JP7361575B2 - Calibration curve generator and automatic analyzer - Google Patents

Description

Embodiments of the present invention relate to a calibration curve generation device and an automatic analysis device.

An automatic analyzer adds reagents corresponding to various test items to a test sample such as blood containing a component to be detected, and causes the reagent to react with a specific component contained in the test sample. The automatic analyzer analyzes the components of the test sample corresponding to the test items by optically measuring this reaction, for example.

In such an automatic analyzer, a technique is known that uses a latex agglutination method to increase the sensitivity of measurement. In the latex agglutination method, a reagent in which an antibody is bound to the surface of latex particles, which are insoluble carriers, is added to a test sample to prepare a reaction solution. In the reaction solution, the antigen contained in the test sample binds to the antibody on the surface of the latex particles, causing the latex particles to aggregate. Then, in the process of aggregation of latex particles, the concentration of the target to be detected in the sample is measured by irradiating the reaction solution with light and measuring the degree to which the light weakens as it passes through the reaction solution, that is, the absorbance. .

In order to measure the concentration of the detection target contained in the test sample based on absorbance, it is necessary to generate a calibration curve in advance that determines the relationship between the absorbance and the concentration of the detection target in the test sample. There is. To generate a calibration curve, an automatic analyzer adds a reagent to a standard sample whose concentration is known in advance, and generates a reaction curve showing the change in absorbance measured after the addition for multiple concentrations. There is a need. Then, using a graph representing this reaction curve, a calibration curve can be obtained by associating the absorbance at a predetermined timing after adding the reagent with the known concentration of the standard sample on a one-to-one basis.

However, in reaction curves generated for standard samples with different concentrations, a hook phenomenon occurs for the high concentration standard sample, and over time, the absorbance shown in the high concentration reaction curve becomes smaller than that of the lower concentration standard sample. A phenomenon occurs in which the absorbance becomes lower than the absorbance shown in the reaction curve. This is a phenomenon that occurs when the reaction with the reagent is suppressed even though the standard sample to be measured has a high concentration. For this reason, measures have been taken such as setting the absorbance measurement interval to use the interval before the hook phenomenon occurs, and having the automatic analyzer output an error when the hook phenomenon occurs.

On the other hand, when actually measuring a low-concentration test sample, the absorbance measured at a photometric timing when the reaction between the sample and reagent has progressed to a certain extent and the difference in absorbance between different low concentrations becomes clear. It is preferable to determine the concentration using Further, even if the automatic analyzer outputs an error, it cannot be said to be a sufficient solution to the hook phenomenon.

JP2019-082477A Japanese Patent Application Publication No. 2011-226909 Japanese Patent Application Publication No. 2019-060813

An object of the present embodiment is to provide a calibration curve generation device and an automatic analyzer that can generate an appropriate calibration curve based on a reaction curve that is a measurement result of a standard sample.

The calibration curve generation device according to the present embodiment includes a dispensing unit that dispenses and adds a reagent containing an insoluble carrier on which a component that binds to the detection target is immobilized to a standard sample containing the detection target at a known concentration. , a photometry unit that optically measures a reaction solution in which the reagent is added to the standard sample; and an approximation function that approximates a reaction curve representing the measurement results of the standard sample at a plurality of different concentrations measured by the photometry unit. a calibration curve generation unit that generates a calibration curve based on parameters of the derived approximation function, the calibration curve changing an interval in the reaction curve for deriving the approximation function based on the measurement result; A generation unit.

Further, the automatic analyzer according to the present embodiment includes the above-mentioned calibration curve generation device, and the dispensing unit dispenses and adds the reagent to the test sample containing the detection target at an unknown concentration. The photometry section optically measures a reaction solution in which the reagent is added to the test sample, and also uses an approximation function that approximates a reaction curve representing the measurement result of the test sample measured by the photometry section. and a detection target concentration calculation unit that calculates the concentration of the detection target in the test sample based on the parameters of the derived approximation function and the calibration curve read from the storage unit.

FIG. 1 is a block diagram showing the functional configuration of an automatic analyzer according to an embodiment. 2 is a diagram showing an example of the configuration of an analysis mechanism in the automatic analyzer shown in FIG. 1. FIG. The figure showing an example of the measured value and reaction curve about a standard sample. A diagram illustrating a method of deriving an approximation function for a reaction curve using a certain reaction curve (a state in which the accuracy of approximation is low). A diagram illustrating a method of deriving an approximation function for a reaction curve using a certain reaction curve (a state in which the interval for deriving the approximation function is shortened to improve the accuracy of approximation). Diagram explaining a method for deriving an approximation function for a reaction curve using a certain reaction curve (As a result of further increasing the accuracy of approximation by further shortening the interval for deriving the approximation function, the accuracy of approximation reaches the predetermined standard) ). FIG. 2 is a diagram showing reaction curves of standard samples with a plurality of different concentrations and the derived approximate functions, clearly indicating the intervals from which the approximate functions were derived. The figure which shows an example of the calibration curve produced|generated based on the derived approximation function. FIG. 4 is a diagram in which the measured values and reaction curve of a certain test sample are added to the measured values and reaction curve of FIG. 3. The figure explaining an example of the method of calculating the concentration of the detection target of a test sample based on slope a which is a measurement value of the test sample.

The automatic analyzer according to this embodiment will be described below with reference to the drawings. In the following description, components having substantially the same functions and configurations will be denoted by the same reference numerals, and repeated description will be given only when necessary.

(Automatic analyzer)
FIG. 1 is a block diagram showing an example of the functional configuration of an automatic analyzer 1 according to the present embodiment. The automatic analyzer 1 shown in FIG. 1 includes, for example, an analysis mechanism 2, an analysis circuit 3, a drive mechanism 4, an input interface 5, an output interface 6, a communication interface 7, a storage circuit 8, and a control circuit. 9.

The automatic analyzer 1 is a device that measures the concentration of a sample, etc. using a latex agglutination method, and various carrier particles can be used as an insoluble carrier added to the reagent. As the carrier particles, for example, latex particles, polystyrene, polystyrene latex, silica particles, etc. can be used.

The analysis mechanism 2 adds reagents used in each test item set for the sample to a sample such as a standard sample or a test sample. The analysis mechanism 2 measures a reaction solution obtained by adding a reagent to a sample, and generates, for example, standard data and test data. In this embodiment, the standard data represents absorbance measurement data for a standard sample containing a known concentration of a detection target. Further, the test data represents absorbance measurement data for the test sample.

The analysis circuit 3 is a processor that analyzes the standard data and test data generated by the analysis mechanism 2 and generates calibration data, analysis data, and the like. The calibration data includes, for example, information regarding a calibration curve generated based on standard data. Further, the analysis data includes information regarding, for example, the concentration of the detection target contained in the test sample, which is obtained by analyzing the test data based on the calibration data.

The analysis circuit 3 executes the operation program stored in the storage circuit 8 and generates calibration data, analysis data, etc. by realizing a function corresponding to this operation program. For example, the analysis circuit 3 uses 1) standard data obtained for a standard sample with a known absorbance and a concentration of 0, and a plurality of standard samples with known concentrations, and 2) standard data set in advance for these standard samples. A calibration curve is generated based on the concentration and 3) preset photometry timing, and calibration data including information regarding this calibration curve is calculated. Further, the analysis circuit 3 generates analysis data based on the test data, calibration data including a calibration curve of the test item corresponding to the test data, and preset photometry timing. The analysis circuit 3 outputs the generated calibration data, analysis data, etc. to the control circuit 9.

The drive mechanism 4 drives the analysis mechanism 2 under the control of the control circuit 9. The drive mechanism 4 is realized by, for example, a gear, a stepping motor, a belt conveyor, a lead screw, or the like.

The input interface 5 receives, for example, settings such as analysis parameters for each test item related to a sample requested to be measured from an operator or via the hospital network NW. The input interface 5 is realized by, for example, a mouse, a keyboard, a touch pad on which instructions are input by touching the operation surface, and the like. The input interface 5 is connected to the control circuit 9 , converts an operation instruction input from an operator into an electrical signal, and outputs the electrical signal to the control circuit 9 . Note that in this embodiment, the input interface 5 is not limited to one that includes physical operation parts such as a mouse and a keyboard. For example, an electrical signal processing circuit that receives an electrical signal corresponding to an operation instruction input from an external input device provided separately from the automatic analyzer 1 and outputs this electrical signal to the control circuit 9 is also an input interface. Included in example 5.

The output interface 6 is connected to the control circuit 9 and outputs a signal supplied from the control circuit 9. The output interface 6 is realized by, for example, a display circuit, a printed circuit, and the like. Display circuits include, for example, CRT displays, liquid crystal displays, organic EL displays, LED displays, plasma displays, and the like. Note that in this embodiment, the display circuit also includes a processing circuit that converts data representing a display target into a video signal and outputs the video signal to the outside. The printed circuit includes, for example, a printer. Note that in this embodiment, the printing circuit also includes an output circuit that outputs data representing a printing target to the outside.

The communication interface 7 is connected to, for example, an intra-hospital network NW, and connects the automatic analysis device 1 to the intra-hospital network NW. The communication interface 7 performs data communication with an HIS (Hospital Information System) via the hospital network NW. Note that the communication interface 7 may perform data communication with the HIS via a laboratory information system (LIS) connected to the hospital network NW.

The storage circuit 8 is constituted by a processor-readable recording medium such as a magnetic or optical recording medium or a semiconductor memory. Note that the memory circuit 8 does not necessarily need to be realized by a single memory device. For example, the memory circuit 8 can also be realized by a plurality of memory devices.

Furthermore, the storage circuit 8 stores an operation program executed by the analysis circuit 3 and an operation program executed by the control circuit 9. The storage circuit 8 stores information regarding calibration curves related to reagents held within the analysis mechanism 2. Although details will be described later, a calibration curve for reagents used in the analysis mechanism 2 is generated by the automatic analyzer 1 and stored in the storage circuit 8 as calibration data. The calibration data stored in the storage circuit 8 also includes, for example, data regarding preset photometry timing for reagents for each test item.

The photometry timing represents the time point at which information such as absorbance used when generating calibration data including a calibration curve is acquired. That is, the photometric timing represents, for example, the elapsed time from the time when a reagent containing carrier particles, which are insoluble carriers on which a component that binds to a detection target is immobilized, is added to a standard sample. Further, the photometry timing represents the time point at which information such as absorbance used when generating analysis data is acquired. In other words, the photometric timing represents, for example, the time elapsed since the reagent containing particles of the insoluble carrier was added to the test sample.

That is, the storage circuit 8 stores the calibration data generated by the analysis circuit 3 for each inspection item. Furthermore, the storage circuit 8 stores the analysis data generated by the analysis circuit 3 for each test sample.

The control circuit 9 is a processor that functions as the core of the automatic analyzer 1. The control circuit 9 executes the operation program stored in the storage circuit 8 to realize a function corresponding to the operation program. Note that the control circuit 9 may include a storage area that stores at least part of the data stored in the storage circuit 8.

FIG. 2 is a schematic diagram showing an example of the configuration of the analysis mechanism 2 shown in FIG. As shown in FIG. 2, the analysis mechanism 2 of the automatic analyzer 1 according to the present embodiment includes a reaction disk 201, a constant temperature section 202, a sample disk 203, a first reagent storage 204, and a second reagent storage 205. It is composed of:

The reaction disk 201 transports the reaction container 2011 along a predetermined path. Specifically, the reaction disk 201 holds a plurality of reaction containers 2011 arranged in a ring shape. The reaction disk 201 is rotated and stopped alternately at predetermined time intervals by the drive mechanism 4.

Reaction container 2011 is made of glass, for example. The reaction container 2011 has a quadrangular column shape and has an opening at the top. Of the first to fourth side walls forming a quadrangular prism, light emitted from a light source provided in the photometry unit 214 is incident from the outer surface of the first side wall. Of the first to fourth side walls, the light incident from the outer surface of the first side wall is emitted from the outer surface of the second side wall that faces the first side wall.

The constant temperature section 202 stores a heat medium set at a predetermined temperature. The constant temperature section 202 raises the temperature of the reaction liquid contained in the reaction container 2011 to a predetermined temperature and keeps it warm by immersing the reaction container 2011 in the stored heat medium.

The sample disk 203 holds a plurality of sample containers containing samples. The sample disk 203 is rotated by the drive mechanism 4. In this embodiment, a sample containing a component to be detected is appropriately referred to as a test sample.

The first reagent storage 204 cools a plurality of reagent containers containing a first reagent that reacts with a predetermined component contained in the standard sample and the test sample. The first reagent is, for example, a buffer containing bovine serum albumin (BSA). A reagent label is attached to the reagent container. An optical mark representing reagent information is printed on the reagent label. Any pixel code, such as a one-dimensional pixel code or a two-dimensional pixel code, is used for the optical mark. The reagent information is information regarding the reagent contained in the reagent container, and includes, for example, the reagent name, reagent manufacturer code, reagent item code, bottle type, bottle size, capacity, manufacturing lot number, and expiration date. .

Further, the first reagent storage 204 cools a plurality of standard sample containers containing standard samples. Each of the plurality of standard sample containers contains standard samples of the same component but with different concentrations. Note that the standard sample container may be held on the sample disk 203.

A reagent rack 2041 is rotatably provided in the first reagent storage 204 . The reagent rack 2041 holds a plurality of reagent containers and a plurality of standard sample containers arranged in an annular shape. The reagent rack 2041 is rotated by the drive mechanism 4. Furthermore, a reader (not shown) is provided in the first reagent storage 204 to read reagent information from a reagent label attached to a reagent container. The read reagent information is stored in the storage circuit 8.

A first reagent suction position is set at a predetermined position on the first reagent storage 204 . The first reagent suction position is, for example, a position where the rotation trajectory of the first reagent dispensing probe 209 and the movement trajectory of the openings of the reagent containers and standard sample containers arranged in an annular manner in the reagent rack 2041 intersect. established in

The second reagent storage 205 cools a plurality of reagent containers containing a second reagent that is paired with a first reagent in a two-reagent system. The second reagent is a solution containing an insoluble carrier, for example, carrier particles, on which an antigen or antibody that binds to or dissociates from a predetermined antigen or antibody contained in a sample through a specific antigen-antibody reaction is immobilized. It may be an enzyme, a substrate, an aptamer, or a receptor that binds or dissociates due to a specific reaction. A reagent rack 2051 is rotatably provided within the second reagent storage 205 .

The reagent rack 2051 holds a plurality of reagent containers arranged in an annular shape. Note that in the second reagent storage 205, a standard sample container containing a standard sample may be kept cold. The reagent rack 2051 is rotated by the drive mechanism 4. Further, a reader (not shown) is provided in the second reagent storage 205 to read reagent information from a reagent label attached to a reagent container. The read reagent information is stored in the storage circuit 8.

A second reagent suction position is set at a predetermined position on the second reagent storage 205 . The second reagent suction position is provided, for example, at a position where the rotational trajectory of the second reagent dispensing probe 211 and the movement trajectory of the openings of the reagent containers arranged in an annular shape on the reagent rack 2051 intersect.

Further, the analysis mechanism 2 of the automatic analyzer 1 shown in FIG. 2 further includes a sample dispensing arm 206, a sample dispensing probe 207, a first reagent dispensing arm 208, a first reagent dispensing probe 209, It includes a second reagent dispensing arm 210, a second reagent dispensing probe 211, a first stirring unit 212, a second stirring unit 213, a photometry unit 214, and a cleaning unit 215.

Sample dispensing arm 206 is provided between reaction disk 201 and sample disk 203. The sample dispensing arm 206 is provided so as to be vertically movable and horizontally rotatable by the drive mechanism 4 . Sample dispensing arm 206 holds a sample dispensing probe 207 at one end.

The sample dispensing probe 207 rotates along an arcuate rotation trajectory as the sample dispensing arm 206 rotates. The opening of the sample container held by the sample disk 203 is located on this rotating orbit. Further, a sample discharge position for discharging the sample sucked by the sample dispensing probe 207 into the reaction container 2011 is provided on the rotational trajectory of the sample dispensing probe 207 . The sample discharge position is provided at a position where the rotational trajectory of the sample dispensing probe 207 and the movement trajectory of the reaction container 2011 held on the reaction disk 201 intersect.

The sample dispensing probe 207 is driven by the drive mechanism 4 and moves in the vertical direction directly above the opening of the sample container held by the sample disk 203 or at the sample discharge position. Further, the sample dispensing probe 207 aspirates the sample from the sample container located directly below it under the control of the control circuit 9 . Further, the sample dispensing probe 207 discharges the aspirated sample into the reaction container 2011 located directly below the sample discharge position under the control of the control circuit 9.

The first reagent dispensing arm 208 is provided near the outer periphery of the first reagent storage 204 . The first reagent dispensing arm 208 is provided so as to be vertically movable and horizontally rotatable by the drive mechanism 4 . The first reagent dispensing arm 208 holds a first reagent dispensing probe 209 at one end.

The first reagent dispensing probe 209 rotates along an arcuate rotation trajectory as the first reagent dispensing arm 208 rotates. A first reagent suction position is provided on this rotational trajectory. Further, a first reagent dispensing position is set on the rotational trajectory of the first reagent dispensing probe 209 for discharging the first reagent or standard sample aspirated by the first reagent dispensing probe 209 into the reaction container 2011. ing. The first reagent discharge position is provided at a position where the rotational trajectory of the first reagent dispensing probe 209 and the movement trajectory of the reaction container 2011 held on the reaction disk 201 intersect.

The first reagent dispensing probe 209 is driven by the drive mechanism 4 and moves in the vertical direction at the first reagent suction position or the first reagent discharge position on the rotating orbit. Further, the first reagent dispensing probe 209 aspirates the first reagent or standard sample from the reagent container located directly below the first reagent suction position under the control of the control circuit 9. Further, the first reagent dispensing probe 209 discharges the aspirated first reagent or standard sample into the reaction container 2011 located directly below the first reagent discharge position under the control of the control circuit 9 . That is, the first reagent dispensing probe 209 is an example of a dispensing section in this embodiment.

The second reagent dispensing arm 210 is provided near the outer periphery of the first reagent storage 204 . The second reagent dispensing arm 210 is provided so as to be vertically movable and horizontally rotatable by the drive mechanism 4 . The second reagent dispensing arm 210 holds a second reagent dispensing probe 211 at one end.

The second reagent dispensing probe 211 rotates along an arcuate rotation trajectory as the second reagent dispensing arm 210 rotates. A second reagent suction position is provided on this rotational trajectory. Further, a second reagent discharging position is set on the rotational trajectory of the second reagent dispensing probe 211 for discharging the second reagent sucked by the second reagent dispensing probe 211 into the reaction container 2011. The second reagent discharge position is provided at a position where the rotational trajectory of the second reagent dispensing probe 211 and the movement trajectory of the reaction container 2011 held on the reaction disk 201 intersect.

The second reagent dispensing probe 211 is driven by the drive mechanism 4 and moves in the vertical direction at the second reagent suction position or the second reagent discharge position on the rotating orbit. Further, the second reagent dispensing probe 211 aspirates the second reagent from the reagent container located directly below the second reagent suction position under the control of the control circuit 9. Further, the second reagent dispensing probe 211 discharges the aspirated second reagent into the reaction container 2011 located directly below the second reagent discharge position under the control of the control circuit 9. That is, the second reagent dispensing probe 211 is an example of a dispensing section in this embodiment.

The first stirring unit 212 is provided near the outer periphery of the reaction disk 201. The first stirring unit 212 has a first stirring arm 2121 and a first stirring bar provided at the tip of the first stirring arm 2121. The first stirring unit 212 uses a first stirrer to stir the mixture of the standard sample and the first reagent contained in the reaction container 2011 located at the first stirring position on the reaction disk 201. Further, the first stirring unit 212 uses a first stirring bar to stir the mixed liquid of the test sample and the first reagent contained in the reaction container 2011 located at the first stirring position on the reaction disk 201. .

The second stirring unit 213 is provided near the outer periphery of the reaction disk 201. The second stirring unit 213 has a second stirring arm 2131 and a second stirring bar provided at the tip of the second stirring arm 2131. The second stirring unit 213 uses a second stirring bar to stir the mixed solution of the standard sample, the first reagent, and the second reagent contained in the reaction container 2011 located at the second stirring position on the reaction disk 201. do. Further, the second stirring unit 213 uses a second stirring bar to stir the mixed liquid of the test sample, the first reagent, and the second reagent contained in the reaction container 2011 located at the second stirring position.

The photometry unit 214 optically measures the reaction liquid of the sample, the first reagent, and the second reagent discharged into the reaction container 2011. Photometry unit 214 includes a light source and a photodetector. The photometry unit 214 emits light from a light source under the control of the control circuit 9. The irradiated light enters the reaction container 2011 through the first side wall and exits from the second side wall opposite to the first side wall. The photometry unit 214 detects the light emitted from the reaction container 2011 using a photodetector. The photometry unit 214 is an example of a photometry section in this embodiment.

Specifically, for example, the photodetector is placed at a position on the optical axis of the light irradiated onto the reaction container 2011 from the light source. The photodetector detects the light that has passed through the reaction solution of the standard sample, first reagent, and second reagent in the reaction container 2011, and generates standard data expressed by absorbance based on the intensity of the detected light. . In addition, the photodetector detects the light that has passed through the reaction solution of the test sample, the first reagent, and the second reagent in the reaction container 2011, and based on the intensity of the detected light, the Generate data. The photometry unit 214 outputs the generated standard data and test data to the analysis circuit 3 as measurement results.

The cleaning unit 215 cleans the inside of the reaction container 2011 after the measurement of the reaction liquid by the photometry unit 214.

As shown in FIG. 1, the control circuit 9 executes an operation program stored in the storage circuit 8 to realize a function corresponding to the program. For example, the control circuit 9 implements a system control function 91, a calibration control function 92, and a measurement control function 93 by executing an operation program. In this embodiment, a case will be described in which the system control function 91, the calibration control function 92, and the measurement control function 93 are realized by a single processor, but the present invention is not limited to this. For example, a control circuit may be configured by combining a plurality of independent processors, and the system control function 91, the calibration control function 92, and the measurement control function 93 may be realized by each processor executing an operation program.

The system control function 91 is a function that centrally controls each part of the automatic analyzer 1 based on input information input from the input interface 5.

The calibration control function 92 is a function that controls the analysis mechanism 2 and the drive mechanism 4 so as to generate standard data. Specifically, the control circuit 9 executes the calibration control function 92 at a predetermined timing. The predetermined timing is, for example, during initial setting, when starting up the apparatus, during maintenance, and when an instruction to start a calibration operation is input by an operator.

When the calibration control function 92 is executed, the control circuit 9 controls the analysis mechanism 2 and the drive mechanism 4. By controlling the analysis mechanism 2 and the drive mechanism 4, the analysis mechanism 2 generates standard data. Specifically, for example, by being driven by the drive mechanism 4, the first reagent dispensing probe 209 of the analysis mechanism 2 sucks the standard sample from the first reagent storage 204, and transfers the sucked standard sample to the reaction container 2011. Discharge to. Subsequently, the first reagent dispensing probe 209 sucks the first reagent from the first reagent storage 204 and discharges the sucked first reagent into the reaction container 2011 into which the standard sample has been discharged. Subsequently, the first stirring unit 212 stirs the solution in which the first reagent is added to the standard sample.

Next, the second reagent dispensing probe 211 aspirates the second reagent from the second reagent storage 205 and discharges the aspirated second reagent into the mixture of the standard sample and the first reagent. Subsequently, the second stirring unit 213 stirs the solution in which the second reagent is added to the mixed liquid. The photometry unit 214 generates standard data by optically measuring a reaction solution obtained by stirring a standard sample, a first reagent, and a second reagent. The photometry unit 214 outputs the generated standard data to the analysis circuit 3. The photometry unit 214 repeats the measurement of the reaction liquid a preset number of times at a preset period, and outputs the generated standard data to the analysis circuit 3. The analysis mechanism 2 repeats the above operation for standard samples having a plurality of preset concentrations, and outputs the generated standard data to the analysis circuit 3. Note that the order in which the standard sample, first reagent, and second reagent are discharged into the reaction container 2011 is not limited to the above order, and the order can be changed arbitrarily.

The measurement control function 93 is a function that controls the analysis mechanism 2 and the drive mechanism 4 so as to generate test data. Specifically, the control circuit 9 executes the measurement control function 93 in response to a predetermined instruction. The predetermined instructions include, for example, an instruction to start a measurement operation input by the operator, an instruction indicating that a preset time has arrived, and the like.

When the measurement control function 93 is executed, the control circuit 9 controls the analysis mechanism 2 and the drive mechanism 4. By controlling the analysis mechanism 2 and the drive mechanism 4, the analysis mechanism 2 generates test data. Specifically, by being driven by the drive mechanism 4, the sample dispensing probe 207 of the analysis mechanism 2 sucks the test sample from the sample disk 203 and discharges the sucked test sample into the reaction container 2011. Subsequently, the first reagent dispensing probe 209 sucks the first reagent from the first reagent storage 204 and discharges the sucked first reagent into the reaction container 2011 into which the test sample has been discharged. Subsequently, the first stirring unit 212 stirs the solution in which the first reagent is added to the test sample.

Next, the second reagent dispensing probe 211 sucks the second reagent from the second reagent storage 205 and discharges the sucked second reagent into the liquid mixture of the test sample and the first reagent. Subsequently, the second stirring unit 213 stirs the solution in which the second reagent is added to the mixed liquid. Subsequently, the photometry unit 214 generates test data by optically measuring a reaction liquid obtained by stirring the test sample, the first reagent, and the second reagent. The photometry unit 214 outputs the generated test data to the analysis circuit 3. The photometry unit 214 repeats the measurement of the reaction liquid a preset number of times at a preset period, and outputs the generated test data to the analysis circuit 3.

Furthermore, the analysis circuit 3 shown in FIG. 1 executes an operation program stored in the storage circuit 8 to realize a function corresponding to the program. For example, the analysis circuit 3 implements the calibration data generation function 31 and the analysis data generation function 32 by executing an operation program. Note that in this embodiment, a case will be described in which the calibration data generation function 31 and the analysis data generation function 32 are realized by a single processor, but the present invention is not limited to this. For example, an analysis circuit may be configured by combining a plurality of independent processors, and each processor may execute an operation program to realize the calibration data generation function 31 and the analysis data generation function 32.

The calibration data generation function 31 is a function that generates calibration data based on the standard data generated by the analysis mechanism 2. Specifically, upon receiving the standard data generated by the analysis mechanism 2, the analysis circuit 3 executes the calibration data generation function 31. When the calibration data generation function 31 is executed, the analysis circuit 3 generates a calibration curve based on standard data that is measurement data including absorbance regarding standard samples of different concentrations. This generated calibration curve is stored in the storage circuit 8 as calibration data. Therefore, the calibration data generation function 31 is an example of a calibration curve generation section in this embodiment.

The analysis data generation function 32 is a function that generates analysis data by analyzing the test data generated by the analysis mechanism 2. Specifically, upon receiving the test data generated by the analysis mechanism 2, the analysis circuit 3 executes the analysis data generation function 32. When the analysis data generation function 32 is executed, the analysis circuit 3 reads calibration data including information regarding the calibration curve from the storage circuit 8. The analysis circuit 3 generates analysis data including information regarding the concentration of the detection target in the test sample based on the test data and calibration data.

(Generation of calibration curve)
Next, an example of generation of a calibration curve in the automatic analyzer 1 according to the present embodiment will be described in detail. In the following, a case will be described in which the absorbance of each of a plurality of standard samples with different concentrations is measured using the automatic analyzer 1 described above in a hospital, etc., and a calibration curve is generated based on the measured absorbance. explain. Note that the automatic analyzer 1 according to the present embodiment plays a role as a calibration curve generation device when generating a calibration curve.

The calibration curve is generated, for example, every morning by an operator such as a laboratory technician at a hospital. That is, the operator starts the automatic analyzer 1 and causes the analysis circuit 3 to execute the calibration data generation function 31. When the calibration data generation function 31 of the analysis circuit 3 is executed, the control circuit 9 controls the analysis mechanism 2 and the drive mechanism 4 to generate a calibration curve, and the generated calibration curve is stored in the storage circuit 8 as calibration data. be remembered.

When generating a calibration curve, the analysis circuit 3 and control circuit 9 generate a time course (reaction curve) for the standard sample. For example, standard samples S1 to S8 with known concentrations are dispensed into reaction vessels 2011-1 to 2011-8, respectively. For example, the concentration of standard sample S1 is 0, the concentration of standard sample S2 is 0.5 ng/ml, the concentration of standard sample S3 is 1 ng/ml, the concentration of standard sample S4 is 2 ng/ml, It is assumed that the concentration of the standard sample S5 is 4 ng/ml, the concentration of the standard sample S6 is 8 ng/ml, the concentration of the standard sample S7 is 16 ng/ml, and the concentration of the standard sample S8 is 32 ng/ml.

Subsequently, the first reagent, which is a buffer solution, is discharged and added to the standard samples S1 to S8 dispensed into the reaction vessels 2011-1 to 2011-8, respectively. Standard samples S1 to S8 to which the first reagent has been added are stirred. After stirring, the mixed liquids contained in the reaction containers 2011-1 to 2011-8 are incubated at a predetermined temperature for a predetermined period of time. After the incubation, a second reagent containing carrier particles on which a component that binds to the detection target in the standard sample is immobilized is added to the mixed liquid contained in each of the reaction containers 2011-1 to 2011-8. The mixture to which the second reagent is added is stirred.

The reaction solutions of the standard samples S1 to S8, the first reagent, and the second reagent contained in the reaction containers 2011-1 to 2011-8, respectively, are irradiated with light while being incubated at a predetermined temperature for a predetermined period of time. . Specifically, for example, after the second reagent is added to the standard samples S1 to S8, the reaction vessels 2011-1 to 2011-8 are each irradiated with light from a light source 33 times at a cycle of 4.6 seconds. be done. The transmitted light that has passed through the reaction vessels 2011-1 to 2011-8 is detected by a photodetector. Based on the detected light intensity, a time course, which is a reaction curve for the standard sample, is obtained. That is, in each of the first cycle to the 33rd cycle, the absorbance of the reaction solution is measured, and the absorbance is measured 33 times for each of the standard samples S1 to S8. The measurement data that is the measurement result becomes standard data and is output from the analysis mechanism 2 to the analysis circuit 3.

FIG. 3 is a diagram showing examples of measured values and time courses (reaction curves) for standard samples S1 to S8. FIG. 3 shows the absorbance measured from the 17th cycle to the 33rd cycle in reaction solutions using standard samples S1 to S8 having different concentrations with respect to the detection target. In FIG. 3, the square marks represent the measured values of absorbance, and the lines connecting the square marks represent the reaction curve. The reaction curve C1 is calculated based on the absorbance of each cycle of the standard sample S1. Similar to the reaction curve C1, the reaction curves C2 to C8 are calculated based on the absorbance of each cycle of the standard samples S2 to S8, respectively. For standard samples S2 to S4 with low concentrations, the amount of increase in reaction time and the amount of increase in absorbance are approximately proportional. On the other hand, for standard samples S5 to S8 with medium to high concentrations, the absorbance approaches saturation as the reaction time elapses.

As can be seen from FIG. 3, the aggregation reaction of the carrier particles contained in the second reagent has the characteristic that as the concentration of the sample increases, the absorbance becomes saturated, causing a hook phenomenon. Therefore, in this embodiment, an approximation function that approximates the reaction curves C1 to C8 of the standard samples S1 to S8 is derived, and a calibration curve is generated based on the derived approximation function. In particular, in this embodiment, the reaction curves C1 to C8 are linearly approximated using a linear function, and a calibration curve is generated based on this linear function.

4 to 6 are diagrams for explaining the process of deriving an approximation function that approximates a reaction curve in this embodiment. That is, FIGS. 4 to 6 show examples of reaction curves generated based on measured values for a certain standard sample, with the solid line showing the reaction curve and the dotted line showing the approximate function. In the graph, the vertical axis represents absorbance, and the horizontal axis represents time (cycle).

First, as shown in FIG. 4, the calibration data generation function 31 of the analysis circuit 3 linearly approximates the reaction curves from the 19th cycle to the 33rd cycle using a linear function to derive an approximate function. That is, the reaction curves from the 19th cycle to the 33rd cycle are approximated by a linear function of the form y=ax+b.

Next, the calibration data generation function 31 of the analysis circuit 3 calculates the coefficient of determination for the derived approximation function to determine the accuracy of the approximation. Here, the coefficient of determination is a value indicating the degree of approximation between the reaction curve generated based on the measured value of absorbance and the linear function that approximated the reaction curve. The closer this coefficient of determination is to 1, the more similar the two are. In other words, deriving an approximate function in this embodiment means finding parameters a and b of a linear function of y=ax+b so that the coefficient of determination is the smallest. In the example of FIG. 4, the coefficient of determination is 0.0091. Therefore, it can be seen that the accuracy of approximation between the reaction curve and the derived linear function is low, and the two are far apart.

Therefore, as shown in FIG. 5, the calibration data generation function 31 of the analysis circuit 3 narrows the interval for deriving the approximate function. In this embodiment, the 19th cycle, which is the starting point of the reaction curve, is kept unchanged, and the end points of the reaction curve are sequentially shifted in the direction of the starting point, thereby shortening the interval for deriving the approximate function. . This is because, as can be seen from the time course (reaction curve) in Figure 3, the hook phenomenon occurs at the end of the 33 cycles, and this is to avoid this hook phenomenon and derive the approximate function. . Furthermore, by observing the shape of the reaction curves for standard samples S6 to S8 with high concentrations, it can be expected that by shortening the interval for deriving the approximation function, the coefficient of determination can be expected to improve even if it is approximated by a linear function of y=ax+b. It is from.

In the example of FIG. 5, the end point is moved from the 33rd cycle to the 27th cycle, which is an earlier cycle, and an approximation function that approximates the reaction curve from the 19th cycle to the 27th cycle is derived. By shortening the interval for deriving the approximate function in this way, the coefficient of determination increases to 0.7237. In this embodiment, a predetermined threshold is set for this coefficient of determination, and when the coefficient of determination exceeds the predetermined threshold, it is determined that the derived approximation function approximates the reaction curve with higher accuracy than a predetermined standard. Then, determine the approximation function. Here, it is assumed that the threshold value of the coefficient of determination is 0.9, for example. Therefore, in the approximation function shown in FIG. 5, since the coefficient of determination is less than or equal to the threshold value of 0.9, the calibration data generation function 31 further shortens the interval for deriving the approximation function.

That is, as shown in FIG. 6, the calibration data generation function 31 of the analysis circuit 3 moves the end point from the 27th cycle to the 24th cycle, which is an earlier cycle, and changes the reaction curve from the 19th cycle to the 24th cycle. Derive an approximation function that approximates . By shortening the interval for deriving the approximate function in this way, the coefficient of determination increases to 0.9898. As a result, the approximate function in FIG. 6 exceeds the threshold value of 0.9 for the coefficient of determination, so the calibration data generation function 31 of the analysis circuit 3 determines the parameter a of the approximate function y=ax+b at this time. and parameter b are determined as parameters of an approximation function that approximates this reaction curve. That is, y=ax+b, which is determined based on the calculated parameters a and b, is determined to be the approximate function of the reaction curves shown in FIGS. 4 to 6, and the derivation of the approximate function is completed.

The calibration data generation function 31 of the analysis circuit 3 derives this approximate function for the reaction curves C1 to C8 of all standard samples S1 to S8. FIG. 7 shows an example of a time course in which the approximate functions derived for the standard samples S1 to S8 are superimposed on the respective reaction curves C1 to C8, with the solid line indicating the reaction curve and the dotted line indicating the approximate function. It shows. Further, in FIG. 7, the reaction curve and the approximate function are drawn only in the section where the approximate function was derived. Therefore, the length of the horizontal axis of the reaction curve and the approximation function indicates the length of the section in the reaction curve from which the approximation function was derived.

As shown in FIG. 7, in the reaction curves C1 to C8 of the standard samples S1 to S8, as the concentration of the sample increases, the interval for deriving the approximate function becomes shorter. This is because, as can be seen from Figure 3, as the concentration of the standard sample increases, it becomes difficult to approximate the long section of the reaction curve with the linear function y=ax+b, and it is only possible to approximate the short section of the reaction curve. It is. As a result, cycles at the end of the reaction curve where the hook phenomenon occurs at high concentrations can be eliminated.

Next, the calibration data generation function 31 of the analysis circuit 3 generates a calibration curve using the slope a of the approximation function y=ax+b as the measured value. That is, a calibration curve is generated using parameter a as a measured value for a known concentration of a standard sample. FIG. 8 is a diagram showing an example of a calibration curve generated by the calibration data generation function 31 of the analysis circuit 3. In FIG. 8, a calibration curve is drawn for each of the standard samples S1 to S8 illustrated in FIG. 7, using a parameter a indicating the slope of the approximation function y=ax+b as a measured value. Further, in the graph shown in FIG. 8, the vertical axis represents the slope a, and the horizontal axis represents the concentration.

Specifically, the slope a of the approximate function for standard samples S1 to S8 in the graph shown in FIG. 7 is 0.0001, 0.0106, 0.0157, 0.0215, 0.0261, and 0.0329, respectively. , 0.0422, 0.0573. In addition, the concentrations of standard samples S1 to S8 are 0, 0.5 ng/ml, 1 ng/ml, 2 ng/ml, 4 ng/ml, 8 ng/ml, 16 ng/ml, and 32 ng/ml, respectively. , are plotted on the graph shown in FIG. 8, and the calibration curve according to the present embodiment is generated by linearly interpolating and connecting each plot with a straight line. Alternatively, a calibration curve may be generated by connecting each plot with a smooth curve. The calibration curve generated in this manner is output from the analysis circuit 3 to the storage circuit 8 and stored as calibration data.

Furthermore, the analysis circuit 3 causes the storage circuit 8 to store data regarding photometry timing in addition to the calibration data. That is, in this embodiment, the information that measurements are performed 33 times with a cycle of 4.6 seconds, which is the timing at which standard samples S1 to S8 are measured when generating a calibration curve, is also included in the data regarding the photometry timing. It is stored in the memory circuit 8 as .

As is clear from these descriptions, when the automatic analyzer 1 is used to generate a calibration curve, the automatic analyzer 1 functions as a calibration curve generator.

(Generation of analysis data)
Next, an example of the operation in which the automatic analyzer 1 generates analysis data will be described in detail.

For example, the control circuit 9 executes the measurement control function 93 when an instruction to start a measurement operation is input from an operator. When the measurement control function 93 is executed, the control circuit 9 generates test data regarding a predetermined test item by controlling the analysis mechanism 2 and the drive mechanism 4.

When the analysis circuit 3 receives the test data output from the analysis mechanism 2, it executes the analysis data generation function 32. When the analysis data generation function 32 is executed, the analysis circuit 3 reads out the calibration data stored for the test item corresponding to the test data from the storage circuit 8.

FIG. 9 shows a graph in which the reaction curve D of the test data is additionally drawn on the time course (reaction curve) of FIG. 3. That is, the analysis data generation function 32 of the analysis circuit 3 generates the measurement result of measuring the absorbance of the reaction solution at the same photometry timing as the photometry timing that generated the calibration curve for the test sample containing the detection target at an unknown concentration, and the measurement result. A reaction curve D is generated based on the photometry timing. Then, using the same method as explained using FIGS. 4 to 6, an approximation function that approximates the reaction curve D of the test data is derived for the reaction curve D of the test data. As mentioned above, in this embodiment, this approximation function is a linear function of y=ax+b.

Next, the analysis data generation function 32 of the analysis circuit 3 calculates the concentration of the sample based on the calibration curve shown in FIG. 8, using the slope a of y=ax+b as the measured value of the test sample. In the example of FIG. 9, if the slope a of the approximation function y=ax+b is 0.0238, the concentration of the test sample can be calculated as 3 ng/ml from the calibration curve of FIG. In other words, in this embodiment, each plot of the calibration curve is connected with a straight line by linear interpolation, so the concentration can be determined by proportionally dividing the plot of the measured values located between the plots. It can be calculated.

FIG. 10 shows a graph for explaining the process of proportionally dividing between plots, and is a graph showing an enlarged view of the standard sample S4 and standard sample S5 of the calibration curve shown in FIG. . In the above example, the plot of standard sample S4 has a slope a of 0.0215 and a concentration of 2 ng/ml. On the other hand, the plot of standard sample S5 has a slope of 0.0261 and a concentration of 4 ng/ml. Therefore, the relationship (0.0238-0.0215):(0.0261-0.0238)=(x-2):(4-x) holds true. By determining x from this, the concentration of the test sample is calculated to be 3 ng/ml.

Next, the analysis data generation function 32 of the analysis circuit 3 outputs the calculated concentration of the test sample to the control circuit 9 as analysis data. The control circuit 9 stores the analysis data including the calculated concentration of the detection target in the test sample in the storage circuit 8, for example, so that the operator can obtain it as a measurement result after the fact. Further, the control circuit 9 may output the analysis data including the calculated concentration of the detection target of the test sample from the output interface 6 and display it on a display circuit or print it on a print circuit. can.

As is clear from these descriptions, the analysis data generation function 32 of the analysis circuit 3 functions as a detection target concentration calculation unit when calculating the concentration of the detection target in the test sample.

As described above, according to the automatic analyzer 1 according to the present embodiment, when generating a calibration curve using the standard samples S1 to S8, each reaction curve in the time course of the standard samples S1 to S8 is approximated. By deriving an approximation function and using at least some of the parameters of this approximation function to generate a calibration curve, it is possible to accurately measure the test sample even if a hook phenomenon occurs in the time course. A standard curve can be generated.

(Modified example)
In the embodiment described above, the approximation function used by the calibration data generation function 31 to approximate the reaction curve is a linear function, but this approximation function is not limited to a linear function. For example, an nth-order function (n is a natural number) can be used as the approximation function. In this case, the approximation function used by the calibration data generation function 31 is
can be expressed as the measured value for generating the calibration curve.
can be used.

Specifically, when n=2, that is, when the approximation function is a quadratic function, the reaction curve can be approximated in the form y=a ₂ x ² +a ₁ x+a ₀ . In this case, for example, the calibration data _generation function 31 _can generate a calibration ^curve using a ₂ ² + a 1 ² in the derived approximation function y = a 2 x 2 + a ₁ x + a ₀ as a measured value. . Which parameters to use and how to calculate the measured values of the calibration curve is a matter to be determined through repeated tests, and various methods may be employed. That is, various measured values, which are the vertical axis used when generating the calibration curve, can be employed.

for example,
For the approximation function, the measured value in generating the calibration curve is the sum of cubes.
can be used. Or,
For the approximation function, the measured value is the root mean squared value.
You can also use Furthermore, it is not necessary to use all the parameters; for example, the measured value may be calculated using one specific parameter.

Furthermore, the approximation function used by the calibration data generation function 31 to approximate the reaction curve is not an n-th order function, but may also be a nonlinear curve such as a logistic curve or an interpolation curve such as a spline. That is, all kinds of functions that can approximate the reaction curve can be used as the approximation function.

Furthermore, in the embodiment described above, it is determined that the derived approximation function approximates the reaction curve with higher accuracy than a predetermined standard, using a coefficient of determination representing the degree of approximation between the reaction curve and the approximation function. Therefore, the approximation function was determined to be the approximation function that approximates the reaction curve, but the criterion for measuring the accuracy of the approximation is not limited to the coefficient of determination. For example, the degree of approximation may be measured using a correlation coefficient between the reaction curve and the approximation function, and it may be determined whether the two are approximated with higher accuracy than a predetermined standard.

Furthermore, in the embodiment described above, if the accuracy of the approximation between the reaction curve and the approximation function is below a predetermined standard, the end point of the section for deriving the approximation function in the reaction curve is moved to an earlier cycle. However, the method of shortening the interval for deriving the approximation function of the reaction curve is not limited to this. For example, the interval for deriving the approximation function in the reaction curve may be shortened by moving the starting point of the interval to a slower cycle.

Furthermore, the interval may be shortened by moving both the start point and the end point of the interval for deriving the approximation function in the reaction curve. That is, the starting point of the section for deriving the approximation function in the reaction curve may be moved to a later cycle, and the end point thereof may be moved to an earlier cycle. In this case, the amount of movement of the starting point and the amount of movement of the end point may be the same or different.

For example, the starting point of the section for deriving the approximation function in the reaction curve may be delayed by two cycles, and the ending point may also be delayed by two cycles. Alternatively, for example, the starting point of the section for deriving the approximation function in the reaction curve may be delayed by one cycle, and the ending point thereof may be delayed by three cycles.

Furthermore, the starting point and ending point of the section for deriving the approximation function in the reaction curve may be alternately moved. For example, if the accuracy of the approximation between the response curve and the approximation function is below a predetermined criterion, first move the starting point of the interval in the reaction curve from which the approximation function is derived to a slower cycle, and the accuracy of the approximation still remains. If it is below a predetermined standard, the end point may be moved to an earlier cycle.

As can be seen from the above, when the accuracy of the approximation between the reaction curve and the approximation function is below a predetermined standard, the calibration data generation function 31 By moving at least one of the end points, the section can be shortened.

Although several embodiments have been described above, these embodiments are presented only as examples and are not intended to limit the scope of the invention. The novel apparatus and methods described herein can be implemented in a variety of other forms. Furthermore, various omissions, substitutions, and changes can be made to the apparatus and method described in this specification without departing from the spirit of the invention. The appended claims and their equivalents are intended to cover such forms and modifications as fall within the scope and spirit of the invention.

DESCRIPTION OF SYMBOLS 1...Automatic analyzer, 2...Analysis mechanism, 3...Analysis circuit, 4...Drive mechanism, 5...Input interface, 6...Output interface, 7...Communication interface, 8...Storage circuit, 9...Control circuit, 31...Calibration data Generation function, 32... Analysis data generation function, 91... System control function, 92... Calibration control function, 93... Measurement control function, 201... Reaction disk, 202... Constant temperature section, 203... Sample disk, 204... First reagent storage, 205... Second reagent storage, 206... Sample dispensing arm, 207... Sample dispensing probe, 208... First reagent dispensing arm, 209... First reagent dispensing probe, 210... Second reagent dispensing arm, 211... Second reagent dispensing probe, 212...First stirring unit, 213...Second stirring unit, 214...Photometry unit, 215...Washing unit, 2011...Reaction container, C1-C8...Reaction curve, D...Reaction curve, S1- S8...Standard sample

Claims (10)

a dispensing unit that dispenses a standard sample containing a detection target at a known concentration into a reaction container and a reagent containing an insoluble carrier on which a component that binds to the detection target is immobilized ;
a photometry unit that optically measures a reaction solution of the standard sample and the reagent;
a calibration curve generation unit that derives an approximation function that approximates a reaction curve representing the measurement results of the standard samples at a plurality of different concentrations measured by the photometry unit, and generates a calibration curve based on the parameters of the derived approximation function; a calibration curve generation unit that changes an interval for deriving the approximation function in the reaction curve based on the measurement results;
A calibration curve generation device comprising:
The calibration curve generation unit is configured to change an interval in the reaction curve for deriving the approximation function based on the accuracy of approximation of the approximation function derived based on the measurement results to the reaction curve. 2. The calibration curve generation unit, when the derived approximation function approximates the reaction curve with higher accuracy than a predetermined standard, sets the derived approximation function as the approximation function of the reaction curve. Calibration curve generator. If the accuracy of approximation of the derived approximation function to the reaction curve is below the predetermined standard, the calibration curve generation unit shortens the section of the reaction curve in which the approximation function is derived, The calibration curve generation device according to claim 2 , wherein an approximation function that approximates the reaction curve is derived again. The calibration curve generation device according to claim 3 , wherein the calibration curve generation unit moves at least one of a start point and an end point of the section to be derived when shortening the section in the reaction curve for deriving the approximate function. . The calibration curve generation unit determines the accuracy of approximation between the reaction curve and the approximation function by determining the accuracy of approximation between the reaction curve generated based on the measured value of absorbance and the approximation function that approximates the reaction curve. 5. The calibration curve generation device according to claim 4 , wherein the calibration curve generation device makes the determination by calculating a coefficient of determination , which is a value indicating the degree of . The calibration curve generation unit determines that the derived approximation function approximates the reaction curve with higher accuracy than a predetermined standard when the coefficient of determination of the derived approximation function exceeds a predetermined threshold. The calibration curve generation device according to item 5 . The calibration curve generation device according to any one of claims 1 to 6 , wherein the approximation function is an nth-order function (n is a natural number). The calibration according to claim 7 , wherein the approximation function is a linear function of y=ax+b, and the calibration curve generation unit generates the calibration curve using parameter a as a measured value for a known concentration of the standard sample. Line generator. The calibration curve generation device according to any one of claims 1 to 8 , further comprising a storage unit that stores the calibration curve generated by the calibration curve generation unit. The dispensing unit dispenses and adds the reagent to the test sample containing the detection target at an unknown concentration,
The photometry section optically measures a reaction solution in which the reagent is added to the test sample, and
An approximation function that approximates the reaction curve representing the measurement result of the test sample measured by the photometry unit is derived, and the test sample is calculated based on the parameters of the derived approximation function and the calibration curve read from the storage unit. a detection target concentration calculation unit that calculates the concentration of the detection target in the test sample;
A calibration curve generation device according to claim 9 ;
An automatic analyzer equipped with