Method for measuring component concentration

Abstract

To provide a method for reducing deviation between a component concentration measurement value in whole blood and a component concentration measurement value in plasma.SOLUTION: In one aspect, a method for measuring a plasma component concentration using a whole blood sample includes measuring a whole blood component concentration using a whole blood sample by an electrochemical sensor method, calculating a correction value using a whole blood component concentration measurement value obtained by the measurement, a hematocrit value of the whole blood sample, and a response index of a sensor used for measuring the whole blood component concentration, and calculating a plasma component concentration using the correction value and the whole blood component concentration measurement value.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] The present invention relates to a method for measuring the concentration of a component in blood using a whole blood sample. [Background technology]

[0002] In the medical field, electrochemical methods are widely used to measure the concentrations of biological components. Among these methods, electrochemical methods are used to measure the glucose concentration in blood. Typically, the glucose concentration is measured as the concentration in plasma. However, this requires that whole blood be centrifuged in advance, which is a complicated procedure. Therefore, it has been proposed to measure the glucose concentration in whole blood and then correct it to the glucose concentration in plasma (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 9-318634 Summary of the Invention [Problem to be solved by the invention]

[0004] The method disclosed in Japanese Patent Laid-Open No. 9-318634 discloses that a whole blood sample is used to measure the glucose concentration (EP) measured by the equilibrium point method and the glucose concentration (DI) measured by the first derivative method, and these are then converted to the glucose concentration (GL) in a plasma sample using the following formula: GL = EP + a × (EP - DI) + b (1) In the above formula (1), a and b are constants.

[0005] However, the present inventors have found a problem in that the glucose concentration obtained by the above method may deviate from the measured glucose concentration (plasma value (true value)) when actually measured in plasma. Through further research, they have found that one of the causes of the discrepancy is the hematocrit value, and that the discrepancy increases as the hematocrit value increases. They have found that this discrepancy problem is particularly pronounced when the glucose concentration is high.

[0006] Therefore, the present disclosure provides a method, a measurement device, and a program that can measure the concentration of plasma components from a whole blood sample regardless of the hematocrit value.The present disclosure provides a method and a program that can measure or determine the hematocrit value from a whole blood sample. [Means for solving the problem]

[0007] In one aspect, the present disclosure relates to a method for measuring plasma component concentrations using a whole blood sample, the method including measuring the whole blood component concentrations using a whole blood sample by an electrochemical sensor method, calculating a correction value using the whole blood component concentration measurement value, the hematocrit value of the whole blood sample, and a response index of the sensor, and calculating the plasma component concentration using the correction value and the whole blood component concentration measurement value.

[0008] In another aspect, the present disclosure relates to a method for measuring plasma glucose concentration using a whole blood sample, the method including: obtaining a glucose concentration measurement value (EP) by an equilibrium point method and a glucose concentration measurement value (DI) by a first derivative method using the whole blood sample using a glucose sensor method; obtaining a whole blood glucose concentration value (GL) using the obtained glucose concentration measurement value (EP) and glucose concentration measurement value (DI) according to the following equation (1); obtaining a correction value (CR) using the whole blood glucose concentration value (GL), the hematocrit value (Hct value) of the whole blood sample, a sensor response index, and a reference response index r according to the following equation (9); and obtaining a plasma glucose concentration (GL2) using the whole blood glucose concentration value (GL) and the correction value (CR) according to the following equation (10). GL = EP + a×(EP - DI) + b ···(1) In formula (1), a is a constant where 0.5 ≤ a ≤ 3.0, and b is a constant where 0 < b ≤ 10. CR = Hct value × correction value determination coefficient p × (reference responsiveness index r / responsiveness index) × [GL - [(Hct value × axis determination coefficient m + axis determination coefficient n) × (responsiveness index / reference responsiveness index r)]] , ,

[0011] ···(9) In formula (9), the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants. GL2 = GL - CR ···(10)

[0009] In still other aspects, the present disclosure relates to an apparatus for measuring the plasma component concentration using a whole blood sample, comprising a measurement unit that measures the component concentration of the whole blood sample by an electrochemical sensor method, and a control unit that calculates the plasma component concentration from the measurement value obtained by the measurement unit. The control unit calculates a correction value using the whole blood component concentration measurement value obtained by the measurement unit, the hematocrit value of the whole blood sample, and the responsiveness index of the sensor, and calculates the plasma component concentration using the obtained correction value and the whole blood component concentration measurement value.

[0010] In still other aspects, the present disclosure relates to a program for determining the plasma component concentration from a whole blood sample, comprising a correction value calculation step of calculating a correction value using a measurement value obtained by measuring the whole blood component concentration using a whole blood sample by an electrochemical sensor method, the hematocrit value of the whole blood sample, and the responsiveness index of the sensor, and a concentration calculation step of calculating the plasma component concentration using the correction value and the measurement value.

[0011] In still other aspects, the present disclosure relates to a program for determining plasma glucose concentration using a whole blood sample. The program includes a measurement step of measuring glucose concentration by an equilibrium point method and a first derivative method using a whole blood sample by a glucose sensor method; a first concentration calculation step of calculating a whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step; a correction value calculation step of calculating a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL) obtained in the first concentration calculation step, the hematocrit value (Hct value) of the whole blood sample, the response index of the sensor, and a reference response index r; and a second concentration calculation step of calculating a plasma glucose concentration (GL2) by the following formula (10) using the whole blood glucose concentration value (GL) and the correction value (CR). GL = EP + a × (EP - DI) + b ···(1) In formula (1), a is a constant where 0.5 ≤ a ≤ 3.0, and b is a constant where 0 < b ≤ 10. CR = Hct value × correction value determination coefficient p × (reference response index r / response index) × [GL - [(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index r)]] 2 ···(9) In formula (9), the correction value determination coefficient p, the reference response index r, and the axis determination coefficients m and n are constants. GL2 = GL - CR ···(10)

[0012] In still other aspects, the present disclosure relates to a method for measuring a hematocrit value using a whole blood sample, the method comprising: obtaining, by a glucose sensor method, a glucose concentration measurement value (EP) by an equilibrium point method and a glucose concentration measurement value (DI) by a first derivative method using the whole blood sample; obtaining a whole blood glucose concentration value (GL) by the following formula (1) using the obtained glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method; and obtaining a hematocrit value by the following formula (12) using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL). GL = EP + a×(EP - DI) + b ···(1) In formula (1), a is a constant with 0.5 ≤ a ≤ 3.0, and b is a constant with 0 < b ≤ 10. Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × [(GL) [Hct決定係数u] ···(12) In formula (12), Hct determination coefficients s, t, u are constants.

[0013] In still other aspects, the present disclosure relates to a program for determining a hematocrit value using a whole blood sample, the program causing execution of: a measurement step of measuring glucose concentration by an equilibrium point method and a first derivative method using a whole blood sample by a glucose sensor method; a first concentration calculation step of calculating a whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step; and a hematocrit value calculation step of calculating a hematocrit value by the following formula (12) using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL). GL = EP + a×(EP - DI) + b ···(1) In formula (1), a is a constant with 0.5 ≤ a ≤ 3.0, and b is a constant with 0 < b ≤ 10. Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t] × [(GL) [Hct決定係数u] ] ···(12) In equation (12), the Hct determination coefficients s, t, and u are constants. [Effects of the Invention]

[0014] According to the present disclosure, the plasma component concentrations can be measured from a whole blood sample regardless of the hematocrit value. According to the present disclosure, the hematocrit value can be measured from a whole blood sample. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a graph showing the difference between plasma glucose concentration values ​​and whole blood glucose concentration values ​​due to differences in hematocrit values. [Figure 2] FIG. 2 is a graph showing the difference between plasma glucose levels and whole blood glucose levels due to differences in sensor responsiveness. [Figure 3] FIG. 3 is a graph in which a quadratic approximation equation is applied to the discrepancy between plasma glucose measurements and whole blood glucose measurements. [Figure 4] Figure 4 is a graph showing the hematocrit value and axis position expressed as a linear equation. [Figure 5] FIG. 5 is a graph showing the hematocrit value based on the whole blood glucose concentration and the difference between the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method (DI). [Figure 6] FIG. 6 is a diagram showing an example of the appearance of an embodiment of a measurement device. [Figure 7] FIG. 7 is a schematic diagram showing an example of the configuration of a reaction cell in one embodiment of the measuring device. [Figure 8] FIG. 8 is a flowchart showing the procedure for measuring plasma glucose concentration in one embodiment. [Figure 9] FIG. 9 is a flowchart showing the procedure for measuring plasma glucose concentration in one embodiment. [Figure 10]FIG. 10 is a flowchart showing the procedure for measuring plasma glucose concentration in one embodiment. [Figure 11] FIG. 11 is a flowchart showing the flow of hematocrit value measurement in one embodiment. [Figure 12A] FIG. 12A is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.049 and Hct was 25%. [Figure 12B] FIG. 12B is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.049 and Hct was 42%. [Figure 12C] FIG. 12C is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.049 and Hct was 50%. [Figure 12D] FIG. 12D is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.049 and Hct was 65%. [Figure 13A] FIG. 13A is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.043 and Hct was 25%. [Figure 13B] FIG. 13B is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.043 and Hct was 42%. [Figure 13C] FIG. 13C is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.043 and Hct was 50%. [Figure 13D] FIG. 13D is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.043 and Hct was 65%. [Figure 14A] FIG. 14A is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.042 and Hct was 25%. [Figure 14B] FIG. 14B is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) at Hct 42% and the measured plasma glucose concentration when the responsiveness index was 0.042. [Figure 14C] FIG. 14C is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.042 and Hct was 50%. [Figure 14D] FIG. 14D is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.042 and Hct was 65%. [Figure 15A] FIG. 15A is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.038 and the Hct was 25%. [Figure 15B] FIG. 15B is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.038 and Hct was 42%. [Figure 15C] FIG. 15C is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.038 and Hct was 50%. [Figure 15D] FIG. 15D is a graph showing the deviations between the measured glucose concentration (GL) and corrected glucose concentration (GL2) and the measured plasma glucose concentration when the responsiveness index was 0.038 and Hct was 65%. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure provides a method for measuring the concentration of a component in plasma (plasma component concentration) from a whole blood sample comprising blood cells and liquid components, characterized in that the component concentration (EP) for the sample is determined by the equilibrium point method and the component concentration (DI) is determined by the first derivative method, and correction is performed using a correction formula including the product of a term related to the hematocrit value in the sample and a term related to the response index of the sensor.

[0017] In the present disclosure, a "whole blood sample" refers to blood collected from a subject that has not been subjected to a process for separating serum or plasma. However, the "whole blood sample" in the present disclosure may be one that has been subjected to an anticoagulation treatment or a dilution treatment with a reaction buffer when carrying out the measurement method of the present disclosure, or one that has not been subjected to these treatments. In one or more embodiments, the whole blood sample in the present disclosure does not contain serum or plasma.

[0018] In one or more embodiments, the term "plasma component concentration" used herein refers to the concentration of the component measured in a plasma sample, the concentration of the component corresponding to the concentration of the component in plasma, or the concentration of the component converted from the value of the component concentration measured in a whole blood sample. In one or more embodiments, the plasma component concentration used herein includes a plasma component concentration calculated by measuring the component concentration from a whole blood sample using the method of the present disclosure and correcting the obtained measurement value. One or more non-limiting embodiments of the plasma component concentration include plasma glucose concentration (glucose concentration in plasma).

[0019] In the present disclosure, "sensor responsiveness" refers to one of the performance indicators of a sensor used in measurements using an electrochemical sensor method, and in one or more embodiments, refers to an indicator that indicates the accuracy and rapidity of the sensor's response to changes in the concentration of a target substance. In the present disclosure, "sensor responsiveness index" refers to an indicator of the responsiveness of a sensor used in measurements of whole blood component concentrations using an electrochemical sensor method, and in one or more embodiments, can be determined as described below.

[0020] The electrochemical sensor method refers to a method for measuring the concentration of components in a biological sample such as blood using a sensor that converts a state into an electrical signal by utilizing the oxidation-reduction potential. As the electrochemical sensor method, in one or more embodiments, a glucose sensor method or the like can be mentioned.

[0021] In one or more embodiments, the measurement of glucose concentration by the glucose sensor method can be performed using a glucose sensor as described in Japanese Patent Application Laid-Open No. 2004-170401. As the glucose sensor, in one or more embodiments, a sensor or the like that converts a state into an electrical signal by utilizing the oxidation-reduction potential can be mentioned. As the method for measuring glucose concentration using the glucose sensor method, in one or more embodiments, there are an equilibrium point method and a first derivative method.

[0022] The glucose concentration in blood usually refers to the glucose concentration in plasma. However, from the viewpoint of measurement simplicity, as in the method described in Patent Document 1, measurement is performed using whole blood, and the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method are obtained, and these measurement values are converted into the glucose concentration (GL) in plasma by the following formula (1). GL = EP + a×(EP - DI) + b (1) In the above formula (1), a is a constant of 0.5 ≤ a ≤ 3.0, and b is a constant of 0 < b ≤ 10.

[0023] The measurement of glucose concentration by the equilibrium point method is performed by continuously measuring the output (current value) of the hydrogen peroxide electrode after the start of measurement (i.e., after injecting the sample into the cell) until it becomes substantially constant (equilibrium state) for a standard solution with a known glucose concentration, obtaining in advance the relationship between the constant output (sensor output value in the equilibrium state) and the glucose concentration as a calibration curve, and then measuring the output of the hydrogen peroxide electrode for a sample with an unknown glucose concentration, and similarly continuing the measurement until the output becomes substantially a constant value (equilibrium state), and obtaining the glucose concentration based on the calibration curve from the constant value (sensor output value in the equilibrium state). In other words, the rate of decomposition of glucose by glucose oxidase is proportional to the glucose concentration in the buffer solution, but since the amount of glucose decomposed by the enzyme is minute, the glucose concentration hardly changes, and therefore the rate of hydrogen peroxide production is constant in the steady state. The equilibrium point method uses the constant correlation that exists between this constant output value and the glucose concentration in the buffer solution as a calibration curve. In this equilibrium point method, a sufficient time (e.g., about 10 seconds) is required for the output to reach a constant value after the start of measurement. When blood cells are present in the liquid sample to be measured (e.g., a whole blood sample), this time is known to be sufficient for the glucose contained in the liquid within the blood cells to diffuse into the buffer solution against the resistance of the cell membranes of the blood cells. Therefore, the glucose that contributes to the glucose concentration (EP) measured by the equilibrium point method is both the glucose dissolved in the liquid components contained in the liquid sample and the glucose dissolved in the liquid within the blood cells.

[0024] On the other hand, the first-order differential method for measuring glucose concentration involves measuring the relationship between the output (current) of a hydrogen peroxide electrode and measurement time after the start of measurement for a standard solution with a known glucose concentration. Based on this, a calibration curve is then calculated, which shows the relationship between the maximum time change in output (the derivative of the output with respect to time, i.e., the rate of output) and the glucose concentration. Then, the time change in the output of the hydrogen peroxide electrode is measured for a sample with an unknown glucose concentration, and the maximum time change is similarly determined. The glucose concentration is then calculated from this maximum value based on the calibration curve. In other words, when the time change in output is determined by differentiating the relationship between the electrode output and time, a curve with a maximum value is obtained. The first-order differential method utilizes the constant correlation between the maximum value of the obtained curve and the glucose concentration in the buffer solution as a calibration curve. In such a first-order differential method, it is known that after measurement is started, it takes only a few seconds (for example, about 2 seconds) for the amount of change in output over time to reach a maximum value.

[0025] The present inventors have found that the glucose concentration (GL) obtained by the method of Patent Document 1 actually deviates from the glucose concentration measured using plasma, and that one of the reasons for this is due to the hematocrit value of the whole blood sample. That is, they have found that the greater the hematocrit value of the sample, the greater the deviation between the glucose concentration value in plasma and the glucose concentration value in whole blood. Measurement of glucose concentration using whole blood by the glucose sensor method can be performed using a glucose sensor and a reaction cell, as described in, for example, Japanese Patent Application Laid-Open No. 2004-170401. However, the present inventors have found that the responsiveness of the glucose sensor used for measurement may fluctuate, and that this fluctuation is one of the causes of the above-mentioned discrepancy; that is, when the responsiveness of the sensor decreases, the discrepancy between the glucose concentration value in plasma and the glucose concentration value in whole blood (plasma glucose concentration value) increases.

[0026] In one or more embodiments, the glucose sensor is composed of an electrode (hydrogen peroxide electrode) and a glucose oxidase-immobilized enzyme membrane (GOD membrane), with the GOD membrane attached to the tip of the electrode in an exposed state. A reaction cell is filled with a buffer solution, and the glucose sensor is inserted into the reaction cell so that the GOD membrane is in contact with the buffer solution in the reaction cell. A sample (blood) is introduced into the reaction cell, and the hydrogen peroxide produced during the process of glucose decomposition into gluconic acid in the GOD membrane is measured with the electrode, thereby measuring the glucose concentration in the blood. The responsiveness of the glucose sensor can be calculated using the formula (2) described below when periodically calibrating using an internal standard solution (glucose concentration: 150 mg / dL).

[0027] Figure 1 is a graph showing the difference between plasma glucose concentration values ​​at different hematocrit values ​​and whole blood glucose concentration values ​​obtained using the above formula (1). It can be seen that the higher the hematocrit value and the higher the glucose concentration, the greater the difference (absolute difference) from the plasma glucose concentration.

[0028] Figure 2 is a graph showing the difference between plasma glucose and whole blood glucose values ​​due to differences in sensor responsiveness. The sensor responsiveness index can be calculated using the following formula from the maximum differential value (DIF) of the sensor output when measuring samples with known glucose concentrations (0 mg / dL, 150 mg / dL) and the sensor output value (IV) when the sensor output is in equilibrium. Responsiveness index r=DIF / IV (2) IV=K STD -K0···(3) K STD The sensor output value (maximum A / D value) when the glucose concentration is 150 mg / dL and the equilibrium state is reached when measuring a sample. K0 is the sensor output value (maximum A / D value) when the equilibrium state is reached during measurement of a sample with a glucose concentration of 0 mg / dL. DIF=dK STD -dK0···(4) dK STD is the maximum value of the differential value of the sensor output (A / D value) when measuring a sample with a glucose concentration of 150 mg / dL. dK0 is the maximum value of the differential value of the sensor output (A / D value) when measuring a sample with a glucose concentration of 0 mg / dL.

[0029] In the above formula (1), the component concentration (EP) is calculated by the equilibrium point method using the above K STD and K0, the component concentration (DI) can be calculated by the following equation (5). STD and dK0, it can be calculated by the following equation (6). EP=(K sample -K0) / (K STD -K0) × 150 mg / dL (5) DI=(dK sample -dK0) / (dK STD -dK0) × 500 mg / dL (6) K sample is the sensor output value (maximum A / D value) when the equilibrium state is reached during the measurement of the test sample. dK sampleis the maximum differential value of the sensor output (A / D value) when measuring the test sample.

[0030] The inventors noted from Figures 1 and 2 that, in both cases of an increase in hematocrit value and a decrease in the sensor response index, as the whole blood glucose measurement value increases, the absolute difference (dissociation) from the plasma value (true value) changes in a convex parabolic curve.

[0031] In the course of further research, we plotted graphs for each hematocrit value, with the deviation (absolute difference) between plasma glucose measurements and whole blood glucose measurements on the vertical axis and whole blood glucose measurements on the horizontal axis, as shown in Figure 3. As a result, we found that when a quadratic approximation equation was applied, the slope of the deviation (absolute difference) between plasma and whole blood measurements varied depending on the hematocrit value; specifically, the slope increased with increasing hematocrit (change in slope). We also found that the position of the apex of the quadratic approximation equation varied depending on the hematocrit value; specifically, the apex of the quadratic curve shifted in the negative direction with increasing hematocrit (change in axis). Furthermore, we found that a similar trend was observed for the decrease in the sensor's response index, and found that it would be preferable to apply these to the correction equation.

[0032] Based on these findings, the inventors discovered that by correcting the "change in slope" and "change in axis" of the component concentration (EP) by the equilibrium point method and the component concentration (DI) by the first derivative method using the response index of the sensor used to measure the hematocrit value and component concentration in the sample, specifically by correcting using a correction equation including the product of a term related to the hematocrit value and a term related to the response index of the sensor, it is possible to correct the measurement value from a whole blood sample to the measurement value from a plasma sample, thereby reducing the deviation from the plasma value (true value).

[0033] First, we considered how to correct the "change in tilt." Based on Figure 3, which shows the deviation (absolute difference) between whole blood glucose concentration (GL) and plasma glucose concentration measurements due to differences in hematocrit value, a quadratic approximation equation was created to express the deviation between whole blood glucose concentration and plasma glucose concentration measurements. As shown in Figures 1 and 3, we focused on the fact that the slope of the quadratic approximation equation changes (increases) depending on the hematocrit value (Hct value) and increases by a certain coefficient (correction value determination coefficient p). Therefore, we obtained the "correction value determination coefficient p" from the slope of the approximation equation and the hematocrit value (Hct value). Furthermore, as shown in Figure 2, we focused on the fact that the deviation (absolute difference) from the plasma glucose concentration measurement increases with a decrease in the sensor's responsiveness index. By multiplying the obtained "correction value determination coefficient p" by [reference responsiveness index / responsiveness index], we derived the following equation (7), which can correct the slope. (Slope correction) = Hct value × correction value determination coefficient p × (reference response index / response index) (7)

[0034] The reference response index r is the response index measured using a standard solution with a glucose concentration of 150 mg / dL.

[0035] Next, we considered how to correct the "axis change." We found that the axis (vertex position) of the quadratic approximation equation shifts in the negative direction as the hematocrit value increases in Figure 3. We plotted the hematocrit value on the horizontal axis and the axis position on the vertical axis, and expressed this as a linear equation in Figure 4. By defining the slope of this linear equation as the axis determination coefficient m and the intercept as the axis determination coefficient n, we derived a linear equation (axis position = Hct value × m + n) that can determine the axis position according to the hematocrit (Hct value) value. Furthermore, as shown in Figure 2, we noted that the deviation (absolute difference) from the measured plasma glucose concentration increases as the sensor's responsiveness index decreases. By multiplying the obtained axis position determination equation (= Hct value × m + n) by [reference responsiveness index / responsiveness index], we derived the following equation (8), which can correct the axis. (Axis correction) = (Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index) (8)

[0036] Since the deviation (absolute difference) from the measured plasma glucose concentration value changes like a convex parabola, the correction formula (the following formula (9)) for obtaining the correction value (CR) for correcting the whole blood glucose concentration value (GL) was derived using the above formula (7) for correcting the slope and the above formula (8) for correcting the axis. Corrected value (CR) = Hct value × correction coefficient of determination p × (reference response index r / response index) × [whole blood glucose concentration value (GL) - {(Hct value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index r)}] 2 ···(9) Finally, noting that the deviation (absolute difference) from the measured plasma glucose concentration increases with an increase in hematocrit value and a decrease in sensor responsiveness, we obtained equation (10) that can correct the measured plasma glucose concentration to the corrected glucose concentration (GL2), which is the plasma glucose concentration with a reduced deviation (absolute difference), by subtracting this correction value (CR) from the whole blood glucose concentration value (GL). Corrected glucose concentration (GL2) = Whole blood glucose concentration value (GL) - Corrected value (CR) (10)

[0037] [Component concentration measurement method] In one aspect, the present disclosure relates to a method for measuring plasma component concentrations using a whole blood sample. The measurement method of the present disclosure includes measuring the whole blood component concentrations using a whole blood sample by an electrochemical sensor method, calculating a correction value using the whole blood component concentration measurement value obtained by the measurement, the hematocrit value of the whole blood sample, and a response index of a sensor used to measure the whole blood component concentration, and calculating the plasma component concentration using the correction value and the whole blood component concentration measurement value. According to the present disclosure, the plasma component concentrations can be measured from the whole blood sample regardless of the hematocrit value.

[0038] In one or more embodiments, the correction value may be calculated using the following formula (a): Corrected value = hematocrit value × corrected value coefficient of determination p × (reference response index r / response index) × [measured whole blood component concentration - {(hematocrit value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index)}] 2 (a) In the above formula (a), the hematocrit value is the hematocrit value of the whole blood sample, the responsiveness index is the responsiveness index of the sensor used to measure the concentration of the whole blood component, and the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.

[0039] In one or more embodiments, the plasma component concentration can be calculated using the following formula (b). Plasma component concentration = measured whole blood component concentration - corrected value (b) In the above formula (b), the measured whole blood component concentration value can be obtained by measuring the whole blood component concentration using a whole blood sample using an electrochemical sensor method, and the correction value can be calculated using the above formula (a).

[0040] In one or more embodiments, the plasma component in the method of the present disclosure may include glucose in plasma. Thus, in another aspect, the present disclosure relates to a method for measuring a glucose concentration (GL2) using a whole blood sample. In the present disclosure, "glucose concentration (GL2)" refers to the glucose concentration in plasma.

[0041] The method for measuring a glucose concentration (GL2) of the present disclosure includes measuring the glucose concentration at the equilibrium point and by the first derivative method using a whole blood sample using a glucose sensor, and obtaining a glucose concentration measured at the equilibrium point (EP) and a glucose concentration measured by the first derivative method (DI). Measurement of the glucose concentration at the equilibrium point and by the first derivative method can be performed by a known method using a glucose sensor, and in one or more embodiments, can be performed with reference to Patent Document 1, Japanese Patent Laid-Open No. 2004-170401, etc.

[0042] The method for measuring the glucose concentration (GL2) of the present disclosure includes obtaining the whole blood glucose concentration value (GL) by the following formula (1) using the obtained glucose concentration measurement value (EP) and glucose concentration measurement value (DI). GL = EP + a×(EP - DI) + b ···(1) In formula (1), a is a constant where 0.5 ≤ a ≤ 3.0, and b is a constant where 0 < b ≤ 10. a and b in formula (1) are constants, which are determined according to the sensor used for measurement and the measurement conditions, and can be set during the calibration of the sensor and / or device used for measurement in one or more embodiments. Specifically, measurements are performed using a plurality of samples (standard solutions) with known glucose concentrations (for example, 0 mg / dL, 150 mg / dL), the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method are obtained, and a and b can be obtained by applying the obtained values to the above formula (1). In one or more non-limiting embodiments, a is 0.5 or more and 3.0 or less, and b is 0 or more and 10 or less. In one or more non-limiting embodiments, a = 1.3 and b = 4.6 can also be used.

[0043] The method for measuring the glucose concentration (GL2) of the present disclosure includes obtaining a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL) obtained by formula (1), the hematocrit value (Hct value) of the whole blood sample, the response index of the sensor, and the reference response index r. CR = Hct value × correction value determination coefficient p × (reference response index r / response index) × [GL - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index r)}] 2 ···(9) In formula (9), the correction value determination coefficient p, the reference response index r, and the axis determination coefficients m, n are constants, and can be obtained by the method described later in one or more embodiments.

[0044] In one or more embodiments, the hematocrit value (Hct value) in Equation (b) and Equation (9) may be a hematocrit value measured in advance using a whole blood sample to be used for measurement, or a hematocrit value obtained using the hematocrit value measurement method of the present disclosure described below. In one or more embodiments, the hematocrit value can be measured using a commonly known microhematocrit method or an automated blood cell measuring device.

[0045] The responsiveness index in formulas (b) and (9) is an index that can evaluate the responsiveness of the glucose sensor used in the measurement, and can be determined by measurements during calibration using samples (standard solutions) of known glucose concentrations. In one or more embodiments, the responsiveness index can be calculated using formula (2) above using the maximum differential value (DIF) of the sensor output when samples of known glucose concentrations (0 mg / dL, 150 mg / dL) are measured, and the sensor output value (IV) when the sensor output is in an equilibrium state.

[0046] The reference responsiveness index r in Equation (b) and Equation (9) is a constant. The deviation (absolute difference) between the whole blood glucose concentration value (GL) and the measured plasma glucose concentration varies depending on the sensor's responsiveness index. Therefore, in one or more embodiments, the reference responsiveness index r is a standard for evaluating fluctuations in the sensor's responsiveness index and can be predetermined for each sensor (device). In one or more non-limiting embodiments, the responsiveness index when the glucose concentration is 150 mg / dL can be used as the reference responsiveness index r, and in one or more non-limiting embodiments, the reference responsiveness index r can be set to 0.049.

[0047] The coefficient of determination p of the correction value in Equation (b) and Equation (9) is a constant. In one or more embodiments, measurements are performed using a plurality of samples (standard solutions) having known hematocrit values ​​and glucose concentrations, a graph is created for each hematocrit value showing the relationship between the whole blood glucose concentration value (GL) and the measured plasma glucose concentration, and the coefficient of determination p can be calculated from the hematocrit value (Hct value) and the slope of the quadratic approximation equation obtained from the graph.

[0048] The axis determination coefficients m and n in Equation (b) and Equation (9) are constants. In one or more embodiments, the position of an axis corresponding to the hematocrit value is determined from a graph created in the same manner as in calculating the correction value determination coefficient p, and a linear equation is found with the obtained axis position as the vertical axis and the hematocrit value as the horizontal axis. The slope of the linear equation can be determined as the axis determination coefficient m, and the intercept can be determined as the axis determination coefficient n.

[0049] The method for measuring glucose concentration (GL2) of the present disclosure includes obtaining the glucose concentration (GL2) using the whole blood glucose concentration value (GL) and the correction value (CR) obtained by the above equation (9) using the following equation (10): GL2=GL-CR (10)

[0050] Although the present disclosure is described using glucose concentration, it is applicable to measuring the concentration of other constituents besides glucose that can be measured by electrochemical sensors.

[0051] In one or more embodiments, the method of the present disclosure may be implemented as a component concentration measurement program or a glucose concentration measurement program executed by a processor.

[0052] [program] In still other aspects, the present disclosure relates to a program for determining plasma component concentrations using a whole blood sample. The program of the present disclosure includes a correction value calculation step of calculating a correction value using a measurement value obtained by measuring the concentration of a whole blood component using a whole blood sample by an electrochemical sensor method, the hematocrit value of the whole blood sample, and the response index of the sensor used for the measurement of the whole blood component concentration, and a concentration calculation step of calculating the plasma component concentration using the correction value and the measurement value, and is a program for causing these steps to be executed.

[0053] In still other aspects, the present disclosure relates to a program for determining plasma glucose concentration using a whole blood sample. The program of this aspect includes a measurement step of measuring the glucose concentration by the equilibrium point method and the first derivative method using a whole blood sample by the glucose sensor method, a first concentration calculation step of calculating the whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step, a correction value calculation step of calculating a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL) obtained in the first concentration calculation step, the hematocrit value (Hct value) of the whole blood sample, the response index of the sensor, and the reference response index r, and a second concentration calculation step of calculating the plasma glucose concentration (GL2) by the following formula (10) using the whole blood glucose concentration value (GL) and the correction value (CR), and is a program for causing these steps to be executed. GL = EP + a×(EP - DI) + b ···(1) In formula (1), a is a constant such that 0.5 ≦ a ≦ 3.0, and b is a constant such that 0 < b ≦ 10. CR = Hct value × correction value determination coefficient p × (reference response index r / response index) × [GL - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index r)}] 2 ···(9) In formula (9), the correction value determination coefficient p, the reference response index r, and the axis determination coefficients m and n are constants. GL2 = GL - CR ···(10)

[0054] In one or more embodiments, the program of the present disclosure may be supplied to a system or device via a network or a storage medium and executed by a processor in the system or device by reading and executing the program. In one or more embodiments, examples of the processor include a central processing unit (CPU), a microprocessing unit (MPU), a graphics processing unit (GPU), a microprocessor, a processor core, a multiprocessor, an application-specific integrated circuit (ASIC), and a field programmable gate array (FPGA). In one or more embodiments, the program may be executed by a dedicated circuit, a logic circuit (hardware) formed in an integrated circuit (IC) chip, a large-scale integration (LSI), or the like.

[0055] [Measuring equipment] In yet another aspect, the present disclosure relates to an apparatus for measuring plasma component concentrations using a whole blood sample. The apparatus of the present disclosure includes a measurement unit that measures component concentrations of a whole blood sample using an electrochemical sensor method, and a control unit that calculates plasma component concentrations from measurements obtained by the measurement unit, wherein the control unit calculates a correction value using the whole blood component concentration measurements obtained by the measurement unit, the hematocrit value of the whole blood sample, and a response index of a sensor used to measure the whole blood component concentrations in the measurement unit, and calculates plasma component concentrations using the obtained correction value and the whole blood component concentration measurements. In one or more embodiments, the measurement apparatus of the present disclosure is capable of measuring plasma component concentrations from a whole blood sample using the measurement method of the present disclosure.

[0056] In one or more embodiments, the measurement unit includes at least an electrochemical sensor having a measurement electrode and a reaction cell that can be filled with a buffer solution and into which the electrochemical sensor can be inserted. Examples of the electrochemical sensor include a glucose sensor in one or more embodiments. The measurement unit may include a voltage source or the like that applies a predetermined voltage to the glucose sensor in one or more embodiments.

[0057] In one or more embodiments, the measurement unit can measure the glucose concentration by the equilibrium point method and the first derivative method using a whole blood sample by the glucose sensor method, thereby obtaining a glucose concentration measurement value (EP) by the equilibrium point method and a glucose concentration measurement value (DI) by the first derivative method.

[0058] In one or more embodiments, the control unit may include calculating the whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method. GL = EP + a×(EP - DI)+b ···(1) In formula (1), a is a constant with 0.5 ≤ a ≤ 3.0, and b is a constant with 0 < b ≤ 10.

[0059] In one or more embodiments, the control unit may include calculating a correction value (CR) by the following formula (a) or formula (9) using the whole blood glucose concentration value (GL), the hematocrit value (Hct value) of the whole blood sample, and the response index of the sensor. Correction value (CR)=Hct value × correction value determination coefficient p × (reference response index r / response index) × [whole blood component concentration measurement value - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index)}] 2 ···(a) Correction value (CR)=Hct value × correction value determination coefficient p × (reference response index r / response index) × [GL - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index r)}] 2 ···(9) In the above equations (a) and (9), the Hct value is the hematocrit value of the whole blood sample, the responsiveness index is the responsiveness index of the sensor used to measure the whole blood component concentration or the whole blood glucose concentration value (GL), and the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.

[0060] In one or more embodiments, the control unit may calculate the plasma constituent concentration or the plasma glucose concentration (GL2) using the following formula (b) or formula (10). Plasma component concentration = measured whole blood component concentration - corrected value (CR) (b) GL2=GL-CR (10)

[0061] In one or more embodiments, the measurement device of the present disclosure has a memory unit. In one or more embodiments, the memory unit can record the measurement method of the present disclosure and / or store the program of the present disclosure. In one or more embodiments, the memory unit may record the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n.

[0062] [Calculation of hematocrit value] The inventors further focused on the relationship between hematocrit and the difference (EP-DI) between the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method. Figure 5 shows a graph illustrating the relationship between hematocrit and the difference (EP-DI) between the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method (DI) using a whole blood sample. The inventors found that, as shown in Figure 5, the difference (EP-DI) between the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method increases as the hematocrit increases. The inventors further found that, as shown in Figure 5, the hematocrit and the difference (EP-DI) between the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method (DI) can be approximated by a linear equation depending on the glucose concentration (GL) obtained using a whole blood sample, and that the slope β of the linear equation becomes gentler as the glucose concentration increases. A graph of the relationship between the obtained slope β and the whole blood glucose concentration value (GL) (vertical axis: slope β, horizontal axis: GL) was created according to the sensor's response index. As a result, the slope β and the whole blood glucose concentration value (GL) were approximated by the power of the following equation (11). β = S × [GL] U ···(11) This showed that the slope β could be calculated from the whole blood glucose concentration value (GL). Furthermore, it was found that the coefficient U of the power approximation formula is almost constant and does not depend on the sensor's response index, while the coefficient S varies depending on the sensor's response index. Furthermore, an approximate line was created using the coefficient S corresponding to the sensor's response index, and the coefficient used to calculate the hematocrit value was derived from the obtained approximate line. Specifically, the slope of the approximate line was defined as "Hct determination coefficient slope s" and its intercept as "Hct determination coefficient intercept t."

[0063] As described above, "EP-DI" increases in proportion to the hematocrit value, the slope β is a power of the whole blood glucose concentration value (GL) as shown in the above formula (11), and the coefficient S depends on the response index of the sensor. From these facts, the inventors have obtained the glucose concentration measurement value (EP) by the equilibrium point method, the glucose concentration measurement value (DI) by the first derivative method, and the response index of the sensor obtained by measuring a whole blood sample by the glucose sensor method, and derived the following formula (12) for calculating the hematocrit value (Hct value). Hct value = (EP - DI) × {[Hct determination coefficient s] × response index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12)

[0064] Conventionally, the hematocrit value has been determined by separately centrifuging a whole blood sample to measure the height of the red blood cell layer or directly measuring the volume of red blood cells. However, by using the above formula (12), in one or more embodiments, the hematocrit value (Hct value) can be calculated using the measurement values obtained during glucose concentration measurement without centrifuging the whole blood sample or measuring the red blood cell volume.

[0065] The present disclosure further relates, in other aspects, to a method for measuring the hematocrit value using a whole blood sample. The method for measuring the hematocrit value of the present disclosure includes obtaining the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method using a whole blood sample by the glucose sensor method, obtaining the whole blood glucose concentration value (GL) by the following formula (1) using the obtained glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method, and obtaining the hematocrit value by the following formula (12) using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL). GL = EP + a × (EP - DI) + b ···(1) In formula (1), a is a constant with 0.5 ≦ a ≦ 3.0, and b is a constant with 0 < b ≦ १०. Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × Responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) In formula (12), the Hct determination coefficients s, t, and u are constants and can be determined by the above method.

[0066] In still other aspects, the present disclosure is a program for determining a hematocrit value using a whole blood sample, which includes a measurement step of measuring the glucose concentration by the equilibrium point method and the first derivative method using the whole blood sample by the glucose sensor method, and a first concentration calculation step of calculating the whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step, and a hematocrit value calculation step of calculating the hematocrit value by the following formula (12) using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL). The present disclosure relates to a program for executing these steps. GL = EP + a × (EP - DI) + b ···(1) In formula (1), a is a constant with 0.5 ≤ a ≤ 3.0, and b is a constant with 0 < b ≤ 10. Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × Responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) In formula (12), the Hct determination coefficients s, t, and u are constants and can be determined by the above method.

[0067] From this, the hematocrit value can be obtained by formula (12), and this hematocrit value may be used for the calculation of the correction value (CR).

[0068] Hereinafter, an embodiment of the method of the present disclosure will be described with reference to the drawings.

[0069] 6 is a diagram showing an example of the appearance of a measurement device according to this embodiment. This embodiment will be described by taking as an example a case where plasma glucose concentration is measured using a whole blood sample. The method of the present disclosure is not limited to this, and may be applied to the measurement of plasma components other than glucose.

[0070] As shown in FIG. 6, the measurement device 1 is composed of a main body 10, a sample supply unit 11, and a bottle unit 12. A panel 13 is provided on the upper front of the main body 10. The panel 13 can be used to operate the device and display analyzed measurement values. The sample supply unit 11 is provided on the lower front of the main body 10, and can accommodate multiple sample containers 14 filled with samples (whole blood samples). The bottle unit 12 is composed of a standard solution container 15 filled with an internal standard solution, a buffer solution container 16 filled with a buffer solution, a cleaning solution container 17 filled with a cleaning solution, and a drain container 18 that can store wastewater discharged from the measurement device 1, and the containers 15, 16, 17, and 18 are each connected to the main body 10 by a tube.

[0071] A reaction cell to which a glucose sensor can be attached is built into the main body 10 , and this glucose sensor and reaction sensor can at least constitute the measurement section of the measurement device 1 . 7 shows an example of the configuration of a reaction cell 21 equipped with a glucose sensor 22. A stirring bar 23 is disposed inside the reaction cell 21, and a buffer solution can be introduced into the reaction cell 21 through a channel at the bottom. A sample container 14 filled with a sample (whole blood sample) is placed in the sample supply unit 11, and the sample (whole blood sample) in the sample container 14 is aspirated by a nozzle (not shown) attached to the main body 10 and supplied into the reaction cell 21 from the top of the reaction cell 21. The stirring bar 23 can be rotated by a stirrer 24 placed below the reaction cell 21, thereby stirring the sample and buffer solution in the reaction cell 21. 7, the glucose sensor 22 has an electrode 22a, and a glucose oxidase-immobilized enzyme membrane (GOD membrane) 22b attached to the tip of the electrode 22a. A hole for attaching the glucose sensor 22 is formed in the side of the reaction cell 21, and the GOD membrane 22b is inserted into the reaction cell 21 from the side through the hole, and in this state the glucose concentration in the sample (whole blood sample) is measured.

[0072] An embodiment of measuring plasma glucose concentration using a whole blood sample will be described below.

[0073] Figures 8 to 10 are flowcharts for explaining one embodiment of plasma glucose concentration measurement using the measurement device 1 shown in Figure 6. The control unit of the measurement device 1 controls the measurement in the measurement unit according to the measurement flows in Figures 8 to 10 and executes processing etc. using the obtained measurement values. The control unit reads out information etc. necessary for processing etc. from the recording unit as necessary.

[0074] First, a glucose sensor 22 is attached to the reaction cell 21 of the measurement device 1, and the measurement device 1 (glucose sensor 22) is calibrated. Calibration can be performed by driving a buffer supply pump (not shown) to fill the reaction cell 21 with a buffer solution from the buffer solution container 16 through a tube, then driving a standard solution supply pump (not shown) to supply a standard solution from the standard solution container 15 through a tube to the reaction cell 21, and measuring the glucose concentration in the standard solution. By performing calibration, the constants a and b in the above equation (1) and the responsiveness indices in equations (b) and (9) can be determined. The determined constants a and b and responsiveness indices can be stored in the memory unit of the measurement device 1. Calibration of the measurement device 1 does not need to be performed for each sample measurement, but can be performed when a predetermined number of measurements have been performed, when a new glucose sensor 22 is attached to the reaction cell 21, or the like.

[0075] Next, a plurality of sample containers 14 filled with whole blood samples are placed in the sample supply unit 11. A buffer supply pump (not shown) is driven to fill the reaction cell 21 with buffer from the buffer container 16 through a tube (S801). A nozzle (not shown) is driven to insert the nozzle into the sample container 14, and then a sample pump (not shown) is driven to aspirate the whole blood sample into the nozzle. The whole blood sample aspirated into the nozzle is then introduced into the reaction cell 21 through the tube (S802). Once the whole blood sample has been supplied to the reaction cell 21, the measurement unit starts measuring the glucose concentration (S803), and the glucose concentration in the whole blood sample (whole blood glucose concentration) is obtained (S804). As shown in FIG. 9, the acquisition of the whole blood glucose concentration (S804) may be performed by acquiring a glucose concentration measurement value (EP) using the equilibrium point method (S904) and a glucose concentration measurement value (DI) using the first derivative method (S905), and then using these measurements and the constants a and b obtained by the above calibration to acquire the whole blood glucose concentration value (GL) using the following equation (1) (S906). GL = EP + a × (EP - DI) + b (1)

[0076] Next, a correction value is obtained (S805). The correction value can be obtained (S805) using the whole blood glucose concentration value (GL), the hematocrit value of the whole blood sample, and the responsiveness index obtained by the above calibration. The hematocrit value of the whole blood sample may be a value measured in advance, or a value obtained using the whole blood glucose concentration value (GL) as described below. The correction value (S805) may be obtained by using the whole blood glucose concentration value (GL), the hematocrit value (Hct value) of the whole blood sample, and the responsiveness index, etc., to obtain the correction value (CR) according to the following formula (9) (S907), as shown in FIG. 9. CR = Hct value × correction coefficient of determination p × (reference response index r / response index) × [GL - {(Hct value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index r)}] 2 ···(9) In the above equation (9), the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n may use values ​​pre-recorded in the memory unit, or may use values ​​obtained by the above calibration.

[0077] Then, the plasma glucose concentration is acquired (S806). The plasma glucose concentration can be acquired (S806) using the whole blood glucose concentration value (GL) acquired in S804 and the correction value (CR) acquired in S805. The plasma glucose concentration (S806) may be determined by using the whole blood glucose concentration value (GL) and the correction value (CR) to obtain the plasma glucose concentration (GL2) according to the following equation (10) (S908), as shown in FIG. 9. GL2=GL-CR (10)

[0078] The hematocrit value of the whole blood sample used in obtaining the correction value (S805) may be obtained using the glucose concentration measurement value (EP) obtained by the equilibrium point method in S1004, the glucose concentration measurement value (DI) obtained by the first derivative method in S1005, and the whole blood glucose concentration value (GL) obtained in S1006, as shown in FIG. 10, using the following equation (12) (S1007). Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) In the above formula (12), the Hct determination coefficients s, t, and u may use values ​​pre-recorded in the storage unit, or may use values ​​obtained by the above calibration. The correction value (CR) may be obtained (S1008) and the plasma glucose concentration (GL2) may be obtained (S1009) using the hematocrit value obtained in S1007.

[0079] Below, an example will be described in which the hematocrit value is measured using a whole blood sample to be used for measuring the plasma glucose concentration, separately from or in parallel with the measurement of the plasma glucose concentration using a whole blood sample.

[0080] FIG. 11 is a flowchart for explaining one embodiment of hematocrit value measurement using the measurement device 1 shown in FIG.

[0081] The calibration of the measuring device 1 can be carried out in the same manner as in the measurement of plasma glucose concentration described above.

[0082] A plurality of sample containers 14 filled with whole blood samples are placed in the sample supply unit 11. A buffer solution supply pump (not shown) is driven to fill the reaction cell 21 with buffer solution from the buffer solution container 16 through a tube (S1101). A nozzle (not shown) is driven to insert the nozzle into the sample container 14, and then a sample pump (not shown) is driven to aspirate the whole blood sample into the nozzle. The whole blood sample aspirated into the nozzle is then introduced into the reaction cell 21 through a tube (S1102). Once the whole blood sample has been supplied to the reaction cell 21, the measurement unit begins measuring the glucose concentration (S1103), and obtains a glucose concentration measurement value (EP) using the equilibrium point method (S1104) and a glucose concentration measurement value (DI) using the first derivative method (S1105).

[0083] Using the obtained EP and DI, and the constants a and b obtained in the above calibration, the whole blood glucose concentration value (GL) is obtained by the following equation (1) (S1106). GL = EP + a × (EP - DI) + b (1)

[0084] Next, the hematocrit value is obtained using the EP, DI, and GL according to the following formula (12) (S1107). Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) In the above formula (12), the Hct determination coefficients s, t, and u may use values ​​pre-recorded in the storage unit, or may use values ​​obtained by the above calibration.

[0085] The contents of each document mentioned herein are incorporated by reference as part of this disclosure. [Example]

[0086] Samples with various glucose concentrations and hematocrit values ​​were prepared. Whole blood samples were left at room temperature to undergo glycolysis, resulting in a sample with a glucose concentration of 0 mg / dL. Glucose solution was added to the 0 mg / dL sample to produce samples with glucose concentrations of 10 mg / dL, 30 mg / dL, 50 mg / dL, 70 mg / dL, 100 mg / dL, 150 mg / dL, 200 mg / dL, 300 mg / dL, 400 mg / dL, 500 mg / dL, and 600 mg / dL. Plasma was added or removed from each sample to adjust the hematocrit to 25%, 40%, 50%, or 65%.

[0087] The analytical equipment used was four Adams Glucose GA-1180 glucose analyzers manufactured by Arkray, Inc. The samples were measured using the whole blood analysis mode of the Adams Glucose GA-1180, and the whole blood glucose concentration value (GL) was obtained using the above formula (1).

[0088] Prior to the measurement, the device (glucose sensor) was calibrated, and the response index r of each device was calculated from the sensor output using equations (2) to (4). [Table 1]

[0089] The glucose concentration was measured using samples with adjusted glucose concentration and hematocrit value, and the obtained glucose concentration value (GL) was corrected for the whole blood sample measurement value using the above formula (9) and the following parameters to obtain the corrected glucose concentration value (plasma glucose concentration) (GL2). [Table 2]

[0090] The results are shown in Figures 12 to 15. Figures 15 to 12 show the deviations between the measured glucose concentration (GL) and the corrected glucose concentration (plasma glucose concentration) (GL2) and the glucose concentration measured from plasma when the responsiveness indexes were 0.038, 0.042, 0.043, and 0.049, respectively.

[0091] As shown in Figures 12 to 15, it can be seen that the glucose concentration value (plasma glucose concentration) (GL2) corrected by the method disclosed herein has a smaller deviation from the glucose concentration measurement value measured from plasma than the glucose concentration measurement value (GL) obtained by the method described in Patent Document 1.

[0092] The present disclosure further relates to one or more of the following non-limiting embodiments. [A1] A method for measuring plasma component concentrations using a whole blood sample, comprising: measuring the concentration of a whole blood component using a whole blood sample by an electrochemical sensor method; calculating a correction value using the whole blood component concentration measurement value obtained by the measurement, the hematocrit value of the whole blood sample, and a response index of the sensor used to measure the whole blood component concentration; and calculating the plasma component concentration using the correction value and the whole blood component concentration measurement value. [A2] calculating the correction value by the following formula (a); The method according to [A1], comprising: correcting the measured whole blood component concentration using the calculated correction value according to the following formula (b) to correct to the plasma component concentration: Corrected value = hematocrit value × corrected value coefficient of determination p × (reference response index r / response index) × [measured whole blood component concentration - {(hematocrit value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index)}] 2 (a) Plasma component concentration = measured whole blood component concentration - corrected value (b) [In formula (a), the hematocrit value is the hematocrit value of the whole blood sample, the responsiveness index is the responsiveness index of the sensor used for measuring the whole blood component concentration, and the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.] [A3] The method according to [A1] or [A2], wherein the component is glucose. [A4] A method for measuring plasma glucose concentration using a whole blood sample, comprising: obtaining a glucose concentration measurement value (EP) by an equilibrium point method and a glucose concentration measurement value (DI) by a first derivative method using a whole blood sample by a glucose sensor method; obtaining a whole blood glucose concentration value (GL) by the following formula (1) using the obtained glucose concentration measurement value (EP) and glucose concentration measurement value (DI); GL = EP + a×(EP - DI) + b ···(1) [In formula (1), a is a constant satisfying 0.5 ≦ a ≦ 3.0, and b is a constant satisfying 0 < b ≦ 10.] obtaining a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL), the hematocrit value (Hct value) of the whole blood sample, the responsiveness index of the sensor used for glucose concentration measurement by the glucose sensor method, and the reference responsiveness index r; CR = Hct value × correction value determination coefficient p × (reference responsiveness index r / responsiveness index) × [GL - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (responsiveness index / reference responsiveness index r)}] 2 ···(9) [In formula (9), the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.] obtaining a plasma glucose concentration (GL2) by the following formula (10) using the whole blood glucose concentration value (GL) and the correction value (CR); GL2 = GL - CR ···(10) A method comprising the above steps. [A5] The method according to any one of [A1] to [A4], further comprising calculating the hematocrit value (Hct value) of the whole blood sample by formula (12). Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × (GL) [Hct決定係数u]} ···(12) [In formula (12), the Hct determination coefficients s, t, and u are constants.] [A6] An apparatus for measuring the plasma component concentration using a whole blood sample, comprising a measurement unit that measures the whole blood component concentration of the whole blood sample by an electrochemical sensor method, and a control unit that calculates the plasma component concentration from the measurement value obtained by the measurement unit, where the control unit calculates a correction value using the whole blood component concentration measurement value obtained by the measurement unit, the hematocrit value of the whole blood sample, and the responsiveness index of the sensor used for measuring the whole blood component concentration in the measurement unit, and calculates the plasma component concentration using the obtained correction value and the whole blood component concentration measurement value. A measuring device [A7] A program for determining the plasma component concentration from a whole blood sample, comprising a correction value calculation step of calculating a correction value using the measurement value obtained by measuring the whole blood component concentration using a whole blood sample by an electrochemical sensor method, the hematocrit value of the whole blood sample, and the responsiveness index of the sensor used for measuring the whole blood component concentration, a concentration calculation step of calculating the plasma component concentration using the correction value and the measurement value, and a program for executing the above steps [A8] A program for determining the plasma glucose concentration using a whole blood sample, comprising a measurement step of measuring the glucose concentration by the equilibrium point method and the first derivative method using a whole blood sample by the glucose sensor method, a first concentration calculation step of calculating the whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step, GL = EP + a × (EP - DI) + b ···(1) [In formula (1), a is a constant with 0.5 ≦ a ≦ 3.0, and b is a constant with 0 < b ≦ 10.] A correction value calculation step of calculating a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL) obtained in the first concentration calculation step, the hematocrit value (Hct value) of the whole blood sample, the response index of the sensor used for glucose concentration measurement, and the reference response index r; CR = Hct value × correction value determination coefficient p × (reference response index r / response index) × [GL - {(Hct value × axis determination coefficient m + axis determination coefficient n) × (response index / reference response index r)}] 2 ···(9) [In formula (9), the correction value determination coefficient p, the reference response index r, and the axis determination coefficients m and n are constants.] A second concentration calculation step of calculating the plasma glucose concentration (GL2) by the following formula (10) using the whole blood glucose concentration value (GL) and the correction value (CR); GL2 = GL - CR ···(10) A program for executing the above. [A9] Further, the program according to [A8], including a hematocrit value calculation step of calculating the hematocrit value (Hct value) of the whole blood sample by the following formula (12). Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × response index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) [In formula (12), the Hct determination coefficients s, t, and u are constants.] [A10] A method for measuring the hematocrit value (Hct value) using a whole blood sample, obtaining a glucose concentration measurement value (EP) by the equilibrium point method and a glucose concentration measurement value (DI) by the first derivative method using the whole blood sample by the glucose sensor method; obtaining a whole blood glucose concentration value (GL) by the following formula (1) using the obtained glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method; GL = EP + a × (EP - DI) + b ···(1) [In formula (1), a is a constant with 0.5 ≦ a ≦ 3.0, and b is a constant with 0 < b ≦ 10.] Using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL), obtain the hematocrit value (Hct value) according to the following formula (12), Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) [In formula (12), the Hct determination coefficients s, t, and u are constants.] A method including this. [A11] A program for determining the hematocrit value (Hct value) using a whole blood sample, A measurement step of measuring the glucose concentration by the equilibrium point method and the first derivative method using a whole blood sample by the glucose sensor method, A concentration calculation step of calculating the whole blood glucose concentration value (GL) according to the following formula (1) using the glucose concentration measurement value (EP) by the equilibrium point method and the glucose concentration measurement value (DI) by the first derivative method obtained in the measurement step, GL = EP + a × (EP - DI) + b ···(1) [In formula (1), a is a constant with 0.5 ≤ a ≤ 3.0, and b is a constant with 0 < b ≤ 10.] A hematocrit value calculation step of calculating the hematocrit value (Hct value) according to the following formula (12) using the glucose concentration measurement value (EP), the glucose concentration measurement value (DI), and the whole blood glucose concentration (GL), Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u]} ···(12) [In formula (12), the Hct determination coefficients s, t, and u are constants.] A program for executing this. [B1] A method for measuring the component concentration in a whole blood sample, characterized by correcting the measurement value obtained with the whole blood sample to the measurement value obtained with the plasma sample by correcting using a correction formula including the product of the term related to the hematocrit value and the term related to the responsiveness of the sensor in the sample. [B2] A method for measuring the concentration of a component in a whole blood sample according to [B1], in which the measured value from a plasma sample is used as a corrected component concentration, and the measured value of the concentration of a whole blood component is corrected to the corrected component concentration using the following formula: Corrected component concentration = measured whole blood component concentration - corrected value Corrected value = hematocrit value × correction coefficient of determination × (reference response index / response index) × [measured whole blood component concentration - [(hematocrit value × axis coefficient of determination + axis coefficient of determination) × (response index / reference response index)]] 2 [Explanation of symbols]

[0093] 1. Measuring equipment 10 Main body 11 Sample supply section 12 Bottle Unit 13 Panels 14 Sample container 15 Standard solution container 16 Buffer container 17 Cleaning solution container 18 Drain container 21 Reaction Cell 22 Glucose sensor 22a electrode 22b GOD membrane 23 Stirring bar 24 Starla

Claims

1. A method for measuring plasma component concentrations using a whole blood sample, comprising: measuring the concentration of a whole blood component using a whole blood sample by an electrochemical sensor method; calculating a correction value using the whole blood component concentration measurement value obtained by the measurement, the hematocrit value of the whole blood sample, and a response index of the sensor used to measure the whole blood component concentration; and calculating the plasma component concentration using the correction value and the whole blood component concentration measurement value.

2. Calculating the correction value by the following formula (a); The method of claim 1, further comprising: correcting the measured whole blood component concentration using the calculated correction value according to the following formula (b) to correct it to the plasma component concentration: Corrected value = hematocrit value × corrected value coefficient of determination p × (reference response index r / response index) × [measured whole blood component concentration – {(hematocrit value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index)}] 2 ...(a) Plasma component concentration = measured whole blood component concentration - corrected value (b) [In formula (a), the hematocrit value is the hematocrit value of the whole blood sample, the responsiveness index is the responsiveness index of the sensor used to measure the concentration of the whole blood component, and the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.]

3. The method of claim 1 , wherein the component is glucose.

4. 1. A method for measuring plasma glucose concentration using a whole blood sample, comprising: Obtaining a glucose concentration measurement value (EP) by an equilibrium point method and a glucose concentration measurement value (DI) by a first derivative method using a whole blood sample by a glucose sensor method; Using the obtained glucose concentration measurement value (EP) and glucose concentration measurement value (DI), obtain a whole blood glucose concentration value (GL) according to the following formula (1); GL=EP+a×(EP-DI)+b...(1) [In formula (1), a is a constant in the range of 0.5≦a≦3.0, and b is a constant in the range of 0<b≦10.] obtaining a correction value (CR) by the following formula (9) using the whole blood glucose concentration value (GL), the hematocrit value (Hct value) of the whole blood sample, the response index of the sensor used in the glucose concentration measurement by the glucose sensor method, and a reference response index r; CR = Hct value × correction coefficient of determination p × (reference response index r / response index) × [GL - {(Hct value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index r)}] 2 ...(9) [In equation (9), the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.] Using the whole blood glucose concentration value (GL) and the correction value (CR), obtain a plasma glucose concentration (GL2) according to the following formula (10): GL2=GL-CR...(10) A method comprising:

5. The method according to claim 3 or 4, further comprising calculating the hematocrit value (Hct value) of the whole blood sample using equation (12). Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u] ...(12) [In equation (12), the Hct determination coefficients s, t, and u are constants.]

6. An apparatus for measuring plasma component concentrations using a whole blood sample, a measuring unit that measures the concentrations of whole blood components in a whole blood sample by an electrochemical sensor method; a control unit that calculates plasma component concentrations from the measurement values ​​obtained by the measurement unit, The control unit calculating a correction value using the whole blood component concentration measurement value obtained by the measurement unit, the hematocrit value of the whole blood sample, and a response index of a sensor used to measure the whole blood component concentration by the measurement unit; The measurement device calculates the plasma component concentration using the obtained corrected value and the whole blood component concentration measurement value.

7. 1. A program for determining plasma constituent concentrations from a whole blood sample, comprising: a correction value calculation step of calculating a correction value using a measurement value obtained by measuring the concentration of a whole blood component using a whole blood sample by an electrochemical sensor method, the hematocrit value of the whole blood sample, and a response index of a sensor used to measure the concentration of the whole blood component; a concentration calculation step of calculating plasma component concentrations using the corrected values ​​and the measured values; A program to execute.

8. 1. A program for determining plasma glucose concentration using a whole blood sample, comprising: a measuring step of measuring the glucose concentration of a whole blood sample by a glucose sensor method using an equilibrium point method and a first derivative method; a first concentration calculation step of calculating a whole blood glucose concentration value (GL) by the following formula (1) using the glucose concentration measured by the equilibrium point method (EP) and the glucose concentration measured by the first derivative method (DI) obtained in the measurement step; GL=EP+a×(EP-DI)+b...(1) [In formula (1), a is a constant in the range of 0.5≦a≦3.0, and b is a constant in the range of 0<b≦10.] a correction value calculation step of calculating a correction value (CR) using the whole blood glucose concentration value (GL) obtained in the first concentration calculation step, the hematocrit value (Hct value) of the whole blood sample, the responsiveness index of the sensor used to measure the glucose concentration, and a reference responsiveness index r according to the following formula (9): CR = Hct value × correction coefficient of determination p × (reference response index r / response index) × [GL - {(Hct value × axis coefficient of determination m + axis coefficient of determination n) × (response index / reference response index r)}] 2 ...(9) [In equation (9), the correction value determination coefficient p, the reference responsiveness index r, and the axis determination coefficients m and n are constants.] a second concentration calculation step of calculating a plasma glucose concentration (GL2) using the whole blood glucose concentration value (GL) and the correction value (CR) according to the following formula (10); GL2=GL-CR...(10) A program to execute.

9. 9. The program according to claim 8, further comprising a hematocrit value calculation step of calculating a hematocrit value (Hct value) of the whole blood sample using the following formula (12): Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u] ...(12) [In equation (12), the Hct determination coefficients s, t, and u are constants.]

10. A method for measuring hematocrit (Hct) using a whole blood sample, comprising: Obtaining a glucose concentration measurement value (EP) by an equilibrium point method and a glucose concentration measurement value (DI) by a first derivative method using a whole blood sample by a glucose sensor method; Using the obtained glucose concentration measured value (EP) by the equilibrium point method and the glucose concentration measured value (DI) by the first derivative method, a whole blood glucose concentration value (GL) is obtained according to the following formula (1); GL=EP+a×(EP-DI)+b...(1) [In formula (1), a is a constant in the range of 0.5≦a≦3.0, and b is a constant in the range of 0<b≦10.] Obtaining a hematocrit value (Hct value) using the measured glucose concentration (EP), the measured glucose concentration (DI), and the whole blood glucose concentration (GL) according to the following formula (12): Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u] ...(12) [In equation (12), the Hct determination coefficients s, t, and u are constants.] A method comprising:

11. 1. A program for determining hematocrit (Hct) using a whole blood sample, comprising: a measuring step of measuring the glucose concentration of a whole blood sample by a glucose sensor method using an equilibrium point method and a first derivative method; a concentration calculation step of calculating a whole blood glucose concentration value (GL) using the glucose concentration measured value (EP) by the equilibrium point method and the glucose concentration measured value (DI) by the first derivative method obtained in the measurement step, according to the following formula (1); GL=EP+a×(EP-DI)+b...(1) [In formula (1), a is a constant in the range of 0.5≦a≦3.0, and b is a constant in the range of 0<b≦10.] a hematocrit value calculation step of calculating a hematocrit value (Hct value) using the measured glucose concentration (EP), the measured glucose concentration (DI), and the whole blood glucose concentration (GL) according to the following formula (12): Hematocrit value = (EP - DI) × {[Hct determination coefficient s] × responsiveness index + [Hct determination coefficient t]} × {(GL) [Hct決定係数u] ...(12) [In equation (12), the Hct determination coefficients s, t, and u are constants.] A program to execute.

Images