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

Abstract

This information processing device is provided with a processor. The processor: analyzes post-drug treatment waveform data which is waveform data indicating electrical change in accordance with the pulsation of cardiomyocytes and is acquired after the administration of a drug candidate substance to the cardiomyocytes; and presents an abnormal waveform candidate included in a boundary region that is set in advance as a boundary between abnormal waveforms and normal waveforms.

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] Evaluation items for toxicity assessment include items that focus on morphologically abnormal waveforms in drug-treated waveform data, such as EAD (Early After Depolarization), and WO 2022 / 176310 describes a technology for detecting abnormal waveforms representing EAD, etc., based on drug-treated waveform data.

[0004] However, in determining an abnormal waveform in a toxicity evaluation test, there are cases where it can be reliably determined to be abnormal and cases where it is near the border between abnormal and normal, and in the case near the border, a final visual confirmation by the user is required. The technology described in WO 2022 / 176310 has a problem in that, because it is unclear whether it is a case where it can be reliably determined to be abnormal or a case near the border, the number of cases where the user must visually confirm becomes enormous, resulting in a heavy workload.

[0005] One embodiment of the technology of the present disclosure provides an information processing device, an operating method of an information processing device, and an operating program of an information processing device that can reduce the user's workload in determining abnormal waveforms in toxicity evaluation tests compared to conventional methods.

[0006] In order to achieve the above-mentioned object, the information processing device of the present disclosure is an information processing device equipped with a processor, which analyzes drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is obtained after administering a drug candidate substance to the cardiomyocytes, and presents abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal.

[0007] As a method for presenting abnormal waveform candidates, the processor may display the drug-treated waveform data and then display the portion of the drug-treated waveform data that corresponds to the abnormal waveform candidate in a manner that makes it distinguishable from the other portions.

[0008] The boundary region may be a range between two different criteria.

[0009] The abnormal waveform candidate may be a waveform that is a candidate for an abnormal waveform that indicates any of the abnormalities of EAD, DAD, and cardiac arrest.

[0010] The processor may present a waveform that falls between the first and second peaks in the beat cycle and falls within a boundary region as a candidate abnormal waveform for EAD.

[0011] The processor may present a waveform that falls between the second peak in one beat cycle and the first peak in the next beat cycle and falls within a boundary region as a candidate abnormal waveform for DAD.

[0012] The processor may present a waveform in which the first peak in the beat cycle is included in the boundary region and the second peak is not detected as a candidate abnormal waveform related to cardiac arrest.

[0013] The post-drug treatment waveform data may be 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.

[0014] The method of operating an information processing device according to the disclosed technology is a method of operating an information processing device equipped with a processor, in which the processor analyzes drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is obtained after administering a drug candidate substance to the cardiomyocytes, and presents candidate abnormal waveforms that fall within a boundary region that is preset as the boundary between abnormal and normal.

[0015] The operating program of an information processing device according to the technology of the present disclosure is an operating program of an information processing device equipped with a processor, and causes the processor to execute processes including analyzing drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is obtained after administering a drug candidate substance to the cardiomyocytes, and presenting abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal.

[0016] According to the technology of the present disclosure, the workload on the user in determining abnormal waveforms in toxicity evaluation tests can be reduced compared to conventional techniques.

[0017] 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 presenting abnormal waveforms and abnormal waveform candidates. A flowchart illustrating a processing procedure for abnormal waveform detection. FIG. 14 is a diagram illustrating an example of pre-processing. FIG. 15 is a diagram illustrating an example of criteria for determining abnormal waveforms. FIG. 16 is a diagram illustrating an example of two criteria and a boundary region. FIG. 17 is a diagram illustrating another example of two criteria and a boundary region. FIG. 18 is a diagram illustrating a modified example of the manner in which abnormal waveform candidates are presented.

[0018] Hereinafter, embodiments of the technology of the present disclosure will be described with reference to the drawings.

[0019] 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).

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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).

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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).

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Figure 8 shows waveform variations under the same measurement conditions. Figure 8 shows multiple waveform data output from each electrode 41 of the microelectrode array 40 in one well 32, and each waveform data represents pre-administration waveform data before the drug candidate substance is administered. The pre-administration waveform data shown in Figure 8 are superimposed with the first peak P1 time aligned. As shown in Figure 8, the pre-administration waveform data vary in the time of the second peak P2, resulting in variations in the FPD. There is also variation in the ISI. There is also variation in the amplitude A2 of the second peak P2.

[0042] 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.

[0043] Some of the waveform data from channels CH1 to CH16 is not suitable for toxicity assessment of drug candidate substances. Therefore, for example, the waveform data from channels CH1 to CH16 is judged to be suitable for use in toxicity assessment based on pre-administration waveform data before the drug candidate substance is administered. Then, wells 32 capable of outputting suitable waveform data are used for toxicity assessment.

[0044] 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.

[0045] Figure 10 shows changes in waveform 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. It is believed that such waveform disturbances occur when the toxicity of the drug candidate substance inhibits the ion channels in the cardiomyocytes described above.

[0046] 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 point before and after administration, but the slope and shape of the waveform between the two peaks P1 and P2 change before and after administration. Furthermore, the quantitative and morphological characteristics of the waveform data also change depending on the concentration of the drug candidate substance administered. 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 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, and the slope and shape of the waveforms of the two peaks P1 and P2 also change significantly, particularly at ultra-high drug candidate concentrations. 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.

[0047] 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.

[0048] As shown in FIG. 11 , EAD is a phenomenon in which depolarization occurs before the second peak P2. EAD appears in the waveform data of extracellular potentials as an abnormal convex waveform with a minus peak, dropping between the first peak P1 and the second peak P2. As shown in FIG. 12 , DAD is a phenomenon in which depolarization occurs after the second peak P2. DAD appears as an abnormal convex waveform with a minus peak, dropping between the second peak P2 and the first peak P1 of the next cycle. As shown in FIG. 13(A) , in the case of cardiac arrest, signals such as peaks at the time of pulsation are not observed in the waveform data of extracellular potentials. FIG. 13(A) shows a case in which pulsation has completely stopped, which is a typical example of cardiac arrest. In addition to FIG. 13(A) , cardiac arrest may also be evaluated as occurring when, for example, there is some amplitude indicating pulsation, but no peaks or other signals are observed, 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 does not drop much in the negative direction, and its absolute value is equal to or less than a certain value (for example, a threshold THC). The second feature (feature 2 in Fig. 13(B)) is that the second peak P2 cannot be confirmed. By determining an abnormal waveform based on these features, it is possible to evaluate Fig. 13(B) as cardiac arrest in addition to Fig. 13(A).

[0049] 11 to 13 show typical examples of abnormal waveforms, which can be reliably determined to be abnormal. As in the prior art, such typical cases can be relatively easily processed mechanically, for example, by the analysis unit 61 detecting abnormal waveforms using an abnormality detection algorithm.

[0050] However, in reality, in addition to such typical cases, there are also cases near the boundary between abnormal and normal, as shown in Figure 14(A). In the example shown in Figure 14(A), there is a convex waveform with a peak in the negative direction before the second peak P2, and such a waveform is suspected to be EAD. In addition, there is a peak after the second peak P2 that is suspected to be DAD. These peaks are cases near the boundary where it is difficult to determine whether they are normal or abnormal at first glance in terms of amplitude, sharpness, etc.

[0051] Therefore, the analysis unit 61 has a function of analyzing post-administration waveform data (an example of post-drug treatment waveform data) after administration of a drug candidate substance and presenting abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal. Specifically, the analysis unit 61 has a function of presenting the user with cases near the boundary shown in Figure 14(A) to explicitly inform the user of the locations that the user should visually check.

[0052] As shown in Fig. 14(B) as an example, the analysis unit 61 presents abnormal waveform candidates by displaying an index M indicating abnormal waveform candidates included in the boundary region in the post-administration waveform data. In the example shown in Fig. 14(B), the index M is displayed on the post-administration waveform data, and the abnormal waveform candidates are displayed so that they can be distinguished from other parts.

[0053] 15 is a flowchart showing an example of an abnormal waveform detection procedure executed by the analysis unit 61. In step S1000, the analysis unit 61 acquires post-administration waveform data to be analyzed. The analysis target may be all of the post-administration waveform data measured on the MEA plate 30, or, for example, a portion of the post-administration waveform data in which the concentration of the administered drug candidate substance is high and detection of an abnormal waveform is highly necessary. Of course, it may also be a portion of the post-administration waveform data for which the user performed primary screening.

[0054] In step S2000, the analysis unit 61 performs preprocessing. The preprocessing includes smoothing the post-administration waveform data and removing unnecessary parts. For example, the smoothing process involves calculating a moving average value in the time direction for the amplitude values ​​of the post-administration waveform data and regenerating the post-administration waveform data using the moving average value. This removes small peaks such as high-frequency noise from the post-administration waveform data, allowing the post-administration waveform data to form a smooth curve.

[0055] In the case where the abnormal waveforms of the EAD and DAD shown in Figures 11 and 12 are to be detected, the first peak P1 is an unnecessary portion, and therefore the unnecessary portion removal process is a process of removing the first peak P1 and the portions before and after it from the post-administration waveform data, as shown as an example in Figure 16. By performing such unnecessary portion removal process, the amount of data to be analyzed is reduced, and therefore the processing time for waveform analysis can be shortened.

[0056] As shown in FIG. 16 , the analysis unit 61 detects a first peak P1 from the post-administration waveform data shown in FIG. 16(A) based on the amplitude value and the pulsation period, and cuts out a certain period of time before and after the detected first peak P1. Alternatively, a method of cutting out ¼ of each of the pulsation period starting from the first peak P1 may be used. As a result, as shown in FIG. 16(B), post-administration waveform data is obtained that includes the second peak P2 and the portions before and after it, but from which the first peak P1 has been removed. Note that when the abnormal waveform of cardiac arrest shown in FIG. 13(B) is to be detected, the first peak P1 is not removed, but only other unnecessary portions are removed.

[0057] After performing such preprocessing, the analysis unit 61 proceeds to step S3000. In step S3000, the analysis unit 61 detects an abnormal waveform from the post-administration waveform data using the judgment criteria. The judgment criteria are used to detect an abnormal waveform by comparing them with the post-administration waveform data. The judgment criteria are stored in memory 24 as reference information 29.

[0058] In step S3000, in order to detect a clearly abnormal waveform, a first judgment criterion 91 is used as the judgment criterion, as shown in FIG. 17. FIG. 17 shows an example of detecting EAD. An abnormal waveform representing EAD is a convex waveform with a peak in the negative direction. The analysis unit 61 first searches the post-administration waveform data for a convex waveform that protrudes in the negative direction by more than a reference value. The analysis unit 61 then determines whether the convex waveform found is an abnormal waveform.

[0059] For example, a requirement for an abnormal waveform indicating EAD is that there is a potential change of a certain value or more in the negative direction over a certain period of time near the peak. In other words, a condition for determining an abnormal waveform indicating EAD is that the convex waveform has a certain sharpness. Therefore, the first determination criterion 91 uses an inverted triangle with a vertex in the negative direction, and the slope of the hypotenuse of the inverted triangle is the standard for sharpness. For example, the inverted triangle of the first determination criterion 91 has a base length of 200 mS in the time direction and a height of 30 μV in the amplitude direction. This means that for a convex waveform with a peak in the negative direction to be determined as an abnormal EAD waveform, the potential must have a sharpness of 30 μV or more in the negative direction over 100 mS, half of 200 mS. Of course, the specific value of the first determination criterion 91 is merely an example and may be adjusted depending on the measurement conditions, the characteristics of the myocardium being measured, and other factors.

[0060] 17, when the peak of the waveform SP1 and the vertex 0 of the first judgment criterion 91 are superimposed so that they coincide with each other, the waveform is in a region that exceeds all of the points 1 to 4 on the hypotenuse of the first judgment criterion 91. In this case, the analysis unit 61 determines that the waveform SP1, which is a convex waveform, is an abnormal waveform and detects it as such. On the other hand, the analysis unit 61 does not detect as an abnormal waveform any waveform that falls below even one of the points 1 to 4 of the first judgment criterion 91. In this way, in step S3000, the detection of an abnormal waveform is performed using the first judgment criterion 91.

[0061] Next, in step S4000, the analyzer 61 detects abnormal waveform candidates contained in a boundary region, which is a region that is set in advance as the boundary between abnormal and normal.

[0062] The boundary region 93 shown as an example in FIG. 18 is a range between the first judgment criterion 91 and the second judgment criterion 92. The second judgment criterion 92 is a criterion with a lower sharpness than the first judgment criterion 91. The second judgment criterion 92 has an inverted triangular shape with the same height as the first judgment criterion 91 but a different base length. The second judgment criterion 92 has a base length of 400 mS, twice that of the first judgment criterion 91. In other words, the first judgment criterion 91 requires a change of 30 μV in 100 mS, while the second judgment criterion 92 requires a change of 30 μV in 200 mS, and the slope of the hypotenuse is also gentler. The first judgment criterion 91 is a criterion for detecting a convex waveform that can be reliably determined to be an abnormal waveform, while the second judgment criterion 92 is a criterion established to prevent an abnormal waveform from being overlooked. Therefore, the second judgment criterion 92 is used to detect a convex waveform that is closer to normal than the first judgment criterion 91.

[0063] The analysis unit 61 determines and detects a convex waveform that falls within the boundary region 93 as an abnormal waveform candidate. In the example shown in Fig. 18, the convex waveform shown as waveform SP2 passes through points 1 to 4 of the first judgment criterion 91 and points 1 to 4 of the second judgment criterion 92, and is therefore included in the boundary region 93. Such waveform SP2 is detected as an abnormal waveform candidate. Waveform SP3 has a gentler slope than waveform SP2 and is not included in the boundary region 93, so it does not fall under either an abnormal waveform or an abnormal waveform candidate and is determined to be normal.

[0064] In steps S3000 and S4000, the analysis unit 61 detects abnormal waveforms and abnormal waveform candidates in the DAD in the same manner as in the EAD.

[0065] 19 shows an example of an abnormal waveform and candidate abnormal waveform that exhibit the characteristic of cardiac arrest shown in FIG. 13B, "the absolute value of the negative peak of the first peak P1 is equal to or less than a certain value," and these waveforms are detected using two criteria: a first threshold THC1 and a second threshold THC2. The first threshold THC1 corresponds to the threshold THC shown in FIG. 13B. The absolute value of the negative peak of the waveform SP4 is equal to or less than the first threshold THC1. In other words, the peak of the waveform SP4 is closer to 0 than the first threshold THC1, a value that can be reliably determined to be abnormal, and therefore the waveform SP4 is determined to be an abnormal waveform.

[0066] The second threshold THC2 is a standard established to prevent abnormal waveforms from being overlooked, and the range between the first threshold THC1 and the second threshold THC2 is the boundary region 94. Waveforms that fall within the boundary region 94, such as waveform SP5, have a larger absolute value of the negative peak than waveform SP4 and are closer to normal values. In other words, waveform SP5 has a larger negative potential drop than waveform SP4. Such a waveform SP5 is detected as an abnormal waveform candidate. The absolute value of the negative peak of waveform SP6 exceeds the second threshold THC2. In other words, waveform SP6 has a potential drop in the negative direction more than the second threshold THC2. Therefore, it is neither an abnormal waveform nor an abnormal waveform candidate, and is determined to be normal.

[0067] As an example, the first threshold THC1 is 110 μV, and the second threshold THC2 is 100 μV. In the case of the first peak P1, the absolute value of the negative peak of a normal waveform is approximately 200 μV. By using the second threshold THC2 in addition to the first threshold THC1, it is possible to detect abnormal waveform candidates that are in a border region 94 that is closer to normal than abnormal waveforms that can be reliably determined to be abnormal. Of course, the specific values ​​of the first threshold THC1 and the second threshold THC2 are merely examples, and may be adjusted depending on the measurement conditions, the characteristics of the myocardium being measured, and the like.

[0068] In step S5000, the output unit 62 displays the abnormal waveforms and abnormal waveform candidates detected in steps S3000 and S4000 on the display unit 21 as the detection results.

[0069] 14(B), the abnormal waveform candidate is displayed in such a manner that the portion corresponding to the abnormal waveform candidate is distinguishable from the other portions by displaying the post-administration waveform data on the screen of the display unit 21 and then attaching an index M to the portion corresponding to the abnormal waveform candidate. Furthermore, the abnormal waveform is displayed using, for example, an index different from the index M of the abnormal waveform candidate.

[0070] As described above, the processor 23 analyzes post-drug treatment waveform data (e.g., post-administration waveform data), which is waveform data representing electrical changes (e.g., changes in extracellular potential) corresponding to the pulsation of cardiomyocytes and which is acquired after administering a drug candidate substance to cardiomyocytes, and presents abnormal waveform candidates that fall within a predetermined boundary region that is the boundary between abnormal and normal, thereby making it easier for the user to identify portions of the post-drug treatment waveform data that require final confirmation by the user. This reduces the user's workload in determining abnormal waveforms in toxicity evaluation tests, compared to conventional methods that do not present abnormal waveform candidates.

[0071] For example, when a user visually checks post-administration waveform data (an example of post-drug treatment waveform data), the user must look at the waveform data over several minutes, search for suspected abnormal waveform locations, and check them in detail. If such visual check work were to be performed for each channel of each well 32 of the MEA plate 30, the amount of work would be enormous. It may take more than 10 hours to visually check all of the locations of a single MEA plate 30. If potential abnormal waveforms are presented, the user's workload would be reduced because the task of searching for suspected abnormal waveform locations would be simplified.

[0072] In addition, the processor 23 presents abnormal waveform candidates by displaying drug-treated waveform data (post-administration waveform data, as an example), and then displaying the post-administration waveform data in a manner that allows the parts that correspond to abnormal waveform candidates to be distinguished from other parts, making it easy to recognize abnormal waveform candidates.

[0073] 14(B) shows an example in which the index M is used to present the abnormal waveform candidate, but this is of course only one example, and other examples are also possible. For example, as shown in FIG. 20, the abnormal waveform candidate may be presented as text information such as "This is an abnormal EAD (or DAD) candidate waveform." Alternatively, the color, thickness, or density of the abnormal waveform candidate may be changed in the post-administration waveform data.

[0074] Furthermore, the boundary region is set as a range between two different criteria, which makes it easier to simplify the determination process compared to when three or more criteria are combined.

[0075] The abnormal waveform candidates are waveforms that are candidates for abnormal waveforms that indicate any of the abnormalities of EAD, DAD, and cardiac arrest. These are frequently used in the evaluation of cardiotoxicity and are therefore highly convenient.

[0076] The processor 23 also presents, as an abnormal waveform candidate for EAD, a waveform that drops between the first peak P1 and the second peak P2 in the pulsation cycle of cardiomyocytes and falls within a boundary region. The processor 23 also presents, as an abnormal waveform candidate for DAD, a waveform that drops between the second peak P2 in the pulsation cycle and the first peak P1 in the next cycle and falls within a boundary region. The processor 23 also presents, as an abnormal waveform candidate for cardiac arrest, a waveform in which the first peak P1 in the pulsation cycle falls within a boundary region and the second peak P2 is not detected. Because abnormal waveform candidates for EAD, DAD, and cardiac arrest are detected using these criteria, each abnormal waveform candidate can be detected using a relatively simple procedure.

[0077] In the above embodiment, an example is shown in which abnormal waveform candidates representing EAD, DAD, and cardiac arrest are detected, but this is just an example, and other abnormal waveform candidates may also be detected.

[0078] Furthermore, the post-drug treatment waveform data (post-administration waveform data, for example) is waveform data acquired using an MEA plate 30 having a plurality of electrodes 41 on the bottom and a plurality of wells in which cardiomyocytes can be placed. The waveform data acquired using the MEA plate 30 requires a large number of waveform data items to be confirmed, and therefore the technology of the present disclosure is particularly effective.

[0079] In the above embodiment, as shown in Figure 14(B), the abnormal candidate waveform is presented by displaying the post-administration waveform data and then displaying the portion of the post-administration waveform data that corresponds to the abnormal waveform candidate, but the post-administration waveform data does not have to be displayed. For example, it is also possible to simply present the time at which the abnormal waveform candidate appears without displaying the post-administration waveform data.

[0080] In the above embodiment, an example was described in which an abnormal waveform was detected in addition to an abnormal waveform candidate. However, an embodiment in which only an abnormal waveform candidate is detected without detecting an abnormal waveform is also possible. For example, it is relatively easy for a user to detect an abnormal waveform that can be clearly determined to be abnormal, even when visually checking. In contrast, an abnormal waveform candidate may be overlooked by visual checking alone, so careful checking is required. Therefore, even if only an abnormal waveform candidate is detected, the effect of reducing the user's workload can be achieved.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] The above description allows the understanding of the following technologies. [Supplementary Item 1] An information processing device including a processor, wherein the processor analyzes post-drug treatment waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and is acquired after administering a drug candidate substance to the cardiomyocytes, and presents abnormal waveform candidates falling within a boundary region set in advance as the boundary between abnormality and normality. [Supplementary Item 2] The information processing device according to Supplementary Item 1, wherein the processor presents the abnormal waveform candidates by displaying the post-drug treatment waveform data and then displaying a portion of the post-drug treatment waveform data that corresponds to the abnormal waveform candidate in a manner that enables it to be distinguished from the other portions. [Supplementary Item 3] The information processing device according to Supplementary Item 1 or Supplementary Item 2, wherein the boundary region is a range between two different criteria. [Supplementary Item 4] The information processing device according to any one of Supplementary Items 1 to 3, wherein the abnormal waveform candidate is a waveform that is a candidate for an abnormal waveform representing any one of EAD, DAD, and cardiac arrest. [Supplementary Item 5] The information processing device of Supplementary Item 4, wherein the processor presents, as an abnormal waveform candidate related to EAD, a waveform that drops between the first and second peaks in a pulsation cycle and is included in a boundary region. [Supplementary Item 6] The information processing device of Supplementary Item 4 or Supplementary Item 5, wherein the processor presents, as an abnormal waveform candidate related to DAD, a waveform that drops between the second peak in a pulsation cycle and the first peak of the next cycle and is included in a boundary region. [Supplementary Item 7] The information processing device of any one of Supplementary Item 4 to Supplementary Item 6, wherein the processor presents, as an abnormal waveform candidate related to cardiac arrest, a waveform in which the first peak in a pulsation cycle is included in a boundary region and the second peak is not detected. [Supplementary Item 8] The information processing device of any one of Supplementary Item 1 to Supplementary Item 7, wherein the drug-treated waveform data is waveform data acquired using an MEA plate having a plurality of electrodes provided on its bottom and a plurality of wells in which cardiomyocytes can be placed.[Supplementary Item 9] An operating method for an information processing device having a processor, wherein the processor analyzes post-drug treatment waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and which is obtained after administering a drug candidate substance to the cardiomyocytes, and presents abnormal waveform candidates which fall within a boundary region which is preset as the boundary between abnormal and normal. [Supplementary Item 10] An operating program for an information processing device having a processor, which causes the processor to execute processes including: analyzing post-drug treatment waveform data, which is waveform data representing electrical changes in response to the pulsation of cardiomyocytes and which is obtained after administering a drug candidate substance to the cardiomyocytes, and presenting abnormal waveform candidates which fall within a boundary region which is preset as the boundary between abnormal and normal.

[0086] 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.

[0087] 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.

[0088] The disclosure of Japanese Patent Application No. 2024-052147, 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 analyzes drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is obtained after administering a drug candidate substance to the cardiomyocytes, and presents abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal.

2. The information processing device according to claim 1, wherein the processor presents the abnormal waveform candidate by displaying the drug-treated waveform data and then displaying the portion of the drug-treated waveform data that corresponds to the abnormal waveform candidate in a manner that makes it distinguishable from other portions.

3. The information processing device according to claim 1, wherein the boundary region is a range between two different criteria.

4. The information processing device according to claim 1, wherein the abnormal waveform candidate is a waveform that is a candidate for an abnormal waveform that indicates any one of EAD, DAD, and cardiac arrest.

5. The information processing device according to claim 4, wherein the processor presents a waveform that falls between the first and second peaks in the beat cycle and is included in the boundary region as the abnormal waveform candidate related to the EAD.

6. The information processing device according to claim 4, wherein the processor presents a waveform that falls between the second peak in the beat cycle and the first peak in the next cycle and is included in the boundary region as a candidate abnormal waveform related to the DAD.

7. The information processing device according to claim 4, wherein the processor presents a waveform in which the first peak in the beat cycle is included in the boundary region and in which the second peak is not detected as the abnormal waveform candidate related to cardiac arrest.

8. The information processing device according to claim 1, wherein the post-drug treatment 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.

9. A method for operating an information processing device having a processor, wherein the processor analyzes drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and is obtained after administering a drug candidate substance to the cardiomyocytes, and presents abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal.

10. An operating program for an information processing device having a processor, which causes the processor to execute processing including: analyzing drug-treated waveform data, which is waveform data representing electrical changes corresponding to the pulsation of cardiomyocytes and which is obtained after administering a drug candidate substance to the cardiomyocytes; and presenting abnormal waveform candidates that fall within a boundary region that is preset as the boundary between abnormal and normal.

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