Measuring equipment

Abstract

To stably and accurately measure a biological index regardless of individual difference and difference in a measurement environment.SOLUTION: A measuring device includes a light source of a middle infrared region, a photodetector for detecting light outputted from the light source and reflected at a measurement object, and an information processing device for determining a biological index of the measurement object on the basis of an output of the photodetector. The light source emits light of a first wavelength selected from the wavenumbers of 970 cm-1 or more and 1010 cm-1 or less, and light of a second wavelength selected from the wavenumbers of 950 cm-1 or more and 990 cm-1 or less and different from the first wavelength, and the information processing device determines the biological index of the measurement object from first absorbance of the light of a first wavelength and second absorbance of the light of a second wavelength.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a biological index measuring device. [Background technology]

[0002] In recent years, the number of diabetes patients has been increasing worldwide, creating a demand for non-invasive blood glucose measurement that does not require blood sampling. Various optical sensing methods have been proposed, including those using near-infrared, mid-infrared, and Raman spectroscopy. Of these, the mid-infrared region is a fingerprint region where glucose absorption is high, allowing for greater measurement sensitivity than the near-infrared region. In addition to blood glucose levels, biomarkers such as hemoglobin concentration, blood lipids, blood proteins, and blood tumor DNA can also be measured non-invasively in the mid-infrared region.

[0003] To accurately measure glucose concentration in the mid-infrared region, the glucose absorption peak wavenumber of 1035 cm -1 , 1080cm -1 , and 1110 cm -1 A method using the above has been proposed (see, for example, Patent Document 1). Summary of the Invention [Problem to be solved by the invention]

[0004] Measurement of general biomarkers using mid-infrared light is affected by individual differences in digestion, absorption, and metabolism from before to after a meal, as well as differences in the measurement environment, making it difficult to achieve accurate and stable measurements.

[0005] An object of the present invention is to provide a non-invasive biomarker measuring device with improved measurement stability and accuracy. [Means for solving the problem]

[0006] In one aspect, the measurement device comprises: a light source in the mid-infrared region; a photodetector that detects light output from the light source and reflected by the object to be measured; an information processing device that determines a biological index of the measurement object based on the output of the photodetector; Equipped with The light source is 970 cm -1 More than 1010cm -1 Light of the first wavelength selected from the following wave numbers and 950 cm -1 Above, 990cm -1 emitting light of a second wavelength different from the first wavelength selected from the following wave numbers, The information processing device determines a biomarker of the measurement object from a first absorbance of the light of the first wavelength and a second absorbance of the light of the second wavelength. [Effects of the Invention]

[0007] Non-invasive measurement of biomarkers with improved measurement stability and accuracy is achieved. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a schematic diagram of a measurement device according to an embodiment. [Figure 2] FIG. 1 is a diagram illustrating a hardware configuration of an information processing device. [Figure 3] FIG. 2 is a diagram illustrating the operation of the measuring device. [Figure 4] FIG. 2 is a diagram illustrating the operation of the measuring device. [Figure 5] FIG. 2 is a diagram illustrating the operation of the measuring device. [Figure 6] FIG. 10 is a diagram illustrating an example of control timing of the measurement device. [Figure 7] FIG. 10 is a diagram in which the mean values ​​of the coefficients of determination are mapped to the sense wavelength and the base wavelength. [Figure 8] FIG. 1 is an enlarged view of area A. [Figure 9] This is a graph in which the absorbance of each data point around 990 cm −1 is overlaid. [Figure 10] This is a graph in which the absorbances determined from one sense wavelength and two base wavelengths are overlaid. [Figure 11] FIG. 1 is an enlarged view of region B. [Figure 12]FIG. 10 is an enlarged view of the first mapping range in region B. [Figure 13] FIG. 10 is an enlarged view of the second mapping range in region B. [Figure 14] This is a graph in which the absorbance of each data point around 1160 cm −1 is overlaid. [Figure 15] FIG. 1 is an enlarged view of area C. [Figure 16] This is a graph in which the absorbance of each data point around 1740 cm −1 is overlaid. [Figure 17] FIG. 10 is a diagram showing the range of high correlation between estimated blood glucose level changes and typical blood glucose level changes in humans. DETAILED DESCRIPTION OF THE INVENTION

[0009] In this embodiment, a biomarker such as a blood glucose level is measured using at least two wavelengths within a specific wavenumber range. In the field of infrared spectroscopy, the term "wavenumber" is generally used, but since the wavenumber k is expressed as the number of waves contained per unit length (1 / λ), in the following description, "wavenumber" and "wavelength" will be used synonymously.

[0010] At least one of the two or more wavelengths may be used to normalize the measurement data obtained by the measurement optical system. By using the normalization wavelength, it is possible to correct constantly changing measurement conditions, such as variations in the contact state between the measurement optical element and the measurement site on the object.

[0011] To obtain stable measurement results regardless of individual differences, we identify an appropriate range for selecting two or more wavelengths. Specifically, we collect measurement data in the mid-infrared range from a wide range of subjects, different meal contents, and different measurement times, and determine the appropriate wavelength range from the correlation between the collected data and the transition of typical biomarkers from before to after a meal.

[0012] A typical transition in a biomarker, for example, blood glucose levels, is a series of changes in which blood glucose levels are low before a meal, peak 40 minutes after a meal, and then return to pre-meal levels 180 minutes later. Two or more wavelengths are selected for measurement from wavelength ranges that show a high correlation between the collected data and this typical transition. This allows for stable and accurate non-invasive measurement of biomarkers, regardless of individual differences.

[0013] <Device configuration> Fig. 1 is a schematic diagram of a measurement device 1 according to an embodiment. The measurement device 1 includes a measurement optical system 10 and an information processing device 30. In Fig. 1, a data logger 25 for recording data is disposed between the measurement optical system 10 and the information processing device 30, but the measurement results obtained by the measurement optical system 10 may also be input directly to the information processing device 30.

[0014] The measurement optical system 10 includes a light source device 11, a switch 12, a measurement optical element 17, and a photodetector 18. Depending on the design and arrangement of the optical path, optical elements such as multiplexers / demultiplexers 13 and 14 may be inserted between the light source device 11 and the measurement optical element 17. A dichroic prism, a half mirror, a polarizing beam splitter / combiner, etc. may be used as the multiplexers / demultiplexers 13 and 14. A light-guiding member 15 or 16 may be connected to at least one of the incident side and the exit side of the measurement optical element 17. An optical fiber, an optical mirror, etc. may be used as the light-guiding members 15 and 16. The dashed lines inside the measurement optical system 10 indicate the optical paths from each light source to the light-guiding member 15.

[0015] The light source device 11 outputs light of at least two wavelengths selected from a specific wavenumber range. The specific wavenumber range is determined in advance so that biological indicators can be measured stably regardless of individual differences or differences in measurement conditions. The determination of the wavenumber range will be described in detail later.

[0016] 1 uses three light sources 111, 112, and 113, each outputting light of a different wavelength, but this is not limiting. A single variable wavelength light source or a light source that emits light over a wide wavelength range may be used as the light source device 11. Examples of light sources that can be used over a wide wavelength range include lamp light sources, light emitting diodes (LEDs), and super luminescent diodes (SLDs). Similar measurements can also be performed using a combination of a wide wavelength range infrared lamp and a wavelength filter, or a combination of a wide wavelength range infrared lamp and a spectrometer such as a Fourier transform infrared spectrometer (FTIR).

[0017] When a light source with a wide wavelength range is used, a wavelength filter for extracting a desired wavelength may be provided on the output side of the light source device 11 as needed. Alternatively, multiple light-receiving elements may be used in the photodetector 18, and a wavelength filter may be placed on the input side of each light-receiving element. The number of wavelengths used for measurement is not limited to three, and may be two wavelengths or four or more wavelengths. When individual light sources 111, 112, and 113 are used, a portion of the output light from each light source may be monitored to correct output fluctuations.

[0018] The switch 12 switches the wavelength of light incident on the measurement optical element 17. In the example of Fig. 1, switching elements 121, 122, and 123 are provided on the output sides of the light sources 111, 112, and 113, respectively, but this is not limiting and each light source may be controlled to be on or off. When a single wavelength-tunable light source is used, a selector for the light source wavelength may be used.

[0019] As long as the wavelength of the light irradiated onto the measurement site can be changed, there is no limitation on the specific configuration of the switch 12. A shutter that selectively blocks the light emitted from the light sources 111, 112, and 113 may be used, or a switch that switches each of the light sources 111, 112, and 113 on and off may be used.

[0020] The light of the wavelength selected by the switch 12 is guided to the measurement optical element 17 via the multiplexer / demultiplexer 13, 14 or the light guide member 15 as necessary. The measurement optical element 17 has a contact surface 171 that comes into contact with the object to be measured. During measurement, the contact surface 171 of the measurement optical element 17 is pressed against the object to pick up the return light from the measurement site, i.e., the light that has been optically absorbed at the measurement site.

[0021] Light incident on the measurement optical element 17 is attenuated at the interface between the measurement site and the contact surface 171 by an amount corresponding to the optical absorption spectrum of the medium being measured. The attenuated light emitted from the measurement optical element 17 contains information about the interior of the medium being measured. In the case of non-invasive measurement using light in the mid-infrared region, an ATR (Attenuated Total Reflection) prism can be used as the measurement optical element 17. The ATR prism is suitable for spectroscopy in the mid-infrared region where the optical absorption of glucose and glycogen is observed.

[0022] The ATR method is a measurement method that uses the "evanescent field" that appears when infrared light is incident on a high-refractive index ATR prism and total reflection occurs at the interface between the prism and the medium being measured. When the ATR prism is pressed against the object being measured and measurement is performed, the evanescent field that has been extruded is absorbed by the object being measured.

[0023] In the case of infrared light, the light penetrates from the ATR prism to the measurement site only a few microns deep, and does not reach the capillaries that are located at depths of several hundred microns. However, it is known that components such as blood plasma in blood vessels seep into skin and mucosal cells as tissue fluid (interstitial fluid). By detecting components such as glucose present in this tissue fluid as optical absorption spectrum intensity or absorbance, it is possible to measure biomarkers.

[0024] To measure the optical absorption spectrum intensity using the seepage of the magnetic field, it is desirable to use the oral mucosa, which has no epidermis, or the earlobe or lip, which has a thin epidermis, as the measurement site.

[0025] The light emitted from the measurement optical element 17 is detected by the photodetector 18 as an optical signal containing biological information. When the light guiding member 16 is used, the optical signal from the measurement optical element 17 may be received by the photodetector 18 via the light guiding member 16. The photodetector 18 converts the received optical signal into an electrical signal and outputs it to the data logger 25. The information recorded in the data logger 25 is supplied to the information processing device 30, where it is processed to estimate the target biological index. As mentioned above, the function of the data logger 25 may be incorporated into the information processing device 30.

[0026] When using the output of a single photodetector 18 as shown in Figure 1, the signal from the photodetector 18 is processed in synchronization with the switching timing of the switching elements 121 to 123, so that the single photodetector 18 can appropriately measure absorbance at multiple different wavelengths.

[0027] The information processing device 30 has, as functional blocks, a data processing unit 31, a biological index estimation unit 32, a switching control unit 33, and a timing control unit 34. The data processing unit 31 calculates the absorbance of the measured object for each wavelength from the light intensity of each wavelength detected by the photodetector 18. The absorbance A at wave number k is expressed as follows: A(k)=-log 10 (I / I0) (1) where I0 is the intensity of the light incident on the measurement optical element 17, i.e., the intensity of the light emitted from the light source. I is the intensity of the light emitted from the measurement optical element 17 and detected by the photodetector 18.

[0028] The biomarker estimator 32 estimates biomarkers based on the absorbance at each wavelength using a prediction formula described below. The switching controller 33 controls the operation of the switch 12 in the measurement optical system 10. The timing controller 34 controls the timing of recording and capturing the detection results of the photodetector 18 in synchronization with the wavelength switching. The switching controller 33 may be provided external to the information processing device 30. In that case, the external switching controller and the information processing device 30 may be connected by cable or wirelessly, and the switching control for the measurement optical system 10 and the timing of data capture in the information processing device 30 may be synchronized.

[0029] In this embodiment, two or more wavelengths suitable for estimating a biomarker are set in the measurement device 1, and the biomarker estimator 32 stably and accurately estimates the biomarker based on the absorbance at the two or more wavelengths.

[0030] Fig. 2 is a hardware configuration diagram of information processing device 30H. Information processing device 30H is a hardware reconfiguration of the functions of information processing device 30 in Fig. 1. Information processing device 30H has a central processing unit (CPU) 301, random access memory (RAM) 302, read-only memory (ROM) 303, auxiliary storage device 304, input device 305, display device 306, external interface (I / F) 307, and communication interface (I / F) 308, which are interconnected by bus 309.

[0031] The CPU 301 and the main storage devices RAM 302 and ROM 303 are directly connected to the main bus, and other devices may be connected to the main bus via internal interfaces. In Fig. 2, for simplicity of illustration, the devices are shown as being interconnected by a bus 309.

[0032] 1 can be realized by a CPU 301, a RAM 301, and a ROM 302. Apart from the CPU 301, a memory-embedded ASIC (application specific integrated circuit) or a programmable logic device (PLD) may be provided, and the functions of the switching control unit 33 and the timing control unit 34 may be allocated to the ASIC or the PLD.

[0033] The ROM 303 stores programs, parameters, etc. required for processing executed by the CPU 301. A prediction formula used to estimate a biological index may be stored in the ROM 303. The RAM 302 can be used as a work area for calculation processing by the CPU 301.

[0034] The data supplied from the data logger 25 and the biometric indicators estimated by the CPU 31 may be recorded in the ROM 303 or the auxiliary storage device 304 .

[0035] The input device is a user interface such as a touch panel or keyboard. The display device 306 displays the results of data processing by the CPU 31 and estimated biomarkers. The external interface 307 is used to connect to the data logger 25 and the light source device 11 and switch 12 of the measurement optical system 10. The communication interface 308 is used for data communication with a network or an external server. The biomarkers estimated by the CPU 31 may be transmitted to the subject or the like via the network or an external server.

[0036] 3, 4, and 5 show an example of the operation of the measurement optical system 10. In Fig. 3, light of a first wavelength output from the light source 111 is selected. If the switching elements 121 to 123 are shutters, the switching element 121 opens and the switching elements 122 and 123 close, so that only the light emitted from the light source 111 is guided to the measurement optical element 17. If the switching elements 121 to 123 are on / off switches (or current injection switches) for the light sources 111 to 113, the light source 111 is turned on and the light sources 112 and 113 are turned off, and light of the first wavelength is output from the light source 111.

[0037] The light of the first wavelength passes through the multiplexer / demultiplexers 13 and 14 and the light-guiding member 15 and enters the measurement optical element 17. As described above, the contact surface 171 of the measurement optical element 17 is pressed against the measurement site of the object to be measured, and the optical signal of the first wavelength that has been attenuated at the measurement site is detected by the photodetector 18 via the light-guiding member 16.

[0038] 4, light of the second wavelength output from light source 112 is selected. When switching elements 121 to 123 are shutters, switching element 122 opens and switching elements 121 and 123 close, so that only the light emitted from light source 112 is guided to measurement optical element 17. When switching elements 121 to 123 are on / off switches (or current injection switches) for light sources 111 to 113, light source 112 is turned on and light sources 111 and 113 are turned off, and light of the second wavelength is output from light source 112.

[0039] The light of the second wavelength passes through the multiplexer / demultiplexers 13 and 14 and the light-guiding member 15 and enters the measurement optical element 17. The optical signal of the second wavelength that has been attenuated at the interface between the measurement optical element 17 and the object to be measured passes through the light-guiding member 16 and is detected by the photodetector 18.

[0040] 5, light of the third wavelength output from light source 113 is selected. When switching elements 121 to 123 are shutters, switching element 123 opens and switching elements 121 and 122 close, so that only the light emitted from light source 113 is guided to measurement optical element 17. When switching elements 121 to 123 are on / off switches (or current injection switches) for light sources 111 to 113, light source 113 is turned on and light sources 111 and 112 are turned off, and light of the third wavelength is output from light source 113.

[0041] The light of the third wavelength passes through the multiplexer / demultiplexers 13 and 14 and the light-guiding member 15 and enters the measurement optical element 17. The optical signal of the third wavelength, which is attenuated at the interface between the measurement optical element 17 and the object to be measured, passes through the light-guiding member 16 and is detected by the photodetector 18. In this way, the optical absorption spectrum intensity of the object to be measured for the light of each wavelength is detected.

[0042] 6 is a diagram showing an example of the control timing of the measurement device 1. The operation timing of the switching elements 121, 122, and 123 and the timing of light incidence on the photodetector 18 are shown on the time axis. A value of "1" on the vertical axis indicates a state in which light is irradiated onto the object to be measured, i.e., the shutter is open or the light source is ON. A value of "0" indicates a state in which no light is irradiated, i.e., the shutter is closed or the light source is OFF.

[0043] When the switching element 121 is open and the switching elements 122 and 123 are closed, the measurement light of the first wavelength is incident on the photodetector 18. When the switching element 122 is open and the switching elements 121 and 123 are closed, the measurement light of the second wavelength is incident on the photodetector 18. When the switching element 123 is open and the switching elements 121 and 122 are closed, the measurement light of the third wavelength is incident on the photodetector 18.

[0044] When all of the switching elements 121 to 123 are closed (off section in the figure), no measurement light is incident on the photodetector 18, but background light, for example, radiation from the object to be measured and radiation from the measurement optical system 10, can be detected.

[0045] The detection results of photodetector 18 when all switching elements 121 to 123 are closed may be stored in data processing unit 31 as correction values, and measurement results of each wavelength obtained at adjacent times may be corrected. For example, the correction values ​​may be subtracted from the received light intensity of each of the measurement light of the three wavelengths. This correction makes it possible to eliminate the influence of characteristic fluctuations due to changes in the ambient temperature or the temperature of the object being measured, fluctuations in the sensitivity of photodetector 18 due to temperature changes, the influence of radiated light from the object being measured or the measuring instrument, etc.

[0046] The same correction value does not necessarily have to be applied to the detection results of the three wavelengths obtained within one switching cycle. For example, the correction value obtained during a certain off-period may be applied to the detection results of the two wavelengths obtained immediately before that off-period and the detection result of the one wavelength obtained immediately after that off-period. This reduces the time lag between background light measurement and correction.

[0047] Correction does not necessarily have to be performed after obtaining the measurement results for the three wavelengths. For example, an off period can be provided between measurements at each wavelength, and measurements and corrections can be repeated in the following order: measurement at the first wavelength → measurement and correction of background light → measurement at the second wavelength → measurement and correction of background light → measurement at the third wavelength → measurement and correction of background light... This method allows the detected value for each measurement wavelength to be corrected using the correction value obtained most recently.

[0048] The influence of disturbances is effectively eliminated by switching the detection interval (interval with value "1") and off interval (interval with value "0") of the photodetector 18 at short intervals. Furthermore, the contact state between the measurement optical element 17 and the measurement site may change during measurement, causing the obtained absorbance to fluctuate. However, by providing off intervals at short intervals, it is possible to absorb the fluctuations in absorbance due to changes in the contact state, etc., and improve measurement accuracy.

[0049] Prior to actual measurement, the output intensity of each of light sources 111, 112, and 113 may be changed in stages. The linearity of photodetector 18 can be corrected by checking the change in the light intensity received by photodetector 18 in response to the change in light source output intensity. Over a very short period of time when it can be assumed that there are no changes in the measurement target or measurement environment, the output intensity of the light source and the light intensity received by photodetector 18 should be linearly proportional. However, if the linearity of photodetector 18 is poor, a region will occur where the output intensity of the light source and the light intensity received by photodetector 18 deviate from the linear proportionality. In this case, the influence of the nonlinearity of photodetector 18 may be eliminated by using only data from the linear region obtained in advance.

[0050] <Identifying the wavelength range suitable for measurement> Next, a description will be given of a suitable wavelength range to be used for measuring a biomarker. In the embodiment, at least a wavelength selected from the following wavelength range is used. (A) Wave number 970cm -1 More than 1010cm -1 The first wavelength selected from the following range and the wave number 950 cm -1 Above, 990cm -1 The second wavelength is selected from the following ranges: (B) Wave number 1130cm -1 Above, 1220cm -1 Two wavelengths selected from the following range: In particular, wavenumber 1156 cm -1 ~1164cm -1 The first wavelength and the wave number 1164 cm -1 ~1174cm -1 The second wavelength combination, or wave number 1134 cm -1 ~1146cm -1The first wavelength and the wave number 1170 cm -1 ~1216cm -1 The correlation is high when the second wavelength is combined with the first wavelength. (C) Wave number 1700cm -1 Above, 1760cm -1 Two wavelengths selected from the following ranges:

[0051] When using wavelength range (A), at least 970 cm -1 More than 1010cm -1 The absorbance at a first wavelength selected from the following range and 950 cm -1 Above, 990cm -1 A biomarker can be estimated from the absorbance at a second wavelength selected from the following range:

[0052] When using wavelength range (B), 1130 cm -1 Above, 1220cm -1 Biomarkers can be estimated from absorbance at at least two wavelengths selected from the following ranges: wavenumber 1156 cm -1 ~1164cm -1 The absorbance obtained with the first wavelength of light and the wavenumber of 1164 cm -1 ~1174cm -1 When using the absorbance obtained with light of the second wavelength, or the wavenumber 1134 cm -1 ~1146cm -1 The absorbance obtained with the first wavelength of light and the wavenumber of 1170 cm -1 ~1216cm -1 When the absorbance obtained with the light of the second wavelength is used, the estimation accuracy is improved.

[0053] When using wavelength range (C), 1700 cm -1 Above, 1760cm -1 Biomarkers can be estimated from absorbance at least two wavelengths selected from the following ranges:

[0054] It is not necessary to use only one of the wavelength ranges (A) to (C), but two or more wavelengths may be selected by combining wavelength ranges (A) to (C). The basis for these wavelength ranges will be explained using blood sugar (glucose) as an example of a biomarker.

[0055] In this embodiment, blood glucose levels are measured stably and accurately regardless of individual differences in metabolism from before to after a meal, or differences in the measurement environment or measurement conditions. First, to reduce the variability in measurement results due to individual differences, blood glucose measurement results are collected from multiple subjects with multiple different meal contents over a wide time range from 100 minutes before to 250 minutes after a meal. The correlation between the obtained measurement results and a typical blood glucose level transition (low before a meal, peaking 40 minutes after a meal, and then returning to pre-meal levels 180 minutes after a meal) is calculated, and the wavelength range where the correlation is high is identified.

[0056] Furthermore, in order to reduce the influence of variations in the contact state between the measurement optical element 17 (for example, an ATR prism) and the measurement site, the following prediction formula is used: y=a×x(sense) / x(base)+b (2) where y is the blood glucose level estimated from the measurement results of the photodetector 18, x(sense) is the absorbance at the sense wavelength that is sensitive to the molecules contained in glucose, and x(base) is the absorbance at the base wavelength that normalizes the contact state of the ATR prism. x(sense) and x(base) correspond to the absorbance A(k) in equation (1). "a" and "b" are coefficients of a linear equation that performs sensitivity correction from the absorbance ratio [x(sense) / x(base)] to the blood glucose level value y. Since coefficients a and b depend on individual differences between devices and people, they may be updated by learning during data collection and actual measurement. For example, when the sense wavelength is 980 cm -1 , base wavelength 986 cm -1 In this case, the values ​​would be a=-1900, b=2000, etc.

[0057] By dividing the absorbance measured at the sense wavelength by the absorbance at the reference base wavelength, it is possible to correct for variations in the contact state that occur with each measurement. In this study, the base wavelength and sense wavelength were not distinguished when specifying the wavelength range, so for convenience they are referred to as the base wavelength and sense wavelength. However, in practice, the found base wavelength can be used as the absorption wavelength of the object being measured, and the sense wavelength can be used as the reference wavelength. In other words, the identified base wavelength and sense wavelength are valid even if they are reversed.

[0058] As an example, the lip is used as the measurement site and the light absorption spectrum intensity of the lip is measured. A lamp light source of a Fourier transform infrared spectrometer is used as the light source, and the light absorption spectrum intensity of the lip is measured for each wavelength.

[0059] Using the above prediction formula (2), we calculate the correlation with the typical change in blood glucose levels before and after a meal, taking one meal per person as one series. Blood glucose levels are measured by multiple subjects at random times between 100 minutes before and 250 minutes after eating, with multiple different meal contents.

[0060] Figure 7 is a diagram in which the coefficient of determination for each series obtained is mapped against the sense wavelength (first wavelength) and base wavelength (second wavelength). The horizontal axis is the base wavelength, the left vertical axis is the sense wavelength, and the right vertical axis is the coefficient of determination. The coefficient of determination is expressed as the mean of the square of the correlation coefficient R and is an index of prediction accuracy. The correlation here is the correlation between the blood glucose levels before and after meals obtained from each person and their typical trends, as described above.

[0061] In the map in Figure 7, lighter colors indicate stronger correlations. Areas A, B, and C with high correlations are indicated by circles. Area A is 970±20cm -1 (i.e. 950cm -1 Above, 990cm -1 (below) and 990±20cm -1 (i.e. 970cm -1 More than 1010cm -1The combination of base wavelengths (or the reverse combination) of the wavelengths (A) and (B) is the basis for the wavelength range (A) above.

[0062] Region B is 1130 cm -1 From 1220cm -1 As will be described later, in region B, the wavelengths of the first and second wavelengths are selected from the range of 1130 cm -1 From 1220cm -1 Within this range, there are two combination regions where the correlation is particularly high. Region B is the basis for the wavelength range (B) above.

[0063] Region C is 1700 cm -1 From 1760cm -1 and the sense wavelength of 1700cm -1 From 1760cm -1 Region C is the basis for the wavelength range (C) above.

[0064] <Measurement in Area A> Figure 8 is an enlarged view of region A. -1 Above, 990cm -1 In the range of the first wavelength (e.g., sense wavelength) below 980 cm -1 The coefficient of determination is large. 970cm -1 More than 1010cm -1 In particular, in the range of the second wavelength (e.g., base wavelength) below 986 cm -1 The coefficient of determination is large.

[0065] Even when multiple people are measuring different meal contents at any time between 100 minutes before and 250 minutes after eating, the first wavelength is set to 950 cm -1 Above, 990cm -1 Select from the following range and set the second wavelength to 970cm -1 More than 1010cm -1 By selecting from the following ranges, blood glucose levels can be estimated with high accuracy.

[0066] By using two or more wavelengths selected from the above range and estimating blood glucose levels based on the absorbance at each wavelength according to prediction formula (2), stable and accurate measurements are possible from before to after meals.

[0067] By using the absorbance ratio, which is the absorbance at the sense wavelength divided by the absorbance at the reference base wavelength, it is possible to correct for variations in the contact condition between the ATR prism and the lips, which varies from measurement to measurement.

[0068] Figure 9 shows the 990cm -1 The data obtained at the sense wavelength near the 990cm wavelength are overlaid with the absorbance normalized to the base wavelength near the sense wavelength. Although the normalized absorbance varies depending on the data, when viewed as a whole, -1 There is a small absorbance peak around 950 cm. This peak is the absorption peak due to the CHOH group of glucose. As shown in area A of the determination coefficient map in Figure 7, -1 Above, 990cm -1 The sense wavelength is selected in the following range, and 970 cm -1 More than 1010cm -1 It has been found that combinations of base wavelengths selected in the following ranges, or vice versa, are suitable for detecting glucose.

[0069] The light source device 11 of the measurement device 1 in FIG. -1 Above, 990cm -1 The first wavelength selected in the following range and 970cm -1 More than 1010cm -1 Blood glucose level measurement is performed by setting the second wavelength selected from the following range: This allows stable and accurate non-invasive blood glucose level measurement to be achieved regardless of individual differences or fluctuations in the contact state between the measurement optical element 17 and the measurement site.

[0070] The wavelengths used in the biomarker measurement are not limited to one sense wavelength and one base wavelength. For example, in addition to the sense wavelength and base wavelength described above, a second base wavelength may be used, such as 950 cm -1 Above, 990cm -1The following range or 970cm -1 More than 1010cm -1 You can also select from the following ranges. In addition to the two wavelengths above, 950 cm is also used to reduce noise during measurement by averaging. -1 More than 1010cm -1 Two or more wavelengths, for example, about 5 wavelengths or 20 wavelengths, may be used within the following range: Alternatively, the second base wavelength may be selected from region B or region C.

[0071] The absorbance is defined as a function of the base wavelength so that the ratio of the absorbance at the first base wavelength to the absorbance at the second base wavelength is 1. For example, if the horizontal axis is the base wavelength and the vertical axis is the absorbance at the base wavelength, the intercept is found so that the slope of the line is 1. The absorbance obtained at the sense wavelength is divided by the absorbance at the base wavelength expressed by this linear equation, and the blood glucose level is estimated from prediction equation (2).

[0072] As an example, the first base wavelength is 954 cm -1 Set 1202 cm as the second base wavelength. -1 and divide the absorbance at the sense wavelength by the linear equation for the absorbance at the base wavelength.

[0073] Figure 10 shows the absorbance obtained from one sense wavelength and two base wavelengths, which are overlaid. -1 and 1202cm -1 , the sense wavelength is 992 cm -1 As shown in Figure 10, the -1 The CH2OH peak in the vicinity can be extracted, allowing for accurate prediction of blood glucose levels. Using three wavelengths results in a higher coefficient of determination than measuring with two wavelengths.

[0074] Instead of setting the sense wavelength and the base wavelength to specific wavelengths, an average of a series of wavelengths included in the above wavelength range may be used as at least one of the sense wavelength and the base wavelength. For example, the absorbance of the sense wavelength may be set to 992 cm -1 ~994cm -1Alternatively, the average value of the absorbance measured at wavelengths between may be used. This can reduce measurement noise. Alternatively, the average value of the absorbance over a predetermined range of wavelengths may be used in addition to the sense wavelength and base wavelength of a specific wavelength.

[0075] As the third wavelength, a wavelength selected from region B or region C may be used. For example, in addition to the sense wavelength selected in region A and the predicted value at the base wavelength, a wavelength of 1700 cm -1 ~1760cm -1 The final predicted value may be calculated by combining the average values ​​of the predicted values ​​from multiple viewpoints. Since blood glucose levels are predicted from multiple viewpoints, the estimation accuracy is improved.

[0076] <Measurement in area B> Figure 11 is an enlarged view of region B. In region B, both the sense wavelength and the base wavelength are 1130 cm -1 Above, 1220cm -1 The coefficient of determination is large in the following range: Within region B, there are combinations of sense wavelength and base wavelength that give particularly high coefficients of determination.

[0077] The first combination is the region located near the diagonal line in Figure 11. If one of the base wavelength and the sense wavelength is the first wavelength and the other is the second wavelength, then First wavelength: 1156cm -1 ~1164cm -1 Second wavelength: 1164cm -1 ~1174cm -1 The coefficient of determination is high for the combination of Figure 12. Figure 12 shows an enlarged view of the vicinity of this combination range.

[0078] The second combination is a vertically elongated region extending below the diagonal line in Fig. 11 or a horizontally elongated region extending above the diagonal line. If one of the base wavelength and the sense wavelength is the first wavelength and the other is the second wavelength, then: First wavelength: 1134cm -1 ~1146cm -1 Second wavelength: 1170cm-1 ~1216cm -1 The coefficient of determination is high for the combination of 1170cm. Figure 13 is an enlarged view of the vicinity of the second combination range. -1 ~1216cm -1 The base wavelength is 1134cm -1 ~1146cm -1 By using this sense wavelength, the correlation between the measurement results and the typical transition of blood glucose levels becomes high.

[0079] Even when multiple people have different dietary habits and measure their blood glucose levels at any time between 100 minutes before and 250 minutes after eating, accurate blood glucose levels can be estimated by selecting the sense wavelength and base wavelength from the first or second combination.

[0080] Using two or more wavelengths selected from region B and estimating blood glucose levels based on the absorbance at each wavelength according to prediction formula (2), stable and accurate measurements are possible from before to after a meal. By using the absorbance ratio, which is the absorbance at the sense wavelength divided by the absorbance at the reference base wavelength, it is possible to correct for variations in the contact state between the ATR prism and the lips, which varies from measurement to measurement.

[0081] Figure 14 shows the 1160cm -1 The data obtained at the surrounding sense wavelengths are overlaid with the absorbance normalized to the base wavelength near the sense wavelength. Although the normalized absorbance varies depending on the data, the absorbance at 1160 cm -1 There is an absorbance peak around 1130 cm. This peak is an absorption peak due to the pyranose ring of glucose. As shown in the coefficient of determination map in Figure 11, -1 Above, 1170cm -1 It can be seen that two wavelengths selected in the following ranges are suitable for detecting glucose.

[0082] The light source device 11 of the measurement device 1 in FIG. -1 Above, 1220cm -1Blood glucose levels are measured by setting the first and second wavelengths selected within the following ranges. This allows stable and accurate non-invasive blood glucose level measurement to be achieved regardless of individual differences or fluctuations in the contact state between the measurement optical element 17 and the measurement site.

[0083] The wavelengths used in biomarker measurements are not limited to one sense wavelength and one base wavelength. For example, 1130 cm -1 Above, 1220cm -1 In addition to the sense wavelength and base wavelength selected in the following ranges, a second base wavelength may be used. -1 Above, 1220cm -1 You can select from the following ranges, or you can select from Area A (950 cm -1 More than 1010cm -1 below), or region C (1700 cm -1 Above, 1760cm -1 You may choose from the following ranges:

[0084] When a second base wavelength is used, the absorbance is defined as a function of the base wavelength so that the ratio of the absorbance at the first base wavelength to the absorbance at the second base wavelength is 1. With the base wavelength on the horizontal axis and the absorbance at the base wavelength on the vertical axis, the intercept is determined so that the slope of the line is 1. The absorbance obtained at the sense wavelength is divided by the absorbance at the base wavelength expressed by this linear equation, and the blood glucose level is estimated using prediction formula (2). Using three wavelengths results in a higher coefficient of determination than measurement using two wavelengths.

[0085] Instead of setting specific wavelengths as the sense wavelength and the base wavelength, the average of the absorbance of a series of wavelengths included in region B may be used as at least one of the sense wavelength and the base wavelength. Alternatively, in addition to the sense wavelength and the base wavelength being set to specific wavelengths, the average of the absorbance of a predetermined wavelength range may be used. For example, the absorbance of at least one of the sense wavelength and the base wavelength, or the third absorbance, may be set to 1162 cm -1 ~1168cm -1Alternatively, the average absorbance of the blood glucose level may be used. This reduces measurement noise. Since blood glucose levels are predicted from multiple perspectives (glucose components), prediction accuracy is improved.

[0086] <Measurement in area C> Figure 15 is an enlarged view of region C. In region C, both the sense wavelength and the base wavelength are 1700 cm -1 Above, 1760cm -1 The coefficient of determination is large in the following range. If one of the base wavelength and the sense wavelength is the first wavelength and the other is the second wavelength, First wavelength: 1738±8cm -1 Second wavelength: 1748±8cm -1 The combination of the sense wavelength and base wavelength is 1743±8cm. -1 If the first wavelength is wave1 and the second wavelength is wave2, the particularly bright range enclosed by the frame in FIG. 15 (the range with a large coefficient of determination) is Wave2=1743cm -1 -(wave1-1743cm -1 )±8cm -1 It may also be expressed as:

[0087] Figure 16 shows the 1740cm -1 The data obtained at the surrounding sense wavelengths are overlaid with the absorbance normalized to the base wavelength near the sense wavelength. -1 ~1744cm -1 An absorbance peak is observed around 1740cm -1 Near this point, there are absorption peaks for carbonyl groups due to C=O bonds. By detecting substances related to intracellular glucose metabolism, such as ketone bodies such as acetoacetate and 3-hydroxybutyrate, G6P, F6P, and pyruvate present in the cytosol, and intracellular acetyl-CoA (coenzyme A), blood glucose concentrations can be regressed and estimated.

[0088] A wavelength selected from region C may be combined with a wavelength selected from region A or a wavelength selected from region B. This allows the blood glucose level to be estimated from various components in the blood, improving measurement accuracy.

[0089] Up to this point, we have mainly estimated blood glucose levels using two wavelengths. To further improve the estimation accuracy, it is possible to estimate blood glucose levels based on the cross-correlation value between the absorption spectrum of the glucose solution and the absorption spectrum of the person being measured. A high cross-correlation between the absorption spectrum of the glucose solution and the absorption spectrum of the person being measured indicates that the absorption spectrum of the person being measured contains a large amount of glucose.

[0090] When estimating blood glucose levels based on cross-correlation values, it is desirable to correct for differences and variations in the degree of contact between the human body and the ATR prism to capture minute changes. For example, before calculating the cross-correlation, it is preferable to pre-process and normalize the absorption spectrum of the glucose aqueous solution and the absorption spectrum of the subject. The absorption spectrum of glucose (the substance to be measured) may be measured in advance and stored in an internal or external memory of the information processing device 30. The pre-processing may be performed by the data processing unit 31 of the information processing device 30. As an example, the pre-processing is divided into three stages.

[0091] First, the absorbance value of the neighboring wavenumber is divided. The output of the divided spectrum, absorbance_d(i), is expressed by the following formula: absorbance_d(i) =[absorbance(i) / absorbance (i-r1)]-1 (3) Here, absorbance(i) is the absorbance at wavenumber i, and r1 is a value that specifies the wavenumber distance at which normalization is performed. When absorbance(i) and absorbance (i-r1) are the same value, the output of the division spectrum will be 0.

[0092] Next, to capture minute changes, the value of the neighboring wavenumber is subtracted from the divided value. The output of the difference spectrum, absorbance_d2(i), is expressed by the following formula: absorbance_d2(i) = absorbance_d(i) - absorbance_d(i-r2) (4) Here, r2 is a value that specifies how many wave numbers apart the subtraction is performed.

[0093] Furthermore, to reduce the variation in the data, a moving average filter is applied to the output of the difference spectrum for smoothing. The spectrum abs(i) after applying the moving average filter is expressed by the following equation:

number

[0094] Here, N is the range over which the moving average filter takes the average.

[0095] If the absorption spectrum of the glucose aqueous solution that has been pretreated as described above is taken as ref, and the absorption spectrum of the subject that has been similarly pretreated is taken as abs, the cross-correlation value is expressed as follows:

number

[0096] Here, "corr" is the cross-correlation value, "st" is the start wavelength of the wavelength range in which cross-correlation is obtained, and "en" is the end wavelength of the wavelength range in which cross-correlation is obtained. The cross-correlation value "corr" is linearly transformed using the following formula to obtain the target biometric indicator, which in this example is the estimated blood glucose level "estimated_glucose." Estimated_glucose=a×(corr)+b (5) Here, a and b are coefficients obtained by fitting using data labeled with true blood glucose levels.

[0097] The above method can estimate blood glucose levels from the absorption spectrum of a subject. However, depending on the wavelength range, the spectrum of the glucose solution may not contain any clues, such as absorption peaks or dips, or may contain peaks or dips of substances other than glucose that fluctuate, hindering estimation. Therefore, it may be desirable to use an appropriate wavelength range.

[0098] Figure 17 shows the range of high correlation between blood glucose level changes estimated by cross-correlation and typical blood glucose level changes in an average person. The correlation coefficient between the estimated blood glucose level (estimated_glucose) calculated from the cross-correlation value for the absorption spectrum of the subject measured at predetermined times after a meal and typical blood glucose level changes after a meal in an average person is shown by a shading indicator. The vertical axis represents the start wavelength "st" and the horizontal axis represents the end wavelength "en."

[0099] In Figure 17, there is a range (bright area) where the correlation is clearly good. The highest correlation is obtained at st = 982.5 cm ―1 , en=997.5cm -1 This wavelength range is thought to measure the absorption of the CH2OH group of glucose. This wavelength range is consistent with the results of the wavelength range (A) suitable for the above measurement. In wavelength range (A), -1 More than 1010cm -1 Light of the first wavelength selected from the following wave numbers and 950 cm -1 Above, 990cm -1 The use of light with a second wavelength selected from the following wave numbers also suggests that a high correlation can be obtained in estimation using the cross-correlation value. Using this wavelength range enables accurate estimation of blood glucose levels. This estimation method can be applied not only to humans, but also to estimating blood glucose levels in animals and other internal substances.

[0100] Although wavelength selection has been described above using blood glucose measurement as an example, the non-invasive measurement of the present invention is not limited to blood glucose measurement. The technical concepts of wavelength selection and determination in the embodiments can also be applied to the measurement of other biomarkers, such as proteins and tumor DNA in the blood.

[0101] As described above, when selecting a third or fourth wavelength in addition to the two wavelengths, it is possible to combine regions A, B, and C. This allows stable and accurate measurement of biological indices regardless of individual differences or differences in the measurement environment. [Explanation of symbols]

[0102] 1. Measuring equipment 10 Measurement optical system 11 Light source device 111, 112, 113 light source 12 Switch 121, 122, 123 Switching elements 13, 14 Multiplexer / demultiplexer 15, 16 Light guide member 17 Measuring optics 18 Photodetector 25 Data Logger 30 Information processing equipment 31 Data processing section 32 Biometric index estimation unit 33 Switching control section 34 Timing control section [Prior art documents] [Patent documents]

[0103] [Patent Document 1] Patent No. 5376439

Claims

1. a light source in the mid-infrared region; a photodetector that detects light output from the light source and reflected by the object to be measured; an information processing device that determines the blood glucose level of the measurement object based on the output of the photodetector; Equipped with The light source is 970 cm －１ Above, 1010cm －１ light having a first wavelength selected from the wave numbers below, and 950 cm －１ Above, 990cm －１ light having a second wavelength different from the first wavelength selected from the wave numbers below; and －１ Above, 1760cm －１ or less than 1130 cm －１ Above, 1220cm －１ Emitting light of a third wavelength selected from the following wave numbers: the information processing device determines the blood glucose level of the measurement object from a first absorbance of the light of the first wavelength, a second absorbance of the light of the second wavelength, and a third absorbance of the light of the third wavelength. Measuring equipment.

2. a light source in the mid-infrared region; a photodetector that detects light output from the light source and reflected by the object to be measured; an information processing device that determines the blood glucose level of the measurement object based on the output of the photodetector; Equipped with The light source is 1130 cm －１ Above, 1220cm －１ light having a first wavelength and a second wavelength different from each other and selected from the following wave numbers: 1700 cm －１ Above, 1760cm －１ Below, 970cm －１ Over 1010cm －１ or less, or 950 cm －１ Over 990cm －１ Emitting light of a third wavelength selected from the following wave numbers: the information processing device determines the blood glucose level of the measurement object from a first absorbance of the light of the first wavelength, a second absorbance of the light of the second wavelength, and a third absorbance of the light of the third wavelength. Measuring equipment.

3. The wave number of the first wavelength is 1156 cm －１ Above, 1164cm －１ is as follows: The wave number of the second wavelength is 1164 cm －１ Above, 1174cm －１ is The measuring device according to claim 2 .

4. The wave number of the first wavelength is 1134 cm －１ Above, 1146cm －１ is as follows: The wave number of the second wavelength is 1170 cm －１ Above, 1216cm －１ is The measuring device according to claim 2 .

5. the information processing device estimates the blood glucose level based on a value obtained by dividing the first absorbance by the second absorbance. The measuring device according to any one of claims 1 to 4.

6. the information processing device determines a normalization line such that a ratio of the second absorbance to the third absorbance becomes 1, and normalizes the first absorbance using the normalization line. The measuring device according to any one of claims 1 to 5.

7. a measurement optical element disposed between the light source and the photodetector and configured to emit reflected light from the measurement object toward the photodetector; The measuring device according to any one of claims 1 to 6, further comprising:

8. the measurement optics is an attenuated total internal reflection prism; 8. The measuring device according to claim 7.

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