JP5426644B2 - Non-invasive measuring device - Google Patents

Description

  The present invention relates to a noninvasive measurement apparatus that non-invasively measures glucose in a subject optically via a measurement probe.

  There are several prior art methods for non-invasive measurement and quantification of the concentration of analytes in the human body, especially glucose. Common to these methods is generally to bring an optical probe into contact with a body part, perform a series of optical measurements, and collect an optical signal set. The detected optical signals or the derived optical parameters calculated from these signals are then correlated with the blood glucose concentration quantified by the reference method to establish a calibration relationship. The calibration relationship is also called a calibration model. This calibration model, derived from patient data, is a mathematical formula that relates the measured signal to glucose concentration. When using a non-invasive glucose monitor for patient care, the glucose concentration is quantified by using the currently measured light signal and a previously established calibration relationship.

  Non-invasive measurement of glucose (NI measurement) quantification methods fall into two broad categories, direct methods that track molecular properties and indirect methods that track the effects of glucose on tissue properties. A direct method to track glucose intrinsic properties such as near infrared (NIR) absorption coefficient, mid-infrared absorption coefficient, optical rotation, Raman shift band, and NIR photoacoustic signal is independent of other body analytes And the ability to detect glucose in tissues or blood that is independent of the body's physiological state. Indirect methods for tracking the effects of glucose on tissue optical properties include methods that measure tissue scattering coefficient, interstitial fluid (ISF) refractive index, and sound propagation in tissue.

  The method of tracking glucose molecular properties encounters a very weak signal that can be considered specific for glucose. Biological noise, probe repositioning errors, person-to-person variations, and measurement noise can overwhelm small changes in glucose-specific signals. Indirect methods of tracking the effect of glucose on tissue properties face significant challenges due to the non-specific relationship between calculated parameters and glucose concentration, which is obvious for the case of quantifying scattering coefficient changes . Khalil reviewed the non-invasive measurement and calibration methods for glucose quantification. For example, see general remarks (Non-Patent Documents 1 and 2). Due to the low level of the signal and the complexity of the biological system being measured, special signal processing and data processing methods must be used to set up calibration and prediction algorithms.

  Multivariate analysis was commonly used in data processing to quantify the concentration of components in complex mixtures. Multivariate analysis is also used to extract glucose related information from noisy data sets. For example, academic papers (Non-Patent Documents 3 and 4) can be referred to. Multivariate analysis was used for data analysis of noninvasively measured glucose measurements based on near infrared (NIR) spectral measurements and temperature effects on the spectra. For example, see non-patent documents 5, 6, 7, 8, 9 and 10 of academic papers. The use of multivariate analysis for noninvasive measurement glucose calibration was disclosed in US Pat.

A simple way to establish a calibration model is to fit the measured non-invasive measurement data to a glucose concentration that is obtained by approximation of the true value by being quantitatively measured invasively. Regression methods such as linear least squares (LLS) fitting or partial least squares (PLS) fitting are commonly used. The calibration correlation coefficient (R _c ) and calibration standard error (SEC) are then calculated.

The calibration model can then be verified by checking the ability to predict one data point using the remaining data points as a calibration set. The method is repeated for each data point in the set. This is known as leave-one-out cross validation (LOOCV). The prediction and reference values are then used to calculate the standard error (SECV) and cross-validation correlation coefficient (R _cv ) for cross-validation prediction. A low SECV and a high R _cv indicate the effectiveness of the calibration model. These R _cv and SECV values can be used with care to show the predictive ability of the model. In particular, care should be taken when only a small number of data points are available. Since the LOOCV procedure involves the use of data points from the same set of experiments, the effect of pseudo-correlation with instrument or experiment time-dependent events is likely to occur. True prediction can only be achieved by using independent calibration and prediction data sets obtained over various time periods. The two calculated prediction parameters are the prediction correlation coefficient (R _p ) and the standard error of prediction (SEP).

The quality of non-invasive measurement is mainly determined by the standard error (SEP) and the magnitude of the predicted correlation coefficients R _p of the prediction. A low SEP indicates a successful quantification when combined with a high correlation coefficient. There is a need to prevent the possibility of (a) a narrow range of analyte concentrations, (b) accidental correlation with other time-dependent events, and (c) overfitting of experimental data. Great care must be taken to avoid the effects of overfitting. The calibration (training) set and the prediction set need to be separated over time. The number of measurement data points must be greater than the number of terms for independent parameters such as spectrum, temperature, distance, etc. of the calibration model equation.

  A high SEP can be interpreted in one of three ways: That is, (a) the calibration model lacks glucose-specific information, (b) the glucose prediction is limited by measurement noise, or (c) the glucose prediction is biological background noise in the body part, and the body Limited by the repositioning error of the probe with respect to a portion of Biological variables such as circulation parameters, skin surface conditions, skin moisture content, circadian rhythm effects, and temperature changes are examples of noise sources that have not yet been considered in sufficient detail in the non-invasive measurement quantification of glucose It is. Changes in these biological variables over time have not been considered in the prior art.

  There may be a simultaneous correlation between circadian variation in glucose concentration in human blood and circadian periodicity of body temperature and other vital signs. It is important to separate the effects of circadian body temperature and blood flow effects on non-invasive measurements, so they do not confuse the signals used to calculate blood glucose concentration.

  Calibration of a non-invasive measurement glucose device requires that various invasively quantified glucose concentrations and corresponding non-invasive measurement signals are available. One calibration approach is that the in-vivo measured signal induces a change in glucose concentration over an observable range. This is accomplished by using an oral glucose tolerance test (OGTT) or a meal tolerance test (MTT). All these procedures are described in the prior art. In OGTT, a known load, generally 75 g glucose, is given to a fasting subject, and the glucose concentration is tracked over time.

  MTT is similar to OGTT except that a carbohydrate load is administered as a meal rather than a glucose load. Data generated during the test period can be used to predict glucose concentration from subsequent non-invasive measurements. The response of the non-invasive measuring device can depend on calibration based on correlated OGTT or MTT data, and can embody non-glucose related physiological effects so that the response of the non-invasive measuring device Resulting in a unique calibration model.

  When random sampling over time cannot be performed, time-dependent artifacts can affect the results of multivariate calibration. In addition to device-related time variables, the circadian rhythm of the human body already discussed can result in a pseudo-time-dependent biological background that is superimposed on MTT data points sequentially. OGTT and MTT data are required to prove that specific non-invasive measurement signals vary due to induced glucose concentration changes, but establish a reliable calibration of signal versus blood glucose over time Not enough for that.

  A calibration method that is less affected by time-dependent effects is a random spot test that is performed during the day and at random time periods. This approach allows the use of data points that cover multiple physiological conditions and avoid circadian rhythm-related correlations. It avoids mostly device-related accidental correlations. This type of study, called a long-term study, involves tracking changes in the patient's glucose concentration over an extended period of more than three weeks and months.

  In a long-term study, Samann et al (11) reported the long-term accuracy and stability of human finger diffuse reflectance over the 800-1350 nm spectral range. The spectrum of 10 patients with diabetes was evaluated. A personal calibration model was calculated for each patient from the spectrum and recorded at the beginning of the study. These models were then applied to calculate blood glucose levels from subsequently acquired spectra recorded after 84-169 days. The long-term accuracy and stability of the calibration model, expressed as the root mean square error of prediction, varied from 3.1 to 35.9 mmol / L, which is for use in quantifying clinically significant glucose concentrations Is too expensive. The results indicate the need to improve the long-term stability of detection and calibration methods and to understand the underlying physiological processes over time. It also shows that the calibration model varies over time. Samann et al did not consider updating the calibration model, nor did it provide a way to update the calibration model over its long-term study time.

Burmeister et al (supra, Non-Patent Document 8) performed NIR (1430-2000 nm) transmission through the tongue of five subjects with type 1 diabetes five times per day over a 39-day period. And investigated. The tongue has a high vascular distribution, no SC (epidermis), little adipose tissue, is a homogeneous body part, has a nearly constant temperature, and is 5-6 mm aqueous The tongue was chosen because it provides an effective path length. Both sets of predictive data points were obtained on different days. Instead of OGTT or MTT, expanding data collection over a few weeks (random series of spot inspections) reduces contamination of the dataset due to temporal effects. The PLS calibration model was generated for different individuals. The model was used to predict the blind sample concentration (every 5 measurements) or the back of the data with SEP> 3 mmol / L and R _p , which varies from individual to individual. The tongue does not have a stratum corneum or skin layer, but the predictive data is of limited sensitivity, but better than that of skin disclosed by Samann et al (supra, Non-Patent Document 11). Burmeister et al did not consider updating the calibration model, nor did it provide a way to update the calibration model over its long-term study time.

  Khalil (Non-Patent Document 1) states, “Noninvasive measurement because the response of a noninvasive measurement device can embody non-glucose related physiological effects depending on calibration based on correlated OGTT or MTT data. The response of the device results in a calibration model that is specific to the individual examined, which calibration model needs to be updated regularly using invasive testing. However, Khalil did not provide a way to update the calibration model over time. Khalil also did not discuss calibration model updates to overcome the effects of seasonal variations on the signal.

  Skin characteristics vary depending on environmental conditions. Non-patent document 12 of Forst et al performed skin thickness measurement and blood flow measurement on diabetic and non-diabetic subjects. The test was performed in a climate chamber where the temperature was stepped from 25 ° C. to 9 ° C. and then gradually increased again to 25 ° C. Measurements were performed on forearm skin. The skin temperature dropped from 32 ° C. to 24.5 ° C. at 9 ° C. and reached 28.6 ° C. again at 25 ° C. Skin thickness and skin blood flow followed a similar pattern as ambient temperature changed. Although skin thickness and blood flow were lower for diabetic subjects than for non-diabetic subjects, the response to environmental changes was similar. Therefore, skin blood circulation and skin thickness vary with environmental conditions. Temperature fluctuations in the climate chamber mimic seasonal temperature changes over time and examine extreme environmental effects on instruments and subjects.

  Skin hydration varies from season to season. For example, in winter the skin is dry and desquamating, and in summer it is moist and flexible. Therefore, it is necessary to update the calibration relationship of non-invasive optical measurements as time progresses and over time between two or more seasons where skin characteristics can change in response to changing environmental conditions. is there.

  There is a need to derive a more powerful and stable calibration model that covers various physiological conditions and the effects of seasonal and environmental changes on the properties of human tissues, especially human skin.

US Pat. No. 4,974,581 US Pat. No. 5,435,309

O. S. Khalil, “Non-Invasive Glucose Measurement Technologies: An update from 1999 to the down of the new millennium”, Diabetes Technol 6: 6th 6th. O. S. Khalil, “Spectroscopic and clinical aspects of noninvasive glucose measurements”, Clinical Chemistry 1999; 45: 165-177. D. M.M. Haaland et al, “Application of new least analysis methods for the quantitative analysis of multicomponent samples”, Appl. D. M.M. Haaland et al, “Multivariate least-squares methods applied to quantitative analysis of multicomponent samples”, Appl Spectrosc 1985; 39: S-J Yeh et al, “Monitoring blood glucose changes in cutaneous tissue by temperature-modulated reflected measurement measurements”, Clin Chem 92: 3 3 49. S. F. Malin et al, "Noninvasive prediction of glucose by near-indiffused diffuse reflectance spectroscopy", Clin Chem 1999; 45: 1651-1658. Gabrery I.M. et al, "Transcutaneous glucose measurement using near infrared spectroscopic cure hypoglycemia", Diabetes Care 1999; 22: 2026-2032. J. et al. J. et al. Burmeister et al, “Noninvasive blood glucose measurements by near-infrared transmission spectroscopy human tunes”, Diabetes Techno2: 16 Robinson et al, “Noninvasive glucose monitoring in diabetic patents: A preliminary evaluation” Clin Chem 1992; 38: 1618-22. Ward et al, "Postpronial blood-glucose determination by quantitative intermediate spectroscopy", Appl Spectrosc 1992; 46: 959-65. Samnan et al, "Non-invious blood glucose monitoring by means of near infraspect spectroscopy: Investigation of long-term-in-the-city, and 406 Forst et al, “Impact of environmental temporary on skin thickness and micro-broad blood flow in Diabetic and non-diabetic subjects”

  An object of the present invention is to improve calibration accuracy for seasonal and physiological variations in tissue properties.

  One aspect of the present invention is to measure a measurement probe that is in contact with a subject, a light source and a photodetector connected to the measurement probe, and information that is optically non-invasive and related to glucose in the subject. A non-invasive measuring apparatus having a computer unit that controls the light source and the photodetector and predicts a glucose level from an output of the photodetector by a calibration model. Recalibration means for updating the calibration model by executing regression calculation based on data acquired by measurement and a corresponding reference measurement value, and using the calibration model updated by the recalibration means A non-invasive measurement apparatus comprising: a calculation means for predicting a glucose concentration from data acquired by non-invasive measurement That.

The figure which shows the structure of the noninvasive measurement apparatus of glucose by this embodiment. In this embodiment, the external view of a noninvasive measurement apparatus. The figure which shows the mode at the time of a measurement in this embodiment. FIG. 4 is a diagram illustrating a data stream based on a periodic recalibration cycle every three days and calibration model updates in the present embodiment. In this embodiment, the figure which shows the data stream based on the periodic recalibration cycle and the update of a calibration model every 7 days. The figure which shows the procedure for improving the calibration relationship for clarifying the seasonal and physiological fluctuation | variation of the tissue characteristic with time passage in this embodiment, and improving the prediction precision of a noninvasive glucose value.

Hereinafter, embodiments of the present invention will be described with reference to the drawings.
First, in the outline of the present embodiment, the calibration relationship for clarifying seasonal and physiological fluctuations of tissue characteristics with the passage of time is improved to improve the prediction accuracy of a noninvasive glucose value. . The method has the following steps (see FIG. 5).

(A) Perform non-invasive measurements (NI measurements) and reference invasive (I) measurements on multiple calibration days to obtain multiple data points per day. This set of data points obtained over multiple days is referred to as a calibration set.

(B) Perform regression calculations on non-invasive and invasive measurement reference data points using linear least squares (LLSQ) or partial least squares (PLS) fitting to obtain a calibration relationship. Quantify the standard error of calibration (SEC) and the calibration correlation coefficient (R _c ). Check if it is within the specified range. If it is within an acceptable range, the calibration is determined to be successful.

(C) Perform a set of non-invasive measurements and reference invasive measurements at random time periods within each day over one or more weeks. This data point set obtained over multiple days is referred to as the prediction set.

(D) Regression calculations with respect to non-invasive measurement (NI) and invasive measurement (I) reference data points using linear least squares (LLSQ) or partial least squares (PLS) fitting to obtain predictive relationships. Execute. Quantifying the standard error (SEP) and predicted correlation coefficient prediction _{(R P).} Check if it is within the specified range. If it is within an acceptable range, the prediction is determined to have been successfully verified.

(E) After establishing a calibration model and confirming the ability of the model and device to predict glucose values, obtain random non-invasive measurement data points and use the calibration model and non-invasive measurement signal; Random non-invasive measurements are performed to predict glucose levels. The resulting glucose value is used to assess the patient's blood glucose status and to manage the patient's treatment.

(F) Periodically recalibrate the device and model by performing one non-invasive measurement to obtain a non-invasive measurement data point and a corresponding blood glucose reference measurement to obtain a glucose reference value. Non-invasive measurement data points and invasive data point sets include recalibration data points. A calibration relationship is used to predict the glucose value for the recalibration data point. Non-invasive measurement Confirms the difference between the quantified glucose value accuracy, the predicted value and the invasively quantified value. The difference must be acceptable (within the range of acceptable SEP values) for each standard value.

(G) Update the calibration model using the following steps:
a) Return to the calibration data set with n _c points.
b) skip the first data point to have (n _c -1) non-invasive measurement data points and corresponding invasive glucose values;
c) adding a non-invasive measurement input of recalibration data points and a corresponding invasive glucose value to have (n _c ) non-invasive measurement data points and corresponding invasive glucose values;
d) re-run the calibration relationship using non-invasive measurement data points vs. linear least squares fitting (LLSQ) or partial least squares fitting (PLS) of glucose, e) re-predict recalibration data points and improve accuracy Quantify and, if acceptable, continue or repeat blood sampling and non-invasive measurements,
(H) Repeat the recalibration and update process at regular time intervals covering seasonal and environmental changes, so that the updated calibration model is a seasonal, physiological to non-invasive measurement And based on data points representing the effects of environmental change.

  Repeating the recalibration and update process at regular intervals, e.g., weekly, skipping the earliest calibration point, adding the latest recalibration point, and rerunning the calibration relationship are added. The calibration model is updated by shifting the time reference by the specified period. After multiple recalibration data points replace the original number of calibration data points, the updated calibration data set represents data points obtained in different seasons of the year. By repeating the process, it is possible to have multiple calibration models per year that correspond to multiple environmental conditions over a year. A renewal process performed on a regular basis, for example every week or every three days, results in a seasonally adjusted calibration relationship for non-invasive quantification of glucose.

  FIG. 1 shows a noninvasive measurement apparatus for glucose according to this embodiment. The probe 1 includes a thermoelectric module 2 as a heating element and a pad 3 that contacts the skin of the subject. The amount of heat generated by the thermoelectric module 2 is adjusted by the temperature controller 4. Further, the temperature adjustment operation of the temperature controller 4 is under the control of the computer 5. The computer 5 is responsible for temperature non-invasive measurement processing control and calibration update processing control as well as temperature adjustment control. A substantially central portion of the probe 1 is formed with a cylindrical opening, into which optical fibers 8 and 9 are inserted. A light source 6 is optically coupled to the optical fiber 8, and a photodetector (signal detector) 7 is optically coupled to the optical fiber 9.

  The optical fiber 8 is placed in the center, and a plurality of optical fibers 9 surround it. The maximum distance between the optical fiber 8 and the optical fiber 9 is less than 2 mm. That is, the optical fibers 8 and 9 are bundled in a substantially circular range having a diameter of 4 mm. For the measurement, a drop of silicon oil is applied to the skin of the subject and wiped off, leaving a very thin layer of oil on the skin to enhance thermal conductivity.

  2A and 2B show typical appearances of the noninvasive measurement apparatus according to the present embodiment. An arm tray 25 recessed in a groove shape is formed in a part of the housing (housing) 10 of the apparatus. The surface of the measurement probe 1 is exposed at a substantially central portion of the arm tray 25. Fixed platforms 13 are provided at both ends of the arm tray 25, respectively. At the time of measurement, a part of the arm of the subject (measurement site) is in contact with the surface of the probe 1, and the subject lies on the arm tray 25.

Below, the calibration update process by control of the computer 5 is demonstrated.
(Noninvasive measurement data calibration, calibration data set or training set)
The calibration data set is multi-point (n _c ) non-invasive measurement data collected over a specific time period that includes various physiological conditions. A period such as one or two weeks is sufficient. The number n _c of the data points, the linear least squares method, partial least squares, using an artificial neural network (ANN), etc., are used to establish the calibration models. The calibration data set is also called a training data set.

(Non-invasive glucose calibration relationship or calibration model)
One way to establish a calibration model is to fit the data obtained from the measured non-invasive measurements to the invasive quantitatively determined glucose concentration. For the fitting, a regression method such as linear least squares (LLS) or partial least squares (PLS) is adopted. For example, the linear calibration model is expressed by the following equation (1).

[Glucose] = a ₀ + Σ _i a _i × P (k, l, m) (1)
In formula (1), [glucose] is the glucose concentration, a _i is the regression coefficient, P is the measured parameter, k, l, m are various wavelengths, distances, temperatures, etc. There are various restrictions. Equation (1) is also known as a calibration model. The calibration correlation coefficient R _c and the calibration standard error SEC are then quantified.

  The measured parameter P may be an optical parameter value quantified at one wavelength or in a wavelength band (spectral band). The optical parameters include the following:

a: Absorbance value for each wavelength
b: Log (I / I _reference ) value for each wavelength (where I is the diffusely reflected light intensity, and I _reference is the diffusely reflected reference light intensity, and both values are quantified at a plurality of wavelengths. )
c: Diffuse reflectance value for each wavelength
d: Local reflectance value for each combination of wavelength and light source-detector distance
e; Local reflectance value for each combination of wavelength, light source-detector distance, distance, and temperature (see Yeh et al, supra).
f: Absorption coefficient for each wavelength, scattering coefficient, or both calculated values
g: Calculated value of absorption coefficient, scattering coefficient, or both for each combination of wavelength and temperature
h; Photoacoustic signal or Raman shift The main difference between in vitro and in vivo calibration experiments is that the human body has a time-dependent physiological effect that is evident in circadian rhythms. In resting state, heart rate, blood pressure, blood circulation, respiration, body temperature and skin blood flow undergo circadian periodicity. These parameters approach their maximum again between 8 am and noon and between 4 pm and 7 pm. They are at a minimum again between 1 pm and 3 pm and between 10 pm and 6 am the next morning. This regular periodicity for normal healthy people is disrupted by changes in environmental conditions and certain diseases. On the other hand, glucose concentrations in healthy individuals who do not have diabetes and in patients with in-control diabetes vary in the day and follow a regular shape. In general, morning glucose levels are low (fasting glucose). The glucose level increases substantially after breakfast, decreases to the lowest point before noon, increases again after lunch and dinner, and settles to low values at night. This shape is distorted in diabetic patients. Deviating from this pattern requires interference such as insulin injection or sugar intake as needed. Strict glycemic control can bring the diabetic patient's daily glucose fluctuation pattern back closer to that of a healthy person.

  It is important that the calibration data set covers as many physiological conditions as possible and that the data points used to build it are obtained randomly and at various day-time zones. Using one specific day-time zone, such as a morning or noon data point, ties the fitting algorithm to a specific time behavior of the signal and not to a true signal change due to glucose concentration.

(Glucose data set or non-invasive measurement data set or test data set)
True prediction can only be achieved by using independent calibration and prediction data points obtained over different time periods. Another set of data points n _P obtained at different time periods, such as other weeks, is used to test the ability of the calibration model to predict glucose values. A predictive data set is also known as a test set. Glucose value associated with the data points of the non-invasive measurement prediction data sets, total number in n _P, are quantified then from the parameter derived from the calibration relationship and non-invasive measurement signal value or these signals. Two calculations predicted parameters were are R _P, and SEP are, in order to predict the glucose value at different time intervals, is used to verify the capability of the method.

(Non-invasive glucose quantitative data points)
After completing the calibration and verifying the predictive accuracy of the model, the computer unit 5 is used to quantify the glucose concentration from the measured non-invasive measurement parameters and the stored calibration relationship. Thus, random individual non-invasive measurement data points are collected and the glucose value for each data point is predicted using a calibration relationship. The resulting glucose value is then used in assessing the patient's blood glucose status and the patient's treatment options. A glucose quantification data point is a non-invasive measurement data point that is used to predict a glucose level without obtaining an accompanying reference blood glucose level. It is not part of the calibration or prediction set and can be quantified at any time.

(Non-invasive glucose recalibration data points)
As in the case of in vitro diagnostic devices, non-invasive measurement devices need to be recalibrated. In vitro reagent kits use instrument / reagent kit combinations to verify that the calibrator set used to set the standard curve, and that the instrument and / or reagent kit have been run to set standards. The execution control device set is periodically executed. Instrument calibration is performed to confirm instrument performance drift and reagent kit degradation, or changes in environmental or operating conditions.

  Calibration of the extracorporeal device is accomplished by using a synthetic calibration material that has a known concentration of the analyte of interest and performs the test using the same equipment and reagents. The instrument signal of each calibration solution is fitted to the calibrator concentration. A standard curve is obtained and used to calculate the concentration of the analyte in the sample. The calibration can be repeated periodically and the longer the time between calibrations, the better the reagent / instrument system.

  In addition to using a calibrator, an execution controller is sometimes used to verify the performance of each execution during instrument calibration. The execution controller is a solution having a known concentration of the analyte and having a concentration range assigned to it. It is run as a sample during instrument operation. The analyte concentration value in the execution controller is checked to determine if it is within a specific concentration range of the execution controller. If the quantified value of the analyte concentration is outside the predetermined range, the instrument needs to be recalibrated by redoing the standard curve or a new standard curve needs to be established for the reagent kit. is there.

  In the case of a home glucose monitor (HGM), each of a number of test strips has a calibration strip and one or more control solutions. The calibration strip is used to set the calculation parameters for the handheld device to calculate the glucose concentration using the strip from this particular lot. The calibrator solution is an aqueous glucose solution having a known glucose concentration. A drop of calibrator solution is placed on a test strip inserted in the instrument and the glucose value is quantified. If the calibrator glucose value quantified by the in vitro diagnostic device is within a predetermined range, both the instrument and the test strip lot are considered acceptable and the reported glucose value is useful for diabetes management. used.

  In the case of non-invasive measurements, there is no equivalent set of controllers and calibrators for quantifying standard curves for measurements and instruments. There is no similar reagent that quantifies instrumental deviations from established calibration relationships. Both calibration and periodic recalibration for non-invasive devices are not discussed in the prior art.

Providing a method for recalibrating a non-invasive glucose measuring device in consideration of the following matters is one of the important factors in this embodiment.
a) The data actually measured from the patient is essential to calibrate the non-invasive measuring device and confirm the recalibration.
b) The skin changes its properties depending on the degree of disease and hydration changes of the stratum corneum depending on environmental conditions such as temperature and humidity.
c) Rough skin, blood flow.
d) Skin hydration varies from season to season, in winter the skin is dry and desquamating, and in summer it is moist and soft.
e) The physiological state of the patient changes with time. Blood flow to the skin varies with temperature, blood flow varies with temperature, humidity, and physical activity, and blood flow varies with disease progression.
f) Collagen structure and collagen glycation vary with time depending on the degree of blood glucose control.

  The need to update the calibration relationship as time progresses arises from the fact that the skin changes its properties in response to changes in environmental conditions. Forst et al ("Impact of environmental temporary on-skin thickness and diabetic papers in non-diabetic and non-diabetic subjects" The specimen was subjected to skin thickness measurement and blood flow measurement. The test was conducted in a climate chamber where the temperature was stepped from 25 ° C. to 9 ° C. and then gradually increased again to 25 ° C. Measurements were performed on forearm skin. The skin temperature dropped from 32 ° C. to 24.5 ° C. at 9 ° C. and reached 28.6 ° C. again at 25 ° C. Skin thickness and skin blood flow followed a similar pattern as ambient temperature changed. Although skin thickness and blood flow were lower for diabetic subjects than for non-diabetic subjects, the response to environmental changes was similar. Therefore, skin blood circulation and skin thickness vary with environmental conditions. Temperature fluctuations in the climate chamber are performed to mimic seasonal temperature changes over time and to examine extreme environmental effects on equipment and subjects.

  Skin thickness and blood flow to the skin, or blood circulation, vary with environmental temperature, and both skin absorption and scattering coefficients vary with environmental conditions. A decrease in blood circulation results in a decrease in skin absorption coefficient, and a change in thickness results in a change in skin scattering coefficient. The skin acts as a light window while measurements are performed. Changes in the optical properties of the skin result in movement of the metric. Furthermore, prior to Simonsen and Gratton (supra), changes in glucose concentration were shown to affect the magnitude of the scattering coefficient. This environmentally induced change in skin absorption and scattering coefficients affects the ability to predict glucose values based on calibration relationships performed at different environmental conditions when the skin has different properties.

  Since it is necessary to recalibrate the non-invasive measurement device, the recalibration data points are defined as follows: With reference blood glucose levels, one non-invasive measurement data point used to predict glucose levels can be quantified at regular time intervals (frequency) such as every 3 days or weekly. Recalibration data points must be randomly distributed over multiple time periods throughout the day. For example, it is possible to divide a day into 2 to 4 hours, such as early morning, late in the morning, before lunch, after lunch, late afternoon, before dinner, and after dinner. Glucose values and non-invasive measurements are performed at each time period and are used for recalibration.

  It is important that the recalibration data points obtained at various times of the day cover as many physiological conditions as possible. The data points used to update the calibration relationship must be obtained randomly and at various times during the day. Using only one specific time zone, such as a morning or noon data point, ties the fitting algorithm to a specific time behavior of the signal and does not lead to a true change in glucose concentration. The difference between the value predicted from the non-invasive measurement data points and the calibration relationship and the blood glucose level quantified by the reference method is used to establish the measurement accuracy and possible deviation from calibration.

  This embodiment is a method for improving the prediction of non-invasive glucose values by improving the calibration relationship to account for seasonal and physiological variations in tissue properties over time. The method includes the following steps.

a) Perform non-invasive measurements and reference invasive measurements on multiple calibration days to obtain multiple data points per day. This set of data points obtained over multiple days is a calibration set. The calibration days are, for example, 1 to 2 weeks. Since at least 30 data points are required for use in the calibration model, the data measurement is repeated 4 or 5 times per day and 4 or 5 data points are collected.

b) Perform regression calculations on data acquired by non-invasive and invasive measurements using linear least squares (LLSQ) or partial least squares (PLS). The regression process results in a calibration relationship or calibration model. Regression parameters are quantified: standard error of calibration (SEC) and calibration correlation coefficient (R _c ). The computer unit 5 confirms that the calculated regression parameters are found to yield a good calibration model and are within the ranges specified for the measurement method and apparatus. If SEC and _Rc are within acceptable ranges, the calibration is determined to be successful and the calibration model is determined to be usable to predict the glucose value.

c) Performing a set of non-invasive measurements and reference invasive measurements on a plurality of data points at other time periods and randomly sampled times of the day. This data point set obtained over multiple days is used as the prediction set.

d) Perform regression calculations on non-invasive measurements and invasive (I) data points using linear least squares (LLSQ) or partial least squares (PLS) and the calibration model established in step (c). Performing a regression calculation on the predictive data set results in a predictive regression parameter set. Quantifying the standard error (SEP) and predicted correlation coefficient prediction _{(R P).} Check if the regression parameters are within the specified range. If they are within an acceptable range, the predictions can be successfully verified and the device and calibration and prediction models can be used for patient glucose quantification.

e) After establishing a calibration model and establishing its ability to predict glucose values, obtain random non-invasive measurement data points and use calibration relationships and non-invasive measurement signals to predict glucose values In order to perform random non-invasive measurements. The resulting glucose value is used for patient diabetes management and evaluation of patient treatment.

f) Perform a periodic recalibration procedure by performing one non-invasive measurement to obtain a non-invasive measurement data point and a corresponding blood glucose reference measurement to obtain a glucose reference value. Non-invasive measurement data points and invasive data point sets include recalibration data points.

g) Update the calibration model using the following steps:

a. Back to the calibration data set,
b. Skip the first data point to have (n _c -1) non-invasive data points and corresponding invasive glucose values;
c. To have (n _c ) non-invasive data points and corresponding invasive glucose values, add non-invasive measurement inputs of recalibration data points and corresponding invasive glucose values;
d. Rerun the calibration relationship n _c data points using LLSQ or PLS fitting noninvasive data point to invasively quantify glucose value,
e. Use the updated calibration relationship to predict the glucose concentration of the recalibration data point, quantify accuracy, and continue or repeat blood sampling and non-invasive measurement, if acceptable,
h) Iterating the recalibration and renewal process over a long period of time covering seasonal and environmental changes, so that the renewed calibration model is a seasonal, physiological and non-invasive measurement Be based on data points that represent the effects of environmental change.

Calibration standard error and calibration correlation coefficient are calibration parameters for noninvasive measurement quantification of glucose. They must meet multiple acceptance criteria to indicate a successful calibration. For example, for non-invasive quantification of glucose, the value R _c is preferably high. Therefore, R _c values in the range 0.7 <R _c <0.9 are acceptable. However, R _c values in the range 0.8 <R _c <0.95 are preferred. Limitations such as 0.9 <R _c <0.99 are more preferred. The acceptable range of calibration standard errors depends on the blood glucose range in which the device is used. Therefore, if the device is used to detect only hyperglycemic amplitudes above 200 mg / dl, the SEC value is in the range of 20 mg / dL <SEC <40 mg / dL. A smaller range is preferred, such as 20 mg / dL <SEC <30 mg / dL. A strict range such as 18 mg / dL <SEC <24 mg / dL is more preferable.

Standard error of prediction and prediction correlation coefficient are prediction parameters for non-invasive measurement quantification of glucose. They must meet multiple acceptance criteria to indicate a successful calibration. For example, for non-invasive determination of glucose, the value R _P is higher is preferable. _{R P} values thus _0.7 <range of R P <0.9 is acceptable. However, _{0.8 <R P} values in the range of R P <0.95 is preferable. Limitations such as 0.9 <R _P <0.99 are more preferred. The acceptable range of SEP depends on the blood glucose range in which the device is used. Therefore, if the device is used to detect only hyperglycemic amplitudes above 200 mg / dl, the SEP value is in the range of 20 mg / dL <SEP <40 mg / dL. A smaller range is preferred, such as 20 mg / dL <SEP <30 mg / dL. A strict range such as 18 mg / dL <SEP <24 mg / dL is more preferable.

  If the device is used within the range of hypoglycemia and normoglycemia, i.e. reduced to less than 100 mg / dL, the acceptable range of SEC and SEP must be lower and more stringent. Thus, for example, standard errors in calibration and prediction need to be in the range of 10-18 mg / dL to give glucose values that can be used for patient diabetes management in the range of hypoglycemia and normoglycemia. It is.

  By periodically repeating the recalibration process at regular time intervals, the recalibration data points are quantified and checked for accuracy. The earliest calibration point is removed, the latest recalibration point is added, and the calibration regression relationship is re-executed, the calibration relationship is updated, and the calibration time domain is shifted by the applied period. Removing the earliest calibration point, adding the latest recalibration point, and re-executing the calibration relationship calibrate the calibration relationship to capture changing physiological and seasonal conditions.

  Updating one data point in the calibration set once a week by using 30 data points in the calibration set and replacing one data point in the calibration set with a recalibration data point is To have a calibration set with 12 data points from the original calibration data set and 18 recalibration data points spread over 16 weeks, 120 days (4 months) from the start of the recalibration procedure. After 242 days (about 8 months) from the start of the recalibration procedure, we have a calibration set with all 30 data points fully updated. The 30 data points span over 30 weeks and cover a wide range of physiological and seasonal environmental conditions.

  Period and other size calibrations, and prediction data sets and other frequencies can be used to update the calibration procedure.

  If calibration-related updates are affected every 3 days, all 30 calibration data points are updated and replaced with recalibration data points 87 days (less than 3 months) after the start of the recalibration procedure. The calibration curve can be updated every three months, resulting in a more rigorous (in-season) calibration model. In the case of Samann et al (supra), a long-term study was performed over 84-169 days and could be updated within a data point set representing the physiological and seasonal conditions of non-invasive measurements.

  The calibration update method according to this embodiment is applied to the case of a single user who calibrates the apparatus. Therefore, the calibration model is individual specific and varies with movement over time depending on environmental conditions.

The following is a specific example of the calibration update method according to the present embodiment.
FIG. 3 illustrates a non-invasive sensor recalibration scheme using the seasonal calibration update method of the present invention. The data stream is based on regular recalibration cycles every 3 days and calibration model updates.

  The device and model are used to examine the patient's glucose concentration between day 14 and day 16. The calibration model is updated every third day, 17, 20, 23, 26, 29th day, and the like. For brevity, not all recalibration dates are shown in FIG. In the middle of these days, not shown in FIG. 3, the device and model are again used to examine the patient's glucose concentration and provide the glucose value to allow the patient's blood glucose level to be managed. Is done. When calibration-related updates are performed every 3 days, all 30 calibration data points used in this embodiment are updated 87 days after the start of the recalibration procedure, covering approximately one season, And replaced with recalibration data points.

  FIG. 4 illustrates a non-invasive sensor recalibration scheme using the seasonal calibration update method of the present embodiment. The data stream is based on regular recalibration cycles every 7 days and calibration model updates.

  The device and model are used to examine the patient's glucose concentration between day 14 and day 19. The calibration model is updated every 7 days, 20, 27, 34, 41, 48 days, etc. In between these days (not shown in FIG. 4), the device and model are used again to test the patient's glucose concentration and provide a glucose value to allow the patient's blood glucose level to be managed. Is done.

  Update one data point in the calibration set once a week by using 30 data points in the calibration set of this embodiment and replacing one data point in the calibration set with a recalibration data point Doing 120 days from the beginning of the recalibration procedure to have a calibration set with 12 data points from the original set obtained over a one week period and 18 recalibration data points spread over 16 weeks ( 4 months). The calibration set has all 30 calibration data points fully updated 242 days (approximately 8 months) after the start of the recalibration procedure. The 30 data points for the calibration set span over 30 weeks and cover a wide range of physiological and seasonal environmental conditions. The renewal period covers two or more seasons. It may be preferred to use a shorter every third day calibration procedure to keep the calibration points within one season.

  Note that the present invention is not limited to the above-described embodiment as it is, and can be embodied by modifying the constituent elements without departing from the scope of the invention in the implementation stage. In addition, various inventions can be formed by appropriately combining a plurality of components disclosed in the embodiment. For example, you may delete a some component from all the components shown by embodiment. Furthermore, constituent elements over different embodiments may be appropriately combined.

  DESCRIPTION OF SYMBOLS 1 ... Probe, 2 ... Thermoelectric module, 3 ... Pad, 4 ... Temperature controller, 5 ... Computer, 6 ... Light source, 7 ... Photodetector, 8, 9 ... Optical fiber.

Claims (2)

A measurement probe in contact with the subject;
A light source and a photodetector connected to the measurement probe;
A computer unit that is optically non-invasive and controls the light source and the light detector to measure glucose-related information in the subject, and predicts the glucose value from the output of the light detector by a calibration model; A non-invasive measuring device comprising:
The computer unit is
Recalibration means for updating the calibration model by performing regression calculations based on data acquired by non-invasive measurements on different days and corresponding reference measurements;
A noninvasive measurement apparatus comprising: a calculation unit that predicts a glucose concentration from data acquired by noninvasive measurement using the calibration model updated by the recalibration unit.   2. The noninvasive measurement apparatus according to claim 1, wherein the recalibration means changes the position of the data point used for recalibration every measurement date.

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