Automated analyzer

Abstract

The present invention comprises: a specimen installation unit on which a specimen to be analyzed is placed; a first analysis unit which performs an analysis different from mass spectrometry on the specimen; a second analysis unit which performs mass spectrometry on the specimen; a specimen conveyance unit which conveys the specimen among the specimen installation unit, the first analysis unit, and the second analysis unit; and a control unit which controls the specimen installation unit, the first analysis unit, the second analysis unit, and the specimen conveyance unit. The control unit controls such that a target component in the specimen is measured by the first analysis unit and in cases where a first value, which is a measured value of the target component measured by the first analysis unit, is out of a predetermined range, the target component and a related substance of the target component are measured by the second analysis unit and the accuracy of the first value is verified on the basis of a second value, which is a measured value of the target component measured by the second analysis unit, and a third value, which is a measured value of the related substance measured by the second analysis unit. This configuration makes it possible to improve analysis accuracy while suppressing an increase in measurement time.

Description

Automated analyzer

[0001] The present invention relates to an automated analyzer.

[0002] An automated analyzer reacts a blood, urine, or other biological sample (hereinafter referred to as a specimen) with an analytical reagent that specifically reacts with a measurement target component in the sample, and quantitatively detects the complex generated by this reaction, thereby automatically performing the measurement of the measurement target component to the output of the result. For example, biochemical analyzers and immunoassay analyzers are known. In addition, in an automated analyzer, in addition to functions such as biochemical analyzers and immunoassay analyzers, there is also a composite automated analyzer having a function of a mass spectrometer that quantifies components in a specimen by measuring the mass and amount of ions generated by ionization of the constituent components in the specimen.

[0003] As a technology related to a composite automated analyzer, for example, in Patent Document 1, by pretreatment by an immunoassay method, a measurement target in a sample solution is captured using an antibody, the captured measurement target is quantified, the measurement target is recovered from the waste liquid in which the measurement target has been quantified, and the recovered measurement target is mass-analyzed by a mass spectrometry method, and an immunoassay method for measuring the components of the measurement target performed by the immunoassay method is disclosed.

[0004] International Publication No. 2010 / 092958

[0005] In immunoassay, a so-called cross-reaction is known as a problem in which a similar component other than the measurement component reacts with the antibody and gives a positive error to the measurement value. On the other hand, in mass spectrometry, while it is possible to perform quantitative analysis of metabolites that cannot be distinguished from the measurement target component in immunoassay while avoiding the cross-reaction that is a problem in immunoassay, there is a problem that complicated pretreatment is required and the measurement time is long compared to immunoassay.

[0006] The present invention has been made in view of the above, and an object thereof is to provide an automated analyzer capable of improving the analysis accuracy while suppressing an increase in the measurement time.

[0007] The present invention includes multiple means for solving the above problems, but to give one example, it comprises a sample placement unit on which a sample to be analyzed is placed, a first analysis unit that performs an analysis different from mass spectrometry on the sample, a second analysis unit that performs mass spectrometry on the sample, a sample transport unit that transports the sample between the sample placement unit, the first analysis unit, and the second analysis unit, and a control unit that controls the sample placement unit, the first analysis unit, the second analysis unit, and the sample transport unit, wherein the control unit measures a target component in the sample with the first analysis unit, and if the first value, which is the measured value of the target component measured with the first analysis unit, is outside a predetermined range, the control unit measures the target component and related substances with the second analysis unit, and verifies the accuracy of the first value based on the second value, which is the measured value of the target component measured with the second analysis unit, and the third value, which is the measured value of the related substances.

[0008] According to the present invention, it is possible to improve analytical accuracy while suppressing an increase in measurement time.

[0009] This is a schematic diagram showing the overall configuration of an automated analyzer. This is a schematic diagram showing an example of the configuration of an immunoassay analyzer. This is a schematic diagram showing an example of the configuration of a mass spectrometer. This is a flowchart showing the processing flow of an automated analyzer. This is a diagram showing an example of measurement results from an immunoassay analyzer. This is a diagram showing an example of measurement results from an automated analyzer.

[0010] Hereinafter, embodiments of the present invention will be described with reference to the drawings.

[0011] In this embodiment, an automated analyzer having an immunoassay analyzer and a mass spectrometer is used as an example for explanation. However, the present invention is not limited to this, and for example, it can also be applied to an automated analyzer that employs another analytical device with a different analytical principle than the mass spectrometer instead of the immunoassay analyzer.

[0012] Figure 1 is a schematic diagram showing the overall configuration of the automated analyzer according to this embodiment.

[0013] In Figure 1, the automated analyzer 100 is generally composed of a sample placement device 110 on which the sample to be analyzed is placed, a sample transport device 120 for transporting the sample, an immunoassay analyzer 130 (first analysis unit) for performing immunoassay processing on the sample, a mass spectrometer 140 (second analysis unit) for performing mass spectrometry processing on the sample, and a control device 150 for controlling the overall operation of the automated analyzer 100.

[0014] Multiple sample containers containing blood, urine, or other biological samples (hereinafter referred to as "samples") are placed on the sample placement device 110 by, for example, an operator. Although not shown in the figures, the sample placement device 110 employs, for example, a sample rack capable of holding and transporting one or more sample containers, and is configured as a so-called rack type, where the placement and removal of sample containers from the sample placement device 110, as well as the transport from the sample placement device 110 to and from the various parts of the automated analyzer 100, are performed in units of sample racks holding sample containers.

[0015] The sample transport device 120 transports sample containers between the sample setting device 110, the immunoassay analyzer 130, and the mass spectrometer 140. Although not shown in the figures, the sample transport device 120 is composed of, for example, a belt conveyor that transports sample racks on which sample containers are mounted, and a branching distribution mechanism that changes the destination of the sample racks.

[0016] Figure 2 is a schematic diagram showing an example of the configuration of an immunoassay analyzer.

[0017] In Figure 2, the immunoassay analyzer 130 is generally composed of a sample loading / unloading unit 131 that loads samples transported via the sample transport device 120 into the immunoassay analyzer 130 and unloads them back into the sample transport device 120, a reagent storage unit 132 that stores reagents used for sample analysis, a reaction unit 135 that performs a reaction between the sample and the reagent, a sample dispensing unit 133 that dispenses samples from sample containers placed on a sample rack loaded into the immunoassay analyzer 130 into, for example, reaction cells in the reaction unit 135, a reagent dispensing unit 134 that dispenses reagents from the reagent storage unit 132 into, for example, reaction cells in the reaction unit 135, a measurement unit 136 that measures and analyzes the reaction solution in the reaction unit 135, a washing unit 137 that washes the sample dispensing unit 133, the reagent dispensing unit 134, and the reaction unit 135, and an immunoassay control unit 138 that controls the overall operation of the immunoassay analyzer 130.

[0018] The immunoassay analyzer 130 quantitatively analyzes tumor markers, hormones, infectious diseases, etc. (so-called immune items) in samples such as blood by measuring the products of antigen-antibody reactions between the sample taken in by the sample loading / unloading unit 131 and reagents, under the control of the immunoassay control unit 138. In this embodiment, the term "immunoscopy analyzer" refers to any analyzer capable of measuring general immune items, not limited to the above-mentioned analysis items. After analysis, the sample is loaded from the sample loading / unloading unit 131 to the sample transport device 120 and then transported to the sample setting device 110 or the mass spectrometer 140. The analysis results (measured values) from the immunoassay analyzer 130 are output from the immunoassay control unit 138 to the control device 150.

[0019] Figure 3 is a schematic diagram showing an example of the configuration of a mass spectrometer.

[0020] In Figure 3, the mass spectrometer 140 is generally composed of a sample loading / unloading unit 141 that loads samples transported via a sample transport device 120 into the mass spectrometer 140 and unloads them back into the sample transport device 120, a sample preprocessing unit 142 that collects samples from sample containers placed on a sample rack loaded into the mass spectrometer 140 and performs preprocessing, a chromatograph 143 that separates the target substance contained in the preprocessed sample based on its chemical structure and physical properties, a mass spectrometry unit 144 that ionizes each component separated by the chromatograph 143 and performs quantitative analysis of the target component with a mass detector, and a mass spectrometry control unit 145 that controls the overall operation of the mass spectrometer 140.

[0021] In the preprocessing unit 142, preprocessing such as extraction and purification of the sample is performed, including dispensing the sample from the sample container, deproteinization, and concentration.

[0022] Examples of chromatographs 143 include liquid chromatography (LC) and gas chromatography (GC).

[0023] The mass spectrometry unit 144 is, for example, a mass spectrometer (MS). The mass spectrometer 140 functions as a liquid chromatograph mass spectrometer (LC / MC) by employing, for example, a high-performance liquid chromatograph (HPLC), which is a type of liquid chromatograph.

[0024] The mass spectrometer 140, under the control of the mass spectrometry control unit 145, quantitatively analyzes target components of samples taken in by the sample loading / unloading unit 141, thereby quantitatively analyzing tumor markers, hormones, infectious diseases, etc. (so-called immune items) in samples such as blood. After analysis, the sample is loaded from the sample loading / unloading unit 141 to the sample transport device 120 and then transported to the sample setting device 110 or the immunoassay analyzer 130. The analysis results (measured values) from the mass spectrometer 140 are output from the mass spectrometry control unit 145 to the control device 150.

[0025] Figure 4 is a flowchart showing the processing flow of the automated analyzer.

[0026] In Figure 4, the control device 150 of the automated analyzer 100 first transfers the sample placed in the sample placement device 110 to the immunoassay analyzer 130 (first analysis unit) using the sample transport device 120 (step S100). If multiple samples are to be measured, the samples are transported sequentially according to a predetermined schedule.

[0027] Next, the immunoassay analyzer 130 is controlled via the immunoassay control unit 138 to measure the target components in the sample (step S110). If multiple samples are to be measured, the samples are measured sequentially according to a predetermined schedule.

[0028] Next, it is determined whether the measured value (first value) of the target component measured by the immunoassay analyzer 130 falls within the range defined by a predetermined threshold (step S120). If multiple samples are to be measured, the measurement value (first value) of each sample is determined individually.

[0029] Here, the threshold used in the determination in step S120 is a value that defines the upper and / or lower limits of a predetermined range for determining the characteristics of the measured value (first value), and is defined by experimentally determining in advance the range in which the measured value (first value) is presumed to be normal. In other words, if the measured value (first value) is outside the range defined by the threshold, an abnormality in the measured value (first value) is suspected.

[0030] In this embodiment, tacrolimus contained in the sample is given as an example of the component to be measured, and metabolites of tacrolimus (M-I, M-II, M-III) are given as examples of related substances. Tacrolimus, the component to be measured, is a drug administered to the body, and the predetermined range defines the therapeutic range of the drug (tacrolimus).

[0031] Figure 5 shows an example of measurement results from an immunoassay analyzer.

[0032] Figure 5 illustrates the results of comparing the measured values ​​(first values) of tacrolimus concentration (ng / mL) for multiple samples (No. 001) to (No. 008) with the range defined by a threshold (e.g., 5 to 20 (ng / mL)). For example, for sample (No. 001), the measured value is 6.3 (ng / mL) against the threshold range of 5 to 20 (ng / mL), and since the measured value is within the range, it is presumed that the measured value is normal (OK). Also, for example, for sample (No. 002), the measured value is 25.4 (ng / mL) against the threshold range of 5 to 20 (ng / mL), and since the measured value is outside the range, there is a suspicion of an abnormality in the measured value, and remeasurement using the mass spectrometer 140 is set as described later. Similarly, for sample (No. 006), the measured value was 23.6 (ng / mg) against a threshold range of 5-20 (ng / mL). Since the measured value is outside the range, there is a suspicion of an abnormality in the measured value, and remeasurement using the mass spectrometer 140 is set as described later.

[0033] If the result of the determination in step S120 is YES for a sample, that is, if the measurement value (first value) of the immunoassay analyzer 130 is determined (estimated) to be normal, the measurement value (first value) of the sample is recorded as the official measurement result for the sample, and the process is terminated.

[0034] Furthermore, if the result of the determination in step S120 is NO, that is, if the measurement value (first value) from the immunoassay analyzer 130 is suspected to be abnormal, a re-measurement is set, and then the sample is transferred to the mass spectrometer 140 (second analysis unit) by the sample transport device 120 (step S130).

[0035] Next, the mass spectrometer 140 is controlled via the mass spectrometry control unit 145 to measure the target component in the sample and related substances of the target component (step S140).

[0036] Next, the accuracy of the measurement value (first value) is verified by comparing the measured value (first value) of the target component of the sample in the immunoassay of the mass spectrometer 140 (first value), the measured value (second value) in the mass spectrometry of the immunoassay analyzer 130 (second value), and the measured value (third value) of the related substance (step S150). The verification results are then recorded, and the process is terminated.

[0037] Figure 6 shows an example of measurement results from an automated analyzer.

[0038] Figure 6 shows the results of the following for multiple samples, from sample (No. 001) to sample (No. 008): the measured value (first value), threshold (ng / mL), and judgment result of tacrolimus concentration (ng / mL) measured by the immunoassay analyzer 130; the measured value (second value) of tacrolimus concentration (ng / mL) measured by the mass spectrometer 140; the measured values ​​(third value) of M-I concentration (ng / mL), M-II concentration (ng / mL), and M-III concentration (ng / mL), which are the concentrations of tacrolimus metabolites (related substances); the increase in the immunoassay result due to cross-reactivity (ng / mL); the results of the verification process in the control device 150 (see step S150 in Figure 4); and the verification results. In addition, Figure 6 shows an example where sample (No. 002) and sample (No. 006) are set to be remeasured, similar to Figure 5.

[0039] As shown in Figure 6, the mass spectrometry measurements for the sample (No. 002) set for re-measurement by the mass spectrometer 140 were tacrolimus concentration: 17.4 (ng / mL), M-I concentration: 1.4 (ng / mL), M-II concentration: 5.8 (ng / mL), and M-III concentration: 1.2 (ng / mL). In contrast, the immunoassay measurement from the immunoassay analyzer 130 was tacrolimus concentration: 25.4 (ng / mL). From these results, the increase in immunoassay results due to cross-reactivity is tacrolimus equivalent concentration: 6.1 (ng / mL), M-I contribution: 0.1 (ng / mL), M-2 contribution: 5.5 (ng / mL), and M-III contribution: 0.5. In other words, the verification result is that there is a suspicion of cross-reactivity in the immunoassay measurement from the immunoassay analyzer 130.

[0040] Furthermore, the mass spectrometry measurements for sample (No. 006), which was set to be remeasured using the mass spectrometer 140, were tacrolimus concentration: 21.6 (ng / mL), M-I concentration: 0.8 (ng / mL), M-II concentration: 1.5 (ng / mL), and M-III concentration: 0.0 (ng / mL). In contrast, the immunoassay measurement using the immunoassay analyzer 130 was tacrolimus concentration: 23.6 (ng / mL). From these results, the increase in the immunoassay results due to cross-reactivity is tacrolimus equivalent concentration: 1.5 (ng / mL), M-I contribution: 0.1 (ng / mL), M-2 contribution: 1.4 (ng / mL), and M-III contribution: 0.0. In other words, the verification result is that the immunoassay measurement using the immunoassay analyzer 130 has a certain level of reliability, and the tacrolimus concentration of sample (No. 006) is high.

[0041] The effects of this embodiment, configured as described above, will now be explained.

[0042] In immunoassay, a known challenge is cross-reactivity, where similar components other than the target component react with the antibody, leading to a positive error in the measurement. On the other hand, mass spectrometry avoids the cross-reactivity problem in immunoassay and allows for the quantitative analysis of metabolites that cannot be distinguished from the target component in immunoassay. However, compared to immunoassay, it requires more complex sample preparation and has longer measurement times.

[0043] In contrast, in the present embodiment, a specimen placement unit (e.g., the specimen placement device 110) on which a specimen to be analyzed is placed, a first analysis unit (e.g., the immunoassay device 130) that performs an analysis different from mass spectrometry on the specimen, a second analysis unit (e.g., the mass spectrometer 140) that performs mass spectrometry on the specimen, a specimen transport unit (e.g., the specimen transport device 120) that transports the specimen among the specimen placement unit, the first analysis unit, and the second analysis unit, and a control unit (e.g., the control device 150) that controls the specimen placement unit, the first analysis unit, the second analysis unit, and the specimen transport unit are provided. The control unit measures a target component in the specimen with the first analysis unit, and when a first value, which is a measured value of the target component measured by the first analysis unit, is outside a predetermined range, measures the target component and a related substance of the target component with the second analysis unit, and verifies the accuracy of the first value based on a second value, which is a measured value of the target component measured by the second analysis unit, and a third value, which is a measured value of the related substance. Thus, it is possible to improve the analysis accuracy while suppressing an increase in the measurement time.

[0044] In the present embodiment, the immunoassay device 130 is exemplified as an analysis device having a different analysis principle from the mass spectrometer 140. However, instead of this, the present invention can also be applied to an automatic analyzer employing a biochemical analyzer. A biochemical analyzer is an analyzer that measures sugars, cholesterol, proteins, enzymes, etc. (so-called biochemical items) in a specimen such as blood by measuring a product resulting from the reaction between a specimen and a reagent. Some biochemical analyzers can measure some analysis items related to immune sera, tumor markers, coagulation tests, etc., which are different from general biochemical items, and these are also included in the category of biochemical analyzers.

[0045] <Supplementary Note> The present invention is not limited to the above-described embodiment, and various modifications and combinations within the scope not departing from the gist thereof are included. Also, the present invention is not limited to those having all the configurations described in the above embodiment, and those in which a part of the configuration is deleted are also included. Further, each of the above configurations, functions, etc. may be realized by designing a part or all of them, for example, with an integrated circuit. Also, each of the above configurations, functions, etc. may be realized by software by a processor interpreting and executing a program for realizing each function.

[0046] 100...Automatic analyzer, 110...Sample loading device, 120...Sample transport device, 130...Immunoanalyte analyzer, 131...Sample loading / unloading unit, 132...Reagent storage unit, 133...Sample dispensing unit, 134...Reagent dispensing unit, 135...Reaction unit, 136...Measurement unit, 137...Washing unit, 138...Immunoanalyte control unit, 140...Mass spectrometer, 141...Sample loading / unloading unit, 142...Pre-processing unit, 143...Chromatograph, 144...Mass spectrometry unit, 145...Mass spectrometry control unit, 150...Control device

Claims

1. An automated analyzer comprising: a sample placement unit on which a sample to be analyzed is placed; a first analysis unit that performs an analysis different from mass spectrometry on the sample; a second analysis unit that performs mass spectrometry on the sample; a sample transport unit that transports the sample between the sample placement unit, the first analysis unit, and the second analysis unit; and a control unit that controls the sample placement unit, the first analysis unit, the second analysis unit, and the sample transport unit, wherein the control unit measures a target component in the sample using the first analysis unit; if the first value, which is the measured value of the target component measured by the first analysis unit, is outside a predetermined range, it measures the target component and related substances using the second analysis unit; and verifies the accuracy of the first value based on the second value, which is the measured value of the target component measured by the second analysis unit, and the third value, which is the measured value of the related substances.

2. An automated analyzer according to claim 1, characterized in that the related substance is a metabolite of the target component.

3. An automated analyzer according to claim 1, wherein the target component is a drug administered to a living organism, and the predetermined range is the therapeutic range of the drug.

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