Method for determining presence or absence of abnormality in liquid chromatograph mass spectrometry device, and processing device

Abstract

The following configuration has been adopted in order to provide a method for determining the presence or absence of an abnormality in a liquid chromatograph mass spectrometry device, and a processing device, with which it is possible to determine the presence or absence of an abnormality in the device by automatically confirming that a measurement signal value of an internal standard substance is not varying.　A method for determining the presence or absence of an abnormality in a liquid chromatograph mass spectrometry device, and a processing device, the method including a step in which a sample being measured, mixed with an internal standard substance having a predetermined concentration, is analyzed a plurality of times using the same liquid chromatograph mass spectrometry device, and a step in which the presence or absence of an abnormality in the liquid chromatograph mass spectrometry device is determined on the basis of a time-series variation in the analysis results of a plurality of liquid chromatograph mass spectrometry analyses performed using the same liquid chromatograph mass spectrometry device, wherein the determination of the presence or absence of an abnormality based on the time-series variation in the analysis results is a determination based on at least one of a monotonically increasing variation and a monotonically decreasing variation.

Description

Method for determining whether or not a liquid chromatograph mass spectrometer has an abnormality, and processing device

[0001] The present invention relates to a method for determining whether or not an abnormality exists in a liquid chromatograph mass spectrometer, and to a processing device.

[0002] In recent years, processing devices using analytical techniques such as GC / MS (gas chromatography / mass spectrometry) and LC / MS (liquid chromatography / mass spectrometry) have attracted attention as devices capable of separating and detecting multiple components contained in a single sample. LC / MS analytical devices are particularly being applied to the medical field. For example, in therapeutic drug monitoring (TDM), which confirms the efficacy of a drug administered to a patient, individualized dosage and administration methods are set for each patient while monitoring factors related to therapeutic efficacy and side effects.

[0003] When it is necessary to accurately quantify an analyte in an LC / MS system, it is common to use the internal standard method (sometimes called the "internal standard method"). The internal standard method is an analytical method in which a component with similar physical properties to the component to be quantified is contained in all standard samples at a fixed concentration, and the measurement intensity is the intensity ratio of the signal intensity of this component to the component to be quantified.

[0004] When an analyte and an internal standard (sometimes called an "internal standard") are measured simultaneously in a mass spectrometer, the nonlinearity and peak intensity fluctuations of the signal intensities of these two substances due to the state of the instrument will behave in a similar manner.

[0005] In order to quantify analytes in a processing device such as an LC / MS device, it is necessary to prepare a calibration curve by measuring a solution in which multiple analytes to be measured and an internal standard are mixed at two or more different concentrations. Patent Document 1 describes a technology for preparing a calibration curve that enables easy and efficient preparation of standard samples suitable for the measurement concentration ranges of the components to be quantified in quantitative analysis using standard samples containing multiple components.

[0006] JP 2014-115104 A

[0007] In processing devices such as LC / MS systems, variations in the measurement results of internal standards between analytes (in the medical field, analytes are also referred to as "analytes," and therefore, hereinafter, analytes may also be referred to as "analytes") are sometimes observed, even among samples analyzed using the same analytical parameters. In other words, even if a calibration curve can be accurately generated using the technology described in Patent Document 1, accurate measurement results are not necessarily obtained. Potential causes of variation in measurement results include human error during sample preparation or processing, equipment problems that may occur during analysis, and matrix effects in the sample. Therefore, to obtain accurate measurement results, it is necessary to perform sample measurements while confirming that the measurement signal value of this internal standard is not fluctuating.

[0008] An object of the present invention is to provide a method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer, and a processing device that can determine whether or not there is an abnormality in the device by automatically confirming that the measurement signal value of an internal standard substance is not fluctuating.

[0009] The present invention provides a method for determining whether or not an abnormality exists in a liquid chromatograph mass spectrometer, comprising the steps of: analyzing a measurement sample mixed with a predetermined concentration of an internal standard multiple times using the same liquid chromatograph mass spectrometer; and determining whether or not an abnormality exists in the liquid chromatograph mass spectrometer based on a time-series variation in the analysis results of the multiple liquid chromatograph mass analyses performed using the same liquid chromatograph mass spectrometer, wherein the determination of whether or not an abnormality exists based on a time-series variation in the analysis results is based on at least one of a monotonic increase and a monotonic decrease.

[0010] Also, the present invention provides a processing device comprising a sample pretreatment unit, a separation unit, an ionization unit, and a mass analysis unit, and further comprising: a memory unit that stores the results of multiple analyses of a measurement target sample mixed with a predetermined concentration of an internal standard substance; and a judgment unit that judges whether or not there is an abnormality in the processing device based on the trend of fluctuations in the analysis results of the measurement target sample stored in the memory unit, and is characterized in that the judgment unit makes a judgment based on at least one of monotonically increasing and monotonically decreasing fluctuations.

[0011] According to the present invention, a method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer and a processing device can be provided, which can determine whether or not there is an abnormality in the device by automatically confirming that the measurement signal value of an internal standard is not fluctuating.

[0012] 1 is a diagram showing a schematic device configuration of an analytical device (LC / MS device) according to an embodiment of the present invention. FIG. 2 is a flowchart for explaining analytical processing executed in the first and second embodiments of the present invention. FIG. 3 is a diagram showing the concentration of a sample to be measured. Example 1 of fluctuations in signal values ​​of an internal standard when a standard sample, a quality control sample, specimen A, and specimen B are measured. Example 2 of fluctuations in signal values ​​of an internal standard when a standard sample, a quality control sample, specimen A, and specimen B are measured. Example 3 of fluctuations in signal values ​​of an internal standard when a standard sample, a quality control sample, specimen A, and specimen B are measured. An example of a display in which the measurement results of (Example 1) are displayed on a display device. An example of a display in which the measurement results of (Example 2) are displayed on a display device. An example of a display in which the measurement results of (Example 3) are displayed on a display device. An example of a display in which other data is displayed on a display device. An example of a display in which other data is displayed on a display device. A flowchart for explaining a method for determining the presence or absence of an abnormality.

[0013] Hereinafter, an embodiment of the present invention will be described with reference to the drawings.

[0014] Fig. 1(A) is a diagram showing a general configuration of a processing device capable of implementing the present invention. Note that the device configuration and embodiment described below are examples for specifically explaining the invention, and the embodiment is not limited to the described content. Fig. 1(A) assumes an LC / MS device, but the present invention can be applied to any device as long as it is a processing device that uses an internal standard substance.

[0015] The LC / MS device 100 according to this embodiment includes a sample pretreatment unit 101 that dilutes or otherwise processes a sample before introducing it into the device, a separation unit 102 that separates the introduced sample into its components, an ionization unit 103 that ionizes each of the separated components, a mass analysis unit 104 that performs mass analysis processing on each of the ionized components, a sample storage unit 105, an eluent storage unit 106, a device control unit 107 that issues instructions to each unit, controls their operation, and performs calibration curve calculation processing, a display device 108 that outputs the control results obtained by the device control unit 107, an operation unit 109 that is operated by a user to input instructions, and a memory unit 110 that stores signal values.

[0016] In a steady state, the sample pretreatment unit 101 continuously aspirates the eluent contained in the eluent reservoir and continues to deliver the eluent to the separation unit 102 at a constant pressure. Furthermore, in synchronization with the start of measurement, a specified volume of the sample contained in the sample reservoir 105 is injected into the separation unit 102. While a single sample reservoir 105 is shown in the figure, multiple sample reservoirs may be provided, and samples may be supplied sequentially from the multiple sample reservoirs at the start of measurement. Furthermore, the sample pretreatment unit 101 dilutes the sample based on the dilution concentration specified by the user via the operation unit 109, and introduces the diluted sample into the separation unit 102.

[0017] The separation unit 102 has a section called a "column," which is a cylindrical container filled with a packing material that serves as a stationary phase, and separates the sample sent from the sample pretreatment unit 101. The type of separation action can be changed by changing the packing material in the column. For example, if highly polar silica gel is used as the packing material, samples can be separated based on the difference in the polarity of the substances.

[0018] The ionization unit 103 is, for example, an electrospray ionization source (ESI) or atmospheric pressure chemical ionization (APCI), and is capable of ionizing the sample separated in the separation unit.

[0019] The mass analysis unit 104 has an ion mass separation mechanism, such as a quadrupole type, ion trap type, or time-of-flight type, and an ion detector, such as a channeltron, dynode type, or a scintillator and photodetector, that detects the separated ions.

[0020] The device control unit 107 controls the operations of the sample pretreatment unit 101, separation unit 102, ionization unit 103, and mass analysis unit 104, stores the measurement data obtained by the mass analysis unit 104 in the memory unit 110, performs any data processing (including calibration curve calculation processing), and displays the data on the display device 108. The user operates the operation unit 109 as necessary to instruct the device control unit 107 to perform an analysis operation.

[0021] The contents of the signal values ​​stored in the memory unit 110 are shown schematically in Figure 1(B). The boxes in Figure 1(B) indicate that memory areas for those types of signal values ​​are available in the memory unit 110. Cals / QC 111 is an area for storing the measurement results of standard samples (calibrators) used to create calibration curves and control samples (quality controllers) used to periodically check for deviations in measurement results due to abnormalities in the measurement device or reagents. Cals / QC 111 includes an area 113 for storing signal values ​​of known-concentration analytes and an area 114 for storing signal values ​​of internal standards mixed with known-concentration analytes. Furthermore, the area 112 for storing measurement results of general specimens includes an area 115 for storing signal values ​​of unknown-concentration analytes and an area 116 for storing signal values ​​of internal standards mixed with unknown-concentration analytes.

[0022] <Analysis Procedure> Fig. 2 is a flowchart for explaining the most typical analysis procedure according to an embodiment of the present invention. Note that the procedure in Fig. 2 describes only the procedures relevant to explaining the contents of the present invention, and omits procedures that are less relevant to explaining the present invention, such as pretreatment of the analytical sample, preparation and cleanup of the device, or detailed operation of the device during measurement.

[0023] (i) Setting of Analysis Conditions (S102) After the procedure for starting analysis (S101) has been completed, the sample analysis conditions are set (S102). In this step, the analyst (user) sets the analysis conditions using the operation unit 109, and the device control unit 107 receives the analysis conditions. The settings include the number of samples and measurement order, measurement components, number of internal standard samples, number of unknown samples, pressure and temperature of the separation unit, separation time, mass number scan range in the mass analysis unit, and detector sensitivity settings for each component. Information such as the measurement conditions is stored in a storage device built into the device control unit 107 as needed. Alternatively, measurement conditions previously stored in the device control unit 107 may be called up and used.

[0024] (ii) Measurement Sample Setting Process (S103) Next, the device control unit 107 executes the measurement sample setting process (S103). An example of a sample set in this step is shown in FIG. 3. The measurement sample settings in FIG. 3 are displayed on the display device 108, and the user can enter various settings as needed using the operation unit 109. FIG. 3(A) shows a list of concentration settings for standard substances (calibration samples for creating calibration curves: Cals; Calibrator) / quality control samples (QC; Quality Controller) for periodically checking the device status, as well as the internal standard substances (internal standard samples) to be mixed with these samples. For example, in Cals / QC (1), 0.0005 ng / mL of standard substance or quality control sample is mixed with 0.3 ng / mL of internal standard substance. As the sequence progresses from Cals / QC (2) (3) to (8), the concentration of the standard or quality control sample increases, but the concentration of the internal standard is fixed at 0.3 ng / mL. Figures 3(B) and 3(C) are concentration setting lists for specimens A and B, respectively. In the measurement of specimen A, for example, in (A), specimen A, which is the substance to be analyzed, has X 1 ng / mL and is mixed with 0.3 ng / mL of internal standard, as in the case of Cals / QC. As the sequence progresses from (B) (C) to (F), the concentrations increase to Y 1 ng / mL, Z 1 ng / mL, and so on. The setting conditions for the measurement specimen of specimen B are similar.

[0025] To improve the accuracy of abnormality determination, it is desirable to measure the same sample diluted to at least five different concentrations. It is also desirable to measure the samples diluted to at least five different concentrations in chronological order, starting from the lowest concentration to the highest concentration.

[0026] In the measurement sample setting process (S103), the analyst sets all samples necessary for measuring the set samples, and the device control unit 107 accepts them.

[0027] After completing the above settings, when the analyst presses the setting button on the operation unit 109, the device control unit 107 stores the settings and proceeds to the next process (S104).

[0028] (iv) Standard Sample (Cals) Measurement (S104) In the standard sample (Cals) measurement (S104), the device control unit 107 instructs the sample pretreatment unit 101 to dilute the high-concentration standard sample and the internal standard sample according to the standard sample dilution ratios and internal standard sample dilution ratios shown in (1) to (8) in FIG. 3A and mix them. The device control unit 107 then measures the standard sample diluted by the dilution process and mixed with the internal standard sample a total of eight times (1) to (8) (S104). While the high-concentration standard sample and the internal standard sample may be diluted manually by an analyst, the sample pretreatment unit 101 may be equipped with an automatic dispensing function linked to the device control unit 107 to automatically dilute the samples. Alternatively, an automatic dispensing device may be installed separately from the sample pretreatment unit 101 to achieve automatic dilution.

[0029] (vi) Calibration Curve Creation Process (S105) In the calibration curve creation process (S105), the device control unit 107 creates a calibration curve using the standard sample measurement results obtained by repeating the measurement of the number of standard samples (S104).

[0030] (vii) Sample A Measurement Process (S106) Sample A diluted under six dilution conditions (A) to (F) shown in Fig. 3B is continuously measured. The device control unit 107 measures sample A under the same conditions as those used to measure the standard sample.

[0031] (viii) Quality Control Sample Measurement Process (S107) In the first quality control sample (QC) measurement (S107), the device control unit 107 instructs the sample pretreatment unit 101 to dilute the high-concentration quality control sample and the internal standard sample according to the quality control sample dilution ratio and the internal standard sample dilution ratio shown in (1) of FIG. 3A and mix them together. The device control unit 107 then measures the quality control sample diluted by the dilution process and mixed with the internal standard sample (S107). The quality control sample is measured at a predetermined timing so as to be inserted between consecutive measurements of sample A. In the example of FIG. 4 described below, the quality control sample is measured every four measurements of sample A. The quality control sample measurement timing may be set to measure every time an unknown sample (i.e., sample A) is measured, as described above, or may be set to measure at a predetermined interval, for example, every two hours.

[0032] (viii) Sample A Measurement Process (S108) Following the measurement of the quality control sample that interrupted in S107, the measurement of sample A is resumed. The device control unit 107 measures sample A under the same conditions as those used to measure the standard sample.

[0033] (ix) Quality Control Sample Measurement Process (S109) A second quality control sample (QC) measurement (S109) is performed in the same manner as in S107.

[0034] (x) Sample A Measurement Process (S110) Following the measurement of the quality control sample that interrupted in S107, the measurement of sample A is resumed. The device control unit 107 measures sample A under the same conditions as those used to measure the standard sample. The measurement process of sample A continues until the preset number of measurements of sample A have been completed.

[0035] (xi) Quality Control Sample Measurement Process (S111) A third quality control sample (QC) measurement (S111) is performed in the same manner as in S107.

[0036] (xii) Sample B Measurement Process (S112) Sample B diluted under six dilution conditions shown in (K) to (L) of Fig. 3C is continuously measured. The device control unit 107 measures sample B under the same conditions as those used to measure sample A.

[0037] (xiii) Quality Control Sample Measurement Process (S113) A fourth quality control sample (QC) measurement (S113) is performed in the same manner as in S107.

[0038] (xiii) Sample B Measurement Process (S114) Sample B diluted under six dilution conditions shown in (K) to (L) of Fig. 3C is continuously measured. The device control unit 107 measures sample B under the same conditions as those used to measure sample A.

[0039] (xv) Quality Control Sample Measurement Process (S115) A fifth quality control sample (QC) measurement (S115) is performed. The measurement method is the same as in S107. When the preset number of measurements of sample B is completed, the analysis ends (S116).

[0040] 4 to 6 are graphs showing three examples of change patterns of the signal value of the internal standard when a standard sample, a quality control sample, specimen A, and specimen B are measured using the analytical procedure shown in FIG. 2.

[0041] Figure 4 shows Example 1, Figure 5 shows Example 2, and Figure 6 shows Example 3. These examples show that even when the same standard sample, quality control sample, specimen A, and specimen B are measured, the measurement results of the internal standard sample may vary in this way.

[0042] It is effective to display the measurement results of such internal standard samples on the display device 108 in Fig. 1 to inform the instrument operator whether there are any problems with the obtained measurement results. Fig. 7 shows an example of the measurement results of Fig. 4 (Example 1) stored in the memory unit 110 displayed on the display unit. When the upper reference value 201 and the lower reference value 202 of the first signal value during the measurements of Cal (1) to (8) are set as the reference range, the second signals during the measurements of specimens A and B are both within the reference range, so by displaying an indication that the IS signal value is OK on the display device 108, the instrument operator is informed that there are no problems with the measurement results.

[0043] 5 (Example 2) stored in the memory unit 110 is displayed on the display unit. When the upper reference value 201 and the lower reference value 202 of the first signal value during the measurements of Cal (1) to (8) are set as the reference range, the IS signal value of the second signal during the measurement of specimen A was OK in all cases, but during the measurement of specimen B, the IS signal value fell below the immediately preceding value three times in succession, indicating a decreasing trend, and therefore "IS signal value: decreasing trend" was displayed on the display device 108.

[0044] 9 is an example of the measurement results of FIG. 6 (Example 3) stored in the memory unit 110 displayed on the display unit. When the upper reference value 201 and the lower reference value 202 of the first signal value during measurements of Cal (1) to (8) are set as the first reference range, the IS signal values ​​of the second signals during measurements of specimen A are all OK, but the second signal during measurements of specimen B tends to show values ​​that are smaller by a certain value in successive measurements and deviate from the first reference range, so the display unit displays "IS signal value: tendency to be abnormal."

[0045] 10 is an example of a display on the display device 108 of other data stored in the memory unit 110. When the standard deviation of the first signal values ​​during measurements Cal(1) to (8) is 3,225,540, the average is 35,687,500, and CV = standard deviation / average is 0.09, the standard deviation of the second signal values ​​from the first to fourth measurements of sample A is 479,583, the average is 37,550,000, and CV = standard deviation / average is 0.01, so IS signal value: abnormal tendency is displayed on the display device 108 at this point. Furthermore, the standard deviation of the second signal values ​​from the first to fourteenth measurements of sample A is 1,488,934, the average is 37,000,000, and CV = standard deviation / average is 0.04, so the variation is not greater than the predetermined value, and IS signal value: OK is displayed on the display device 108. Furthermore, the standard deviation of the second signal values ​​from the 1st to 14th times for sample B is 308,844, the average value is 32,300,000, and CV = standard deviation / average is 0.01, so the variation is greater than the specified value, and the display device 108 displays IS signal value: tendency to be abnormal.

[0046] 11 is an example of a display on the display device 108 of other data stored in the memory unit 110. When a second reference range is determined based on the first signal value, the second signals during measurement of sample A all have OK IS signal values, but the second signals during measurement of sample B are outside the second reference range. This is characteristic of cases where the IS signal values ​​are neither below nor above the second reference range at consecutive measurement points. The display device 108 displays the IS signal value: abnormal tendency.

[0047] FIG. 12 shows the flow of determining whether or not an abnormality exists. A normal range is set as a first reference range, consisting of an upper reference value 201 and a lower reference value 202 of the first signal value of the internal standard in the standard sample (Cals) measurement (S104), and a determination is made as to whether or not the analysis results are within that range. Even if the analysis results are within the normal range, a determination is made as to whether or not the CV value of the signal values ​​obtained in successive measurements deviates from the CV value of the standard sample (Cals) measurement (S104). Furthermore, a determination is made as to whether or not the signal values ​​obtained in successive measurements are monotonically increasing or decreasing. The accuracy of determining whether or not an abnormality exists can be improved by determining whether or not there is an abnormality based on the results of at least 30 analyses over time.

[0048] The time span for determining whether the signal value is monotonically increasing or decreasing is, for example, the signal value of the internal standard during the standard sample (Cals) measurement (S104), and therefore, is set to the time until Cal is measured again. The timing of the standard sample (Cals) measurement may be determined according to the operation of the device, such as once a day or once a week, or may be determined according to the operation of the device, for example, by measuring the standard sample (Cals) when the QC measurement results are unstable (evaluated by the standard deviation σ).

[0049] Furthermore, since it is necessary to determine whether the measurement results of the internal standard are monotonically increasing or decreasing, it is desirable to make this determination for each measurement. For example, if there were continuous sample orders in the morning, no orders in the afternoon, and then a sudden order in the middle of the night, it is likely that the sample will be measured without re-calibration due to the urgency. Even in such intermittent measurements, it is desirable for the instrument to maintain the signal value of the internal standard within the standard range.

[0050] In recent years, an increasing number of facilities are conducting measurements under the concept of 24-hour non-stop testing, so even if no sample orders have been placed, it is desirable to measure QC and confirm the QC value and internal standard signal value within a set period.

[0051] <Additional Note> The present invention can also be realized by software program code that realizes the functions of the embodiments. In this case, a storage medium on which the program code is recorded is provided to a system or device, and the computer (or CPU or MPU) of the system or device reads the program code stored in the storage medium. In this case, the program code read from the storage medium itself realizes the functions of the above-mentioned embodiments, and the program code itself and the storage medium on which it is stored constitute the present invention. Examples of storage media for providing such program code include flexible disks, CD-ROMs, DVD-ROMs, hard disks, optical disks, magneto-optical disks, CD-Rs, magnetic tape, non-volatile memory cards, and ROMs.

[0052] 101: sample pretreatment section, 102: separation section, 103: ionization section, 104: mass spectrometry section, 105: sample storage section, 106: eluent storage section, 107: device control section, 108: display device, 109: operation section

Claims

1. A method for determining whether or not a liquid chromatograph mass spectrometer has an abnormality, comprising: a step of analyzing a sample to be measured, mixed with an internal standard substance of a predetermined concentration, multiple times using the same liquid chromatograph mass spectrometer; and a step of determining whether or not the liquid chromatograph mass spectrometer has an abnormality based on the time-series fluctuations in the analysis results of the multiple liquid chromatograph mass analyses performed using the same liquid chromatograph mass spectrometer; wherein the determination of whether or not a abnormality has occurred based on the time-series fluctuations in the analysis results is based on at least one of monotonically increasing and monotonically decreasing fluctuations.

2. A method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer as described in claim 1, characterized in that the measurement sample to be analyzed multiple times is a sample obtained by diluting the same sample at different concentrations.

3. A method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer as described in claim 1, characterized in that the sample to be measured for multiple analyses is at least one of a calibration sample, a quality control sample, and a general specimen.

4. A method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer according to claim 1, characterized in that the time series fluctuations in the analysis results are determined to be abnormal based on the results of at least 30 analyses.

5. A method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer according to claim 2, characterized in that the samples obtained by diluting the same sample at different concentrations are diluted to at least five different concentrations.

6. A method for determining whether or not there is an abnormality in a liquid chromatograph mass spectrometer according to claim 5, characterized in that the sample diluted to at least five different concentrations is measured in chronological order from the lowest concentration to the highest concentration.

7. A processing device comprising a sample pretreatment unit, a separation unit, an ionization unit, and a mass analysis unit, the processing device further comprising: a memory unit for storing the results of multiple analyses of a measurement target sample mixed with a predetermined concentration of an internal standard substance; and a judgment unit for judging whether or not there is an abnormality in the processing device based on the tendency of fluctuations in the analysis results of the measurement target sample stored in the memory unit, wherein the judgment unit makes a judgment based on at least one of monotonically increasing and monotonically decreasing fluctuations.

8. A processing apparatus according to claim 7, wherein the measurement sample to be analyzed multiple times is a sample obtained by diluting the same sample at different concentrations.

9. A processing apparatus according to claim 7, wherein the sample to be measured for the multiple analyses is at least one of a calibration sample, a quality control sample, and a general specimen.

10. A processing device according to claim 7, wherein the time-series fluctuations in the analysis results are analyzed to determine whether or not there is an abnormality based on at least 30 analysis results.

11. A processing apparatus according to claim 8, wherein the samples obtained by diluting the same sample at different concentrations are diluted at least five different concentrations.

12. A processing apparatus according to claim 11, wherein the sample diluted to at least five different concentrations is measured in time series in order from the lowest concentration to the highest concentration.

13. A processing device according to any one of claims 7 to 12, characterized in that it comprises a display unit which displays the analysis results in chronological order, and which displays a display indicating a preset appropriate range and the judgment results of the judgment unit on the same screen.

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