Information processing device, operation method for information processing device, and operation program for information processing device

Abstract

This information processing device comprises a processor. By analyzing, using a method independent of dispersion in measurements, the morphology of control waveform data that represents an electrical change corresponding to the pulsation of a cardiomyocyte and that is used for a toxicity evaluation test of a drug candidate substance, the processor determines eligibility of whether or not the control waveform data can be used for the toxicity evaluation test of the drug candidate substance, and presents the determination result of the eligibility.

Description

Information processing device, operating method for information processing device, and operating program for information processing device

[0001] The technology of the present disclosure relates to an information processing device, an operating method for an information processing device, and an operating program for an information processing device.

[0002] In the field of drug discovery, a method using a microelectrode array (MEA) has been developed as a method for evaluating toxicity using cardiomyocytes generated from iPS (induced pluripotent stem) cells (see International Publication No. WO 2022 / 176310). A microelectrode array is an array of multiple microelectrodes, and the microelectrode array is provided at the bottom of each well of a well plate. A well plate with such a microelectrode array provided in each well is called an MEA plate. A sheet of cardiomyocytes is formed at the bottom of each well in contact with the multiple microelectrodes. Each microelectrode outputs waveform data representing extracellular potentials corresponding to the pulsation of cardiomyocytes as a waveform indicating electrophysiological changes. Toxicity evaluation of a drug candidate substance is performed using drug-treated waveform data obtained by administering the drug candidate substance and control waveform data for comparison with the drug-treated waveform data. The control waveform data is, for example, pre-administration waveform data obtained from cardiomyocytes before administration of a drug candidate substance, and the drug-treated waveform data is, for example, post-administration waveform data obtained after administration of a drug candidate substance to the same cardiomyocytes.

[0003] In order to use such drug-treated waveform data for toxicity assessment, the control waveform data must have an ideal waveform that indicates a normal pulsation. If the control waveform data is abnormal, it will be impossible to accurately detect changes caused by the drug candidate substance from the drug-treated waveform data. Therefore, the control waveform data is evaluated for suitability to determine whether it can be used in toxicity assessment tests.

[0004] The eligibility assessment is currently carried out by visual sensory evaluation by humans, but since the amount of data becomes enormous, mechanization of this assessment is desired. International Publication No. 2022 / 176310 describes a method of utilizing a clustering technique with a machine learning model to assess eligibility.

[0005] However, methods using machine learning models sometimes do not adequately reflect the points of human visual sensory evaluation.

[0006] One embodiment of the technology of the present disclosure provides an information processing device, an operating method of the information processing device, and an operating program of the information processing device that can obtain judgment results that are closer to human visual sensory evaluation than conventional methods regarding the suitability of waveform data to be used in toxicity evaluation tests.

[0007] In order to achieve the above-mentioned objective, the information processing device of the present disclosure is an information processing device equipped with a processor, which analyzes the form of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, in a manner that is not dependent on variability between measurements, thereby determining the suitability of the control waveform data for use in toxicity evaluation tests and presenting the results of the suitability determination.

[0008] Preferably, the processor analyzes the morphology of the control waveform data in a manner that is independent of variations in both the time from depolarization to repolarization in a beat cycle and the amplitude corresponding to the repolarization.

[0009] A method that is independent of measurement-to-measurement variability is preferably one that normalizes in time and amplitude to reference waveform data.

[0010] Preferably, the processor excludes from the morphology analysis control waveform data in which at least one of the amplitudes corresponding to depolarization and the amplitude corresponding to repolarization does not satisfy a preset condition.

[0011] The conditions preferably include a first condition that the absolute value of the amplitude corresponding to depolarization is equal to or greater than a certain value, and a second condition that the amplitude corresponding to repolarization is within a preset range.

[0012] It is preferable that the analysis items for analyzing the morphology include items set for each section, the period of the pulsation being divided into a plurality of sections.

[0013] The items set for each section preferably include items using a plurality of approximation curves of different degrees.

[0014] Preferably, the processor determines eligibility using at least one of rule-based, template matching, and machine learning.

[0015] The control waveform data is preferably waveform data acquired using an MEA plate having a plurality of electrodes on the bottom and a plurality of wells in which cardiomyocytes can be placed.

[0016] The processor preferably has a function of indicating whether or not a well can be used for toxicity evaluation testing based on the determination of the suitability of the control waveform data.

[0017] The processor preferably uses post-drug treatment waveform data obtained after administering a drug candidate substance to cardiomyocytes to determine whether or not the well can be used for toxicity evaluation tests.

[0018] In addition to the judgment results, it is preferable to present standard waveform data having a standard form that is recognized as being suitable.

[0019] The method of operating an information processing device disclosed herein is a method of operating an information processing device equipped with a processor, in which the processor analyzes the form of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, to determine the suitability of the control waveform data for use in toxicity evaluation tests and present the results of the suitability determination.

[0020] The operating program of the information processing device disclosed herein is an operating program of an information processing device equipped with a processor, and causes the processor to execute processing including determining the suitability of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, by analyzing the form of the control waveform data, as to whether the control waveform data can be used in toxicity evaluation tests, and presenting the results of the suitability determination.

[0021] The information processing device of the present disclosure is an information processing device equipped with a processor, which normalizes control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization, and presents the normalized control waveform data.

[0022] In addition to the normalized control waveform data, it is preferable to present standard waveform data having a qualified standard form.

[0023] The method of operating an information processing device disclosed herein is a method of operating an information processing device equipped with a processor, in which the processor normalizes control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization, and presents the normalized control waveform data.

[0024] The operating program of the information processing device disclosed herein is an operating program of an information processing device equipped with a processor, and causes the processor to execute processing including normalizing control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, for the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to repolarization, and presenting the normalized control waveform data.

[0025] According to the technology of the present disclosure, it is possible to obtain judgment results for the suitability of waveform data to be used in toxicity evaluation tests that are closer to human visual sensory evaluation than conventional methods.

[0026] 1 is a diagram schematically illustrating an electrical function evaluation system. FIG. 1 is a perspective view illustrating an example of an MEA plate. FIG. 2 is a diagram illustrating an example of a well. FIG. 3 is a diagram illustrating an example of a microelectrode array. FIG. 4 is a block diagram illustrating an example of the hardware configuration of an electrical function evaluation system. FIG. 5 is a block diagram illustrating an example of the functional configuration of an information processing device. FIG. 6 is a diagram illustrating an example of a myocardial waveform. FIG. 7 is a diagram illustrating the variability of pre-administration waveform data. FIG. 8 is a diagram illustrating an example of waveform data output from a microelectrode array. FIG. 9 is a diagram illustrating an example of waveform data that changes due to the administration of a drug candidate substance. FIG. 10 is a diagram illustrating an example of waveform data in which EAD has occurred. FIG. 11 is a diagram illustrating an example of waveform data in which DAD has occurred. FIG. 12 is a diagram illustrating an example of waveform data in which cardiac arrest has occurred. FIG. 13 is a diagram illustrating an example of pre-administration waveform data after normalization. FIG. 14 is a list of analysis items for eligibility determination. FIG. 15 is a diagram illustrating an example of analysis items based on the morphological analysis viewpoint "1-3". FIG. 16 is a diagram illustrating an example of the processing procedure for eligibility determination. FIG. 17 is a diagram illustrating an example of a display form of the determination result of eligibility determination. FIG. 18 is a diagram illustrating an example of a screen that presents whether or not a toxicity evaluation test is successful. FIG. 19 is a diagram illustrating an example of a screen in which a toxicity evaluation test is successful. FIG. 19 is a diagram illustrating an example of a screen in which a toxicity evaluation test is unsuccessful. FIG. 20 is a diagram illustrating an example of using post-administration waveform data to determine the success or failure of a toxicity evaluation test. FIG. 10 is a diagram showing a fourth modified example.

[0027] Hereinafter, embodiments of the technology of the present disclosure will be described with reference to the drawings.

[0028] FIG. 1 schematically illustrates an electrical function evaluation system 2 for measuring the electrical activity of cells. The electrical function evaluation system 2 illustrated in FIG. 1 is composed of a cell culture device 10 and an information processing device 20. The cell culture device 10 enables measurement of waveforms indicating electrophysiological changes in cells (e.g., myocardial waveforms indicating the pulsation of cardiomyocytes) while culturing cells. The cell culture device 10 also controls the culture environment (e.g., temperature, carbon dioxide concentration).

[0029] An MEA plate 30 is used for culturing cells. The cell culture device 10 is provided with a culture chamber 11 that houses the MEA plate 30. The cell culture device 10 is also provided with a sliding lid 12 for opening and closing the culture chamber 11. The MEA plate 30 is mounted in the culture chamber 11 with cells seeded therein. The culture chamber 11 functions as an incubator, enabling long-term cell culture.

[0030] In this embodiment, cardiomyocytes produced from iPS cells are cultured as cells in the cell culture device 10. The cell culture device 10 also measures the extracellular potential representing the myocardial waveform of the cardiomyocytes seeded on the MEA plate 30 using a multipoint measurement method, and outputs waveform data obtained by the measurement to the information processing device 20. The waveform data represents changes in the extracellular potential according to the pulsation of the cardiomyocytes.

[0031] The information processing device 20 is configured by a general computer such as a personal computer. Software for analyzing waveform data input from the cell culture device 10 is installed in the information processing device 20. The information processing device 20 has a display unit 21 and an input unit 22. The display unit 21 is a display device such as a liquid crystal display or an organic EL (Electro Luminescence) display. The input unit 22 is an input device such as a keyboard, a touchpad, or a mouse. The information processing device 20 is connected to the cell culture device 10 by wire or wirelessly. The display unit 21 and the input unit 22 may be configured as external devices connected to the information processing device 20.

[0032] The information processing device 20 has the function of analyzing the input waveform data and presenting the analysis results to the user. The analysis results are used to evaluate the toxicity of drug candidate substances. Drug candidate substances refer to substances such as compounds that are drug candidates created during the drug development process. Drug-treated waveform data obtained by administering a drug candidate substance and control waveform data that is compared with the drug-treated waveform data can be used to evaluate the cardiotoxicity, which is the effect of a drug candidate substance on cardiomyocytes, such as the risk of arrhythmia. The information processing device 20 can present features that appear in the waveform data and indicate the risk of arrhythmia, etc., as analysis results.

[0033] The control waveform data is, for example, pre-administration waveform data obtained from cardiomyocytes before administration of a drug candidate substance, and the drug-treated waveform data is, for example, post-administration waveform data obtained after administration of the drug candidate substance to the same cardiomyocytes. Alternatively, a negative control group of cardiomyocytes not administered with the drug candidate substance and a drug-treated group of cardiomyocytes administered with the drug candidate substance may be prepared, and waveform data obtained from the negative control group may be used as the control waveform data, and waveform data obtained from the drug-treated group may be used as the drug-treated waveform data. In the following, the post-administration waveform data and the pre-administration waveform data may be used as examples of drug-treated waveform data and control waveform data, respectively.

[0034] Fig. 2 shows an example of an MEA plate 30. The MEA plate 30 is a multi-well plate in which a plurality of culture wells (hereinafter simply referred to as wells) 32 are arranged on a substrate 31. The MEA plate 30 shown in Fig. 2 has 48 wells 32. Note that the number of wells 32 provided in the MEA plate 30 is not limited to 48, and may be 24, 96, or the like.

[0035] 3 shows an example of a well 32. The well 32 is a generally cylindrical container with an opening 33 at the top. Cardiomyocytes are seeded so that they adhere to the bottom 34 of the well 32. The well 32 is filled with a culture solution containing a medium. A microelectrode array 40 (see FIG. 4) is provided on the bottom 34 of the well 32, and as an example, the microelectrode array 40 is embedded in the bottom 34.

[0036] FIG. 4 shows an example of a microelectrode array 40. The microelectrode array 40 has a plurality of electrodes 41. In the example shown in FIG. 4, the microelectrode array 40 has 16 microelectrodes (hereinafter simply referred to as electrodes) 41 arranged in a 4×4 square. The electrodes 41 are exposed at the bottom 34 of the well 32 and come into contact with the seeded cardiomyocytes. Each of the electrodes 41 is connected to a potential measurement circuit 50 (described below) via wiring 42. Hereinafter, the electrodes 41 may be referred to as channels CH. The 16 electrodes 41 are also distinguished by being referred to as channels CH1 to CH16.

[0037] 5 shows an example of the hardware configuration of the electrical function evaluation system 2. The cell culture device 10 has a culture chamber 11, a potential measurement circuit 50, and a communication I / F (interface) 51. The potential measurement circuit 50 measures the extracellular potential of cardiomyocytes cultured on the MEA plate 30 housed in the cell culture device 10. Specifically, the potential measurement circuit 50 measures the extracellular potential via each electrode 41 of the microelectrode array 40 provided in each well 32. In other words, the potential measurement circuit 50 measures 16 myocardial waveforms for each well 32.

[0038] The potential measurement circuit 50 transmits the measured myocardial waveform as waveform data to the information processing device 20 via the communication I / F 51. If the number of wells 32 formed in the MEA plate 30 is 48 and the number of microelectrode arrays 40 provided in each well 32 is 16, 768 pieces of waveform data are transmitted from the potential measurement circuit 50 to the information processing device 20. The measurement time for each waveform data is, for example, several minutes, which is a length that includes several tens of beats of the myocardial waveform. Furthermore, the waveform data is transmitted at timings such as before and after administration of the drug candidate substance. As will be described later, the waveform data is measured while changing the concentration of the drug candidate substance, and therefore, post-administration waveform data for different concentrations is transmitted as post-administration waveform data.

[0039] The information processing device 20 includes a processor 23, a memory 24, an input unit 22, a display unit 21, a communication I / F 25, and a bus 26. The processor 23 is a computer that realizes various functions by reading out a program 28 and various data stored in the memory 24 and executing processing. The processor 23 is, for example, a CPU (Central Processing Unit).

[0040] The memory 24 is a storage device that stores the program 28 and various data used by the processor 23 when executing processing. The memory 24 includes, for example, a random access memory (RAM), a read-only memory (ROM), or a storage. The RAM is, for example, a volatile memory used as a work area for the processor 23. The ROM is, for example, a non-volatile memory that holds the program 28 and various data. The ROM is, for example, a flash memory. The storage is, for example, a large-capacity storage device such as a hard disk drive (HDD) or a solid state drive (SSD), which stores an operating system (OS), various data, and the like. The memory 24 may be configured as an external device connected to the information processing device 20. The memory 24 also stores reference information 29 used by the processor 23 to analyze waveform data.

[0041] 6 shows an example of the functional configuration of the information processing device 20. The information processing device 20 realizes various functions by the processor 23 executing processes based on a program 28. These various functions may be realized by hardware. The program 28 is an example of an "operation program" according to the technology of the present disclosure.

[0042] The processor 23 functions as a data acquisition unit 60, an analysis unit 61, and an output unit 62. The data acquisition unit 60 performs an acquisition process to acquire waveform data transmitted from the cell culture device 10. As described above, the waveform data transmitted from the cell culture device 10 includes pre-administration waveform data and post-administration waveform data. The analysis unit 61 performs an analysis process on the acquired waveform data. Details of the analysis process will be described later.

[0043] The output unit 62 performs an output process to output the analysis results of the analysis unit 61 to the display unit 21. The analysis results are presented to the user by the output process. The output process is an example of a process that realizes "presentation" according to the technology of the present disclosure. Note that in this example, the output process shows an example in which the analysis results are output to the display unit 21 of the information processing device 20, but the analysis results may be output to a display device other than the information processing device 20, or the analysis results may be transmitted to another terminal via a network. Presentation of the analysis results is also realized by such output process.

[0044] 7 shows an example of a myocardial waveform. FIG. 7(A) shows a myocardial waveform representing the intracellular action potential of cardiomyocytes, and FIG. 7(B) shows a myocardial waveform representing changes in the extracellular potential of cardiomyocytes measured using the MEA plate 30. The waveform data acquired by the information processing device 20 is the waveform data of the myocardial waveform of FIG. 7(B). The waveform data of the myocardial waveform representing changes in the extracellular potential shown in FIG. 7(B) is an example of "waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes" according to the technology of the present disclosure. The following description will be given taking waveform data representing changes in the extracellular potential as an example.

[0045] Note that waveform data of myocardial waveforms that represent changes in action potential may be used as "waveform data that represent electrical changes in response to the pulsation of cardiomyocytes." When using waveform data that represent changes in action potential, the action potential is measured using a patch clamp method or the like.

[0046] As is well known, cardiomyocytes contain sodium ions (Na ＋ ), calcium ions (Ca ２＋ ), and potassium ions (K ＋) and other ions pass into and out of the cell. When the cell membrane is stimulated, the permeability of the ion channel changes, allowing ions to flow in and out through the ion channel. This causes contraction and expansion of the cardiomyocyte. Contraction and expansion occur periodically, resulting in pulsation. The action potential within the cardiomyocyte changes in response to this pulsation, as shown in Figure 7(A).

[0047] Specifically, when the cell membrane of a cardiac muscle cell is not excited, the potential inside the cell is kept negative and the potential outside the cell is positive, resulting in a polarized state inside and outside the cell. When the cell membrane is stimulated, sodium ions (Na ＋ ) ion channel permeability increases, and sodium ions (Na ＋ ) flow into the cell. As positive ions flow into the cell, the potential inside the cell shifts to positive. This is the beginning of an excited state of the cardiac muscle cell. This state is called depolarization because it transitions in the direction of eliminating the potential difference between the polarized cell and the outside. This change in potential causes calcium ions (Ca ２＋ ) ion channel permeability increases, and calcium ions (Ca ２＋ ) flows into the cell. This keeps the intracellular potential positive for a while. After that, potassium ions (K ＋ ) ion channel permeability increases, and potassium ions (K ＋ ) flows out of the cell, causing the potential inside the cell to return to negative. This causes polarization inside and outside the cell again. This is called repolarization. Repolarization ends the excited state of the cardiac muscle cells. Cardiomyocytes periodically repeat this excited state, which is manifested as pulsation.

[0048] In response to such pulsation, the extracellular potential measured by the MEA plate 30 changes as shown in FIG. 7B. First, when no action potential is generated in the cardiomyocytes, the extracellular potential maintains a reference potential of approximately "0." When depolarization occurs in the cardiomyocytes, the extracellular potential exhibits a nearly vertical rise and fall. This is called the first peak P1. The first peak P1 has peaks in both the positive and negative directions. After the first peak P1, the extracellular potential rises sharply to near the reference potential. Thereafter, while the intracellular potential remains positive, the extracellular potential maintains a potential near the reference potential while gradually rising. Then, when repolarization occurs in the cardiomyocytes, the extracellular potential exhibits a relatively steep rise and fall. The apex of this mountain-shaped waveform that is convex in the positive direction is called the second peak P2.

[0049] 7B, FPD is the field potential duration (FPD), ISI is the interspike interval (ISI), which corresponds to the pulsation period. A1 is the amplitude of the first peak P1, and A2 is the amplitude of the second peak P2. These values ​​vary depending on the state of the cardiomyocytes or various factors at the time of measurement, even under the same measurement conditions.

[0050] Furthermore, in FIG. 7B , SA is the section from the first peak P1 to the second peak P2, and SB is the section after the second peak P2. SA1 to SA3 are sections obtained by further subdividing the section SA. SA1 is a section defined by a certain time period from the first peak P1 until the extracellular potential rises to near the reference potential of "0." SA2 is a section from the end of the section SA1 until the extracellular potential begins to rise toward the second peak P2 near the base of the mountain-shaped waveform with the second peak P2 as its apex. SA3 is a section from the end of the section SA2 to the second peak P2. The morphological characteristics of each of these sections, such as the slope and shape of the waveform in the section SA and the shape of the waveform in the section SB, also vary depending on the various factors described above.

[0051] FIG. 8 shows waveform variation under the same measurement conditions. FIG. 8 shows multiple waveform data output from each electrode 41 of the microelectrode array 40 in one well 32. All waveform data represent pre-administration waveform data prior to administration of a drug candidate. The pre-administration waveform data shown in FIG. 8 are superimposed with the first peak P1 time aligned. As shown in FIG. 8, the pre-administration waveform data vary in the time of the second peak P2, resulting in variation in the FPD. Variation also occurs in the ISI. Therefore, in addition to the duration of the interval SA (see FIG. 7) and interval SB (see FIG. 7), the durations of interval SA2 (see FIG. 7) and interval SA3 (see FIG. 7), which are subdivisions of interval SA, also vary. Furthermore, variation also occurs in the amplitude A2 of the second peak P2. Note that interval SA1 (see FIG. 7) is defined by a fixed time from the first peak P1, so no variation occurs.

[0052] In addition to quantitative characteristics such as time and amplitude, morphological characteristics also vary. For example, there is variation in the shape of the waveform of the extracellular potential in the section SA from the first peak P1 to the second peak P2, and in the section SB after the second peak P2.

[0053] Fig. 9 shows an example of waveform data output from the multiple electrodes 41 included in the microelectrode array 40. Fig. 9 shows waveform data corresponding to each of channels CH1 to CH16. The multiple waveform data shown in Fig. 8 is, for example, data obtained by superimposing the waveform data of each of channels CH1 to CH16 shown in Fig. 9.

[0054] Furthermore, the waveforms shown in Figures 7(B) and 8 show myocardial waveforms before the drug candidate substance is administered, but when the drug candidate substance is administered, the waveform changes depending on the toxicity of the drug candidate substance.

[0055] Figure 10 shows changes in waveforms when a drug candidate substance is administered to cardiomyocytes. Figure 10 shows data obtained by superimposing pre-administration waveform data before administration and post-administration waveform data after administration, with the first peak P1 time aligned. The post-administration waveform data shows multiple post-administration waveform data with different concentrations of the drug candidate substance. The post-administration waveform data shows four types of data when the concentration is changed to four levels: low concentration, medium concentration, high concentration, and ultra-high concentration. The concentrations correspond to the dose of the drug candidate substance.

[0056] As shown in FIG. 10 , the waveform data changes not only in quantitative characteristics such as the FPD (see FIG. 7 ) and the amplitude A2 of the second peak P2 (see FIG. 7 ) but also in morphological characteristics before and after administration of the drug candidate substance. For example, in the example shown in FIG. 10 , the first peak P1 and the second peak P2 appear at the same points before and after administration, but the slope and shape of the waveform in each section SA (see FIG. 7 ) change before and after administration. Furthermore, the quantitative and morphological characteristics of the waveform data also change depending on the concentration of the administered drug candidate substance. In the example shown in FIG. 10 , the higher the concentration of the drug candidate substance, the longer the FPD becomes, and the smaller the amplitude A2 of the second peak P2 becomes. Accordingly, the slope and shape of the waveform in the section SA between the first peak P1 and the second peak P2 also change. In the example shown in FIG. 10 , the length of the FPD changes significantly, particularly at ultra-high drug candidate substance concentrations, and the slope and shape of the waveform in the section SA also change significantly. As a general rule, the higher the concentration, the less sharp the second peak P2 becomes, and the mountain-shaped waveform with the second peak P2 as its apex becomes gentler.

[0057] Toxicity evaluation of a drug candidate substance is performed by analyzing pre-administration waveform data and multiple post-administration waveform data with different concentrations, as shown in FIG. 10, and comparing the analysis results. For example, FPD (see FIG. 7) corresponds to the QT interval (the time from the beginning of the Q wave to the end of the T wave) in an electrocardiogram and is used as an indicator of the risk of arrhythmia caused by the administration of a drug candidate substance. A prolonged QT interval indicates the possibility of causing arrhythmia. Based on FPD, users can evaluate the cardiotoxicity of a drug candidate substance, which is its toxicity to the heart. In addition to FPD, other cardiotoxicity evaluation items include early after depolarization (EAD), delayed after depolarization (DAD), and cardiac arrest.

[0058] As shown in FIG. 11 , EAD is a phenomenon in which depolarization occurs before the second peak P2. As shown in FIG. 12 , DAD is a phenomenon in which depolarization occurs after the second peak P2. Both EAD and DAD appear as abnormal waveforms with negative peaks in the waveform data of extracellular potentials. Furthermore, as shown in FIG. 13(A) , cardiac arrest occurs when signals such as peaks at the time of pulsation are not observed in the waveform data of extracellular potentials. FIG. 13(A) illustrates a case in which pulsation has completely stopped, which is a typical example of cardiac arrest. In addition to FIG. 13(A) , a state in which there is some amplitude indicating pulsation but no signals such as peaks are observed may also be evaluated as cardiac arrest, as shown in FIG. 13(B) . When both FIG. 13(A) and FIG. 13(B) are evaluated as cardiac arrest, cardiac arrest is determined based on the following two features. The first feature (feature 1 in FIG. 13(B)) is that the first peak P1 has a small negative drop and its absolute value is equal to or less than a certain value THC. The second feature (feature 2 in FIG. 13B) is that the second peak P2 cannot be confirmed. By determining the abnormal waveform based on these features, it is possible to evaluate FIG. 13B as cardiac arrest in addition to FIG. 13A.

[0059] To perform such toxicity assessment, the waveform data to be used in the toxicity assessment must be suitable for use in toxicity assessment tests. Suitable refers to the properties that control waveform data (pre-administration waveform data in this example) must possess as waveform data to be compared with in order to assess the toxicity of a drug candidate. As shown in Figure 10, the waveform data changes upon administration of a drug candidate, and in order to properly assess this change, the pre-administration waveform data to be compared with (an example of control waveform data) must be a waveform close to an ideal waveform.

[0060] Therefore, the analysis unit 61 performs the following normalization process on all pre-administration waveform data output from the MEA plate 30, and then analyzes the form of the normalized pre-administration waveform data to determine eligibility.

[0061] The normalization process is performed on the time from the first peak P1 to the second peak P2 and the amplitude A2 of the second peak P2. The time from the first peak P1 to the second peak P2 corresponds to the time of the section SA (see FIG. 7). The time of the section SA is also the time of the FPD described above. Normalization of the time of the section SA is a process of aligning the time of the section SA of each pre-administration waveform data to a constant value. The amplitude A2 of the second peak P2 of each pre-administration waveform data is also normalized by aligning it to a constant value.

[0062] Here, performing such normalization processing and analyzing the morphology of the normalized pre-administration waveform data is an example of "analyzing the morphology of control waveform data in a manner that is independent of variations in both the time from depolarization to repolarization in the pulse cycle and the amplitude corresponding to repolarization" according to the technology disclosed herein.

[0063] As described above, the first peak P1 corresponds to depolarization of cardiomyocytes, the second peak P2 corresponds to repolarization of cardiomyocytes, and the time from the first peak P1 to the second peak P2 corresponds to the time from depolarization to repolarization in a cardiac cycle. In this example, as pre-administration waveform data, which is an example of control waveform data, waveform data representing changes in the extracellular potential at which the first peak P1 and the second peak P2 appear, as shown in FIG. 7(B), is used. As described above, waveform data representing changes in the action potential, as shown in FIG. 7(A), may also be used as pre-administration waveform data. In this case, the analysis unit 61 detects the timing of depolarization and repolarization from waveform data representing changes in the action potential measured by patch clamping or the like, and evaluates the time from depolarization to repolarization. The analysis unit 61 then normalizes the amplitude and time of the waveform data representing changes in the action potential.

[0064] FIG. 14 shows a state in which a normalization process is performed on multiple pre-administration waveform data shown in FIG. 8, which have variations in the time and amplitude A2 (see FIG. 7) of the section SA (see FIG. 7), and the multiple pre-administration waveform data after normalization are superimposed. Because multiple pre-administration waveform data are superimposed, they are shown with a spread in the amplitude direction. In the example of FIG. 14, the time of the section SA is normalized to a constant value TN by the normalization process. The constant value TN is, for example, 0.4 seconds. The amplitude A2 of the second peak P2 is also normalized to a constant value AN. The constant value AN is, for example, 1 mV. The curve Lav shown in FIG. 14 represents the average value of the multiple superimposed pre-administration waveform data. Although the curve Lav is somewhat difficult to see in FIG. 14, it passes through the center of the multiple pre-administration waveform data that vary in the amplitude direction.

[0065] By performing this normalization process, quantitative features such as the time and amplitude of each pre-administration waveform data are ignored, thereby highlighting the morphological features of each pre-administration waveform data. Conventionally, such qualification determinations have been performed by human visual sensory evaluation, but in human visual sensory evaluation, morphological features such as subtle differences in waveform shape are more important than quantitative features such as time and amplitude. By performing this normalization process, the morphological analysis by analysis unit 61 can be made closer to human visual sensory evaluation.

[0066] 15 shows an example of evaluation criteria for determining eligibility. In the example shown in FIG. 15, the evaluation criteria include evaluation criteria for preprocessing and evaluation criteria for morphological analysis. Analysis items based on these evaluation criteria are included in the reference information 29.

[0067] As an example, there are three evaluation viewpoints in the preprocessing, from "0-1" to "0-3." The viewpoint "0-1" is a condition that "the absolute values ​​of the positive and negative amplitudes of the first peak P1 are equal to or greater than a certain value." The viewpoint "0-2" is a condition that "the amplitude A2 of the second peak P2 is within a certain range." The viewpoint "0-3" is a condition that "the ratio of the average value of the section SA to the amplitude A2 of the second peak P2 is within a certain range."

[0068] The analysis unit 61 analyzes the pre-administration waveform data based on the conditions of these viewpoints "0-1" to "0-3" and excludes pre-administration waveform data that does not satisfy the conditions from the morphology analysis target. That is, the analysis unit 61 executes a process to exclude pre-administration waveform data in which at least one of the amplitude A1 of the first peak P1 and the amplitude A2 of the second peak P2 does not satisfy a preset condition from the morphology analysis target. By performing such pre-processing, the processing time for the eligibility determination can be shortened.

[0069] Furthermore, the three viewpoints "0-1" to "0-3" are examples of "a condition in which at least one of the amplitude corresponding to depolarization and the amplitude corresponding to repolarization is preset" according to the technology of the present disclosure. Furthermore, the condition of viewpoint "0-1" is an example of "a first condition in which the absolute value of the amplitude corresponding to depolarization is equal to or greater than a certain value" according to the technology of the present disclosure, and the condition of viewpoint "0-2" is an example of "a second condition in which the amplitude corresponding to repolarization is within a preset range" according to the technology of the present disclosure.

[0070] As shown in FIG. 15 , there are three examples of evaluation viewpoints in the morphological analysis: viewpoints "1-1" to "1-3." viewpoint "1-1" is that "the evaluation index for each section alone, such as the maximum amplitude of section SA3, must be within a certain standard." viewpoint "1-2" is that "the values ​​for each section, such as the ratio of the average amplitudes of section SA2 and section SA3, must be compared, and the difference between them must be within a certain standard." viewpoint "1-3" is that "the indices for evaluating the shape of each section, such as the slope, straightness, and waviness of section SA2, must be within a certain standard. The slope or straightness is evaluated using, for example, linear approximation. The waviness is evaluated using a quadratic or cubic approximation curve."

[0071] More specifically, detailed analysis items are set based on these evaluation criteria, including thresholds and numerical ranges that serve as criteria for judgment.

[0072] 15, the analysis items for analyzing the morphology include items set for each section, with the area around the beat being divided into multiple sections, such as section SA2 and section SA3. By setting items for each section in this way, the analysis process can be simplified compared to when the section division is not performed.

[0073] Furthermore, the analysis items configured for each section include items using multiple approximation curves of different orders, such as viewpoints "1-3." As shown as an example in FIG. 16 , the less undulation there is in the pre-administration waveform data in section SA2, the closer it is to the ideal waveform. As a specific criterion, for example, the ratio of the quadratic approximation error to the cubic approximation error of the waveform in section SA2 is equal to or less than a certain value. As shown as an example in FIG. 16 , first, a quadratic approximation curve and a cubic approximation curve of the pre-administration waveform data are derived in section SA2. Then, the error between the pre-administration waveform data and the quadratic approximation curve is calculated as the quadratic approximation error, and the error between the pre-administration waveform data and the cubic approximation curve is calculated as the cubic approximation error. It is then determined whether the ratio of the quadratic approximation error to the cubic approximation error is equal to or less than a certain value.

[0074] In addition to waviness, when evaluating straightness, multiple approximation curves of different orders may also be used. In this way, the morphology analysis items set for each section include items using multiple approximation curves of different orders, making it possible to analyze the morphology in more detail than when these are not used.

[0075] The specific values, such as thresholds, used for the analysis items for determining eligibility may be values ​​obtained through experiments or simulations, or may be determined based on electrophysiological knowledge, or may be determined using a machine learning model based on ideal waveforms.

[0076] The operation of the above configuration will be described with reference to the flowchart shown in Fig. 17. First, the information processing device 20 acquires pre-administration waveform data measured using the MEA plate 30 from the cell culture device 10 before administration of a drug candidate substance. As an example, the eligibility determination is performed on a channel-by-channel basis for the pre-administration waveform data for 16 channels (see Fig. 9) output from all wells 32 of the MEA plate 30.

[0077] In the eligibility determination, first, the analysis unit 61 performs normalization in step S1000. In step S1000, the analysis unit 61 normalizes the pre-administration waveform data with respect to the time from the first peak P1 to the second peak P2 and the amplitude A2 of the second peak P2. The measurement time for the pre-administration waveform data output from one channel is several minutes, and the acquired pre-administration waveform data includes data for several tens of beats. The analysis unit 61 divides these several tens of beats of pre-administration waveform data into groups of one to two beats and normalizes the time and amplitude of the divided data. As a result, multiple normalized pre-administration waveform data such as those shown in FIG. 14 are generated for each channel.

[0078] In step S2000, the analysis unit 61 analyzes the morphology of the normalized pre-administration waveform data. The morphology analysis is performed for morphology analysis items based on the multiple evaluation perspectives shown in FIG. 15. In this case, the analysis unit 61 performs analysis for each of the pre-processing perspectives "0-1" to "0-3" prior to the morphology analysis items. The analysis unit 61 then excludes from the morphology analysis any pre-administration waveform data that does not satisfy the conditions of each of the pre-processing perspectives "0-1" to "0-3." By performing such pre-processing, the processing time for eligibility determination can be shortened.

[0079] After performing preprocessing, the analysis unit 61 determines whether the pre-administration waveform data that satisfies the preprocessing conditions is consistent with the morphology analysis items. The analysis unit 61 determines whether the data meets the criteria defined in the analysis items based on viewpoints "1-1" to "1-3" shown in FIG. 15. As described above, the analysis items include items that divide the pulsation period into multiple intervals and are set for each interval. Furthermore, the items set for each interval include items that use multiple approximation curves of different orders, as shown in FIG. 16.

[0080] By performing this type of analysis, the analysis unit 61 determines the eligibility of the pre-administration waveform data on a channel-by-channel basis. That is, for one well 32, the eligibility is determined for the pre-administration waveform data for 16 channels, and this is performed for the pre-administration waveform data of all wells 32 on the MEA plate 30. If the pre-administration waveform data is determined to be eligible, the channel that outputs that pre-administration waveform data is also determined to be eligible. A channel determined to be eligible is selected as a golden channel that can be used for toxicity evaluation, for example.

[0081] In step S3000, the analysis unit 61 presents the eligibility determination results to the user by outputting them to the display 20. A screen 71 shown in FIG. 18 is an example of a screen displaying the eligibility determination results. Waveforms for 16 channels of one well 32 are displayed side by side on the screen 71. Channels determined to be eligible are displayed with a bold frame 72, for example, to distinguish them from channels determined to be "ineligible." Of course, the bold frame 72 is an example of an indicator indicating "eligibility," and the indicator may be displayed in a manner other than the bold frame 72. The indicator may be displayed in a manner such as by adding a circle or by inserting the word "eligible." Alternatively, the "ineligible" channels may be hidden and only the "eligible" channels may be displayed.

[0082] Furthermore, for example, if even one of the multiple channels in a well 32 is qualified, the well 32 is also determined to be qualified. A well 32 determined to be qualified is determined to be usable for toxicity evaluation.

[0083] After the qualification determination is completed, the drug candidate substance is administered to each well 32 of the MEA plate 30. Post-administration waveform data is measured by the cell culture device 10. The information processing device 20 performs an analysis of the post-administration waveform data according to the evaluation items of the toxicity evaluation. In this analysis, for example, FPD measurement shown in FIG. 7 and analysis of the presence or absence of abnormal waveforms characteristic of EAD, DAD, and cardiac arrest shown in FIGS. 11 to 13 are performed. The results of these analyses are presented, and the user makes a final evaluation of the toxicity of the drug candidate substance based on the analysis results.

[0084] As described above, the processor 23 of the information processing device 20 analyzes the morphology of control waveform data, which represents electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, using a method that is independent of measurement-to-measurement variability to determine whether the control waveform data is suitable for use in toxicity evaluation tests and presents the eligibility determination results. In the above example, the pre-administration waveform data is an example of control waveform data, and normalization of the pre-administration waveform data is an example of a method for analyzing morphology that is independent of measurement-to-measurement variability. This allows for a determination result regarding the suitability of waveform data for use in toxicity evaluation tests that is closer to a visual human sensory evaluation than conventional methods.

[0085] More details are as follows. As described above, when a person visually determines the eligibility of pre-administration waveform data, attention is focused on the morphological features of the waveform rather than on quantitative features of the waveform, such as amplitude and time. According to the technology of the present disclosure, as an example, a method is adopted that is independent of measurement-to-measurement variability by normalizing the quantitative features. Because morphological features stand out in the normalized pre-administration waveform data, the morphological features are easy to grasp even when mechanical analysis is performed by the analysis unit 61. For example, as described in International Publication No. 2022 / 176310, there have been conventional techniques for mechanically processing eligibility determination using machine learning models. However, conventional techniques using machine learning models do not take into account the normalization of waveform data. In other words, conventional techniques using machine learning models do not employ methods that are independent of measurement-to-measurement variability. Therefore, there is a possibility that feature amounts may be extracted without distinguishing between quantitative and morphological features, and the morphological features may not be appropriately reflected in the determination results due to the influence of the quantitative features. Morphological features are key points in human visual sensory evaluation. According to the technology of the present disclosure, it is possible to determine eligibility based on morphological characteristics, and therefore it is possible to obtain a determination result that is closer to a sensory evaluation by human visual inspection than conventional methods.

[0086] Furthermore, processor 23 analyzes the morphology of control waveform data (e.g., pre-administration waveform data) using a method that is independent of variations in both the time from depolarization (e.g., first peak P1) to repolarization (e.g., second peak P2) in the pulsation cycle and the amplitude A2 of repolarization (e.g., second peak P2). Therefore, compared to when focusing on variations in other parts, it is possible to obtain a determination result that is closer to a visual sensory evaluation by a human.

[0087] Specifically, the normalization is performed as follows. First, the target of normalization is the time corresponding to the horizontal axis of the waveform data and the amplitude corresponding to the vertical axis. The target of normalization is the time from the first peak P1 to the second peak P2 in the pulsation cycle (an example of the time from depolarization to repolarization). This time corresponds to the aforementioned section SA. As shown in FIG. 15 , the morphology analysis items include many morphological characteristics of the section SA. Since these morphology analysis items reflect points that people pay attention to, the greater the number of analysis items in the section SA, the greater the number of points that people pay attention to in this section SA. According to the technology disclosed herein, the time in the section SA is one of the targets of normalization, and therefore the result can be closer to the result of a visual assessment by a human, compared to when the time in the section SA is not used as a target of normalization.

[0088] Furthermore, the amplitude A2 of the second peak P2 is used as the target of amplitude on the horizontal axis. As described above, the morphology of the section SA from the first peak P1 to the second peak P2 is an important target of analysis, and therefore, in order to compare the morphological characteristics of the section SA, it is conceivable to normalize using the amplitude of either the first peak P1 or the second peak P2. With the technology disclosed herein, by normalizing using the amplitude A2 of the second peak P2, which has a relatively small amplitude, it is possible to more appropriately extract changes in the amplitude direction of the section SA than when the amplitude A1 of the first peak P1 is used as the target of normalization.

[0089] In this manner, in the above embodiment, the analyzer 61, which is an example of a processor, analyzes the morphology by a method that is independent of variations in both the time from depolarization to repolarization and the amplitude corresponding to the repolarization, for example, for the control waveform data. This allows for a determination result that is closer to a visual sensory evaluation by a human being than when focusing on variations in other parts.

[0090] As described in the above embodiment, one example of a method that is independent of measurement-to-measurement variability is to normalize the reference waveform data, which can simplify processing compared to methods other than normalization.

[0091] Besides normalization, methods that are not dependent on variations between measurements include, for example, the following method: When performing morphological analysis of the control waveform data, the evaluation value of the morphological analysis is adjusted according to the difference in amplitude and time. The analysis unit 61 performs morphological analysis using the adjusted evaluation value and determines eligibility. In other words, while normalization involves the process of shaping the control waveform data, the method of adjusting the evaluation value of the morphological analysis is a method that performs a process equivalent to normalization as a numerical process without shaping the control waveform data.

[0092] Furthermore, as shown as an example of preprocessing for eligibility determination, the analysis unit 61, which is an example of a processor, excludes control waveform data in which at least one of the amplitudes corresponding to depolarization and repolarization does not satisfy a preset condition from the morphology analysis target. For example, the analysis unit 61 excludes pre-administration waveform data in which at least one of the amplitudes A1 of the first peak P1 and the amplitude of the second peak P2 does not satisfy a preset condition from the morphology analysis target. By performing such preprocessing, waveform data that clearly does not meet the eligibility criteria can be excluded, thereby shortening the eligibility determination processing time. Furthermore, because the determination of whether the conditions are met is based on amplitude, it is easy to identify subjects that should be excluded from the analysis target.

[0093] Furthermore, the analysis target conditions include a first condition that the absolute value of the amplitude corresponding to depolarization is equal to or greater than a certain value, and a second condition that the amplitude corresponding to repolarization is within a predetermined range. For example, the first condition is that the absolute value of the amplitude A1 of the first peak P1 is equal to or greater than a certain value, and the second condition is that the amplitude of the second peak P2 is within a predetermined range. The first and second conditions are among the basic characteristics that qualifying waveform data must have at a minimum with respect to amplitude. Using these first and second conditions makes it possible to appropriately narrow down the morphology analysis targets.

[0094] In the above embodiment, the preprocessing for determining eligibility is performed on normalized waveform data, but the preprocessing may also be performed on control waveform data before normalization (e.g., pre-administration waveform data). This allows inappropriate waveform data to be excluded further upstream.

[0095] Furthermore, the analysis items for analyzing the morphology include items set for each interval, which is obtained by dividing the pulsation period of cardiomyocytes into a plurality of intervals (e.g., interval SA, interval SB, interval SA1, and interval SA2 shown in FIG. 14 ). Because the analysis items include items set for each interval, the analysis process can be simplified compared to when the intervals are not divided.

[0096] Furthermore, the items set for each section include items using multiple approximation curves of different orders, as shown as items "1-3," "1-4," and "1-7" as examples. Because items using multiple approximation curves of different orders are included, more detailed morphology analysis is possible compared to when these approximation curves are not used, and the qualification assessment results can be closer to a visual sensory evaluation by a human.

[0097] The analysis unit 61, which is an example of a processor, determines eligibility using at least one of rule-based, template matching, and machine learning. Rule-based analysis is a method of analyzing morphology by setting conditions such as thresholds and numerical ranges, as in the evaluation criteria shown in FIG. 15 , and determining whether the control waveform data satisfies the set conditions. Template matching is a method of analyzing morphology by comparing standard waveform data serving as a template with the control waveform data, deriving a similarity for each analysis item based on the evaluation criteria, and using the similarity as an evaluation value. Machine learning is a method of determining eligibility using, for example, a machine learning model that inputs control waveform data and outputs eligibility. This machine learning model is a model trained using training data consisting of pairs of training control waveform data and corresponding correct answer data indicating the eligibility determination result. The analysis unit 61 may determine eligibility using any one of multiple methods, such as rule-based analysis, template matching, and machine learning, or a combination of multiple methods.

[0098] Furthermore, the control waveform data (pre-administration waveform data, for example) is waveform data acquired using an MEA plate 30 having a plurality of electrodes 41 provided on the bottom 34 and a plurality of wells 32 in which cardiomyocytes can be placed. Therefore, the technology of the present disclosure is effective for determining the eligibility of a plurality of wells 32 of an MEA plate 30.

[0099] "Variation 1" The processor 23 may have a function of indicating whether or not the wells 32 of the MEA plate 30 can be used for toxicity evaluation tests based on the determination result of the eligibility of the control waveform data (pre-administration waveform data, for example). Here, the suitability of the wells 32 for use in toxicity evaluation tests is referred to as "well eligibility" to distinguish it from the eligibility of the control waveform data. The examples shown in Figures 19 to 21 are examples of a screen 81 that indicates the well eligibility for each well 32 of the MEA plate 30. First, as shown in Figure 19, the screen 81 displays the arrangement of the multiple wells 32 of the MEA plate 30. On the screen 81, the wells 32 are represented by round well icons 82. A total of 24 well icons 82 are arranged in a matrix of 4 rows and 6 columns on the screen 81, corresponding to the number and arrangement of the wells 32 of the MEA plate 30.

[0100] The MEA plate 30 shown in FIG. 2 has a total of 48 wells 32 arranged in 6 rows and 8 columns, but for convenience, the screen 81 is shown in a 4 row by 6 column format in FIGS. 19 to 21.

[0101] As an example of how each column of the MEA plate 30 is used, columns 1 and 2 are used as references, and columns 3 to 6 are used as test subjects. A reference column is a column into which a substance known to be positive (toxic) or negative (non-toxic) is administered. It is normal for abnormal waveforms indicating toxicity to appear in the post-administration waveform data output from each well 32 in the positive column, while it is normal for abnormal waveforms to not appear in the post-administration waveform data of the negative column. However, if the pre-administration waveform data of the wells 32 in these reference columns is not qualified, abnormal waveforms may also appear in the negative column, for example. Therefore, the well qualification of the wells 32 in the reference column is also determined based on the qualification of the pre-administration waveform data.

[0102] The test subject columns are columns into which drug candidate substances with unknown toxicity, which are the subject of toxicity evaluation tests, are administered. In the example of FIG. 19 , different drug candidate substances, Compound 1 to Compound 4, are administered to each test subject column. The toxicity of these test subject Compounds 1 to 4 is evaluated based on post-administration waveform data output from the wells 32 of each column. A prerequisite for proper toxicity evaluation is that the pre-administration waveform data output from each well 32 in the test subject columns is qualified, just like in the reference columns.

[0103] Each row has four wells 32, and well eligibility is determined for each well 32. In this example, the well eligibility of an individual well 32 is determined to be qualified if there is qualified pre-administration waveform data for at least one of the 16 channels of electrodes 41 in each well 32.

[0104] The processor 23 also determines whether the toxicity evaluation test for each substance is successful based on the well eligibility determination results. In this example, because the administered substance differs for each column of the MEA plate 30, the success or failure of the toxicity evaluation test for each substance is presented as the success or failure of the toxicity evaluation test for each column. For example, the toxicity evaluation test for each column is determined to be successful if three of the four wells 32 in a column are well eligible. Furthermore, if two or more wells 32 in a column are unqualified, the toxicity evaluation test for that column is determined to be unqualified. This is because, for example, when determining whether the toxicity evaluation test for a substance is successful, the reliability of the toxicity evaluation test cannot be ensured unless the number of wells 32 determined to be "well eligible" exceeds the number of wells 32 determined to be "unqualified" among the wells 32 used for that substance.

[0105] Furthermore, in this example, a determination is also made as to whether the toxicity evaluation test for the entire MEA plate 30 has been successful. As an example, if the toxicity evaluation test for at least one of the reference columns is unsuccessful, the toxicity evaluation test for the entire MEA plate 30 is determined to have been unsuccessful. For the test columns, if the toxicity evaluation test for even one column is unsuccessful, the toxicity evaluation test for the entire MEA plate 30 is determined to have been successful.

[0106] This will be described in detail with reference to Figures 20 and 21. First, Figure 20 shows an example in which the toxicity evaluation test of the entire MEA plate 30 is determined to be successful, and Figure 21 shows an example in which the toxicity evaluation test of the entire MEA plate 30 is determined to be unsuccessful.

[0107] In Figure 20, a total of three wells 32 have been determined to be "unsuitable wells", namely the well 32 corresponding to row B in the fourth column and the wells 32 corresponding to rows B and C in the sixth column. When a well is determined to be "unsuitable well", the corresponding well icon 82 is displayed so as to be distinguishable from the other well icons 82, as indicated by hatching. As a display mode, the color of the well icon 82 may be changed, or an indicator such as a mark or text information indicating that the well is unsuitable may be displayed. Furthermore, if the well is suitable, the well icon 82 may be displayed to that effect.

[0108] In addition, since two wells 32 in the sixth column are judged to be "well unsuitable," the toxicity evaluation test for compound 4 in the sixth column is judged to be unsuccessful. On the other hand, since only one well 32 in the fourth column is judged to be "well unsuitable," the toxicity evaluation test for the fourth column is judged to be successful. As an example, a bold frame 83 is displayed in columns where the toxicity evaluation test is successful. On the other hand, no bold frame 83 is displayed in columns where the toxicity evaluation test is unsuccessful. In this way, the success or failure of each column of the toxicity evaluation test is displayed in an identifiable manner.

[0109] 20, the toxicity evaluation test for the reference column is successful, and there is also a column for the test subject that has passed the toxicity evaluation test. Therefore, it is determined that the toxicity evaluation test for the entire MEA plate 30 is successful. To indicate this, the outer frame of the screen 81 is displayed with a bold frame 84. Of course, this display format is just an example, and other display formats other than the bold frame 84 may also be used. Furthermore, the screen 81 also displays that the test is successful.

[0110] In the example of Figure 21, a total of six wells 32 have been determined to be "unqualified wells", including wells 32 corresponding to rows A and B in the first column, wells 32 corresponding to row C in the second column, wells 32 corresponding to row B in the fourth column, and wells 32 corresponding to rows B and C in the sixth column. Since there are two wells 32 determined to be "unqualified wells" in the first and sixth columns, the toxicity evaluation test for each column is determined to be unsuccessful. Therefore, no bold frame 83 is displayed in the first and sixth columns.

[0111] Furthermore, in the example of Fig. 21, since the toxicity evaluation test in the first column, which is the reference column, is not successful, the toxicity evaluation test is determined to be failed for the entire MEA plate 30. Therefore, in the example of Fig. 21, the thick frame 84 is not displayed on the screen 81. Furthermore, the screen 81 also displays a message that the test was not successful.

[0112] In this way, the processor 23 has the function of indicating whether or not a well 32 can be used for a toxicity evaluation test based on the eligibility of the control waveform data, allowing the user to easily grasp the well eligibility of each well 32. Furthermore, the success or failure of a toxicity evaluation test for a row made up of multiple wells 32, and the success or failure of a toxicity evaluation test for the entire MEA plate 30 can also be easily indicated based on the well eligibility.

[0113] "Variation 2" While Variation 1 described above is an example in which well eligibility is determined solely based on the determination of the eligibility of control waveform data (e.g., pre-administration waveform data), drug-treated waveform data (e.g., post-administration waveform data) may also be used to determine well eligibility, i.e., whether or not the well 32 can be used for toxicity evaluation testing. Similar to FIG. 10 , FIG. 22 shows an example in which pre-administration waveform data and post-administration waveform data are displayed for comparison. Similarly to FIG. 10 , the post-administration waveform data also includes multiple waveform data with different concentrations of the drug candidate substance. FIG. 22(A) shows an example in which a result is determined to be "eligible," while FIG. 22(B) shows an example in which a result is determined to be "ineligible." In the example shown in FIG. 22(B), waveform data up to high concentrations before and after administration show measurements of extracellular potentials, but no change in potential is observed for waveform data at ultra-high concentrations. This is presumably due to, for example, cardiomyocytes being detached from the bottom 34 of the well 32.

[0114] In such a case, post-administration waveform data cannot be obtained for the ultra-high concentration waveform data, and the toxicity of the drug candidate substance at an ultra-high concentration cannot be evaluated. In such a case, the well 32 may be determined to be "unsuitable for well administration."

[0115] That is, in Modification 2, in addition to the control waveform data, the drug-treated waveform data is also used to determine whether or not the well 32 can be used for a toxicity evaluation test. Since the toxicity evaluation test is ultimately performed based on the drug-treated waveform data, by checking the state of the drug-treated waveform data as in Modification 2, the well suitability can be more appropriately determined.

[0116] Well qualification may be determined based only on drug-treated waveform data, without using control waveform data.

[0117] "Variation 3" Furthermore, as shown in Variation 3 in FIG. 23, in step S3000, the processor 23 may present standard waveform data having a standard form recognized as being suitable, in addition to the result of the qualification determination. The standard waveform data is, for example, data showing an ideal waveform as shown in FIG. 7(B). The standard waveform data may be actual measurement data selected from control waveform data acquired from actual cardiomyocytes, or may be data created by simulation or the like. By presenting such standard waveform data, the user can easily perform a sensory evaluation in which the morphological characteristics of the control waveform data are also visually confirmed. This allows both the determination result of the processor 23 and a visual sensory evaluation to be performed.

[0118] "Variation 4" As shown in Variation 4 in FIG. 24, the processor 23 may simply normalize control waveform data (e.g., pre-administration waveform data) representing electrical changes in response to the pulsation of cardiomyocytes and used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization, and present the normalized control waveform data. That is, in Variation 4 shown in FIG. 24, unlike the examples shown in FIGS. 17 and 23, the processor 23 does not analyze the form of the control waveform data or determine its eligibility. The normalized control waveform data is simply presented. This allows the user to assist in visual sensory evaluation of drug-treated waveform data, such as post-administration waveform data.

[0119] Also in the fourth modification, as in the third modification shown in FIG. 23, standard waveform data having a standard form that is recognized as being suitable may be presented in addition to the control waveform data after normalization.

[0120] In the above embodiment, the hardware structure of the processing units that execute various processes, such as the data acquisition unit 60, the analysis unit 61, and the output unit 62, is the following various processors.

[0121] Various types of processors include CPUs, programmable logic devices (PLDs), dedicated electrical circuits, etc. As is well known, a CPU is a general-purpose processor that executes software (programs) and functions as various processing units. A PLD is a processor such as an FPGA (Field Programmable Gate Array) whose circuit configuration can be changed after manufacturing. A dedicated electrical circuit is a processor such as an ASIC (Application Specific Integrated Circuit) that has a circuit configuration designed specifically to execute specific processing.

[0122] A single processing unit may be configured with one of these various processors, or may be configured with a combination of two or more processors of the same or different types (e.g., multiple FPGAs, a combination of a CPU and an FPGA, etc.). Multiple processing units may also be configured with a single processor. Examples of multiple processing units configured with a single processor include: a first configuration in which a single processor is configured with a combination of one or more CPUs and software, and this processor functions as multiple processing units; and a second configuration in which a processor is used that realizes the functions of an entire system including multiple processing units on a single IC chip, as typified by a system-on-chip (SoC). In this way, the various processing units are configured with one or more of the above-mentioned various processors as a hardware structure.

[0123] Furthermore, the hardware structure of these various processors is, more specifically, an electric circuit made up of a combination of circuit elements such as semiconductor elements.

[0124] The above description allows the understanding of the following technologies. [Supplementary Item 1] An information processing device including a processor, wherein the processor determines the suitability of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in a toxicity evaluation test of a drug candidate substance, for use in the toxicity evaluation test by analyzing the morphology using a method that is not dependent on variability between measurements, to determine whether the control waveform data can be used in the toxicity evaluation test, and presents the eligibility determination result. [Supplementary Item 2] The information processing device according to Supplementary Item 1, wherein the processor analyzes the morphology of the control waveform data using a method that is not dependent on variability in both the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization. [Supplementary Item 3] The information processing device according to Supplementary Item 2, wherein the method that is not dependent on variability between measurements is a method of normalizing the control waveform data with respect to time and amplitude. [Supplementary Item 4] The information processing device of any one of Supplementary Items 2 or 3, wherein the processor excludes from the morphology analysis control waveform data in which at least one of the amplitudes corresponding to depolarization and repolarization does not satisfy a preset condition. [Supplementary Item 5] The information processing device of Supplementary Item 4, wherein the conditions include a first condition that the absolute value of the amplitude corresponding to depolarization is equal to or greater than a certain value, and a second condition that the amplitude corresponding to repolarization is within a preset range. [Supplementary Item 6] The information processing device of any one of Supplementary Items 1 to 5, wherein the analysis items for analyzing the morphology include items set for each interval obtained by dividing the beat cycle into a plurality of intervals. [Supplementary Item 7] The information processing device of Supplementary Item 6, wherein the items set for each interval include items using a plurality of approximation curves of different orders. [Supplementary Item 8] The information processing device of any one of Supplementary Items 1 to 7, wherein the processor determines eligibility using at least one of rule-based, template matching, and machine learning. [Supplementary Item 9] The information processing device according to any one of Supplementary Items 1 to 8, wherein the control waveform data is waveform data acquired using an MEA plate having a plurality of electrodes on the bottom and a plurality of wells in which cardiomyocytes can be placed.[Supplementary Item 10] The information processing device of Supplementary Item 9, wherein the processor has a function of presenting whether or not a well can be used for toxicity evaluation testing based on a determination of the eligibility of the control waveform data. [Supplementary Item 11] The information processing device of Supplementary Item 10, wherein the processor uses drug-treated waveform data obtained after administering a drug candidate to cardiomyocytes to determine whether or not a well can be used for toxicity evaluation testing. [Supplementary Item 12] The information processing device of any one of Supplementary Item 1 to Supplementary Item 11, wherein standard waveform data having a standard form recognized as eligibility is presented in addition to the determination result. [Supplementary Item 13] A method for operating an information processing device having a processor, wherein the processor determines the eligibility of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used for toxicity evaluation testing of a drug candidate, by analyzing the form by a method that is not dependent on variability between measurements, thereby determining the eligibility of the control waveform data for use in toxicity evaluation testing, and presenting the determination result of eligibility. [Supplementary Item 14] An operating program for an information processing device having a processor, the operating program causing the processor to execute processes including: determining the suitability of control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, for use in toxicity evaluation tests by analyzing the morphology by a method independent of measurement-to-measurement variability; and presenting the eligibility determination results. [Supplementary Item 15] An information processing device having a processor, the processor normalizing the control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to repolarization, and presenting the normalized control waveform data. [Supplementary Item 16] The information processing device according to Supplementary Item 15, presenting standard waveform data having a standard morphology recognized as suitable in addition to the normalized control waveform data.[Supplementary Item 17] A method for operating an information processing device having a processor, wherein the processor normalizes control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to repolarization, and presents the normalized control waveform data. [Supplementary Item 18] An operating program for an information processing device having a processor, which causes the processor to execute processes including: normalizing control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to repolarization, and presenting the normalized control waveform data.

[0125] The technology of the present disclosure can also be appropriately combined with the various embodiments and / or various modified examples described above. Furthermore, the technology is not limited to the above embodiments, and various configurations can be adopted without departing from the spirit of the present disclosure. Furthermore, the technology of the present disclosure also covers, in addition to programs, storage media that non-temporarily store programs. The storage medium is, for example, a computer-readable non-temporary storage medium such as a USB (Universal Serial Bus) memory, a flexible disk, or a CD-ROM (Compact Disc Read Only Memory). The program may also be provided online via a network such as the Internet. The technology of the present disclosure also covers, in addition to programs, program products. A program product includes any type of product for providing a program. Like a program, a program product may be provided stored on a computer-readable non-temporary storage medium or provided online.

[0126] The above-described description and illustrations are a detailed explanation of the parts related to the technology of the present disclosure and are merely an example of the technology of the present disclosure. For example, the above description of the configuration, functions, actions, and effects is an explanation of an example of the configuration, functions, actions, and effects of the parts related to the technology of the present disclosure. Therefore, it goes without saying that unnecessary parts may be deleted, new elements may be added, or replacements may be made to the above-described description and illustrations within the scope of the gist of the technology of the present disclosure. Furthermore, to avoid confusion and facilitate understanding of the parts related to the technology of the present disclosure, the above-described description and illustrations omit explanations of common technical knowledge that do not require particular explanation to enable the implementation of the technology of the present disclosure.

[0127] The disclosure of Japanese Patent Application No. 2024-051832, filed on March 27, 2024, is incorporated herein by reference in its entirety. In addition, all documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. An information processing device having a processor, wherein the processor determines the suitability of control waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is used in a toxicity evaluation test of a drug candidate substance, by analyzing the form of the control waveform data using a method that is not dependent on variability between measurements, to determine whether the control waveform data can be used in the toxicity evaluation test, and presents the results of the suitability determination.

2. The information processing device according to claim 1, wherein the processor analyzes the morphology of the control waveform data in a manner that is independent of variations in both the time from depolarization to repolarization in the beat cycle and the amplitude corresponding to the repolarization.

3. The information processing device according to claim 2, wherein the method that is not dependent on variations between measurements is a method that normalizes the control waveform data with respect to the time and the amplitude.

4. The information processing device according to claim 2, wherein the processor excludes from the analysis of the morphology the control waveform data in which at least one of the amplitudes corresponding to the depolarization and the amplitude corresponding to the repolarization does not satisfy a preset condition.

5. The information processing device according to claim 4, wherein the conditions include a first condition that the absolute value of the amplitude corresponding to the depolarization is equal to or greater than a certain value, and a second condition that the amplitude corresponding to the repolarization is within a preset range.

6. The information processing device according to claim 1, wherein the analysis items for analyzing the morphology include items set for each of a plurality of intervals obtained by dividing the pulsation cycle into a plurality of intervals.

7. The information processing device according to claim 6, wherein the items set for each section include items using a plurality of approximation curves of different degrees.

8. The information processing device according to claim 1, wherein the processor determines the eligibility using at least one of a rule base, template matching, and machine learning.

9. The information processing device according to claim 1, wherein the control waveform data is waveform data acquired using an MEA plate having a plurality of electrodes on the bottom and a plurality of wells in which the cardiomyocytes can be placed.

10. The information processing device according to claim 9, wherein the processor has a function of indicating whether or not the well can be used for the toxicity evaluation test based on the determination of the eligibility of the control waveform data.

11. The information processing device according to claim 10, wherein the processor uses drug-treated waveform data obtained after administering the drug candidate substance to the cardiomyocytes to determine whether the well can be used for toxicity evaluation tests.

12. The information processing device according to claim 1, wherein standard waveform data having a standard form that is recognized as suitable is presented in addition to the judgment result.

13. A method for operating an information processing device having a processor, wherein the processor determines the suitability of control waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is used in a toxicity evaluation test of a drug candidate substance, by analyzing the form of the control waveform data using a method that is not dependent on variability between measurements, to determine whether the control waveform data can be used in the toxicity evaluation test, and presents the results of the suitability determination.

14. An operating program for an information processing device having a processor, which causes the processor to execute processing including: determining the suitability of control waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, by analyzing the form of the control waveform data using a method that is not dependent on variability between measurements, to determine whether the control waveform data can be used in the toxicity evaluation tests; and presenting the results of the suitability determination.

15. An information processing device having a processor, wherein the processor normalizes control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization, and presents the normalized control waveform data.

16. The information processing device according to claim 15, wherein standard waveform data having a standard form that is recognized as qualified is presented in addition to the control waveform data after normalization.

17. A method for operating an information processing device having a processor, wherein the processor normalizes control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization, and presents the normalized control waveform data.

18. An operating program for an information processing device having a processor, which causes the processor to execute processing including: normalizing control waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is used in toxicity evaluation tests of drug candidate substances, with respect to the time from depolarization to repolarization in the pulsation cycle and the amplitude corresponding to the repolarization; and presenting the control waveform data after normalization.

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