Calibration method and calibration device

Abstract

To provide a standard sample which is suitable for use in an analyzer 1000 that detects scattered light from a substance in a sample and provide a calibration method.SOLUTION: A user creates a standard sample by diluting a sample including standard particles prepared such that a distribution range of the particle diameter is within a prescribed range with liquid (S10). The created standard sample is stored in a storage unit 312 of an analyzer 1000 (S20). A control device 500 controls a light-emitting diode 316 so as to emit light to the standard sample stored in the storage unit 312 (S30). The control device 500 acquires a detection value from each photodiode 314 (S40). The control device 500 calibrates the analyzer 1000 such that the detection value from the photodiode 314 becomes a predetermined reference value (S50).SELECTED DRAWING: Figure 7

Description

[Technical Field]

[0001] The present disclosure relates to a calibration method for calibrating an analytical device, a calibration standard used to calibrate an analytical device, and a calibration device for calibrating an analytical device. [Background technology]

[0002] 2. Description of the Related Art Analytical devices are known that irradiate a sample with light, detect scattered light from substances in the sample, and analyze the properties of the sample from the obtained detection results.

[0003] Japanese Patent Publication No. 2020-060586 (Patent Document 1) discloses a blood coagulation analyzer that performs analysis of blood coagulation ability by irradiating light onto a measurement sample prepared by adding a reagent to a specimen such as plasma, and detecting and analyzing the resulting scattered light. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2020-060586 Summary of the Invention [Problem to be solved by the invention]

[0005] In such analytical instruments, there are individual differences in the light source and the detector that detects scattered light. Therefore, analytical instruments must be calibrated using a standard reference material. Calibration of analytical instruments is performed, for example, during manufacturing or maintenance of the analytical instrument.

[0006] However, sufficient consideration has not been given to standard samples and calibration methods used in analytical instruments that analyze the properties of a sample based on scattered light from the sample.

[0007] An object of the present disclosure is to provide a calibration method, a standard sample for calibration, and a calibration device suitable for an analytical device that analyzes the properties of a sample based on scattered light from the sample. [Means for solving the problem]

[0008] The calibration method disclosed herein is a method for calibrating an analytical instrument that includes a storage unit for storing a sample, a light source for irradiating the sample stored in the storage unit with light, and a detection unit for measuring scattered light from the sample. The calibration method includes the steps of storing, in the storage unit, a standard sample in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid, acquiring a detection value of the detection unit obtained when the standard sample is stored in the storage unit, and calibrating the analytical instrument so that the detection value becomes a predetermined value.

[0009] The standard sample of the present disclosure is a calibration standard sample used for calibrating an analytical instrument including a light source for irradiating a sample with light and a detection unit for detecting scattered light from the sample. The calibration standard sample is prepared by dispersing standard particles in a liquid, the standard particles being prepared so that the particle size distribution range falls within a predetermined range.

[0010] The calibration device of the present disclosure includes a storage unit for storing a sample, and a light emitting element for irradiating light onto the sample stored in the storage unit. , release An analytical instrument is calibrated, the calibration device comprising an adjustment mechanism for adjusting the brightness of an optical element and a detection unit for measuring scattered light from a sample. The calibration device comprises a processor and a communication port for communicating with the analytical instrument, the processor receiving, via the communication port, from the analytical instrument a value detected by the detection unit when a standard sample, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid, is stored in the storage unit, and the processor outputs, via the communication port, to the analytical instrument a signal for adjusting the brightness of the light-emitting element so that the detection unit obtains a predetermined detection value when the standard sample is stored in the storage unit. [Effects of the Invention]

[0011] According to the present disclosure, standard particles prepared so that the particle size distribution range falls within a predetermined range are used, thereby providing standard samples with consistent scattering characteristics. Furthermore, by performing calibration using such standard samples, a calibration method is provided that minimizes the influence on measurement results caused by differences in the standard samples used during calibration, and a calibration device is provided that is capable of performing calibration that minimizes the influence on measurement results caused by differences in the standard samples used during calibration. As a result, the reproducibility of measurement values ​​is improved. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a diagram functionally illustrating an overall configuration of an analysis device 1000 according to an embodiment. [Figure 2] 1 is a plan view showing an example of the configuration of an analysis table of the analysis device 1000. FIG. [Figure 3] FIG. 2 is a diagram illustrating an example of the configuration of a photometry unit 130. [Figure 4] FIG. 10 is a plan view showing a configuration example of a coagulation port P3a. [Figure 5] FIG. 2 is a block diagram showing an example of a system configuration of an analysis device 1000 and a control device 500. [Figure 6] FIG. 2 is a diagram illustrating an example of the hardware configuration of a control device 500. [Figure 7] 10 is a flowchart showing an example of a calibration procedure for the coagulation port P3a. [Figure 8] FIG. 10 shows the change in scattering intensity of control plasma after the addition of a reagent. [Figure 9] 10 is a graph showing the results of measuring scattered light from a sample. [Figure 10] FIG. 2 is a block diagram showing the configurations of a measurement device 300 and a control device 500. [Figure 11] FIG. 2 is a block diagram showing in more detail the hardware configuration of the measurement device 300 and the control device 500. [Figure 12] 10 is a flowchart showing the procedure by which the control device 500 calibrates the measurement device 300 included in the analysis device 1000. [Figure 13]10 is a flowchart showing a procedure in which the control device 500 receives an input of a reference value used for calibration (modification). [Figure 14] 10 is a flowchart showing a procedure in which the control device 500 calibrates the measurement device 300 included in the analysis device 1000 based on a reference value (variation). DETAILED DESCRIPTION OF THE INVENTION

[0013] Hereinafter, embodiments of the present disclosure will be described in detail with reference to the drawings. In the drawings, the same or corresponding parts are designated by the same reference numerals, and description thereof will not be repeated.

[0014] The analytical device of the present disclosure is configured to dispense a sample into a cuvette using a probe (nozzle) and optically measure the reaction state in the cuvette. In this disclosure, the term "sample" may include a "measurement sample" that is the measurement target, as well as a "standard sample" used for calibration. The "measurement sample" may also be referred to as a "specimen," such as a blood component (plasma). In addition, in this disclosure, disposable cuvettes are used.

[0015] [Overall configuration of the analytical device 1000] 1 is a diagram functionally illustrating the overall configuration of an analyzer 1000 according to an embodiment. The analyzer 1000 described in this embodiment can function as an automatic blood coagulation (fibrinolysis) analyzer.

[0016] 1, the analytical device 1000 includes a cuvette supplying device 110, a cuvette transporting device 120, a stirring device 200, a measuring device 300, and a cuvette waste container 400. In the following, the cuvette supplying device 110, the cuvette transporting device 120, and the cuvette waste container 400 will be simply referred to as the "supplying device 110," the "transporting device 120," and the "waste container 400," respectively.

[0017] The analytical device 1000 further includes a sample dispensing port P1. The supply device 110 includes a cuvette storage unit 111 (hereinafter simply referred to as "storage unit 111") and a supply mechanism 112. The storage unit 111 is configured to be able to store a large number of cuvettes (for example, up to 1000). The supply mechanism 112 supplies the cuvettes stored in the storage unit 111 to the sample dispensing port P1. Details of the storage unit 111 and the supply mechanism 112 will be described later with reference to FIG. 2.

[0018] The sample dispensing port P1 is positioned so that a sample can be dispensed into the cuvette by a sample dispensing device (not shown). When a cuvette is set in the sample dispensing port P1, the sample is dispensed into the cuvette by the sample dispensing device.

[0019] The transfer device 120 includes an arm 121 with a chuck (hereinafter simply referred to as "arm 121") and a drive device 122. The arm 121 has a chuck configured to be able to grip a cuvette. The arm 121 is configured to detachably hold the cuvette with the chuck. The drive device 122 is configured to operate the arm 121 (chuck) to change the position of the chuck. The arm 121 and the drive device 122 will also be described in detail later with reference to FIG. 2.

[0020] The analytical device 1000 further includes multiple ports through which cuvettes can be transferred by the transfer device 120, specifically, an agitation port P2, a photometry port P3, and a waste port P5. The photometry port P3 includes multiple coagulation ports P3a and multiple colorimetric ports P3b. The sample dispensing port P1 is provided with a port sensor that detects the presence or absence of a cuvette. Port sensors may also be provided in other ports (such as the agitation port P2, the photometry port P3, and the waste port P5).

[0021] The stirring port P2 is disposed at a stirring position of the stirring device 200. The stirring device 200 is configured to stir the contents of a cuvette under predetermined conditions (e.g., stirring speed and stirring time) when the cuvette is set in the stirring port P2.

[0022] The coagulation port P3a and the colorimetric port P3b are each disposed in a photometric unit (not shown). Each of the coagulation port P3a and the colorimetric port P3b is provided with a detector (not shown) that detects the irradiated light emitted from a light source.

[0023] The measuring device 300 receives the light intensity detection results from the detectors of the coagulation port P3a and the colorimetric port P3b and performs a predetermined measurement on the contents of the cuvette set in each port. That is, for the coagulation port P3a, the measuring device 300 performs a coagulation measurement of the sample in the cuvette using the light intensity of scattered light detected by the detector. For the colorimetric port P3b, the measuring device 300 measures the absorbance in the cuvette using the light intensity of transmitted light detected by the detector.

[0024] The light source for the coagulation port P3a may be, for example, a light-emitting diode, and the detector provided in the coagulation port P3a may be, for example, a photodiode. The detector in the coagulation port P3a is positioned to detect the amount of 90° scattered light (light scattered in a direction perpendicular to the direction of light irradiation).

[0025] The light source for the colorimetric port P3b may be, for example, a halogen lamp. The wavelength of the light supplied to the colorimetric port P3b may be switched using a filter depending on the analysis conditions. The detector provided at the colorimetric port P3b may be, for example, a photodiode. The detector at the colorimetric port P3b is positioned to detect the amount of transmitted light.

[0026] The analyzer 1000 further includes a reference port P4 for measuring the absorbance in a cuvette set in the colorimetric port P3b. The reference port P4 has the same configuration as each colorimetric port P3b, but no cuvette is set in it, and it is light-shielded with a lid or the like to prevent light other than that from the light source from entering the reference port P4. The absorbance is measured from the ratio (light intensity ratio) between the amount of light detected by the detector provided in the colorimetric port P3b and the amount of light detected by the detector provided in the reference port P4, thereby performing colorimetric analysis of the sample.

[0027] The waste port P5 is configured to collect used cuvettes. The waste port P5 is connected to a waste container 400, for example, through a pipe. When a cuvette is placed in the waste port P5, the cuvette is guided to the waste container 400.

[0028] Configure Analysis Table Fig. 2 is a plan view showing an example of the configuration of the analysis table of the analysis device 1000. Fig. 2 shows three mutually orthogonal axes (X-axis, Y-axis, and Z-axis), where the X-axis and Y-axis indicate the width and depth directions of the analysis device 1000, respectively, and the Z-axis indicates the vertical direction (i.e., the up-down direction). The direction indicated by the arrow on the Z-axis is the upward direction, and the opposite direction is the downward direction (i.e., the direction of gravity).

[0029] 2 and 1, a large number of cuvettes 100 are stored in the storage unit 111. A user can replenish the storage unit 111 with cuvettes 100 through an inlet (not shown) of the storage unit 111. The cuvettes 100 may be made of any material as long as they are light-transmitting, and for example, a material made of transparent acrylic may be used.

[0030] The supply mechanism 112 is configured to take out the cuvettes 100 one by one from the storage section 111 and supply them to the sample dispensing port P1. The supply mechanism 112 may transport the cuvettes 100 in any manner, including, for example, a slide system (gravity system), a belt conveyor system, a roller system, or a slide system. The supply mechanism 112 is configured to receive the detection result of the port sensor of the sample dispensing port P1, and supply the next cuvette 100 to the sample dispensing port P1 when the port P1 becomes empty. However, the present invention is not limited to this, and the supply mechanism 112 may also be configured to supply the cuvettes 100 to the sample dispensing port P1 in accordance with instructions from a control device, which will be described later.

[0031] The arm 21 is a device (sample dispensing device) for dispensing the sample aspirated from the sample aspirating port P21 into the cuvette 100 set in the sample dispensing port P1, and includes a probe 21a and an arm body 21b. The arm body 21b is configured to be rotatable around a rotation axis 23a, and as the arm body 21b rotates, the probe 21a provided at the tip of the arm body 21b can move along an arc-shaped trajectory L2 on the XY plane.

[0032] By rotating the arm body 21b, the probe 21a can move to each of the sample dispensing port P1, the sample suction port P21, the S port P22 (more specifically, ports P22a to P22i), and the washing port P23, which are provided on the track L2. Regarding the S port P22, for example, ports P22a and P22b are detergent ports, ports P22c, P22d, and P22e are buffer solution ports, and ports P22f, P22g, P22h, and P22i are plasma-deficient ports.

[0033] Although not shown, a movable sample rack is provided below the sample suction port P21. A plurality of sample containers are placed on the sample rack. When analyzing a specimen, a blood component (e.g., plasma) or urine sample is placed in each of these sample containers, and when calibrating the analyzer 1000, a standard sample (described below) is placed in each of these sample containers. The sample rack operates to position the sample container to be dispensed directly below the sample suction port P21 before dispensing the sample into the cuvette 100 set in the sample dispensing port P1. The CTS mechanism 24 is provided near the sample suction port P21 and is configured to pierce the cap of the sample container to be dispensed if it has a cap.

[0034] The photometry unit 130 has multiple photometry ports P3 (multiple coagulation ports P3a and colorimetric ports P3b) arranged in an arc. In this example, 14 coagulation ports P3a and 6 colorimetric ports P3b are arranged. The arm 11 is a device for dispensing a reagent aspirated from the suction port P11 into a target cuvette 100 set in the photometry port P3, and includes a probe 11a and an arm body 11b. The arm body 11b is configured to be rotatable around a rotation axis 13a, and by rotating the arm body 11b, the probe 11a provided at the tip of the arm body 11b can move in an arc-shaped trajectory L1 on the XY plane.

[0035] By rotating the arm body 11b, the probe 11a can move to each of the coagulation ports P3a, each of the colorimetric ports P3b, the suction ports P11 and P12, and the washing port P13, which are provided on the track L1. Although not specifically shown, in reality, the probe 11a is composed of two probes to prevent contamination between reagents, and the reagent tray 31a (described below) has an outer tray and an inner tray, so that the reagent (or cleaning solution) on the outer tray and the reagent (or cleaning solution) on the inner tray can be aspirated from the suction ports P11 and P12 using two probes, respectively. The washing port P13 is a port for washing the probe 11a.

[0036] The reference port P4 is provided in a location separate from the photometric port P3 (photometric unit 130). As described above, the reference port P4 has the same configuration as each colorimetric port P3b, but since there is no need to set the cuvette 100 therein, the reference port P4 is placed, for example, inside the analysis device 1000 rather than on the analysis table.

[0037] A reagent tray 31a on which a plurality of reagent containers 1 and a plurality of detergent containers 1a are placed is provided below the suction ports P11, P12, and the reagent tray 31a is provided inside the reagent refrigerator 31. The plurality of reagent containers 1 hold different reagents, and the plurality of detergent containers 1a hold different detergents. The reagent tray 31a is composed of a disk-shaped turntable, and by driving the turntable, the desired reagent container 1 or detergent container 1a can be positioned directly below the suction ports P11, P12.

[0038] The arm 121 includes a chuck 121a and an arm body 121b. The chuck 121a is configured to be able to grip the cuvette 100. The chuck 121a may hold the cuvette 100 in any manner, and the chuck 121a may be a mechanical chuck, a magnetic chuck, or a vacuum chuck. The arm body 121b is configured to be able to rotate together with the rotating body 122a around the rotation axis 13a. When the rotating body 122a rotates, the arm body 121b rotates integrally with the rotating body 122a, and the chuck 121a provided at the tip of the arm body 121b can move so as to describe an arc-shaped trajectory L1 in the XY plane.

[0039] As described above, the arms 11 and 121 have the same center of rotation. A sample dispensing port P1, an agitation port P2, a waste port P5, a plurality of photometric ports P3 (a plurality of coagulation ports P3a and a plurality of colorimetric ports P3b), suction ports P11 and P12, and a washing port P13 are provided on the trajectory L1. The arm 121 can move the chuck 121a to the sample dispensing port P1, the agitation port P2, each photometric port P3, and the waste port P5, and the arm 11 can move the probe 11a to the aspiration ports P11 and P12, the washing port P13, the agitation port P2, and each photometric port P3.

[0040] [Configuration of photometry unit 130] FIG. 3 is a diagram showing an example of the configuration of the photometry unit 130. Referring to FIG. 3, the photometry unit 130 has a plurality of coagulation ports P3a and colorimetric ports P3b arranged in an arc shape. More specifically, the plurality of coagulation ports P3a and colorimetric ports P3b are arranged so that the storage portions of each port are aligned along an arc-shaped trajectory L1. In this example, 14 coagulation ports P3a and 6 colorimetric ports P3b are arranged. Note that the number and arrangement order of the coagulation ports P3a and colorimetric ports P3b are not limited to those shown in the figure.

[0041] Fig. 4 is a plan view showing an example of the configuration of the coagulation port P3a. The coagulation port P3a includes a storage section 312, a light-emitting diode 316 serving as an example of a light source, and a photodiode 314 serving as an example of a detector or light-receiving element. In Fig. 4, the optical axis Li of the irradiation light emitted from the light-emitting diode 316 toward the storage section 312 is schematically shown by a dashed line.

[0042] The storage section 312 is configured to be able to detachably mount the cuvette 100 transferred by the transfer device 120 (arm 121), and is a specific example of a "storage section" for storing a sample.

[0043] The light-emitting diode 316 irradiates light onto the sample (cuvette 100) stored in the storage unit 312. The light-emitting diode 316 is, for example, a red light-emitting diode that irradiates light with a wavelength of 660 nm. However, the light-emitting diode 316 is not limited to this. For example, a light-emitting diode 316 that irradiates light with a wavelength of 405 nm, 570 nm, 730 nm, or 800 nm may be used.

[0044] The photodiode 314 detects light scattered in a predetermined direction from the sample. Specifically, the photodiode 314 is provided in a direction perpendicular to the optical axis Li of the light emitted from the light-emitting diode 316, and detects light scattered at an angle of 90° from the sample. In this embodiment, the photodiode 314 is configured to detect light scattered at an angle of 90° from the sample, but may also be configured to detect light scattered at other angles.

[0045] The coagulation port P3a is used to measure the coagulation time in order to analyze the coagulation function of a sample. Specifically, when a reagent is added to a blood component (e.g., plasma) serving as the sample, a coagulation reaction occurs, converting fibrinogen in the sample to fibrin. While fibrinogen is soluble in water, fibrin is insoluble in water, causing a change in the turbidity of the reaction solution. The photodiode 314 measures the scattered light generated when the reaction solution is irradiated with light as an indicator of the turbidity of the reaction solution. The photodiode 314 measures the scattered light over time. The coagulation time is calculated by applying an algorithm to the reaction curve indicated by the change in scattered light over time.

[0046] [System Configuration] Fig. 5 is a block diagram showing an example of a system configuration of analysis device 1000 and control device 500. Fig. 5 conceptually illustrates only the configuration related to measurement using light, among the configuration of analysis device 1000 shown in Fig. 1. Referring to Fig. 5, analysis device 1000 includes photometry unit 130, robot unit 150, and measurement device 300. Control device 500 is connected to analysis device 1000.

[0047] The photometry unit 130 includes a plurality of coagulation ports P3a, a plurality of colorimetric ports P3b, and a reference port P4.

[0048] The robot unit 150 collectively refers to movable devices such as the arms 11, 21, and 121, the cuvette supply device 110, the CTS mechanism 24, the reagent cooler 31, the reagent tray 31a (see FIG. 2), and the sample rack. The robot unit 150 handles samples using the arm 21, the sample rack, and the CTS mechanism 24, handles reagents using the arm 11, the reagent cooler 31, and the reagent tray 31a, and transports and handles the cuvettes 100 using the supply device 110 and the arm 121. The robot unit 150 is fully automatically controlled by the transport control unit 376 of the measuring device 300.

[0049] The measurement device 300 includes a photometry control unit 370, a data collection unit 372, an AD conversion unit 374, and a transport control unit 376. The photometry control unit 370 controls all photometry in the photometry unit 130 in accordance with instructions from the data collection unit 372. For example, the photometry control unit 370 controls the light-emitting diode 316 when performing measurement using the coagulation port P3a.

[0050] The data collection unit 372 determines the coagulation port P3a from which measurement data is to be acquired in accordance with a data collection instruction from the control device 500, and outputs an instruction to perform measurement at that coagulation port P3a to the photometry control unit 370. Then, the data collection unit 372 acquires measurement data (measurement signal) of scattered light detected by the photodiode 314 of the coagulation port P3a from the AD conversion unit 374, and outputs the collected data to the control device 500.

[0051] The AD conversion unit 374 converts the detection signal from the photodiode 314 of each coagulation port P3a into a digital signal and outputs it as a measurement signal to the data collection unit 372. The transport control unit 376 generates commands for controlling various operations of the robot unit 150 in accordance with instructions from the data processing unit 510 of the control device 500, and controls the various operations of the robot unit 150.

[0052] The control device 500 includes a data processing unit 510 and a storage unit 512. A display device 520 and a keyboard 530 are connected to the control device 500. The control device 500 is configured by, for example, a personal computer. The control device 500 is an example of a calibration device that calibrates the analysis device 1000.

[0053] Various pieces of information related to measurement and calibration are displayed on the display device 520. A user inputs various instructions from a keyboard 530 while looking at the screen of the display device 520. The keyboard 530 is an example of an operation unit. Note that in addition to the keyboard, a mouse, which is another example of an operation unit, may be connected to the control device 500.

[0054] The data processing unit 510 generates various instructions for performing measurements in accordance with measurement instructions from the user, and outputs the various generated instructions to the data collection unit 372 and transport control unit 376 of the measuring device 300. The data processing unit 510 also performs various data processing for performing colorimetric analysis and coagulation analysis based on the various measurement data received from the data collection unit 372 of the measuring device 300.

[0055] Furthermore, data processing unit 510 generates a command to measure a standard sample in accordance with a user's instruction to calibrate analytical device 1000, and outputs the generated command to measuring device 300. Data processing unit 510 then receives the measurement results of the standard sample from measuring device 300, and calibrates each coagulation port P3a so that each output value from each photodiode 314 included in each coagulation port P3a becomes a predetermined value (hereinafter also referred to as a reference value). The calibration method and the standard sample used for calibration will be described later.

[0056] The memory unit 512 stores control programs and various information (data) for executing various processes by the control device 500, and outputs various control programs and information (data) to the data processing unit 510 in accordance with requests from the data processing unit 510.

[0057] [Control device hardware configuration] Fig. 6 is a diagram showing an example of the hardware configuration of control device 500. Referring to Fig. 6, control device 500 includes a CPU (Central Processing Unit) 531, a RAM (Random Access Memory) 532, a storage device 534, and a communication port 535 for communicating with external devices. Data processing unit 510 and storage unit 512 shown in Fig. 5 are realized by the hardware shown in Fig. 6.

[0058] The CPU 531 loads a control program stored in the storage device 534 into the RAM 532 and executes it. This control program is a program in which the procedures for various processes executed by the control device 500 are written. In addition to the control program, the storage device 534 also stores various information and data used in the various processes. The control device 500 executes various processes in the analysis device 1000 in accordance with these control programs and various information and data. Note that the processes are not limited to those executed by software, and can also be executed by dedicated hardware (electronic circuits).

[0059] In addition to a control program describing processing procedures, information or data such as reagent information, analysis schedules, analysis history, calibration information, etc. is registered in the storage device 534. The reagent information is information about each reagent prepared in the reagent tray 31a (FIG. 2) (e.g., reagent ID, reagent type, expiration date, etc.).

[0060] The analysis schedule is determined based on sample information (e.g., the analysis items for each sample) and the availability of each port, etc., in order to efficiently analyze all reserved samples. For example, the analysis schedule includes the timing of each dispensing and measurement, the sample and reagent to be dispensed, and the photometric port P3 (coagulation port P3a and / or colorimetric port P3b) where the measurement will be performed. The analysis schedule is managed for each sample ID (each sample container).

[0061] The analysis history indicates the progress of the analysis, including intermediate steps, and is updated as the analysis progresses. The analysis history includes, for example, the cuvette's movement path (including its current position), the sample and reagent dispensed into the cuvette, the photometric port P3 where the measurement was performed, and the measurement results. The analysis history is managed for each cuvette. By referring to the analysis history, the control device 500 and the user can confirm whether the analysis was performed (or is progressing) according to the analysis schedule.

[0062] The calibration information includes information necessary for calibrating each coagulation port P3a included in the analyzer 1000 and information indicating the calibration results. The information necessary for calibration is, for example, a reference value of the output value from the photodiode 314 that is used as a reference for calibration. The information indicating the calibration results is, for example, a predetermined value set for each light-emitting diode 316 and a correction value set for each photodiode 314 for correcting the detection result.

[0063] [Calibration Procedure] 7 is a flowchart showing an example of a procedure for calibrating the coagulation port P3a. Referring to FIG. 7, a user such as a manufacturer of the analytical device 1000, a user of the analytical device 1000, or a serviceman prepares a standard sample (S10). More specifically, the user prepares the standard sample by diluting a sample (stock solution) containing standard particles prepared so that the particle size distribution range falls within a predetermined range with a liquid (dilution liquid).

[0064] Next, the user stores each of the standard samples in the storage unit 312 (S20). For example, the user dispenses the standard sample into a sample container and places the sample container with the dispensed standard sample on a sample rack. The arm 21 of the analyzer 1000 aspirates the standard sample from the sample container into which the standard sample has been dispensed, and dispenses the standard sample into the cuvette 100 set in the sample dispensing port P1. Note that the maximum amount of liquid that the arm 21 can aspirate is limited, so the arm 21 repeats the operation of aspirating the standard sample from the sample container and dispensing it into the cuvette 100 until the required amount of standard sample has been dispensed into the cuvette 100. The arm 121 then stores the cuvette 100 containing the standard sample that was set in the sample dispensing port P1 in the storage unit 312 of the coagulation port P3a. This achieves the processing of S20. The process of S20 may be realized by the user dispensing a standard sample into each of the multiple cuvettes 100, and then setting the cuvettes 100 containing the standard sample in the storage sections 312 of the coagulation ports P3a.

[0065] The control device 500 controls each light-emitting diode 316 so as to irradiate light onto the standard samples stored in each storage section 312 (S30).

[0066] The control device 500 acquires the detection value from each photodiode 314 (S40).

[0067] The control device 500 calibrates the analysis device 1000 so that the detection values ​​from each photodiode 314 become a predetermined reference value (S50). For example, the control device 500 sets a command value for adjusting the amount of light emitted from the light-emitting diode 316 so that the detection values ​​from the photodiodes 314 become the reference value. Alternatively, the control device 500 calculates a correction value for adjusting the detection values ​​from the photodiodes 314 to the reference value. A specific example of the calibration procedure of the control device 500 will be described in detail later.

[0068] The calibration procedure for the coagulation port P3a shown in Fig. 7 includes a step of preparing a standard sample. The standard sample may be prepared in advance.

[0069] The step (S10) of preparing a standard sample may be performed by the analyzer 1000, rather than by a user. Specifically, the step (S10) of preparing a standard sample may be realized by the analyzer 1000 executing a step of dispensing an undiluted solution into a cuvette and a step of dispensing a diluent into the cuvette into which the undiluted solution has been dispensed. At this time, the undiluted solution is set in a sample rack, for example, in a sample container. The diluent is set in the S port 22 or the reagent container 1, for example. As an example, the analyzer 1000 may prepare a standard sample as follows: First, the arm 21 dispenses a predetermined amount of undiluted solution contained in a sample container into the cuvette 100 supplied to the sample dispensing port P1. Next, the arm 121 moves the cuvette 100 into which the undiluted solution has been dispensed from the sample dispensing port P1 to the coagulation port P3a. Thereafter, the arm 11 dispenses a predetermined amount of diluent solution contained in the reagent container 1 into the cuvette 100 containing the undiluted solution stored in the coagulation port P3a. At this time, the arm 11 dispenses the dilution liquid so that the concentration of the standard particles in the cuvette 100 stored in the coagulation port P3a falls within a predetermined concentration range.

[0070] [Standard sample] The standard sample will now be described in detail. The standard sample is configured by dispersing standard particles, which have been prepared so that the particle size distribution range falls within a predetermined range, in a liquid. The liquid is, for example, water. To easily disperse the standard particles, the viscosity of the liquid is preferably equal to or less than that of water. For example, a user may add water to a sample consisting of standard particles and water to create a standard sample in which the standard particles are dispersed in the liquid.

[0071] The particle diameter of the particles used as the standard particles is selected based on, for example, the wavelength of the light from the light-emitting diode 316 and the angle of the scattered light detected by the photodiode 314. Preferably, the standard particles used are those whose particle diameter distribution peaks at a particle diameter that scatters most of the light in the direction detected by the photodiode 314 when irradiated with light of the wavelength of the light-emitting diode 316.

[0072] For example, when photodiode 314 is arranged to detect 90° scattered light, the particle diameter at the peak of the particle diameter distribution is preferably small. For example, when the wavelength of light emitted from light-emitting diode 316 is 660 nm and photodiode 314 is arranged to detect 90° scattered light, the standard particles preferably have a particle diameter at the peak of the particle diameter distribution of 350 nm or less.

[0073] In this way, the amount of standard particles required to obtain a predetermined scattering intensity can be reduced by selecting a sample having a particle diameter that forms a peak in the particle diameter distribution and that scatters a lot in the direction detected by photodiode 314 when irradiated with light of the wavelength of light-emitting diode 316. From this perspective, it is preferable that the above-mentioned standard particles have a particle diameter that forms a peak in the particle diameter distribution of 350 nm or less.

[0074] Furthermore, if the particle diameters of the particles contained in the standard particles vary widely, it is difficult to intentionally create samples with the same scattering intensity. Therefore, it is preferable that the particle diameters of the particles contained in the standard particles vary little.

[0075] For example, the coefficient of variation (CV), which is an index of particle size distribution (uniformity of particle sizes) and indicates the ratio of standard deviation to the average particle size, is preferably less than 3%. A CV value of less than 3% indicates that a population with a narrow distribution is formed around the average diameter.

[0076] One possible standard sample for calibration is one in which a pigment is mixed into an epoxy resin. However, pigments are not prepared so that the particle size distribution falls within a specified range, and there is a problem in that it is not possible to intentionally create a standard sample that will provide the same scattering intensity as a previously prepared standard sample.

[0077] The standard sample according to the present disclosure is created using standard particles that have been prepared so that the particle size distribution range falls within a predetermined range, and therefore it is possible to intentionally create standard samples that provide similar scattering intensities.

[0078] Furthermore, when attempting to create a standard sample that will provide a similar scattering intensity (scattering intensity within a predetermined range), if a sample with a wide particle size distribution is used, it becomes necessary to dilute the sample while checking the scattering intensity using the reference analytical device 1000 so that the scattering intensity falls within the predetermined range. In contrast, by using a sample with a narrow particle size distribution, the scattering intensity obtained using the reference analytical device 1000 can be kept within the predetermined range by fixing the dilution rate (concentration of standard particles in the standard sample) without having to check the scattering intensity.

[0079] Next, the scattering intensity of a standard sample will be described. The analyzer 1000 according to this embodiment is used to observe the coagulation factor activity in blood. Therefore, it is preferable that the standard sample has a scattering intensity comparable to that obtained when a sample in the middle of a coagulation reaction is measured. In other words, the intensity of scattered light detected when the standard sample is irradiated with light is preferably within the range of the scattered light intensity distribution obtained by measuring the change over time of scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light. From another perspective, it is also preferable that the intensity of scattered light detected when the standard sample is irradiated with light is within a predetermined range. For example, this range is preferably set according to the scattered light intensity distribution obtained by measuring the change over time of scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light.

[0080] FIG. 8 shows the change in scattering intensity of control plasma after the addition of a reagent. More specifically, the change in scattering intensity shown in FIG. 8 indicates the change in voltage detected by the detector due to the change in scattering intensity after adding a reagent to control plasma (Coagpia Control PN I, manufactured by Sekisui Medical Co., Ltd.) using an analyzer 1000 (CP3000, manufactured by Shimadzu Corporation) with prothrombin time and fibrinogen as the measurement items. The change in scattering intensity indicated by the solid line in FIG. 8 is the result obtained when prothrombin time was the measurement item and the reagent (Coagpia PT-N, manufactured by Sekisui Medical Co., Ltd.) was added to the control plasma. The change in scattering intensity indicated by the dashed line in FIG. 8 is the result obtained when fibrinogen was the measurement item and the reagent (Coagpia Fbg Thrombin Reagent, manufactured by Sekisui Medical Co., Ltd.) and diluent (Coagpia Fbg Sample Diluent, manufactured by Sekisui Medical Co., Ltd.) were added to the control plasma. As shown in FIG. 8, the median value of the output voltage falls between 250 mV and 500 mV for all measurement items.

[0081] Therefore, it is preferable that the standard sample is prepared so that the output voltage detected by the detector of the analyzer 1000 (CP3000, manufactured by Shimadzu Corporation) is between 250 mV and 500 mV.

[0082] Next, the relationship between the concentration of standard particles and scattering intensity will be described. The standard particles used were a sample with an average particle diameter of approximately 270 nm, a CV value of 1.6%, and a particle concentration of 1 wt% (product number 3269A, Thermo Fisher Scientific), a sample with an average particle diameter of approximately 300 nm, a CV value of 1.6%, and a particle concentration of 1 wt% (product number 3300A, Thermo Fisher Scientific), and a sample with an average particle diameter of approximately 350 nm, a CV value of 1.9%, and a particle concentration of 1 wt% (product number 3350A, Thermo Fisher Scientific). Here, particle concentration is the ratio of particle mass to sample mass. A stock solution was prepared by diluting the sample 251 times with water (for example, diluting 1 mL of sample with 250 mL of water). The stock solution was further diluted to create multiple samples. The scattered light of the sample was measured using an analyzer 1000 (CP3000, manufactured by Shimadzu Corporation).

[0083] FIG. 9 is a graph showing the results of measuring the scattered light of a sample. The horizontal axis of FIG. 9 shows the dilution series of the stock solution (volume of stock solution / (volume of stock solution+volume of water)), and the vertical axis shows the output voltage corresponding to the scattering intensity. The value of dilution series 0 shows the output voltage obtained when measuring water. The measurement results shown by the dotted line in FIG. 9 are the results of a sample prepared using standard particles with an average particle diameter of 270 nm. The measurement results shown by the solid line in FIG. 9 are the results of a sample prepared using standard particles with an average particle diameter of 300 nm. The measurement results shown by the dashed line in FIG. 9 are the results of a sample prepared using standard particles with an average particle diameter of 350 nm.

[0084] If the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water, the particle concentration of the standard particles contained in the sample in dilution series 1 is approximately 0.004 wt% (= 1 wt% / 251). Similarly, if the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water, the particle concentration of the standard particles contained in the sample in dilution series 0.2 is approximately 0.0008 wt% (= 1 wt% / 251 × 0.2). Below, the particle concentrations of the standard samples are calculated assuming that the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water.

[0085] As shown in Fig. 9, the smaller the dilution series, the lower the output voltage detected as scattered light. Note that the smaller the dilution series, the lower the particle concentration of the standard particles; in other words, the lower the particle concentration of the standard particles, the lower the output voltage detected as scattered light.

[0086] As shown in Figure 9, the output voltage obtained when measuring water was 29.6 mV. Therefore, to reduce the influence of scattering from water, it is preferable that the standard sample be prepared to a concentration that will result in an output value of a predetermined value or higher. For example, it is preferable that the standard sample be prepared to a concentration that will result in an output value of 200 mV or higher.

[0087] When standard particles with an average particle size of 270 nm are used, the output voltage obtained when measuring a sample in the dilution series of 0.4 (particle concentration: approximately 0.0016 wt%) is 228.1 mV. Therefore, when standard particles with an average particle size of 270 nm are used, it is preferable that the particle concentration be adjusted to 0.0016 wt% or more.

[0088] When standard particles with an average particle size of 300 nm are used, the output voltage obtained when measuring a sample in the dilution series of 0.4 (particle concentration: approximately 0.0016 wt%) is 207.5 mV. Therefore, when standard particles with an average particle size of 300 nm are used, it is preferable that the particle concentration be adjusted to 0.0016 wt% or more.

[0089] When standard particles with an average particle size of 350 nm are used, the output voltage obtained when measuring a sample in the dilution series of 0.5 (particle concentration: approximately 0.002 wt%) is 192.9 mV, which is approximately 200 mV. Therefore, when standard particles with an average particle size of 350 nm are used, it is preferable that the particle concentration be adjusted to 0.002 wt% or more.

[0090] Furthermore, as described above, it is preferable that the standard sample is prepared so that the median value of the output voltage detected by the detector of the analyzer 1000 (CP3000, manufactured by Shimadzu Corporation) is between 250 mV and 500 mV.

[0091] When standard particles with an average particle size of 270 nm are used, the output voltage obtained when measuring samples in the dilution series 0.5 (particle concentration: approximately 0.002 wt%) to 1.0 (particle concentration: approximately 0.004 wt%) is approximately 250 mV to approximately 500 mV. Therefore, when standard particles with an average particle size of 270 nm are used, the particle concentration is preferably adjusted to be 0.002 wt% or more and 0.004 wt% or less.

[0092] When standard particles with an average particle size of 300 nm are used, the output voltage obtained when measuring samples in the dilution series 0.5 (particle concentration: approximately 0.002 wt%) to 1.0 (particle concentration: approximately 0.004 wt%) is approximately 250 mV to approximately 500 mV. Therefore, when standard particles with an average particle size of 300 nm are used, it is preferable that the particle concentration be adjusted to between 0.002 wt% and 0.004 wt%.

[0093] When standard particles with an average particle size of 350 nm are used, the output voltage obtained when measuring a sample in dilution series 0.7 (particle concentration: approximately 0.0028 wt%) is 261 mV, and the output voltage obtained when measuring a sample in dilution series 1 (particle concentration: approximately 0.004 wt%) is 375.8 mV. Therefore, when standard particles with an average particle size of 350 nm are used, it is preferable that the particle concentration be adjusted to at least 0.0028 wt% or more.

[0094] In this way, by adjusting the concentration of the standard sample, it is possible to create a model of the state during the clotting reaction, and calibration can be performed using a standard sample similar to the specimen to be measured.

[0095] [Procedure for the control device 500 to calibrate the analytical device 1000 using a standard sample] Before describing the calibration procedure, we will explain the background art. Light-emitting diodes (LEDs) have been widely used as light sources in analytical instruments. However, to ensure a wide measurement range that can accommodate samples of various concentrations, it is necessary to maintain the emission intensity of the light source used in the analytical instrument within a certain range. Therefore, it is extremely important to calibrate the emission intensity of the light source to an appropriate value in the analytical instrument.

[0096] However, because the brightness of LEDs varies greatly from one to another, some production lots may have brightness values ​​that deviate from the standard. Analytical devices may be equipped with a correction circuit that corrects the output value of the light-receiving element. However, if the light-emitting diode's brightness deviates significantly from the standard, the correction circuit cannot adjust the output value of the light-receiving element to the standard value. Therefore, even if the correction circuit is taken into consideration, it is still time-consuming to select LEDs with a certain range of brightness. This can also lead to a decrease in production yield.

[0097] Furthermore, the light-emitting diodes gradually lose their brightness over time. Therefore, to maintain the output value of the light-receiving element at a reference value, calibration is required after each analysis process. The more light-emitting diodes used in an analytical device, the more time-consuming calibration becomes. Furthermore, conventional calibration circuits have often only been implemented during the manufacturing of analytical devices, which has not adequately addressed the degradation of light-emitting diodes over time.

[0098] The luminous efficiency of light-emitting diodes tends to increase year by year. Consequently, the brightness of standard light-emitting diodes in circulation also increases year by year. Therefore, it is becoming increasingly difficult to obtain light-emitting diodes with the same luminous performance as previously used light-emitting diodes. The problem arises when the luminous brightness of newly acquired light-emitting diodes is too high, and the correction circuit installed in the analyzer at the time is unable to correct the output value of the light-receiving element to the appropriate value.

[0099] In view of these problems related to the background art, the following describes a procedure in which the control device 500 calibrates the analytical device 1000 using a standard sample, with reference to FIGS.

[0100] FIG. 10 is a block diagram showing the configurations of the measuring device 300 and the control device 500. The measuring device 300, which constitutes part of the analytical device 1000, includes a substrate 310 corresponding to each of the 14 coagulation ports P3a. A light-emitting diode 316, which is an example of a light-emitting element, and a photodiode 314, which is an example of a light-receiving element, are connected to the substrate 310. The measuring device 300 is configured to be able to communicate with a control device 500, which is an example of a calibration device. As also shown in FIG. 5, a display device 520 and a keyboard 530 are connected to the control device 500.

[0101] The control device 500 outputs a command related to measurement or calibration to the substrate 310 corresponding to the coagulation port P3a to be measured or calibrated. The user operates the keyboard 530 to select the coagulation port P3a to be measured or calibrated.

[0102] Fig. 11 is a block diagram showing in more detail the hardware configuration of the measuring device 300 and the control device 500. Fig. 11 illustrates one of the multiple substrates 310 included in the measuring device 300. The various components of the measuring device 300 shown in Fig. 5 are realized by the hardware shown in Fig. 11.

[0103] The measuring device 300 includes a substrate 310 on which a microcomputer 311, an I / V conversion circuit 313, an amplifier circuit 315, and a current control circuit 319 are mounted. The current control circuit 319 is connected to a light-emitting diode 316. The I / V conversion circuit 313 is connected to a photodiode 314. The light-emitting diode 316 and the photodiode 314 are stored in the coagulation port P3a together with the storage section 312 (see FIG. 4). The measuring device 300 shown in FIG. 10 is provided with a plurality of microcomputers 310. Each microcomputer 311corresponds to each combination of the light emitting diode 316 and the photodiode 314. However, one microcomputer provided in the measuring device 300 311 All the light emitting diodes 316 and photodiodes 314 may be connected to the

[0104] When calibrating the analytical device 1000, a standard sample is stored in the storage unit 312. As the standard sample, for example, the standard sample described above in this embodiment is used.

[0105] The current control circuit 319 controls the forward current If flowing through the light emitting diode 316. The amplifier circuit 315 is configured to amplify the input voltage within a predetermined range of magnification.

[0106] The microcomputer 311 communicates with the control device 500. The control device 500 outputs various commands to the microcomputer 311 via a communication port 535. The various commands include a command regarding the value of the forward current If to be flowed through the light-emitting diode 316 and a command regarding the amplification factor of the amplifier circuit 315. The value of the forward current If and the amplification factor of the amplifier circuit 315 are specified, for example, by a user. The user specifies the value of the forward current If and the amplification factor of the amplifier circuit 315 by operating, for example, a keyboard 530. The values ​​specified by the user are stored in the storage device 534 as part of the calibration information.

[0107] Based on a command from control device 500, microcomputer 311 sets the value of forward current If to be passed by current control circuit 319 and sets the amplification factor of amplifier circuit 315. Current control circuit 319 passes forward current If of the set magnitude through light-emitting diode 316. As a result, light-emitting diode 316 emits light at a brightness that corresponds to the brightness characteristics of light-emitting diode 316 and the magnitude of forward current If.

[0108] Light from the light-emitting diode 316 is irradiated onto the standard specimen in the storage section 312. A portion of the scattered light generated by the standard specimen is incident on the photodiode 314. A current corresponding to the magnitude of the incident light flows through the photodiode 314. The I / V conversion circuit 313 converts the current output by the photodiode 314 into a voltage Vout.

[0109] The I / V conversion circuit 313 transmits the voltage Vout to the amplifier circuit 315. The amplifier circuit 315 amplifies the voltage Vout by a set magnification. As a result, the voltage Vout is amplified to the voltage Vgout. The voltage Vgout is input to the microcomputer 311. The microcomputer 311 A / D converts the input voltage Vgout. The microcomputer 311 outputs the A / D converted value to the control device 500 as the detection value of the detection unit.

[0110] The control device 500 acquires the detection value from the measurement device 300. The control device 500 stores the acquired detection value in the storage device 534 as part of the calibration information. The control device 500 also displays the acquired detection value on the display device 520. The user determines whether the detection value matches the reference value. Of course, if the detection value falls within a range with a certain width around the reference value, it may be determined that the analysis device 1000 has been properly calibrated.

[0111] If the user determines that the detected value does not match the reference value or is not within a certain reference range, the user can reset the forward current If and the amplification factor and instruct the control device 500 to calibrate the analytical device 1000 again.

[0112] FIG. 12 is a flowchart showing the procedure by which the control device 500 calibrates the measuring device 300 included in the analytical device 1000. First, the control device 500 detects the input of a target photometric port number (step S101). In step S101, a port corresponding to a storage unit in which a standard sample has been stored in advance is selected. A notification may be sent to the user to confirm whether or not a standard sample has been stored in the storage unit corresponding to the selected photometric port. The photometric port number is input to the control device 500, for example, by the user operating the keyboard 530. Based on the input photometric port number, the control device 500 identifies the board 310 from which a calibration command is to be output, from among the multiple boards 310 provided in the measuring device 300.

[0113] Next, the control device 500 displays on the display device 520 a screen for setting the forward current If to be passed through the light-emitting diode 316 and the amplification factor of the amplifier circuit 315 (step S102). At this time, the control device 500 may display on the screen the photometry port number of the calibration target.

[0114] Next, the control device 500 receives the input of the forward current If and outputs a command signal for adjusting the forward current If to the measuring device 300 (step S103). The measuring device 300 sets the forward current If corresponding to this command signal in the target current control circuit 319.

[0115] Next, the control device 500 receives the input of the amplification factor and outputs a command signal for adjusting the amplification factor to the measurement device 300 (step S104). The measurement device 300 sets the amplification factor corresponding to this command signal in the target amplifier circuit 315.

[0116] Next, the control device 500 detects an instruction to irradiate light (step S105). The instruction to irradiate light is input to the control device 500, for example, by the user operating the keyboard 530. Next, the control device 500 outputs a command to the measurement device 300 to irradiate light onto the storage unit of the target photometry port number (step S106).

[0117] As a result, a forward current If of a set magnitude flows through the light-emitting diode 316. The light from the light-emitting diode 316 is irradiated onto the standard sample in the storage section 312, generating scattered light. A signal corresponding to the magnitude of the scattered light is detected by the photodiode 314. The detected signal is output to the control device 500 via the I / V conversion circuit 313, the amplifier circuit 315, and the microcomputer 311. The amplifier circuit 315 amplifies the signal by a set magnification.

[0118] The control device 500 receives the detection value from the measuring device 300 (step S107). Next, the control device 500 displays the detection value on the screen (step S108) and ends the processing based on this flowchart. The user compares the detection value with the calibration reference value, and if necessary, reviews the forward current If and the amplification factor, and causes the control device 500 to execute the processing based on this flowchart again. This allows the user to calibrate the detection value obtained for the standard sample to the reference value.

[0119] As described above, according to this embodiment, the forward current If of the light-emitting diode 316 can be adjusted to an appropriate value in relation to a reference value. In addition, according to this embodiment, the amplification factor of the amplifier circuit 315 can be adjusted to an appropriate value, thereby calibrating the detection value output when a standard sample is used to the reference value.

[0120] Therefore, even when light-emitting diodes 316 with individual differences in light emission intensity are used, the analysis device 1000 can be properly calibrated. Furthermore, because the calibration process can be performed using the control device 500, it is easy to calibrate the analysis device 1000 as needed to deal with deterioration over time of the light-emitting diodes 316. Furthermore, even if the only light-emitting diodes available are those that are thought to have excessively high light emission brightness, the analysis device 1000 can be properly calibrated by adjusting the forward current If.

[0121] [Variations] Next, a modified example will be described using Figures 13 and 14. In the processing procedure of Figure 11 described above, the user must compare the detected value with the calibration reference value and, if necessary, revise the forward current If and the amplification factor. Here, as a modified example, a method will be described in which the detected value obtained for a standard sample is automatically calibrated to the reference value in order to reduce the burden on the user. Note that the hardware configuration of this modified example is the same as the configuration shown in Figures 10 and 11.

[0122] 13 is a flowchart showing the procedure by which the control device 500 receives input of a reference value used for calibration. First, the control device 500 displays a screen for setting a reference value on the display device 520 (step S201). The user can input the reference value on the screen of the display device 520 by operating the keyboard 530.

[0123] Next, the control device 500 detects the input of a reference value (step S202). Next, the control device 500 stores the reference value in the storage device 534 (step S203), and ends the processing based on this flowchart.

[0124] The control device 500 may display on the display device 520 a screen on which a reference value can be input for each photometry port number. The control device 500 may also display on the display device 520 a screen on which the concentration of a standard sample used for calibration can be input in addition to the reference value. The control device 500 may also display on the display device 520 a reference value (500 mv), Vout1, Vout2, the scatterer concentration, and the current voltage value for each photometry port number.

[0125] For example, when a standard sample of a first concentration is stored in storage unit 312 corresponding to photometry port number 1, a user may set a first reference value as a detection value obtained when light is irradiated onto the standard sample of the first concentration. In this case, the user can input the first concentration as the concentration of the standard sample corresponding to photometry port number 1 and the first reference value as the reference value corresponding to photometry port number 1 on the screen of display device 520 by operating keyboard 530. It is desirable that control device 500 stores the first concentration and the first reference value as calibration information in storage device 534 in association with photometry port number 1. Furthermore, it is desirable that control device 500 be able to read out calibration information for each photometry port number and calibrate the detection value for each photometry port number.

[0126] 14 is a flowchart showing the procedure by which control device 500 calibrates measuring device 300 included in analysis device 1000 based on the reference value. Control device 500 automatically performs calibration based on the reference value stored in step S203 of FIG. 13, following the procedure described below.

[0127] First, the control device 500 determines whether it is time to perform calibration (step S211). The calibration timing can be set in various ways. For example, a specific date and time may be set as the calibration timing. Alternatively, the timing when the analysis device 1000 is initialized may be set as the calibration timing.

[0128] If the control device 500 determines that it is not time to perform calibration, it ends the processing based on this flowchart. If the control device 500 determines that it is time to perform calibration, it selects the photometry port number to be calibrated (step S212). For example, the control device 500 may initially select photometry port number 1. In this case, the next time calibration is performed, the selected photometry port number may be updated to 2. Alternatively, the control device 500 may select the photometry port number to be calibrated in accordance with a user instruction stored in the storage device 534.

[0129] Next, the control device 500 sets the amplification factor of the amplifier circuit 315 to a predetermined value (step S213). Here, for example, the amplification factor may be set to 2. The amplification factor set here may be stored in the storage device 534 in advance.

[0130] Next, the control device 500 sets the forward current If to a predetermined value (step S214). The predetermined value may be a standard value that takes into consideration the characteristics of the light-emitting diode, etc. The value of the forward current If set here may be stored in advance in the storage device 534. Next, the control device 500 outputs a command to the measurement device 300 to irradiate light onto the storage unit 312 of the target photometry port number (step S215).

[0131] As a result, a forward current If of a set magnitude flows through the light-emitting diode 316. The light from the light-emitting diode 316 is irradiated onto the standard sample in the storage section 312, generating scattered light. A signal corresponding to the magnitude of the scattered light is detected by the photodiode 314. The detected signal is output to the control device 500 via the I / V conversion circuit 313, the amplifier circuit 315, and the microcomputer 311.

[0132] Next, the control device 500 receives the detection value from the measurement device 300 (step S216). Next, the control device 500 determines whether the detection value is within the target range (step S217). The control device 500 determines whether the detection value is within the target range using the reference value and the amplification performance of the amplifier circuit 315.

[0133] A specific example will be given to explain a method for determining whether a detected value is within a target range. A standard sample according to this embodiment is used for calibration. The reference value of the detected value obtained when using the standard sample is set to, for example, 500 mV. The amplifier circuit 315 has the capability to amplify the input signal within a range of, for example, 2 to 22 times.

[0134] At this time, in order to be able to adjust the value of the voltage Vgout output from the amplifier circuit 315 to 500 mV by using the amplification function of the amplifier circuit 315, the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 needs to be 500 / 22 mV or more. Let this voltage be Vout1.

[0135] Also, when the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 is too high, the detected value cannot be adjusted to the reference value. For example, when the amplification factor of the amplifier circuit 315 is set to twice the minimum amplification factor, if the voltage Vout exceeds 500 / 2, the voltage Vgout output from the amplifier circuit 315 will exceed the reference value. Therefore, in order to be able to adjust the value of the voltage Vgout output from the amplifier circuit 315 to 500 mV, the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 needs to be $500 / 2$ mV or less. Let this voltage be Vout2.

[0136] For example, when the amplification factor set in step S213 is 2 and the value (Vgout) detected in step S217 is 40 mV, the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 is 40 / 2 mV. At this time, (40 / 2)<Vout1 holds. Currently, since the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 is too low, even if the amplification factor of the amplifier circuit 315 is adjusted, the detected value cannot be calibrated to the reference value. In this case, the control device 500 determines that the detected value is not within the target range. On the other hand, when the voltage Vout output from the I / V conversion circuit 313 to the amplifier circuit 315 satisfies Vout1≦Vout≦Vout2, the control device 500 determines that the detected value is within the target range. Note that the reference value Vout1≦Vout≦Vout2 (for example, 500 mV) changes linearly according to the concentration of the scatterer.

[0137] The control device 500 may be configured so that the user can freely set the range of the reference value within the range of Vout1 to Vout2. Since minimizing the forward current If extends the life of the LED, it is generally desirable for Vout to be close to Vout1. However, for LEDs with a low light output, it has been observed that if the forward current If is small (i.e., the light output is low), noise occurs in the photodiode output when the LED is turned on and when it switches from OFF to ON and from ON to OFF. For this reason, there is a demand to set the forward current If of an LED with a low light output closer to Vout2 rather than near Vout1. If the range of the reference value can be freely set, the weight of the forward current If and the amplification degree can be freely changed, allowing for more flexible response.

[0138] In this way, the control device 500 determines whether the detection value received in step S216 is within the target range based on the reference value and the amplification factor set in step S213 (step S217). Note that a margin may be set for the reference value. For example, a range of 500±25 mV may be adopted as the reference range with a margin.

[0139] If the control device 500 determines in step S216 that the detected value received is not within the target range, it outputs a command signal to the measuring device 300 to adjust the forward current If of the light-emitting diode 316 (step S218). Specifically, the control device 500 takes into account the determination result of step S217 and outputs to the measuring device 300 a value of the forward current If adjusted so that the detected value falls within the target range. The measuring device 300 resets the value of the forward current If based on the command received from the control device 500. This adjusts the luminance of the light-emitting diode 316 to an appropriate value. The control device 500 then outputs a command to irradiate light again in step S215. This causes the light-emitting diode 316 to irradiate the standard sample with light again. The control device 500 again determines in step S217 whether the detected value is within the target range.

[0140] If the control device 500 determines that the detected value is within the target range, it calculates an amplification factor for matching the detected value with the reference value (step S219). The calculated value is obtained, for example, by calculating "reference value / detected value." Next, the control device 500 sets the calculated amplification factor in the amplifier circuit 315 (step S220), and ends the processing based on this flowchart. By executing the above processing, the luminance of the light-emitting diode 316 and the amplification factor of the amplifier circuit 315 are calibrated to appropriate values.

[0141] According to the modified example described above, the calibration process is automatically performed by the control device 500, further reducing the workload on the user. As a result, it becomes easier to perform the calibration process periodically. In addition, by increasing the number of calibrations, the analytical accuracy of the analyzer 1000 can be maintained. Furthermore, by periodically performing the calibration process on each of the multiple coagulation ports P3a, it is possible to maintain a low level of difference in accuracy between the coagulation ports.

[0142] Furthermore, according to the modified example, since calibration is performed automatically, it is possible to easily perform the work of obtaining measurement results for a dilution series such as that shown in Fig. 9 using standard samples of various concentrations. As a result, it is possible to create a dilution series such as that shown in Fig. 9 using standard samples of various concentrations, and adjust and maintain the linearity of the graph shown in Fig. 9 at multiple points. Furthermore, instead of manually adjusting the scatterer, it is possible to set the undiluted solution of the scatterer in the device and perform multi-point calibration by automatic dilution, thereby achieving automatic calibration, multi-point calibration, and regular calibration all at once.

[0143] 11 to 14, a procedure has been described in which control device 500, which is an example of a calibration device, uses a standard sample to calibrate analytical device 1000. By using a standard sample containing standard particles as described above, a calibration device for obtaining NIST-traceable measurement values ​​can be provided, and as a result, the state of analytical device 1000 that is NIST-traceable can be maintained.

[0144] In the present embodiment, an example has been given in which one light-emitting diode 316 is accommodated in one coagulation port P3a. However, multiple light-emitting diodes may be accommodated in one coagulation port P3a. In this case, a first light-emitting diode that emits light of a first wavelength and a second light-emitting diode that emits light of a second wavelength different from the first wavelength may be accommodated in one coagulation port P3a. In such a configuration, it is desirable to configure the control device 500 so that the forward current If for each of the multiple light-emitting diodes can be adjusted.

[0145] The control device 500 may have a function to apply the calibration procedure for the coagulation port P3a to the colorimetric port P3b as well, and perform calibration using the colorimetric port P3b as the target.

[0146] In the present embodiment, current control circuit 319 is given as an example of a mechanism that allows the brightness of light-emitting diode 316 to be adjusted. Another example of a mechanism that allows the brightness of light-emitting diode 316 to be adjusted is a variable resistor provided in light-emitting diode 316.

[0147] For example, the variable resistor may be provided with an operating unit for adjusting the resistance value of the variable resistor. By operating the operating unit, the resistance value changes, and as a result, the forward current If flowing through the light-emitting diode 316 is adjusted. This makes it possible to adjust the brightness of the light-emitting diode 316. The light-emitting diode 316 may be provided with a digital variable resistor device to which a command signal from the control device 500 can be input. In this case, the digital variable resistor device adjusts the variable resistance value in response to the command signal from the control device 500. As a result, the forward current If flowing through the light-emitting diode 316 is adjusted. This makes it possible to adjust the brightness of the light-emitting diode 316.

[0148] In this embodiment, the control device 500 connected to the analysis device 1000 is given as an example of a calibration device. However, the control device 500 having the above-mentioned calibration function may be provided in the analysis device 1000. For example, the calibration function of the control device 500 may be built into the measurement device 300.

[0149] [Aspect] It will be understood by those skilled in the art that the above-described embodiments are specific examples of the following aspects.

[0150] (Item 1) A calibration method according to one aspect is a method for calibrating an analytical instrument that includes a storage unit for storing a sample, a light source for irradiating the sample stored in the storage unit with light, and a detection unit for measuring scattered light from the sample. The calibration method includes the steps of: storing a standard sample in the storage unit, the standard sample being prepared by dispersing standard particles in a liquid, the standard particles having a particle size distribution within a predetermined range; acquiring a detection value of the detection unit obtained when the standard sample is stored in the storage unit; and calibrating the analytical instrument so that the detection value is a predetermined value.

[0151] Calibration using standard samples with consistent scattering characteristics can reduce the influence on measurement results caused by differences in the standard samples used during calibration, and improve the reproducibility of the measurements. Note that standard particles adopted as standards by the National Institute of Standards and Technology (NIST) may also be used as standard particles, and the use of a standard sample containing such standard particles can provide a calibration method for obtaining measurements that are traceable to NIST.

[0152] (Item 2) In the calibration method described in item 1, the concentration of the standard particles in the standard sample is 0.002 wt% or more.

[0153] With this configuration, the influence of scattered light from the liquid other than the standard particles can be reduced.

[0154] (Item 3) In the calibration method described in Item 2, the concentration of the standard particles in the standard sample is 0.002 wt% or more and 0.004 wt% or less.

[0155] With this configuration, it is possible to create a schematic representation of the state during the clotting reaction, and calibration can be performed using a standard sample similar to the specimen to be measured.

[0156] (Item 4) In the calibration method described in item 2, the concentration of the standard particles in the standard sample is 0.004% or more.

[0157] With this configuration, the influence of scattered light from the liquid other than the standard particles can be reduced.

[0158] (Item 5) In the calibration method described in item 1, the intensity of scattered light detected when a standard sample is irradiated with light is within the range of scattered light intensity distribution obtained by measuring the change over time in scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light.

[0159] With this configuration, it is possible to create a schematic representation of the state during the clotting reaction, and calibration can be performed using a standard sample similar to the specimen to be measured.

[0160] (Item 6) In the calibration method according to any one of items 1 to 5, the ratio of the standard deviation (CV value) to the average particle size of the standard particles is less than 3%.

[0161] This configuration allows samples with the same scattering intensity to be intentionally created. Furthermore, even without checking the scattering intensity, by fixing the dilution ratio (concentration of standard particles in the standard sample), the scattering intensity obtained using the reference analyzer can be kept within a predetermined range, thereby improving the work efficiency when creating standard samples.

[0162] (Item 7) In the calibration method according to any one of items 1 to 6, the peak particle diameter of the standard sample is 350 nm or less.

[0163] With this configuration, the amount of standard particles required to obtain a predetermined scattering intensity can be reduced, and the cost of the standard sample can be reduced.

[0164] (Item 8) The calibration method according to any one of items 1 to 7 further comprises the step of preparing a standard sample by diluting a sample containing standard particles with water.

[0165] By further including a step of diluting the sample with water, an easily available liquid, such calibration makes it possible to prepare only the sample containing the standard particles. This reduces the amount of luggage required by a service technician, for example, when the service technician visits the installation site of an analytical instrument to perform maintenance.

[0166] (Item 9) In the calibration method according to any one of items 1 to 8, the analytical device includes a plurality of reaction units, each including a light source, a detection unit, and a storage unit. In the step of storing a standard sample in the storage unit of the calibration method, the standard sample is stored in the storage unit of each of the plurality of reaction units. In addition, in the step of calibrating the analytical device of the calibration method, each of the plurality of reaction units is calibrated so that the detection value of the detection unit of each of the plurality of reaction units becomes a predetermined value.

[0167] By performing such calibration, when calibrating an analyzer equipped with a plurality of reaction units, it is not necessary to calibrate each reaction unit one by one, and therefore the time required for calibration can be reduced.

[0168] (Item 10) Furthermore, a standard sample for calibration according to one embodiment is a standard sample used to calibrate an analytical device including a light source that irradiates light onto a sample and a detection unit that detects scattered light from the sample, and the standard particles are dispersed in a liquid so that the particle size distribution range falls within a predetermined range.

[0169] The calibration standard sample described in paragraph 10 uses standard particles prepared so that the particle size distribution range falls within a predetermined range, thereby providing a standard sample with consistent scattering characteristics. As a result, calibration using such a standard sample provides a calibration method that reduces the influence on measurement results caused by differences in the standard sample used during calibration, and improves the reproducibility of measurement values. Note that standard particles adopted as NIST standards may be used as the standard particles used in the standard sample, and the use of a standard sample containing such standard particles provides a calibration method for obtaining measurement values ​​traceable to standards established by NIST.

[0170] (Item 11) A calibration device according to one embodiment calibrates an analytical device including a storage unit for storing a sample, a light-emitting element for irradiating light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the brightness of the light-emitting element, and a detection unit for measuring scattered light from the sample. The calibration device includes a processor and a communication port for communicating with analytical device 1000. The processor receives, from the analytical device via the communication port, a value detected by the detection unit when a standard sample, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid, is stored in the storage unit. The processor outputs, to the analytical device via the communication port, a signal for adjusting the brightness of the light-emitting element so that the detection unit obtains a predetermined detection value when the standard sample is stored in the storage unit.

[0171] The calibration device described in paragraph 11 makes it possible to calibrate an analyzer, including the luminance of a light-emitting element, using a standard sample made of standard particles prepared so that the particle size distribution range falls within a predetermined range. This makes it possible to provide a calibration device that can perform calibration while minimizing the influence on measurement results that may occur due to differences in the standard sample used during calibration.

[0172] (Item 12) The calibration device described in item 11 further includes a memory for storing a reference value of the detection value measured by the detection unit when the standard sample is stored in the storage unit, and the processor outputs a signal to the analysis device to adjust the brightness of the light-emitting element so that the reference value is detected by the detection unit.

[0173] In the calibration device described in paragraph 12, the luminance of the light-emitting element is automatically adjusted based on the reference value stored in the memory, thereby reducing the burden of calibration work on the user.

[0174] (Item 13) In the calibration device described in Item 12, the detection unit includes a light receiving element that receives scattered light and an amplification circuit configured to amplify the magnitude of a signal determined based on the output of the light receiving element within a predetermined range of magnification, and the processor outputs a signal to the analysis device that adjusts the brightness of the light emitting element so that a reference value is obtained when the signal determined based on the output of the light receiving element is amplified within a predetermined range of magnification.

[0175] In the calibration device described in paragraph 13, the analyzer can be appropriately calibrated by adjusting the luminance of the light-emitting element and the amplification factor of the amplifier circuit.

[0176] The embodiments disclosed herein are intended to be combined as appropriate within the scope of any technical inconsistency. The embodiments disclosed herein should be considered to be illustrative and not restrictive in all respects. The scope of the present invention is defined by the claims, not by the description of the above-mentioned embodiments, and is intended to include all modifications within the meaning and scope of the claims. [Explanation of symbols]

[0177] 100 cuvette, 130 photometric unit, 150 robot unit, 300 measuring device, 310 board, 311 microcomputer, 312 storage unit, 313 I / V conversion circuit, 314 photodiode (detector), 315 amplifier circuit, 316 light-emitting diode (light source), 319 current control circuit, 370 photometric control unit, 372 data collection unit, 374 conversion unit, 376 transport control unit, 500 control unit, 510 data processing unit, 512 memory unit, 520 display device, 530 keyboard, 531 CPU, 532 RAM, 534 memory device, 535 communication port, 1000 analyzer, P3a coagulation port.

Claims

1. 1. A calibration method for calibrating an analytical device, comprising: the analytical device comprises a storage unit for storing a sample, a light-emitting element for irradiating light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the luminance of the light-emitting element, and a detection unit for measuring scattered light from the sample; The detection unit a light receiving element that receives the scattered light; an amplifier circuit configured to amplify the magnitude of an output signal determined based on the output of the light receiving element by an amplification factor set within a predetermined range; a step of storing a standard sample in the storage unit, the standard sample being prepared by dispersing standard particles in a liquid, the standard particles being adjusted so that the particle size distribution falls within a predetermined range; acquiring a detection value of the detection unit obtained when the standard sample is stored in the storage unit; a step of determining whether an acquired detection value is within a target range using the reference value and the predetermined magnification range so that a predetermined reference value can be obtained from the detection unit when the output signal is amplified within the predetermined magnification range, adjusting the luminance of the light-emitting element so that the acquired detection value falls within the target range when the acquired detection value is not within the target range, and setting an amplification magnification in the amplifier circuit to adjust the acquired detection value to the reference value when the acquired detection value is within the target range.

2. The calibration method according to claim 1 , wherein the concentration of the standard particles in the standard sample is 0.002 wt % or more.

3. The calibration method according to claim 2 , wherein the concentration of the standard particles in the standard sample is 0.002 wt % or more and 0.004 wt % or less.

4. The calibration method according to claim 2 , wherein the concentration of the standard particles in the standard sample is 0.004 wt % or more.

5. 2. The calibration method according to claim 1, wherein the intensity of scattered light detected when the standard sample is irradiated with light is within a range of scattered light intensity distribution obtained by measuring the change over time in scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light.

6. The calibration method according to any one of claims 1 to 5, wherein the ratio of the standard deviation to the average particle size of the standard particles is less than 3%.

7. The calibration method according to any one of claims 1 to 6, wherein the peak particle diameter of the standard particles is 350 nm or less.

8. The calibration method according to any one of claims 1 to 7, further comprising the step of preparing the standard sample by diluting a sample containing the standard particles with water.

9. the analysis device includes a plurality of reaction units, each of which includes the light-emitting element, the detection unit, and the storage unit; In the step of storing the standard sample in the storage unit, the standard sample is stored in the storage unit of each of the plurality of reaction units, A calibration method according to any one of claims 1 to 8, wherein in the step of calibrating the analytical device, each of the plurality of reaction units is calibrated so that the detection value of the detection unit of each of the plurality of reaction units becomes a predetermined value.

10. A calibration device for calibrating an analytical device, comprising: the analytical device comprises a storage unit for storing a sample, a light-emitting element for irradiating light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the luminance of the light-emitting element, and a detection unit for measuring scattered light from the sample; The detection unit a light receiving element that receives the scattered light; an amplifier circuit configured to amplify the magnitude of an output signal determined based on the output of the light receiving element by an amplification factor set within a predetermined range; The calibration device a processor; a communication port for communicating with the analytical device; a memory for storing a reference value of the detection value measured by the detection unit when a standard sample in which standard particles prepared so that the particle diameter distribution falls within a predetermined range are dispersed in a liquid is stored in the storage unit, the processor receives the detection value detected by the detection unit from the analysis device via the communication port when the standard sample is stored in the storage unit; The processor: a signal for adjusting the brightness of the light-emitting element so that the detection value detected by the detection unit falls within the target range when the output signal is amplified within the range of the predetermined magnification is output to the analysis device via the communication port, the signal being used to determine whether the received detection value is within the target range, so that the detection value detected by the detection unit falls within the target range, A calibration device that outputs, when the received detection value is within the target range, a signal to the analysis device via the communication port to set an amplification factor in the amplifier circuit to adjust the received detection value to the reference value.

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