JP2008209350A - Device for measuring blood coagulation time - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood coagulation time measuring method capable of performing highly accurate abnormality determination without being affected by a blood coagulation time PT of a specimen, concerning a method for measuring the blood coagulation time by analyzing a time-series change of an optical signal by using a reagent acting on a blood coagulation factor. <P>SOLUTION: A checking domain and a normal range threshold are set based on the blood coagulation time PT measured by a measuring part and light reception data F(PT) in the blood coagulation time, and it is determined whether the reception data are in a normal range or not, and thereby excellent abnormality determination can be performed without being influenced by the blood coagulation time PT of the specimen. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a blood coagulation time measurement apparatus that measures a blood coagulation time by analyzing an optical signal accompanied by an optical change such as absorption, emission, fluorescence, and scattered light by reacting with a substance in a sample to be analyzed. Is.

  Hereinafter, a conventional blood coagulation time measuring apparatus will be described with reference to FIGS. A conventional blood coagulation time measuring apparatus has a configuration as shown in FIG. 11 (see, for example, Patent Document 1).

  In FIG. 11, plasma to be measured is stored in advance in a transparent test tube 51, and a reagent such as a PT reagent is supplied from the reagent supplier 52 via the pipette 53 to the test tube 51, and light from the LED 54 is emitted. The test tube 1 is irradiated. The scattered light scattered inside the test tube 51 is received by the photodiode 55, and the amount of scattered light is detected.

  The measurement unit 56 includes a detection unit 56a that detects saturation of the scattered light amount, a determination unit 56b that determines whether or not the scattered light amount increases, and the scattered light amount is detected within a predetermined time after detecting the saturation of the scattered light amount. The controller 56c that controls the detector 56a and the determiner 56b so that the process of detecting the next saturation is repeated when it is determined whether or not it further increases, and the saturation of the scattered light amount is finally achieved. When detected, a calculation unit 56d for calculating the coagulation time based on the saturation value is provided, the output signal of the photodiode 55 is processed, and the processing result is displayed on the CRT 57. The measuring unit 56 is composed of a microcomputer comprising a CPU, ROM, and RAM.

  FIG. 12 shows an example of data measured using the conventional blood coagulation time measuring apparatus of FIG. The horizontal axis indicates the elapsed time after mixing the plasma to be measured and the reagent. The vertical axis indicates the amount of received light detected. In this case, the blood coagulation time is measured at a time when the amount of change in the amount of received light is 50% of that saturated. Further, in order to determine whether or not the measurement data is abnormal, the following abnormality determination is performed.

  First, in order to determine an abnormality in the reaction speed, for example, a region where the received light amount is plus or minus 4% centering on the region H2 where the received light amount is 50% of the saturated light amount is set as the check region, and the received light amount within this check region The rate of change is calculated to determine whether it is within the normal range.

  Next, as a determination of the presence or absence of an initial reaction, for example, a check area is set at the beginning of the reaction every 20 seconds after the start of the reaction. ing.

  Furthermore, in order to determine the presence or absence of drift in the reaction curve, two check areas are set, the rate of change in the amount of received light in each check area is obtained, the ratio of the two change rates is further obtained, and within the normal range Judgment is based on whether or not there is. For example, the check area is set to an area where the received light quantity is 46% to 54% of the saturated light quantity (H2-h to H2 + h) and an area where 6% to 14% (H1-h to H1 + h).

Further, as a determination of whether or not the reaction start time is too early, a time when the amount of received light exceeds a predetermined value is obtained to determine whether or not the normal range.
JP 2003-169700 A

  However, in such a conventional blood coagulation time measuring apparatus, the amount of received light to be measured has a large difference not only in the amount of light change but also in the change start time and rate of change due to the difference in blood coagulation ability of the blood to be measured. There exists a subject that it exists and cannot perform abnormality determination with high precision. Since the measurement value of the blood coagulation time is used to determine the dosage of the anticoagulant, the measurement error is highly life-threatening. Therefore, very high reliability is required. If any abnormality is detected in the device or chemical reaction, it is necessary to make the user aware of the abnormality safely and never display an unreliable measurement result.

  I will explain this point a little now. FIG. 13 shows measurement data of the amount of received light actually measured. FIG. 13 shows the difference in profile when the blood coagulation times are different, in other words, when the international standard ratio (hereinafter referred to as INR value) is different. As can be seen from the figure, the larger the INR value, the later the change start time, and the magnitude of change, that is, the rate of change tends to decrease. Further, even with profiles having the same change start time, that is, the same INR value, the magnitude of the change amount and the inclination of the profile, that is, the change rate are different.

  Therefore, in the conventional blood coagulation time measuring device, it is difficult to set an optimal check region due to a difference in change start time and a difference in inclination caused by a difference in INR value, and an optimal abnormality determination threshold is set. There is a problem that it is difficult to do.

  Furthermore, in the conventional blood coagulation time measurement device, the check area for determining abnormality is set based on the saturation value of the amount of received light, so that high-speed measurement can be completed when the maximum differential time is detected There is a problem that the method cannot determine abnormality.

  The present invention has been made to solve these problems, and an object of the present invention is to provide a blood coagulation time measuring apparatus capable of performing abnormality determination with high accuracy and measuring the blood coagulation time.

  In order to solve the above-mentioned problems, the blood coagulation time measurement apparatus of the present invention (Claim 1) uses a reaction reagent that exhibits an optical change that can be observed by reacting with a component involved in the coagulation action contained in blood. A blood coagulation time measuring device for measuring a blood coagulation time by analyzing a change in an optical signal, wherein a light receiver for converting the optical signal into an electric light reception signal, and a light reception signal from the light receiver. A / D converter for converting into digital received light data, a data measuring unit for measuring received light data obtained from the A / D converter at preset time intervals, and a received light measured by the data measuring unit A data holding unit for temporarily holding data, a blood coagulation time calculating unit for obtaining a blood coagulation time based on the light reception data held in the data holding unit, and whether or not there is an abnormality in the measured light reception data Size A check region in which the abnormality determination unit performs abnormality determination based on the blood coagulation time obtained by the blood coagulation time calculation unit and the value of the measured light reception data at the blood coagulation time. And setting a normal range in the check area, and determining whether or not the measured light reception data is within the normal range.

  As a result, the check area and the normal range in the check area can be set according to the blood clotting time of the specimen and the value of the received light data, and highly accurate abnormality determination of the measurement data can be performed without being affected by the blood clotting time of the specimen. It can be carried out. In addition, since it is not necessary to know the saturation value of the received light amount in order to set the check area, it is possible to make a good abnormality determination even in the high-speed measurement method that completes the measurement when the maximum time of the differential value of the received light data is detected. Can be made possible.

  Further, the blood coagulation time measuring device of the present invention (Claim 2) analyzes a change in optical signal using a reaction reagent that shows an optical change that can be observed by reacting with a component involved in the coagulation action contained in blood. A blood coagulation time measuring apparatus for measuring a blood coagulation time by converting a light receiver that converts the optical signal into an electrical light reception signal and a light reception signal from the light receiver into digital light reception data An A / D converter, a data measuring unit that measures received light data obtained from the A / D converter at predetermined time intervals, and temporarily stores each received light data measured by the data measuring unit A data holding unit, a blood coagulation time calculating unit for obtaining a blood coagulation time based on a plurality of light reception data held in the data holding unit, and an abnormality determination for determining whether or not the measured light reception data is abnormal The abnormality determination unit sets at least one determination reference value based on a value in the blood coagulation time obtained by the blood coagulation time calculation unit of the measured light reception data, and the blood Based on the blood coagulation time obtained by the coagulation time calculation unit, a normal upper limit time and a normal lower limit time at which the value of the measured light reception data is equal to the determination reference value are set, and the measured light reception data Determining a time when the value of the value becomes equal to the determination reference value, and determining whether the determined time is within a normal time range set by the normal upper limit time and the normal lower limit time. Is.

  As a result, the normal range of the time when the judgment reference value and the value of the received light data are equal to the judgment reference value can be set according to the blood clotting time of the specimen and the value of the received light data, and is affected by the blood clotting time of the specimen. Therefore, it is possible to determine the abnormality of measurement data with high accuracy. In addition, since it is not necessary to know the saturation value of the received light amount in order to set the check area, it is possible to make a good abnormality determination even in the high-speed measurement method that completes the measurement when the maximum time of the differential value of the received light data is detected. Can be made possible.

  In addition, the blood coagulation time measuring apparatus according to the present invention (Claim 3) analyzes a change in optical signal using a reaction reagent that exhibits an optical change that can be observed by reacting with a component involved in the coagulation action contained in blood. A blood coagulation time measuring apparatus for measuring a blood coagulation time by converting a light receiver that converts the optical signal into an electrical light reception signal and a light reception signal from the light receiver into digital light reception data An A / D converter, a data measuring unit that measures received light data obtained from the A / D converter at predetermined time intervals, and temporarily stores each received light data measured by the data measuring unit A data holding unit, a blood coagulation time calculating unit for obtaining a blood coagulation time based on a plurality of light reception data held in the data holding unit, and an abnormality determination for determining whether or not the measured light reception data is abnormal The abnormality determination unit sets at least one determination reference time based on the blood coagulation time obtained by the blood coagulation time calculation unit, and the blood coagulation time of the measured light reception data Based on the value at the blood coagulation time obtained by the calculation unit, the normal upper limit value and the normal lower limit value of the measured light reception data at the determination reference time are set, and the measured light reception data at the determination reference time is set. A value is obtained, and it is determined whether or not the obtained value is within a normal value range set by the normal upper limit value and the normal lower limit value.

  As a result, the determination reference time and the normal range of the light reception data value at the determination reference time can be set according to the blood coagulation time and the light reception data value of the sample, and measurement can be performed without being affected by the blood coagulation time of the sample. It is possible to perform abnormality determination of data with high accuracy. In addition, since it is not necessary to know the saturation value of the received light amount in order to set the check area, it is possible to make a good abnormality determination even in the high-speed measurement method that completes the measurement when the maximum time of the differential value of the received light data is detected. Can be made possible.

  According to the blood coagulation time measuring apparatus of the present invention, based on the blood coagulation time obtained from the measurement data and the value of the received light amount data at the blood coagulation time, the normal upper limit value and the normal lower limit value in the check area are determined. Because it is set, the check area for determining the abnormality does not depend on the blood coagulation ability of the sample, and is not affected by the change in received light data, the change rate, the difference in reaction start time, etc. There is an effect that abnormality determination can be performed with high accuracy without being affected by the coagulation time.

  Further, according to the blood coagulation time measuring apparatus of the present invention, since it is not necessary to know the saturation value of the received light amount in order to set the check region, the measurement can be completed at the time when the maximum time of the differential value is detected. The measurement method also has an effect of making a good abnormality determination.

(Embodiment 1)
Embodiments of the present invention will be described below with reference to the drawings.
FIG. 1 is a perspective view of blood clotting time measuring apparatus 100 according to Embodiment 1 of the present invention.

  In FIG. 1, the blood coagulation time measuring apparatus 100 according to the first embodiment is provided with an optical bench 6 for installing the test piece 3. The reaction part 4 on the test piece 3 contains a reagent that causes a chemical reaction that changes the fluorescence intensity according to the coagulation reaction of the blood 5. A holder 20 is mounted on the optical bench 6, and an insertion path is formed so that the test piece 3 can be placed at an appropriate measurement position. Furthermore, the holder 20 has an elastic structure, and plays the role of increasing the thermal conductivity by pressing the test piece 3 against the temperature control means 21.

  When the test piece 3 is placed on the optical bench 6 of the blood coagulation time measuring apparatus 100, the reaction section 4 is positioned so as to match the window section 7 provided on the optical bench 6. The test piece 3 is structured to be pressed against the temperature control means 21 by the holder 20. An electrode 22 is provided on the optical bench 6. When measuring a sample using the test piece 3, the test piece is used for the purpose of detecting spotting of the sample or measuring the resistance value of the sample being measured. 3 is connected to an electrode provided on 3. In addition, the blood coagulation time measuring apparatus 100 is provided with a lid 8 that can be opened and closed so that the optical bench 6 can be shielded from light in the closed state for the purpose of preventing intrusion of external light or dust during measurement.

  FIG. 2 is a view showing a cross section of the optical bench 6. Inside the optical bench 6, a temperature control means 21, a light source 9, a light source filter 12, a lens 10, a light receiving filter 13, and a light receiving means 11 are provided.

  The temperature control means 21 controls the temperature of the reaction unit 4 so that the reaction between the blood 5 and the reactant contained in the reaction unit 4 is most activated, or the temperature at which the reaction is most stable. It is a temperature control means for controlling. For example, it can be constituted by a planar heater provided with a heating means such as a thick film resistor and a temperature detection means such as a temperature detection thermistor on an alumina ceramic substrate. Further, when cooling is required such that the control temperature is lower than the operating environment temperature, it can be configured by using a heating and cooling means such as a Peltier element as an alternative to the heating means. Note that the heating or heating / cooling means is merely an example, and any other means can be used as long as it can be heated or cooled. When temperature control is unnecessary, the temperature control means 21 is not necessarily provided.

  The light source 9 is for applying optical energy to the reaction unit 4, and for example, an incandescent bulb, LED, semiconductor laser, organic EL, or the like can be used. The light source 9 is connected to driving means and is controlled so that an optical output is stably obtained during measurement.

  The light source filter 12 is disposed on the optical path emitted from the light source 9, and thereby irradiates the reaction unit 4 with light in a wavelength band selected according to the characteristics of the light source filter 12 among the light emitted from the light source 9. can do. The characteristics of the optical filter 12 include a transmission wavelength band and a cutoff wavelength band determined by the optical wavelength associated with the reaction between the blood 5 and the reaction substance in the reaction unit 4, and a band pass filter, a short pass filter, a long pass filter, and a multi pass. Filters can be used. If the light source 9 has a single wavelength such as a semiconductor laser diode, or only has a specific wavelength bandwidth such as an LED and does not affect the wavelength to be received, the light source filter 12 is necessarily provided. There is no need.

  The lens 10 has a flat side facing the reaction part 4 on the test piece 3 and a curved lens side facing the light receiving means 11. In the present embodiment, the flat surface side is arranged at a position almost in contact with the reaction part 4. Actually, a gap of about 300 to 500 μm is formed to prevent scratches and contamination due to contact. In the present embodiment, the lens 10 is inserted for the purpose of improving the optical efficiency. However, if it is not necessary to increase the amount of received light so much, the lens 10 may not be provided.

  The light having the wavelength selected by the light source filter 12 is incident from the lens curved surface side of the lens 10, is emitted from the flat surface side, and is irradiated to the reaction unit 4.

  A fluorescent substance is generated by the reaction of the reactant 5 in the reaction unit 4 and the spotted blood 5 to show fluorescence characteristics, and emits fluorescence when irradiated with excitation light.

  Fluorescence emitted from the reaction unit 4 enters from the plane side of the lens 10, exits from the curved surface side, passes through the light receiving filter 13, and is received by the light receiving unit 11.

  The light receiving filter 13 is an optical filter for the purpose of transmitting only the fluorescence emitted from the reaction unit 4 and blocking other unnecessary light. The characteristics of the light receiving filter 13 are determined based on the required specifications related to the optical wavelength associated with the reaction between the blood 5 and the reactant in the reaction unit 4, and at least the excitation light source wavelength band is cut off. Filter characteristics are required so as to transmit the wavelength band of the optical signal from. Desirably, a band-pass filter that transmits only the wavelength of the optical signal obtained from the reaction unit 4 and blocks the wavelength of other unnecessary light is desirable. However, depending on the required specifications, a short-pass filter or a long-pass filter may be used. In some cases, a multi-pass filter or the like can be used.

  The optical signal received by the light receiving means 11 is photoelectrically converted and then subjected to a predetermined signal analysis by a signal processing circuit. The signal processing circuit is generally composed of an analog amplifier circuit, an analog-digital conversion circuit, a microprocessor, and the like.

  FIG. 3 is a block diagram showing the configuration of the blood coagulation time measuring apparatus 100. In the figure, the same reference numerals as those in FIGS. 1 and 2 denote the same or corresponding parts. Reference numeral 30 denotes an LED driver for driving the light source 9. A CPU 32 includes a control unit 33, a blood coagulation time calculation unit 34, an abnormality detection unit 35, a data measurement unit 36, and a data holding unit 37. Reference numeral 38 denotes a current-voltage conversion circuit (I / V) that converts the photocurrent output from the light receiving means 11 into a voltage, and 39 denotes an analog-digital conversion circuit (A / D) that converts the analog output of the I / V 38 into a digital signal. It is. Reference numeral 40 denotes an LCD display for displaying measurement results, 41 denotes an output port for outputting data to the outside of the blood coagulation time measuring apparatus 100, 42 denotes an external memory, and 43 denotes a timer for generating an operation clock of the CPU 32. Reference numeral 31 denotes an operation switch, and the control unit 33 of the CPU 32 controls each unit so that a measurement operation is performed according to an operation input from the operation switch 31.

The measurement operation of the blood coagulation time measuring apparatus 100 configured as described above will be described.
FIG. 7 is a flowchart of the measurement operation.

  When the user operates the operation switch 31, the blood coagulation time measuring apparatus 100 shifts to the measurement mode. First, a test piece insertion instruction message is displayed on the LCD display 40 so as to insert the test piece 3 into the user (step S1).

  When the test piece 3 is inserted into a predetermined position of the optical bench 6 to which the holder 20 is attached, it is detected that the test piece 3 is mounted by changing the resistance value between the electrodes of the electrode pins 22 (step). S2). Thereafter, temperature control is performed by the temperature control means 21 so that the reaction part 4 on the test piece 3 reaches a predetermined temperature, for example, 37 ° C. at which the blood coagulation reaction is stabilized (step S3).

  After the temperature reaches a predetermined temperature, a spotting instruction message is displayed on the LCD display 40 so that the blood 5 to be analyzed is spotted on the reaction unit 4 (step S4).

  When spotted by the user, a change in the resistance value between the electrodes occurs, and this is detected to start data measurement (step S5).

  Simultaneously with the start of measurement, a lid closing instruction message is displayed on the LCD display 40 (step S6).

  Thereafter, the light source 9 is turned on by the LED driver 30 every predetermined time, for example, every 5 seconds to irradiate the reaction unit 4 with excitation light, and the light reception signal obtained from the light receiving means 11 is converted into I / V 38 and A Measurement is performed by the data measuring unit 36 through / D39, and the light source 9 is turned off. The light source 9 is turned off in order to reduce disadvantages such as low power consumption, light source life, and fluorescence fading. If there is no particular problem, the light source 9 may not be turned off. In this way, the optical signal intensity obtained from the reaction unit 4 is converted into an electrical signal by the light receiving means 11, amplified by an appropriately configured amplifier circuit, converted into digital data by the A / D 39, and then data measurement The measurement is performed by the unit 36, and the time-series measurement data is temporarily stored by the data holding unit 37 which is a storage unit. For each measurement, the time at which the maximum value is reached is monitored while calculating the first derivative. The time when the first derivative reaches the maximum value is detected, and the measurement is terminated. (Steps S7, S8, S9)

  In many cases, the received light data includes electrical or optical noise, and A / D conversion for each measurement is performed not only once but a plurality of times of sampling. The average value, the center value, and the method of averaging the data excluding the portion where the distribution deviation is large are preferably used. Further, it is desirable to perform calculation after processing by a smoothing process from a plurality of data before and after, for example, an average value, weighted addition value, center value, etc. of the data before and after.

  After the measurement of the received light data, the blood coagulation time calculation unit 34 calculates the blood coagulation time PT value and INR value based on the time series data stored in the data holding unit 37 (step S10).

  Hereinafter, as an example of a method for obtaining the blood coagulation time and the INR value, a calculation method using a first derivative will be shown. As one of the inventive steps of the present invention, since it is also effective for a high-speed measurement method, an example of a calculation unit using a first-order differential is shown, but the present invention is similarly effective even when using other calculation methods. It is not limited to the method.

  FIG. 4 is a diagram showing an example of measurement data. In the figure, 23 is a graph showing the received light signal data, and 24 is a graph showing its first derivative.

  In the light reception data 23, there is a portion where the light reception signal does not change between about 30 seconds from the start of measurement. In this part, since the fluorescence change due to blood coagulation does not occur, the light reception data in this part is due to a steady offset component other than the fluorescence.

  The light reception signal to be measured includes a fluorescence signal obtained from the reaction unit 4 in accordance with a pure blood coagulation reaction and a light reception signal by other unnecessary light. As the latter factor, the component of the light emitted from the light source 9 due to unnecessary light that has been transmitted without being blocked by the light receiving filter 13 among the reflected light reflected by the surface of the lens 10 or the reaction unit 4 is dominant. is there. An electrical offset signal is also included. In the subsequent measurement, it becomes a steady offset signal.

  Hereinafter, a method for calculating the blood coagulation time (PTsec) and the international standard value (INR) in the first embodiment will be described.

(1) The received light data 23 is time-differentiated to obtain a first derivative 24, and a time T1 at which the first derivative 24 becomes maximum is obtained. In FIG. 4, the primary derivative 24 shows a normalized value for easy understanding of the explanation, but it does not need to be normalized.

(2) The point at time T1 on the received light data 23 is obtained.

(3) The points on the light reception data 23 at the points T2, T3, T4, and T5 having a predetermined time relationship are obtained with the time T1 as a reference. For example, assume that the data measurement interval is 5 seconds, T2 is 5 seconds before, T3 is 5 seconds ago, T4 is 10 seconds ago, and T5 is 10 seconds later, based on the time of T1. In this example, the time interval is 5 seconds and the number of sample points is 5. However, as long as the overall performance of the measuring apparatus is not affected, it is desirable to shorten the measurement interval and increase the number of samplings. At least two sample points are used.

(4) An approximate straight line 25 is obtained from the data of five points at times T1, T2, T3, T4, and T5 on the light reception data 23. Here, as long as there is no problem in terms of accuracy, the effect of the present invention can be obtained in the same way even with approximate calculation that is not an accurate approximate line, or with a linear expression that is substantially equivalent to the approximate line. In this example, the approximate straight line is obtained using five points. However, it is desirable to shorten the sampling interval and obtain the approximate straight line 25 from more points. In the case of realizing the simplest processing, the sample points may be T2 and T3, and a straight line including any point from T1 to T3 having an inclination connecting the two points may be used as the approximate straight line 25.

(5) A baseline 26 representing stationary offset data due to factors other than the fluorescence reaction is obtained from the received light data 23. For example, the method of setting the minimum value of the light reception data 23 is the simplest. As another method, a time at which the received light data 23 becomes equal to or greater than a predetermined threshold value may be obtained, and an average value of at least two points of data from the start of measurement until the time when the threshold value is exceeded may be used. In this case, as the data to be employed, it is preferable to employ data included in a predetermined number of data from the minimum value side, or data included in a predetermined% distributed in the minimum value side. In addition, the effects of the present invention can be obtained in the same manner as long as they are substantially equivalent to other methods.

(6) Find the time Tm at the point where the approximate line 25 and the base line 26 intersect.

(7) The blood coagulation time PTsec and the international standard value INR are calculated by the correction formula. The Tm determined above largely depends on the reaction reagent used and the optical detection performance of the measuring instrument, and the correction formula is completely different depending on the measuring method. In addition, the correction formula varies depending on the type of sample to be measured, for example, puncture blood, citrate blood, plasma, and the like. Accordingly, detailed formulas are omitted because they do not affect the effects of the present invention.

  FIG. 5 (a) is a graph obtained by analyzing the data of the clinic study actually performed. The blood clotting time PT measured by the above calculation method is taken as the horizontal axis, and the received light data is the blood clotting time. The time when it becomes 3.0 times the received light data in PT is plotted on the vertical axis, and 160 pieces of data are plotted to show their correlation. Similarly, FIG. 5 (b) is a graph obtained by analyzing the data of the clinic study actually performed. The blood coagulation time PT measured by the above calculation method is taken as the horizontal axis, and the received light data is The time at which the received light data is 2.0 times the blood coagulation time PT is plotted on the vertical axis, and 160 pieces of data are plotted to show these correlations. Similarly, FIG. 5C is a graph obtained by analyzing the data of the clinic study actually performed. The blood coagulation time PT measured by the above calculation method is taken as the horizontal axis, and the received light data is The time when 0.7 times the received light data in the blood coagulation time PT is plotted on the vertical axis, and 160 pieces of data are plotted to show these correlations.

  Here, in each graph, an approximate straight line is drawn by the least square method for 160 pieces of measurement data. The slope a1 of the approximate straight line in FIG. 5A is 1.3293, and the intercept b1 is 0.2867. Further, the slope a2 of the approximate straight line in FIG. 5B is 1.202, and the intercept b2 is −0.7534. Further, the inclination a3 of the approximate straight line in FIG. 5C is 0.8751, and the intercept b3 is 2.0128.

  From the graphs shown in FIGS. 5A to 5C, it can be seen that most of the measurement data is concentrated in the vicinity of the approximate straight line. That is, it can be said that each measurement data has linearity in the correlation even though the blood coagulation time PT value and INR value are different values. Further, when data that is relatively far from the approximate straight line, that is, measurement data surrounded by circles, are individually analyzed, the profile of the received light data 23 is distorted, and the measured blood coagulation time PT value and INR are measured. The value measurement error was found to be very large. Further, it was found that the received light data 23 of the data in the vicinity of the approximate straight line has very little profile distortion and little measurement error of the measured blood coagulation time PT value and INR value.

  From the above analysis, there is a relationship between the blood coagulation time PT value and INR value and the deviation from the approximate line, and the larger the deviation, the greater the profile distortion and the greater the measurement error of the blood coagulation time PT value and the NR value. Can be said to be high. Therefore, whether the deviation from the reference is within a range between the upper limit threshold and the lower limit threshold by setting the upper limit threshold and the lower limit threshold with a predetermined error rate, for example, within ± 15% as the normal range, with the approximate straight line as a reference. By judging whether or not, it is possible to exclude data that may have a large measurement error.

  Therefore, assuming that the approximate line is a standard value, an upper limit threshold line and a lower limit threshold line are set so that an error from the standard value becomes a predetermined error rate. For example, when the error rate is set to ± 15%, the dotted line in the graphs of FIGS. 5A, 5B, and 5C is obtained. Data surrounded by a circle is out of the normal range between the upper threshold line and the lower threshold line, and can be determined as abnormal data.

  In the data obtained with the blood coagulation time measurement device we developed, we made an abnormality determination focusing on the time when the blood coagulation time and the light reception data of the blood coagulation time are 3 times, 2 times, and 0.7 times. When applied to other devices, the optimum time conditions are different, so it is necessary to perform a clinic study to find and set the optimum value. Moreover, although the correlation was able to be expressed using an approximate line, when using another apparatus, it may be necessary to express it as an approximate curve instead of an approximate line. In that case, the effect of the present invention can be obtained if the approximate straight line, the upper threshold line, and the lower threshold line are approximate curves.

  In addition, since there are restrictions on CPU performance and memory area, in the first embodiment, three check areas are set. Although it is possible to make an abnormality determination at a single check area, the more areas, the more strict abnormality determination is possible, and it is desirable to set a plurality of check areas.

Hereinafter, the abnormality determination operation in the blood coagulation time measuring apparatus according to the first embodiment will be described.
FIG. 9 is a diagram illustrating a flowchart of the abnormality determination operation.

  First, the blood coagulation time PT calculated by the blood coagulation time calculation unit 34 is received (step S31).

  Next, the received light data F (PT) at the blood coagulation time PT is calculated from the time series data of the received light data held in the data holding unit 37. Since the time series data of the received light data is discrete values measured at a predetermined time interval, there is a very high probability that there is no measurement data that exactly matches the blood coagulation time PT unless the time interval is very short. high. Therefore, it is desirable to interpolate data between discrete data using linear interpolation or polynomial interpolation (step S32).

  Next, determination reference values F1, F2, and F3 are determined using the expressions shown in [Expression 1] to [Expression 3] in order to determine a check region for determining abnormality. In the first embodiment, three points that are three times, two times, and 0.7 times the received light data F (PT) in the blood coagulation time PT are selected as the determination reference values. This magnification is an example and is not limited to this (step S33).

    [Formula 1] F1 = c1 × F (PT) (however, c1 = 3.0)

    [Formula 2] F2 = c2 x F (PT) (however, c2 = 2.0)

    [Formula 3] F3 = c3 x F (PT) (however, c3 = 0.7)

  Next, the time T1 when the measurement data F (t) becomes equal to the determination reference value F1, the time T2 when the measurement data F (t) becomes equal to the determination reference value F2, and the measurement data F (t) equal to the determination reference value F3. Is obtained. Since the received light data F (t) is discrete time-series data, it is desirable to perform data interpolation using linear interpolation or polynomial interpolation. Assuming that the measurement data at time T1 is F (T1), the measurement data at time T2 is F (T2), and the measurement data at time T3 is F (T3), the relational expressions such as [Expression 4] to [Expression 6] are as follows. It is established (step S34).

    [Formula 4] T1: F (T1) = F1 = c1 × F (PT) (however, c1 = 3.0)

    [Formula 5] T2: F (T2) = F2 = c2 × F (PT) (where c2 = 2.0)

    [Formula 6] T3: F (T3) = F3 = c3 × F (PT) (however, c3 = 0.7)

  Next, the upper limit threshold and the lower limit threshold of the normal range at times T1, T2, and T3 are determined. The normal upper threshold at time T1 is T1max, the normal lower threshold at time T1 is T1min, the normal upper threshold at time T2 is T2max, the normal lower threshold at time T2 is T2min, the normal upper threshold at time T3 is T3max, and the normal lower threshold at time T3 The threshold value is T3min. For example, when the normal range is ± 15%, the calculation formulas are as shown in [Formula 7] to [Formula 12].

  a1 and b1 are the slope and intercept of the approximate line shown in FIG. 5A, a2 and b2 are the slope and intercept of the approximate line shown in FIG. 5B, and a3 and b3 are FIG. 5C shows the slope and intercept of the approximate straight line shown in FIG. 5C (step S35).

    [Formula 7] T1max = 1.15 × (a1 × PT + b1)

    [Formula 8] T2max = 1.15 × (a2 × PT + b2)

    [Formula 9] T3max = 1.15 × (a3 × PT + b3)

    [Formula 10] T1min = 0.85 × (a1 × PT + b1)

    [Formula 11] T2min = 0.85 × (a2 × PT + b2)

    [Formula 12] T3min = 0.85 × (a3 × PT + b3)

  The standard value of ± 15% is merely an example, and it is necessary to optimally set based on actual measurement data such as a clinic study depending on the characteristics of the blood coagulation time measurement device and the required accuracy of abnormality determination.

  Next, it is determined whether T1, T2, and T3 obtained in step S34 are not out of the normal range determined in step S35. That is, it is determined whether or not the inequalities shown in [Expression 13] to [Expression 15] are satisfied. If all inequalities are satisfied, it is determined that there is no abnormality, and if any one of them is not satisfied, it is determined that there is an abnormality in the measurement data profile (step S36).

    [Formula 13] T1min <T1 <T1max

    [Formula 14] T2min <T2 <T2max

    [Formula 15] T3min <T3 <T3max

  Finally, processing according to the abnormality determination result is performed. If no abnormality is detected, the blood coagulation time PT and INR value obtained by the blood coagulation time calculation unit are displayed on the LCD display 40 (step S12 in FIG. 7).

  On the other hand, when an abnormality is detected, an error is displayed on the LCD display 40 to allow the user to recognize it (step S13 in FIG. 7). If a printer is connected to the output port 41, the measurement result can be printed as necessary. If a PC is connected to the output port 41, data can be transmitted to the PC. Furthermore, the measurement result can be stored in the external memory 42 in the blood coagulation time measurement device, and the measurement result can be read later.

  As described above, according to the blood coagulation time measuring apparatus of the first embodiment, the determination criterion is based on the value F (PT) in the blood coagulation time PT obtained by the blood coagulation time calculation unit 34 of the measured light reception data. Values F1, F2, and F3 are set, and based on the blood coagulation time PT obtained by the blood coagulation time calculation unit 34, the value of the measured light reception data becomes equal to the determination reference values F1, F2, and F3. The normal upper limit times T1max, T2max, and T3max and the normal lower limit times T1min, T2min, and T3min of the times T1, T2, and T3 are set, and the measured light reception data values are equal to the determination reference values F1, F2, and F3. T2 and T3 are obtained, and it is determined whether or not the obtained time is within a normal time range set by the normal upper limit time and the normal lower limit time. Since the abnormality is determined, the determination reference value and the normal range of the time when the measurement data value is equal to the determination reference value are set according to the blood coagulation time of the specimen and the value of the received light data at the blood coagulation time. It is possible to determine the abnormality of the measurement data with high accuracy without being affected by the blood coagulation time of the specimen. In the first embodiment, since it is not necessary to know the saturation value of the received light amount in order to set the check area, even in the high-speed measurement method in which the measurement is completed when the maximum time of the differential value of the received light data is detected. Good abnormality determination can be performed.

(Embodiment 2)
Hereinafter, a blood coagulation time measuring apparatus according to Embodiment 2 of the present invention will be described.

  The blood coagulation time measurement apparatus according to the second embodiment has the same configuration as the blood coagulation time measurement apparatus 100 according to the first embodiment shown in FIGS. 1 to 3 and differs only in the operation of abnormality determination by the abnormality determination unit 35. Is.

  Hereinafter, the abnormality determination operation in the blood coagulation time measuring apparatus according to the second embodiment will be described.

  FIG. 6A is a graph obtained by analyzing the data of the clinic study actually performed. The horizontal axis represents the received light data at the time of the blood coagulation time PT measured by the calculation method of the first embodiment. The light reception data at a time that is 1.1 times the blood coagulation time PT is plotted on the vertical axis, and 160 pieces of data are plotted to show these correlations. Similarly, FIG. 6 (b) plots 160 data with the light reception data at the time of blood coagulation time PT as the horizontal axis and the light reception data at time 1.2 times the blood coagulation time PT as the vertical axis. Thus, these correlations are shown. Similarly, FIG. 6 (c) plots 160 data with the light reception data at the time of blood coagulation time PT as the horizontal axis and the light reception data at time 1.3 times the blood coagulation time PT as the vertical axis. Thus, these correlations are shown.

  Here, in each graph, an approximate quadratic curve is drawn by the least square method for 160 pieces of measurement data. The quadratic coefficient j1 of the approximate quadratic curve in FIG. 6A is -0.0009, the primary coefficient k1 is 1.6135, and the constant term l1 is -0.99942. Also, the quadratic coefficient j2 of the approximate quadratic curve in FIG. 6B is -0.0024, the primary coefficient k2 is 2.3638, and the constant term l2 is -1.974. Further, the quadratic coefficient j3 of the approximate quadratic curve in FIG. 6C is -0.0039, the primary coefficient k3 is 3.1594, and the constant term l3 is -2.1428.

  It can be seen from the graphs shown in FIGS. 6A to 6C that most measurement data is concentrated in the vicinity of the approximate quadratic curve. Furthermore, when data that is relatively far from the approximate quadratic curve, that is, measurement data surrounded by circles, are individually analyzed, the profile of the received light data 23 is distorted, and the measured blood coagulation time PT value And the measurement error of the INR value was found to be very large. Further, it was found that the received light data 23 of the data in the vicinity of the approximate quadratic curve has very little profile distortion and little measurement error in the measured blood coagulation time PT value and INR value.

  From the above analysis, there is a relationship between the blood coagulation time PT value and INR value and the deviation from the approximate quadratic curve. The larger the deviation, the greater the profile distortion, and the greater the measurement error of the blood coagulation time PT value and the NR value. It can be said that the probability of becoming higher. Therefore, with the approximate quadratic curve as a reference, a deviation from the reference is set to a predetermined error rate, for example, an upper limit threshold and a lower limit threshold are set within a normal range within ± 15%, and within a range between the upper limit threshold and the lower limit threshold. By determining whether there is, it is possible to exclude data that may have a large measurement error.

  Therefore, assuming that the approximate quadratic curve is a standard value, an upper threshold line and a lower threshold line are set so that an error from the standard value becomes a predetermined error rate. For example, when the error rate is set to ± 15%, the dotted line in the graphs of FIGS. 6A, 6B, and 6C is obtained. Data surrounded by a circle is out of the normal range between the upper threshold line and the lower threshold line, and can be determined as abnormal data.

  In the data obtained with the blood coagulation time measurement device we developed, we focused on the light reception data at the blood coagulation time and the light reception data at times 1.1, 1.2, and 1.3 times the blood coagulation time. Although the abnormality determination has been performed, the optimum time conditions differ when applied to other devices. Therefore, it is necessary to perform a clinic study to obtain and set an optimum value.

  In addition, since there are restrictions on CPU performance and memory area, in the second embodiment, three check areas are set. Although it is possible to make an abnormality determination at a single check area, the more areas, the more strict abnormality determination is possible, and it is desirable to set a plurality of check areas.

FIG. 10 shows a flowchart of abnormality determination in Embodiment 2 of the present invention.
First, the blood coagulation time PT calculated by the blood coagulation time calculator 34 is received (step S41).

  Next, the received light data F (PT) at the blood coagulation time PT is calculated from the time series data of the received light data held in the data holding unit 37. As in the first embodiment, it is desirable to interpolate data between discrete data using linear interpolation or polynomial interpolation (step S42).

  Next, determination reference times t1, t2, and t3 are determined using the expressions shown in [Expression 16] to [Expression 18] in order to determine a check region for determining abnormality. In the second embodiment, three points that are 1.1 times, 1.2 times, and 1.3 times the blood coagulation time PT are selected as determination reference times. This magnification is an example and is not limited to this (step S43).

    [Formula 16] t1 = d1 x PT (where d1 = 1.1)

    [Formula 17] t2 = d2 × PT (where d2 = 1.2)

    [Formula 18] t3 = d3 x PT (where d3 = 1.3)

  Next, the received light data f1 (= F (t1)), f2 (= F (t2)), f3 () at the determination reference times t1, t2, and t3 from the time series data of the received light data held in the data holding unit 37. = F (t3)) is calculated based on [Formula 19] to [Formula 21]. Since the time series data of the received light data is a discrete value measured at a predetermined time interval, there is no measurement data that exactly matches the determination reference times t1, t2, and t3 unless the time interval is set to a very short time. The probability is very high. Therefore, it is desirable to interpolate between discrete data using linear interpolation or polynomial interpolation (step S44).

    [Formula 19] f1 = F (t1) = F (d1 × PT) (where d1 = 1.1)

    [Formula 20] f2 = F (t2) = F (d2 × PT) (where d2 = 1.2)

    [Formula 21] f3 = F (t3) = F (d3 × PT) (d3 = 1.3)

  Next, the upper and lower thresholds of the normal range of the received light data f1, f2, and f3 at times t1, t2, and t3 are determined. For example, when the normal range is ± 15%, the calculation formulas are as shown in [Formula 22] to [Formula 27]. Here, f1max is the normal upper limit value of the light reception data f1 at time t1, f2max is the normal upper limit value of the light reception data f2 at time t2, f3max is the normal upper limit value of the light reception data f3 at time t3, and f1min is the light reception data f1 at time t1. , F2min is a normal lower limit value of the light reception data f2 at time t2, and f3min is a normal lower limit value of the light reception data f3 at time t3.

  j1, k1, and l1 are the quadratic coefficient, first-order coefficient, and constant term of the approximate quadratic curve shown in FIG. 6 (a), and j2, k2, and l3 are shown in FIG. 6 (b). The quadratic coefficient, the primary coefficient, and the constant term of the approximate quadratic curve, and j3, k3, and l3 are the quadratic coefficient, the primary coefficient, and the constant term of the approximate quadratic curve shown in FIG. Yes (step S45).

    [Formula 22] f1max = 1.15 × (j1 × F (PT) × F (PT) + k1 × F (PT) + l1)

    [Formula 23] f2max = 1.15 × (j2 × F (PT) × F (PT) + k2 × F (PT) + l2)

    [Formula 24] f3max = 1.15 × (j3 × F (PT) × F (PT) + k3 × F (PT) + l3)

    [Formula 25] f1min = 0.85 × (j1 × F (PT) × F (PT) + k1 × F (PT) + l1)

    [Formula 26] f2min = 0.85 × (j2 × F (PT) × F (PT) + k2 × F (PT) + l2)

    [Formula 27] f3min = 0.85 × (j3 × F (PT) × F (PT) + k3 × F (PT) + l3)

    However,

      j1 = -0.0009, k1 = 1.6135, l1 = -0.9942

      j2 = -0.0024, k2 = 2.3638, l2 = -1.9774

      j3 = −0.0039, k3 = 3.1594, and l3 = −2.1428.

  The standard value of ± 15% is merely an example, and it is necessary to optimally set based on actual measurement data such as a clinic study depending on the characteristics of the blood coagulation time measurement device and the required accuracy of abnormality determination.

  Next, it is determined whether f1, f2, and f3 obtained in step S44 are not out of the normal range determined in step S45. That is, it is determined whether or not the inequalities shown in [Expression 28] to [Expression 30] are satisfied. If all inequalities hold, it is determined that there is no abnormality, and if any one does not hold, it is determined that there is an abnormality in the measurement data profile (step S46).

    [Formula 28] f1min <f1 <f1max

    [Formula 29] f2min <f2 <f2max

    [Formula 30] f3min <f3 <f3max

  Finally, processing according to the abnormality determination result is performed. That is, as in the first embodiment, when no abnormality is detected, the blood coagulation time PT and INR value obtained by the blood coagulation time calculation unit are displayed on the LCD display 40, and when abnormality is detected, the LCD An error is displayed on the display unit 40 so that the user can recognize it. If a printer is connected to the output port 41, the measurement result can be printed as necessary. If a PC is connected to the output port 41, data can be transmitted to the PC. Further, the measurement result can be stored in the external memory 42 in the blood coagulation time measuring device, and the measurement result can be read later.

  As described above, according to the blood coagulation time measurement apparatus of the second embodiment, the determination reference times t1, t2, and t3 are set based on the blood coagulation time PT obtained by the blood coagulation time calculation unit, and Based on the value F (PT) of the measured light reception data at the blood coagulation time PT obtained by the blood coagulation time calculator, the values f1, f2, at the determination reference times t1, t2, t3 of the measured light reception data. The normal upper limit values f1max, f2max, and f3max of f3 and the normal lower limit values f1min, f2min, and f3min are set, and the values f1, f2, and f3 at the determination reference times t1, t2, and t3 of the measured received light data are obtained, and the obtained values Is determined to be within the normal value range set by the normal upper limit value and the normal lower limit value. The determination reference time and the normal range of the received light data at the determination reference time can be set according to the blood clotting time of the specimen and the value of the received light data at the blood clotting time, and are not affected by the blood clotting time of the specimen. Therefore, it is possible to perform highly accurate abnormality determination of measurement data. Also in the second embodiment, as in the first embodiment, since it is not necessary to know the saturation value of the received light amount in order to set the check area, measurement is performed when the maximum time of the differential value of the received light data is detected. Even in the high-speed measurement method that completes the above, good abnormality determination can be performed.

  The blood coagulation time measuring device according to the present invention can eliminate the influence of the difference in the amount of light received by the sample and the reaction start time, and can detect a good abnormality without depending on the blood coagulation ability or the solid difference of the light amount sample. Become. Further, it is not necessary to measure until the blood coagulation reaction is saturated, and it is possible to obtain a good effect even in a high-speed calculation method that performs measurement in a short time.

1 is a perspective view of a blood coagulation time measuring apparatus according to Embodiment 1 of the present invention. Sectional drawing of the optical stand of the blood coagulation time measuring apparatus by Embodiment 1 of this invention 1 is a block diagram of a blood coagulation time measuring apparatus according to Embodiment 1 of the present invention. The figure which shows the measurement flow of the blood coagulation time in the blood coagulation time measuring apparatus by Embodiment 1 of this invention. The figure which shows the measurement data of the clinic study used in Embodiment 1 of this invention The figure which shows the measurement data of the clinic study used in Embodiment 2 of this invention The flowchart figure of the measurement operation | movement in the blood coagulation time measuring apparatus by Embodiment 1 of this invention. The flowchart figure of the calculation of the blood coagulation time in the blood coagulation time measuring apparatus by Embodiment 1 of this invention. The flowchart figure of the abnormality determination operation | movement of the blood coagulation time in the blood coagulation time measuring apparatus by Embodiment 1 of this invention. The flowchart figure of the abnormality determination operation | movement of the blood coagulation time in the blood coagulation time measuring apparatus by Embodiment 2 of this invention. Configuration diagram of a blood coagulation time device using a conventional optical method The figure for demonstrating the measuring method of the blood coagulation time using the conventional optical method Illustration for explaining conventional problems

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Blood coagulation time measuring device 3 Test piece 4 Reaction part 5 Sample 6 Optical stand 7 Window part 8 Cover 9 Light source 10 Lens 11 Light receiving means 12 Light source filter 13 Light receiving filter 20 Holder 21 Temperature control means 22 Electrode 23 Light reception data 24 First derivative 25 Approximate line 30 LED driver 31 Operation switch 32 CPU
33 Control Unit 34 Blood Coagulation Time Calculation Unit 35 Abnormality Determination Unit 36 Data Measurement Unit 37 Data Holding Unit 38 Current Voltage Conversion Circuit 39 Analog-Digital Conversion Circuit 40 LCD Display 41 Output Port 42 External Memory 43 Timer 51 Test Tube 52 Reagent Supply Device 53 Pipette 54 LED
55 Photodiode 56 Measuring unit 57 CRT

Claims (3)

A blood coagulation time measuring device that measures a blood coagulation time by analyzing a change in optical signal using a reaction reagent that exhibits an observable optical change by reacting with a component involved in coagulation in blood. ,
A light receiver for converting the optical signal into an electrical light reception signal;
An A / D converter for converting a light reception signal from the light receiver into digital light reception data;
A data measuring unit that measures received light data obtained from the A / D converter at predetermined time intervals;
A data holding unit for temporarily holding each received light data measured by the data measuring unit;
A blood coagulation time calculation unit for obtaining a blood coagulation time based on a plurality of received light data held in the data holding unit;
An abnormality determination unit for determining whether there is an abnormality in the measured light reception data,
The abnormality determination unit is configured to determine a check region for performing abnormality determination and a normal range in the check region based on the blood coagulation time obtained by the blood coagulation time calculation unit and the value of the measured light reception data at the blood coagulation time. Set and determine whether the measured received light data is within the normal range;
A blood coagulation time measuring apparatus characterized by the above. A blood coagulation time measuring device that measures a blood coagulation time by analyzing a change in optical signal using a reaction reagent that exhibits an observable optical change by reacting with a component involved in coagulation in blood. ,
A light receiver for converting the optical signal into an electrical light reception signal;
An A / D converter for converting a light reception signal from the light receiver into digital light reception data;
A data measuring unit that measures received light data obtained from the A / D converter at predetermined time intervals;
A data holding unit for temporarily holding each received light data measured by the data measuring unit;
A blood coagulation time calculation unit for obtaining a blood coagulation time based on a plurality of received light data held in the data holding unit;
An abnormality determination unit for determining whether there is an abnormality in the measured light reception data,
The abnormality determination unit sets at least one determination reference value based on a value in the blood coagulation time calculated by the blood coagulation time calculation unit of the measured light reception data, and the blood coagulation time calculation unit Based on the blood coagulation time obtained by the above, a normal upper limit time and a normal lower limit time at which the measured light reception data value becomes equal to the determination reference value are set, and the measured light reception data value is Determining a time equal to the determination reference value, and determining whether the determined time is within a normal time range set by the normal upper limit time and the normal lower limit time;
A blood coagulation time measuring apparatus characterized by the above. A blood coagulation time measuring device that measures a blood coagulation time by analyzing a change in optical signal using a reaction reagent that exhibits an observable optical change by reacting with a component involved in coagulation in blood. ,
A light receiver for converting the optical signal into an electrical light reception signal;
An A / D converter for converting a light reception signal from the light receiver into digital light reception data;
A data measuring unit that measures received light data obtained from the A / D converter at predetermined time intervals;
A data holding unit for temporarily holding each received light data measured by the data measuring unit;
A blood coagulation time calculation unit for obtaining a blood coagulation time based on a plurality of received light data held in the data holding unit;
An abnormality determination unit for determining whether there is an abnormality in the measured light reception data,
The abnormality determination unit sets at least one determination reference time based on the blood coagulation time obtained by the blood coagulation time calculation unit, and obtains the measured light reception data by the blood coagulation time calculation unit. Based on the value in the obtained blood coagulation time, set a normal upper limit value and a normal lower limit value of the measured light reception data at the determination reference time, to determine the value of the measured light reception data at the determination reference time, Determining whether the obtained value is within a normal value range set by the normal upper limit value and the normal lower limit value;
A blood coagulation time measuring apparatus characterized by the above.

Images