阅读说明：本技术 自动分析装置 (Automatic analyzer ) 是由 野田和弘 今井健太 佐佐木俊辅 梅木博也 稻叶亨 佐藤航 于 2019-01-15 设计创作，主要内容包括：本发明提供即使自动分析装置分注的溶液的量是少量、有未测量的未知的参数,也能够高精度地预测分注状态的技术。自动分析装置具备：探头,其分注液体；注射器,其产生用于探头分注液体的压力变动；流路,其连接探头和注射器；压力传感器,其测定探头分注液体时的流路内的压力；存储部,其存储压力传感器测定出的压力的时序数据；模拟器,其根据物理模型,计算流路内的液体流动的基准压力波形；判定部,其根据探头分注判定对象的液体时的压力的时序数据和模拟器计算出的基准压力波形的信息,对判定对象的液体的分注状态进行判定。(The invention provides a technique capable of predicting dispensing state with high precision even if the amount of solution dispensed by an automatic analyzer is small and there is an unmeasured unknown parameter. The automatic analysis device is provided with: a probe for dispensing a liquid; a syringe that generates pressure fluctuations for dispensing a liquid by a probe; a flow path connecting the probe and the syringe; a pressure sensor that measures a pressure in the flow path when the probe dispenses the liquid; a storage unit that stores time series data of the pressure measured by the pressure sensor; a simulator for calculating a reference pressure waveform of a liquid flow in the flow path based on the physical model; and a determination unit that determines the dispensing state of the liquid to be determined, based on time-series data of the pressure when the liquid to be determined is dispensed by the probe and information of the reference pressure waveform calculated by the simulator.)

1. An automatic analyzer is characterized by comprising:

a probe for dispensing a liquid;

a syringe that generates pressure fluctuations for dispensing the liquid by the probe;

a flow path connecting the probe and the syringe;

a pressure sensor for measuring a pressure in the flow path when the probe dispenses the liquid;

a storage unit that stores time series data of the pressure measured by the pressure sensor;

a simulator for calculating a reference pressure waveform of the liquid flow in the flow path based on a physical model; and

and a determination unit that determines a dispensing state of the liquid to be determined, based on the time-series data of the pressure when the liquid to be determined is dispensed by the probe and the information of the reference pressure waveform calculated by the simulator.

2. The automatic analysis device according to claim 1,

the simulator receives an input indicative of a dispensing state, and calculates a reference pressure waveform corresponding to the input.

3. The automatic analysis device according to claim 2,

the input includes at least one of a viscosity of the liquid, an amount of bubbles included in the liquid, and a configuration of the bubbles.

4. The automatic analysis device according to claim 2,

the automatic analyzer further includes: and an environment measuring device that measures environment information around the device including at least one of air temperature and outside air pressure.

5. The automatic analysis device according to claim 4,

the input includes a measurement result of the environment measurement device.

6. The automatic analysis device according to claim 5,

the input includes a drive speed of the injector.

7. The automatic analysis device according to claim 1,

the simulator calculates a statistical distance between the time-series data of the pressure and the reference pressure waveform.

8. The automatic analysis device according to claim 7,

the statistical distance is any of a mahalanobis distance, a euclidean distance, a standard euclidean distance, a manhattan distance, a chebyshev distance, a minkowski distance, and a multivariate normal density.

9. The automatic analysis device according to claim 1,

the physical model calculated by the simulator is a one-dimensional fluid equation.

10. The automatic analysis device according to claim 1,

the determination unit compares the time-series data of the pressure with the reference pressure waveform using a bayesian filter.

Technical Field

The present invention relates to an automatic analyzer including a dispensing unit that suctions and discharges a liquid.

Background

An automatic analyzer such as a biochemical analyzer or an immunological analyzer includes a sample dispensing unit for sucking a predetermined amount of a sample such as a biological sample and discharging the sample into a reaction container, a reagent dispensing unit for sucking a predetermined amount of a test reagent and discharging the reagent into a reaction container, and a detection unit for detecting the reagent after the reaction.

Here, the sample dispensing unit and the reagent dispensing unit are constituted by a probe inserted into a liquid, a syringe for driving suction and discharge of the liquid, and a flow path connecting the probe and the syringe. The automatic analyzer inserts a probe into a liquid to aspirate a predetermined amount of the liquid, moves the probe to a different container, and ejects the liquid, thereby dispensing a predetermined amount of the liquid. In addition, in order to prevent a sample component from being brought to the next test in sample dispensing of an automatic analyzer, a disposable tip may be attached to the tip of the probe.

When an automatic analyzer is used, when dispensing a liquid, there is a possibility that an abnormality of the dispensing may occur such as aspiration of air bubbles generated by handling of a specimen container, or clogging of a flow path due to a high viscosity liquid or cellulose such as fibrin in a specimen. Therefore, when an automatic analyzer is used, accurate analysis results can be obtained by accurately detecting dispensing abnormalities.

As a method for detecting an abnormality in dispensing, for example, patent document 1 discloses a technique for detecting an abnormality in dispensing by using, as an index, an integrated value of pressure data in a specific time interval, and a difference between an average pressure calculated at the end of discharge and an average pressure calculated at the time of normal discharge, with respect to a pressure variation at the time of discharging a sample, and comparing these values with a preset threshold value.

As a technique for estimating a measurement value remotely measured by a measurement device, patent document 2 discloses a technique for "obtaining an estimated measurement value of a measurement target that is not affected by environmental fluctuations by a measurement module without stabilizing the measurement value of the measurement target by a control system or the like", that is, a technique for improving the accuracy of measurement data by calculation by the measurement module.

Disclosure of Invention

Problems to be solved by the invention

As described above, the method described in patent document 1 detects the dispensing state by comparing, as indexes, the integral value of pressure data in a specific time interval and the difference between the average pressure calculated at the end of discharge and the average pressure calculated at the time of normal discharge with respect to the pressure fluctuation at the time of discharging a sample, with a preset threshold value. However, when the dispensed amount is small, a large difference between the normal state and the abnormal state cannot be observed in the pressure waveform, and the accuracy of the prediction of the dispensing state deteriorates. For example, when the temperature around the apparatus, the external air pressure, or the like changes, a change in the pressure waveform occurs to the same extent as the difference between the normal pressure waveform and the abnormal pressure waveform, and therefore the accuracy of predicting the dispensing state deteriorates. That is, the method described in patent document 1 is difficult to cope with a change in environment.

In the technique described in patent document 2, parameters such as the presence or absence of bubbles and the viscosity of the liquid, which are not measured by the measuring device, are not the calculation targets of the measurement model. Therefore, there is a problem that the detection of the dispensing state which is not the object of calculation of the model and the prediction of the parameter which is not measured cannot be performed with high accuracy.

The present invention has been made in view of the above-described circumstances, and an object thereof is to provide a technique that can predict a dispensing state with high accuracy even when the amount of a solution dispensed by an automatic analyzer is small and an unmeasured unknown parameter is present.

Means for solving the problems

In order to solve the above problem, an automatic analyzer is provided with: a probe for dispensing a liquid; a syringe that generates pressure fluctuations for dispensing the liquid by the probe; a flow path connecting the probe and the syringe; a pressure sensor for measuring a pressure in the flow path when the probe dispenses the liquid; a storage unit that stores time series data of the pressure measured by the pressure sensor; a simulator for calculating a reference pressure waveform of the liquid flow in the flow path based on a physical model; and a determination unit that determines a dispensing state of the liquid to be determined, based on the time-series data of the pressure when the liquid to be determined is dispensed by the probe and the information of the reference pressure waveform calculated by the simulator.

The present specification includes the disclosure of japanese patent application No. 2018-004327, which forms the basis of the priority of the present application.

Effects of the invention

According to the present invention, even if the amount of solution dispensed by the automatic analyzer is small and there is an unmeasured unknown parameter, the dispensing state can be predicted with high accuracy. The following description of the embodiments will be made to solve the problems, structures, and effects other than those described above.

Drawings

Fig. 1 is a schematic configuration diagram of an automatic analyzer according to embodiment 1.

Fig. 2 is a schematic configuration diagram of a sample dispensing unit according to example 1.

Fig. 3 is a diagram showing fluid movement in the mouthpiece when the automatic analyzer performs suction as one of dispensing states.

Fig. 4 is a diagram showing a calculation flow of a fluid calculation simulator used for suction detection.

Fig. 5 is a diagram showing reference pressure waveforms for normal dispensing and complete suction when the dispensing amount is 4 μ L.

Fig. 6 is a diagram showing a flow of processing for detecting a dispensing state.

Fig. 7 is a two-dimensional plot showing the calculated statistical distance.

Fig. 8 is a diagram showing changes in pressure waveform according to temperature changes.

Fig. 9 is a diagram showing fluid movement when a high-viscosity specimen is aspirated.

Fig. 10 is a diagram showing a reference pressure waveform at the time of suction created by a fluid calculation simulator.

Fig. 11 is a diagram showing a process flow of detecting clogging due to a high-viscosity specimen.

Fig. 12 is a graph in which the viscosity and the corresponding statistical distance input to the physical model are plotted on a two-dimensional plane.

Fig. 13 is a graph showing the distribution of viscosity in degrees of a sample estimated by the automatic analyzer of example 2.

Fig. 14 is a diagram showing a process flow of a fluid calculation simulator using a data assimilation method.

Detailed Description

Hereinafter, embodiments of the present invention will be described with reference to the drawings. The embodiments of the present invention are not limited to the embodiments described below, and various modifications are possible within the scope of the technical idea. In the drawings, the same reference numerals are used to designate corresponding parts in the description of the embodiments, and redundant description is omitted.

< example 1>

First, example 1 of the present invention is explained below. The automatic analyzer according to example 1 detects suction of air bubbles (hereinafter referred to as "suction") which is one of dispensing states.

[ Structure of automatic analyzer ]

Fig. 1 is a schematic configuration diagram of an automatic analyzer 101 according to embodiment 1. In fig. 1, an automatic analyzer 101 includes a rack transport line 103 for transporting a sample rack (sample rack)102, a reagent cooling unit 104, a temperature-controlled disk (reaction disk) 105, a sample dispensing mechanism (sample dispensing mechanism) 106, a reagent dispensing mechanism 107, a consumable transport unit 108, and a detection unit 109.

The specimen rack 102 stores a plurality of specimen containers (specimen containers) 110, the specimen containers 110 store biological specimens (specimens) such as blood and urine, and the specimen rack 102 is transported to the rack transport line 103 in a state where the specimen containers 110 are stored.

The reagent cooling unit 104 accommodates and cools a plurality of reagent containers 111 accommodating various reagents used for analyzing a sample. At least a portion of the upper surface of the reagent cooling unit 104 is covered by the reagent disk cover 112.

The thermostatic disc 105 includes a reaction vessel arrangement portion 114 in which a plurality of reaction vessels 113 for reacting a sample with a reagent are arranged, and a temperature adjustment mechanism (not shown) for adjusting the temperature of the reaction vessels 113 to a desired temperature.

The sample dispensing mechanism 106 includes a rotation driving mechanism and a vertical driving mechanism (not shown), and can dispense a sample from the sample container 110 to the reaction container 113 stored in the thermostatic disc 105 by these mechanisms. The reagent dispensing structure 107 also includes a rotation drive mechanism and a vertical drive mechanism (not shown) in the same manner, and dispenses a reagent from the reagent container 111 to the reaction container 113 accommodated in the thermostatic disc 105 by these drive mechanisms. The detection unit 109 includes a photomultiplier tube, a light source lamp, a spectroscope, and a photodiode (not shown), and has a function of adjusting the temperature thereof to analyze the reaction solution.

Fig. 2 is a schematic configuration diagram of a sample dispensing unit according to example 1. The probe (probe)202 is equipped with an automatically detachable mouthpiece 201, is connected to a syringe (syringe)204 via a flow path 203, and is filled with a liquid inside.

The syringe 204 is composed of a cylinder 204a and a plunger 204b, and the plunger 204b is connected to a syringe drive unit 205. The syringe driving unit 205 drives the plunger 204b up and down with respect to the cylinder 204a, whereby the sample dispensing unit suctions and discharges the sample.

The probe 202 is connected to a motor as a probe driving unit 206, and thereby the probe 202 can be moved to a predetermined position by moving in the horizontal direction and the vertical direction. Further, the syringe drive unit 205 and the probe drive unit 206 are controlled by the control section 207.

In the case of sucking the specimen (sample) 209 in the container 208, air (air-saving) is sucked into the probe 202 and the mouthpiece 201 is attached to the distal end of the probe 202 before the sucking operation so as not to mix the liquid filled in the probe 202 with the specimen 209. Then, the probe 202 is lowered by the probe driving unit 206 until the tip of the mouthpiece 201 reaches the liquid in the specimen 209, and a suction operation is performed. When the specimen suction operation is completed, the probe 202 moves to the specimen discharge position, and the syringe 204 performs the discharge operation.

After the sample 209 is discharged, the water supply pump 210 discharges the washing water 212 in the water supply tank 211 at high pressure, thereby washing the probe 202. The flow path is opened and closed to water supply tank 211 by solenoid valve 213. The solenoid valve 213 is controlled by the control unit 207.

A pressure sensor 214 for measuring the pressure in the channel 203 is connected to a channel system including the probe 202, the channel 203, and the syringe 204 via a branching module 215. Here, in order to measure the pressure fluctuation of the opening portions of the probe 202 and the mouthpiece 201 with high sensitivity, it is desirable that the pressure sensor 214 is provided as close to the probe 202 as possible. The output value of the pressure sensor 214 is amplified by a signal amplifier 216 and converted into a digital signal by an a/D converter 217. The signal after the digital conversion is sent to the determination section 218.

The determination unit 218 includes a sampling unit 219 that samples a signal from the a/D converter 217, a fluid calculation simulator 221 that performs simulation and outputs a calculation result to the comparison unit 220, and a comparison unit 220 that compares the sampling data with the calculation result.

The environment measuring device 222 measures the temperature and the external air pressure (environmental information) of the installation environment of the automatic analyzer 101. The measured environmental information is transmitted to the storage unit 223. The storage unit 223 stores information such as the syringe operation mode, the diameter of the tube, and the length of the tube, which are unique to the device, in addition to the above-described environmental information. The information stored in the storage unit 223 is transmitted to the fluid calculation simulator 221 in the determination unit 218 when the automatic analyzer 101 detects the dispensing state.

The determination unit 218 may be configured as hardware in the device as a dedicated circuit board, or may function as the determination unit 218 by being executed by a processor by reading a program recorded in the storage unit 223. Further, the program may be read and executed by a processor in a server connected to the automatic analyzer 101 by wire or wireless so as to be communicable, and the processor may function as the determination unit 218.

Fig. 3 is a diagram showing the movement of the fluid in the mouthpiece 201 when the automatic analyzer 101 performs suction. Fig. 3 (a) shows the fluid movement when the probe 202 aspirates the specimen 301, and fig. 3 (b) shows the fluid movement when the probe 202 ejects the solution. When the specimen 301 is aspirated, aspiration occurs due to the bubble 302 being erroneously aspirated into the mouthpiece 303. As a cause of the suction, it is conceivable to accidentally detect a liquid surface due to bubbles by handling the sample container, or the like. Further, when vibration or the like occurs while the sample of blood is being transported, air bubbles are generated.

When comparing the case where the bubble moves in the mouthpiece 201 with the case where the specimen 301 moves in the mouthpiece 201, the pressure loss in the pipeline due to the viscosity of the fluid differs. As an example of the physical formula representing the pressure loss due to friction in the pipe, the following Hagen-Poiseuille (Hagen-Poiseuille) formula can be cited.

[ equation 1]

P_loss＝128μLQ/(πd⁴)…(1)

Wherein, P_lossDenotes pressure loss, μ denotes viscosity of the fluid, L denotes a pipe length, pi denotes a circumferential ratio, d denotes a pipe diameter, and Q denotes a flow rate in the pipe. According to the formula (1), since the magnitude of the flow rate is in a proportional relationship with the pressure loss, if the suction state is detected in a step in which the flow rate is large in the suction step and the ejection step, the detection can be easily performed with high accuracy. In this embodiment, since the flow rate in the ejection step is large, the suction state is detected using the pressure data in the ejection step.

Fig. 4 is a diagram showing a calculation flow of the fluid calculation simulator 221 used for suction detection. In this simulator, a simulation of a model in which a solution moves in a pipe in accordance with a one-dimensional fluid equation (the moving direction is set to one dimension of the pipe direction) is performed. Specifically, the fluid calculation simulator 221 divides the pipeline into a plurality of one-dimensional spatial grids and processes the spatial grids. In this case, it is preferable to form a mesh at a position where the diameter of the pipe changes and at a position where the liquid changes to a liquid such as a gas (or a gas changes to a liquid). Further, if the accuracy is insufficient, a finer mesh may be further added to the mesh, or two-dimensional or three-dimensional fluid calculation may be performed. Further, the step size of the mesh may be changed according to the diameter of the pipe, the material of the pipe, the type of fluid, and the like. The environment measuring device 222 measures environmental information around the automatic analyzer 101 and records the information in the storage unit 223. The flow of fig. 4 is explained below.

(S401)

First, the fluid calculation simulator 221 acquires environmental information from the storage unit 223. The environmental information refers to, for example, the temperature around the device, the external air pressure, and the like. The measurement operation of the environment measurement device 222 may be performed before the calculation by the fluid calculation simulator 221, and may be performed, for example, at the time of starting the automatic analyzer 101 or before the dispensing operation. However, it is preferable that the environment measuring device 222 acquires the environment information at a time interval shorter than a time scale (time scale) of a change in temperature, external air pressure, or the like.

(S402)

Next, the fluid calculation simulator 221 sets time t to 0 (initial condition). Here, pipeline information such as the diameter of the pipeline and the material of the pipeline, environmental information such as the ambient temperature and the external air pressure of the automatic analyzer 101, the arrangement of the fluid in the pipeline, and the physical property values of the respective fluids are set. As the fluid arrangement, for example, when the probe 202 is assumed to normally aspirate a sample and calculate a physical model, a state in which a predetermined amount of the sample enters the pipeline is set, and when the probe 202 is assumed to completely aspirate and calculate the physical model, a state in which air enters is set instead of the sample. Alternatively, different initial conditions may be set in accordance with a state in which the viscosity of the dispensed sample is different, an intermediate state between suction and normal aspiration, a state in which a liquid different from the sample, such as a separating agent, is aspirated, or the like. Further, the intermediate state between the suction and the normal suction may also take into account a plurality of initial conditions corresponding to the degree of suction.

In addition, the environment measurement by the environment measurement device 222 and the processing in S401 may be omitted, and in the processing in S402, models having different environmental states may be prepared in which environmental information such as temperature and external air pressure is handled as unknown parameters. Similarly, models having different pipe states, in which pipe information such as pipe diameter and material is also handled as unknown parameters, may be prepared. However, from the viewpoint of improving the accuracy of detection of the dispensing state and reducing the calculation load, it is preferable to use the above-described environmental information and the channel information as known parameters and to use only the fluid arrangement as unknown parameters.

(S403)

Next, the fluid calculation simulator 221 obtains the injection speed from the storage unit 223.

(S404)

The fluid calculation simulator 221 performs calculation of the physical quantities p and u at time t + dt. This is a process of estimating the physical quantity of t + dt from the physical quantity at time t. Here, dt represents a time amplitude for numerical calculation. The physical quantity estimation at the next time is performed according to the following simultaneous equations.

[ formula 2]

[ formula 3]

Where p represents pressure, u represents flow rate, K represents the bulk modulus of the fluid, E represents the Young's modulus of the tubing, b represents the wall thickness of the tube, dx represents the mesh length, ρ represents the fluid density, and λ represents the tube coefficient of friction. In addition, with respect to the subscripts, U denotes a physical quantity on the upstream side of the mesh, and D denotes a physical quantity on the downstream side of the mesh. In addition, with respect to the superscript, n represents a physical quantity at time t, and n +1 represents a physical quantity at time t + dt. An explicit solution is when n is substituted into the superscript, and an implicit solution is when n +1 is substituted.

The second term on the right side of equation (3) represents the pressure loss due to tube friction. As the cause of the pressure loss other than the pipe friction, a change in the diameter of the pipe, a difference in height in the direction of gravity of the pipe, an outlet of the pipe, and the like may be considered, and the effects thereof may be added. In the present embodiment, an implicit solution that emphasizes the stability of numerical calculation is shown, but an explicit solution may be used to shorten the calculation time.

(S405)

The fluid calculation simulator 221 determines the end time when the numerical calculation is ended. When the end time is not reached, the fluid calculation simulator 221 performs the processing of the above steps from S403 again until the end time set in advance. When the end time is reached, the process proceeds to S406. It is desirable that the end timing of the numerical calculation is set to a timing later than the end timing of the injection drive for ejection. This makes it possible to compare the defined pressure waveforms over a longer period of time, thereby improving the accuracy of predicting the dispensing state.

(S406)

The fluid calculation simulator 221 creates a reference pressure waveform and ends the process. The reference pressure waveform refers to data obtained by the fluid calculation simulator 221 calculating the pressure measured by the pressure sensor 214 and arranging the calculated pressure in time series. Here, in order to increase the determination speed, the calculation result and the time at which the calculation result is obtained may be sequentially output from before the end time of the calculation is reached, and the reference pressure waveform may be generated in parallel with the calculation.

Fig. 5 is a diagram showing reference pressure waveforms for normal dispensing and complete suction in the case where the dispensing amount is 4 μ L (μ L). The solid line L1 indicates the pressure of normal dispensing, and the broken line L2 indicates the pressure of complete suction. As shown in fig. 5, it is understood that the pressure difference between the case where a minute liquid amount of 4 μ L is normally dispensed and the case where the liquid is dispensed in a state where the liquid is completely sucked is minute. In the present embodiment, by combining the environmental information and the like with the physical model, the abnormality of the dispensing can be detected with high accuracy from such a slight difference.

Fig. 6 is a diagram showing a flow of processing for detecting a dispensing state. The steps of the processing flow are described below.

(S601)

A reference pressure waveform is created by the fluid calculation simulator 221.

(S602)

The controller 207 controls the syringe drive unit 205 to aspirate a specimen from the probe 202.

(603S)

The controller 207 controls the syringe drive unit 205 to discharge the sample from the probe 202. Simultaneously with the ejection of the sample, time series data of the pressure is collected from the pressure sensor 214. Since the reference pressure waveform is created independently of the suction step and the discharge step, it can be created at any time before the statistical distance between the acquired pressure data and the reference pressure waveform is calculated. However, from the viewpoint of rapidly detecting the dispensing state, it is desirable to end the generation of the reference pressure waveform before the aspiration step. In addition, in order to improve the detection accuracy of the dispensing state, pressure sensors 214 may be provided at a plurality of positions in the pipeline to collect pressure data. In this case, a reference pressure waveform at the position of each pressure sensor 214 may be prepared.

(S604)

The fluid calculation simulator 221 calculates a statistical distance between the acquired pressure data and the reference pressure waveform. At this time, the statistical distance is calculated for both the reference pressure waveform corresponding to normal dispensing and the reference pressure waveform corresponding to suction. As an example of the statistical distance, Euclidean distance (Euclidean distance) of formula (4) may be cited.

[ formula 4]

Here, X represents the euclidean distance, k represents the number of acquired time series data, i represents the time series data number, p_templatePressure value, p, representing a reference pressure waveform_dataIndicating the pressure value at which the pressure data was taken. Further, as the statistical distance, a known distance index such as a Mahalanobis distance (Mahalanobis distance), a Standard euclidean distance (Standard euclidean distance), a Manhattan distance (Manhattan distance), a Chebyshev distance (Chebyshev distance), a Minkowski distance (Minkowski distance), or a Multivariate normal density (Multivariate normal density) may be used. In addition, when there is an abnormality, the statistical distance may be calculated by weighting data at a specific time at which the pressure value is likely to change. Further, the difference between the average values of the pressures and the difference between the integrated values of the pressures may be used as the statistical distance.

(S605)

The comparison unit 220 determines the dispensing state based on the calculation result of the statistical distance. The comparison unit 220 compares, for example, a statistical distance calculated from the reference pressure waveform and the acquisition data for normal dispensing with a statistical distance calculated from the reference pressure waveform and the acquisition data for suction. If the statistical distance calculated from the reference pressure waveform and the acquisition data for normal dispensing is equal to or less than the statistical distance calculated from the reference pressure waveform and the acquisition data for suction (if the acquired pressure data is within the normal range), the process proceeds to S606. If the statistical distance calculated from the reference pressure waveform and the acquisition data for normal dispensing is greater than the statistical distance calculated from the reference pressure waveform and the acquisition data for suction (if the acquired pressure data is outside the normal range), the process proceeds to S607.

Fig. 7 is a two-dimensional plot showing the calculated statistical distance. The graph shows a case where the pressure data of the actual measurement value is separated into normal suction data and suction data by the above-described determination method. As described above, in the present embodiment, the dispensing state can be determined by calculating the statistical distance from the reference pressure waveform and the acquired pressure data.

(S606)

The comparing unit 220 determines that the dispensing state is normal.

(S607)

The comparison unit 220 determines the dispensing state as suction. When the comparison unit 220 determines that the dispensing state is empty, it may display a warning or cancel the subsequent inspection procedure for the sample in order to ensure the accuracy of the analysis result. Further, the amount of the dispensed liquid that is insufficient due to the suction can be compensated for again. By performing the cancellation operation and the compensation, the accuracy of the analysis result can be improved.

As shown in fig. 5, when the automatic analyzer 101 performs a small amount of dispensing of about 4 μ L, the difference between the pressure waveform at the time of normal dispensing and the pressure waveform at the time of complete suction is very small. Further, the pressure waveform changes to the same extent as the difference due to changes in the ambient environment such as temperature and external air pressure, and differences in the injection operation mode inherent to the device. Therefore, when the environmental change and the individual difference of the apparatus are not taken into consideration, the accuracy of abnormality detection of the dispensing state in the case of dispensing a small amount is lowered. The following describes the above-described case specifically by taking an example of temperature change.

Fig. 8 is a diagram showing changes in pressure waveform according to temperature changes. L1, L2, and L3 are pressure waveforms corresponding to normal dispensing when the ambient temperature of the apparatus is 15 ℃, 24 ℃, and 34 ℃. The difference between the respective pressure waveforms is about the same as the difference between the reference pressure waveform corresponding to the suction and the reference pressure waveform corresponding to the normal dispensing shown in fig. 5. That is, if the temperature around the apparatus changes, it is not possible to accurately determine whether the dispensing state is empty suction or normal dispensing.

Therefore, by acquiring the environmental change around, the injection operation characteristic specific to the device, and the characteristic of the tube via the physical model, the detection of the dispensing state can be performed with high accuracy. In the present embodiment, even in a situation where there are unknown parameters such as bubbles generated in a sample such as blood and the viscosity of the sample, the dispensing state can be detected with high accuracy under various environments by performing simulation using a physical model.

Note that the detection of the dispensing state in the present embodiment may be performed using only the reference pressure waveform corresponding to normal dispensing. In this case, the statistical distance between the reference pressure waveform corresponding to normal dispensing and the acquired data is compared with a predetermined threshold value, and if the statistical distance is equal to or less than the threshold value, it is determined as normal, and if it is equal to or more than the threshold value, it is determined as suction. Further, the suction detection may be performed by combining the pressure data at the time of dispensing with information such as an image of the specimen liquid surface, capacitance, and resistance.

The state detection may use pressure data of the suction step instead of pressure data of the ejection step. When the pressure data in the aspiration step is used, the calculation of the statistical distance and the determination of the dispensing state shown in the flowchart of fig. 6 may be performed before the ejection step. When the state is determined before the discharge step and an abnormality is detected, the subsequent dispensing operation including the discharge step is eliminated, thereby reducing the waste of the reagent.

When reference pressure waveforms corresponding to a plurality of intermediate states between the suction state and the normal dispensing state are created during creation of the reference pressure waveforms, the statistical distance between each created reference pressure waveform and the acquired data is calculated, and the dispensing state is determined. In this case, the comparison unit 220 determines that the dispensing state set when the reference pressure waveform with the minimum statistical distance is generated is the actual dispensing state. Thus, the dispensing state can be determined not only to be the 2 types of the normal state and the suction state, but also to be an intermediate state corresponding to the degree of suction. In this case, the automatic analyzer 101 may display a warning or perform insufficient refilling based on the corresponding dispensing amount in the intermediate state.

< example 2>

Next, an automatic analyzer according to example 2 will be described. The automatic analyzer of embodiment 2 has the same hardware configuration as the automatic analyzer 101 of embodiment 1. In example 2, not only the detection of the suction but also the detection of the clogging of the probe were performed. Specifically, in example 2, clogging due to a high-viscosity sample was determined. When the occlusion is detected, abnormality detection is performed, for example, based on pressure data at the time of suction.

Fig. 9 is a diagram showing fluid movement when a high-viscosity specimen is aspirated. The specimen 901 is aspirated by driving the syringe 204 (not shown) through the air 902 and the liquid (system water 903) filling the channel. Fig. 9 (a) is a diagram showing fluid movement in the mouthpiece 904 and the probe 905 during normal suction, and fig. 9 (b) is a diagram showing fluid movement in the mouthpiece 904 and the probe 905 during occlusion. The probe 905 is filled with air 902 and system water 903. Further, the mouthpiece 904 contains air 902, which flows into the specimen 901 during aspiration.

If the cuff 904 or the probe 905 is clogged, the suction amount of the specimen 901 becomes smaller than the driving amount of the plunger 204 b. Therefore, the volume of the branched air 902 expands and the pressure in the pipe becomes low. With this effect, the state of the sample dispensing unit is detected based on the pressure data at the time of aspiration.