states;

(a) mandatory calibration, wherein a display of measurements is blocked until the measuring equipment is calibrated, and (b) recommended calibration, wherein the measuring equipment continues to display measurement results if the user does not calibrate; and

the user interface displays the selected state.

27. The method of claim 20, wherein the minimum number of calibration points is at least 3.

28. The method of claim 20, wherein the minimum number of calibration points is at least 2.