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 acquires second-order differential data by subjecting waveform data, which indicate the change in extracellular potentials in accordance with the pulsation of cardiomyocytes, to second-order differentiation, detects a repolarization time at an action potential of the cardiomyocytes on the basis of the second-order differential data, and presents the results of the detection.

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 JP 2022-505816 A). A microelectrode array is an arrangement 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 the extracellular potential corresponding to the pulsation of the 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] Toxicity assessment items include, for example, an item for evaluating the risk of arrhythmia, focusing on changes in FPD (Field Potential Duration) in waveform data before and after administration. FPD is the time interval between the first and second peaks in the pulsation cycle of waveform data, and corresponds to the time interval between the Q wave and the T wave in an electrocardiogram. The first peak corresponds to the depolarization time in the action potential of cardiomyocytes, and the second peak corresponds to the repolarization time in the action potential.

[0004] Therefore, since it is important to detect the repolarization time in toxicity assessment, JP2022-505816A and WO2021 / 236535A describe a technique for detecting the repolarization time by taking advantage of the correlation between the duration of the extracellular potential and the repolarization time.

[0005] Typically, the repolarization time of an action potential coincides with the appearance time of the second peak, which represents a maximum value, in waveform data representing changes in the extracellular potential. Furthermore, the extracellular potential at the time of repolarization often appears as a maximum value after the first peak. However, depending on the concentration of the administered drug candidate, the waveform of the extracellular potential may be significantly distorted, and the extracellular potential at the time of repolarization may not reach a maximum value or a maximum value. In such cases where the extracellular potential at the time of repolarization is not a maximum value or a maximum value, it may be difficult to detect the repolarization time using conventional methods.

[0006] One embodiment of the technology disclosed herein provides an information processing device, an operating method for an information processing device, and an operating program for an information processing device that can detect the repolarization time more accurately than conventional methods, even if the extracellular potential at the repolarization time is not a maximum or maximum value.

[0007] In order to achieve the above object, the information processing device of the present disclosure is an information processing device equipped with a processor, which obtains second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to the pulsation of cardiomyocytes, detects the repolarization time in the action potential of the cardiomyocytes based on the second-order differential data, and presents the detection result.

[0008] The processor preferably uses two conditions for detecting the repolarization time: a first condition related to the amplitude of a negative peak in the second derivative data, and a second condition related to the amplitude of the waveform data corresponding to the peak.

[0009] The second condition is preferably whether or not the waveform data has a minus drop in the extracellular potential of a certain value or more.

[0010] Preferably, the processor has a function of detecting the repolarization time from the latest candidate time within the pulsation period when multiple candidates for the repolarization time are detected based on the second derivative data.

[0011] The waveform data preferably includes at least post-administration waveform data, out of pre-administration waveform data before the drug candidate substance is administered to the cardiomyocytes and post-administration waveform data after the drug candidate substance is administered.

[0012] When the post-administration waveform data includes multiple post-administration waveform data with different concentrations of the administered drug candidate substance, and when detecting the repolarization time for one target data among the multiple post-administration waveform data, it is preferable that the processor use information on post-administration waveform data other than the target data to detect the repolarization time in the target data.

[0013] The processor preferably has a function of prompting the user for confirmation when the detection accuracy of the repolarization time is below a standard.

[0014] The 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.

[0015] A method for operating an information processing device according to the disclosed technology is a method for operating an information processing device having a processor, in which the processor obtains second-order derivative data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to the pulsation of cardiomyocytes, detects the repolarization time in the action potential of the cardiomyocytes based on the second-order derivative data, and presents the detection result.

[0016] An operating program for an information processing device according to the disclosed technology is an operating program for an information processing device having a processor, and causes the processor to execute processes including obtaining second-order derivative data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to the pulsation of cardiomyocytes, detecting the repolarization time in the action potential of the cardiomyocytes based on the second-order derivative data, and presenting the detection results.

[0017] According to the technology of the present disclosure, even when the second peak is not the maximum value in the pulsation cycle, the second peak can be detected with higher accuracy than in the past, which does not use second-order derivative data.

[0018] 1 is a diagram schematically showing an electrical function evaluation system. FIG. 1 is a perspective view showing an example of an MEA plate. FIG. 2 is a diagram showing an example of a well. FIG. 3 is a diagram showing an example of a microelectrode array. FIG. 4 is a block diagram showing an example of the hardware configuration of an electrical function evaluation system. FIG. 5 is a block diagram showing an example of the functional configuration of an information processing device. FIG. 6 is a diagram showing an example of a myocardial waveform. FIG. 7 is a diagram showing the variability of pre-administration waveform data. FIG. 8 is a diagram showing an example of waveform data output from a microelectrode array. FIG. 9 is a diagram showing an example of waveform data that changes due to the administration of a drug candidate substance. FIG. 10 is a diagram showing an example of waveform data in which EAD has occurred. FIG. 11 is a diagram showing an example of waveform data in which DAD has occurred. FIG. 12 is a diagram showing an example of waveform data in which cardiac arrest has occurred. FIG. 13 is a diagram showing an example of a case in which the repolarization point is not the maximum value. FIG. 14 is an enlarged diagram showing an example of a case in which the repolarization point is not the maximum value. FIG. 15 is a flowchart showing an example of a processing procedure for detecting repolarization time. FIG. 16 is a diagram showing an example of a process for removing unnecessary parts. FIG. 17 is a diagram showing an example of second-order differential data. FIG. 18 is a diagram showing an example of a method for determining repolarization time. FIG. 19 is a diagram showing an example of using different post-administration waveform data to detect repolarization time. FIG. 19 is a diagram showing a warning process for a user.

[0019] Hereinafter, embodiments of the technology of the present disclosure will be described with reference to the drawings.

[0020] 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).

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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).

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 7A and 7B show examples of myocardial waveforms. Fig. 7A shows a myocardial waveform representing the intracellular action potential of cardiomyocytes, and Fig. 7B 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 in Fig. 7B.

[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. 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. The first peak P1 corresponds to the time of depolarization in the action potential, and the second peak P2 corresponds to the time of repolarization in the action potential.

[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 obtained 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] As shown in Figures 8 and 10, the repolarization time of an action potential usually coincides with the appearance time of the second peak P2, which indicates a local maximum value, in waveform data representing changes in the extracellular potential. Furthermore, the extracellular potential at the repolarization time often appears as a maximum value after the first peak P1. However, as shown in Figure 14 as an example, depending on the toxicity of a drug candidate, waveform distortion may be significant, and the extracellular potential at the repolarization time TP may not be a maximum value or a local maximum value. Here, PP indicates the extracellular potential at the repolarization time TP and is called the repolarization point of the extracellular potential.

[0050] In the example shown in Fig. 14, in the waveform data when the concentration of the drug candidate substance is ultra-high, a maximum value MP appears between the first peak P1 and the repolarization point PP in the pulsation cycle, and the repolarization point PP is not the maximum value. Fig. 15 shows an enlarged view of the waveform data of ultra-high concentration shown in Fig. 14.

[0051] In the past, the maximum value at a certain time after the first peak P1 was detected as the second peak P2, and the time at which the second peak P2 appeared was determined to be the repolarization time TP. With this conventional method, as shown in Fig. 15 , if the repolarization point PP is not a maximum value like the second peak P2, the repolarization time TP may be erroneously detected, and the repolarization time TP cannot be detected accurately.

[0052] As described above, when evaluating the toxicity of a drug candidate substance, it is necessary to read the FPD, EAD, and DAD from waveform data. To read the FPD, EAD, and DAD, it is necessary to know where the repolarization time TP is in the waveform data to be evaluated. Therefore, in cases such as those shown in Figure 15 where the repolarization point PP is not a local maximum or maximum value, it is necessary to accurately detect the repolarization time TP.

[0053] The analysis unit 61 detects the repolarization time TP by obtaining second-order differential data of the waveform data, which makes it possible to detect the repolarization time TP from the waveform data even when the repolarization point PP is not at its maximum value.

[0054] 16 is a flowchart showing an example of a processing procedure for detecting the repolarization time TP by the analysis unit 61. Data such as conditions referenced by the analysis unit 61 for detecting the repolarization time TP is stored in the memory 24 as reference information 29.

[0055] In step S1000, the analysis unit 61 acquires waveform data measured by the MEA plate 30. The MEA plate 30 outputs waveform data for 16 channels for each well 32. Of the waveform data for these 16 channels, waveform data that meets the above-described eligibility is selected as the waveform data to be analyzed at the repolarization time TP. The waveform data acquired from the MEA plate 30 is, for example, data measured over several minutes and includes waveforms of several tens of beats. This waveform data also includes information on the pulsation period (corresponding to the pulsation interval ISI in FIG. 7 ), which is the interval between multiple first peaks P1.

[0056] As waveform data, pre-administration waveform data before administration of the drug candidate substance and post-administration waveform data after administration are respectively acquired. Furthermore, as post-administration waveform data, multiple waveform data are acquired with varying concentrations of the drug candidate substance. As shown in Figure 14 , the pre-administration waveform data and multiple post-administration waveform data with different concentrations after administration may have a one-beat period that varies depending on the concentration of the drug candidate substance, so information on the pulsation period is added to each waveform data.

[0057] In step S2000, the analyzer 61 performs preprocessing on the acquired waveform data before performing second-order differentiation. In this preprocessing, waveform data of several tens of beats in length is first divided into segments of, for example, two beats in length, and the resulting two-beat data are superimposed on the basis of the first peak P1 and averaged. Next, the first peak P1, which is unnecessary for detecting the repolarization time TP, is deleted from the averaged waveform data.

[0058] 17, the deletion of unnecessary portions is, for example, a process of deleting a certain period of time TC before and after a first peak P1 corresponding to the beginning and end of one beat. The value of the certain period of time TC before and after the first peak P1 may be different.

[0059] Further, as preprocessing, a process for smoothing the waveform data from which unnecessary portions have been removed is performed. As an example of the smoothing process, a moving average value in the time direction is calculated for the amplitude values ​​of the post-administration waveform data, and the post-administration waveform data is regenerated using the moving average value. This removes small peaks such as high-frequency noise from the post-administration waveform data, allowing the waveform data to form a smooth curve. After completing the preprocessing, the analysis unit 61 proceeds to step S3000 shown in FIG. 16.

[0060] In step S3000, the analyzer 61 obtains second-order differential data by performing second-order differentiation on the waveform data. Fig. 18 shows the waveform data shown in Fig. 15 and its second-order differential data. The analyzer 61 detects the repolarization time TP in the waveform data based on the obtained second-order differential data.

[0061] Specifically, first, in step S4000 shown in FIG. 16 , the analysis unit 61 identifies a waveform portion that satisfies a first condition regarding the second-order differential data and a second condition regarding the waveform data as a candidate portion of the waveform that includes the repolarization point PP, as shown below.

[0062] Specifically, as shown in FIG. 18 , a portion of the waveform data where the extracellular potential drops in the negative direction appears as a negative peak in the second-order derivative data. In the example shown in FIG. 18 , the portion of the waveform data where the extracellular potential drops in the negative direction corresponds to the waveform portion near the maximum value MP and the waveform portion including the change point XP. Therefore, in the second-order derivative data, a negative peak appears in the portion corresponding to these waveform portions. Furthermore, the greater the negative drop in the waveform data, the greater the negative peak drop in the second-order derivative data (i.e., the absolute value of the negative peak). In the example shown in FIG. 18 , the waveform data has a steeper negative drop in the waveform portion corresponding to the change point XP than the maximum value MP. Therefore, the negative peak drop in the second-order derivative data is also greater in the portion corresponding to the change point XP than in the portion corresponding to the maximum value MP.

[0063] The analysis unit 61 first searches for a portion of the second-order differential data that indicates a negative peak, such as the maximum value MP and the change point XP. Then, the analysis unit 61 determines whether the searched portion satisfies the first and second conditions. The first condition is a condition related to the amplitude of the negative peak in the second-order differential data. More specifically, the first condition is a condition that the negative drop (the absolute value of the negative peak) in the second-order differential data is equal to or greater than a certain value. The second condition is a condition related to the amplitude of the waveform data corresponding to the peak in the second-order differential data. More specifically, the second condition is a condition that there is a potential change of equal to or greater than a certain value near the peak.

[0064] In FIG. 18 , as an example, the constant value of the first condition is set to “4” (corresponding to an absolute value in the negative direction). In the second-order differential data, the portion corresponding to the change point XP has a drop in the negative direction of a constant value (“4”) or more, satisfying the first condition. In contrast, the portion corresponding to the maximum value MP has a drop in the negative direction of less than a constant value (“4”), not satisfying the first condition. Regarding the second condition related to the waveform data, the potential change near the peak is ΔAX at the change point XP and ΔAM at the maximum value MP. ΔAX is greater than ΔAM and represents an example of a potential change of a constant value or more, while ΔAM represents an example of a potential change less than a constant value. Therefore, the change point XP satisfies the second condition, but the maximum value MP does not.

[0065] In step S4000, the analyzer 61 performs this determination and identifies a waveform portion including a change point XP that satisfies the condition as a candidate portion including a repolarization point PP. In the example shown in Fig. 18, the waveform portion including the change point XP in the waveform data is identified as the candidate portion including the repolarization point PP.

[0066] 18 shows an example in which only one candidate portion satisfies the first and second conditions, but if there are multiple candidate portions that satisfy the first and second conditions, the analysis unit 61 identifies multiple candidate portions. In this way, the analysis unit 61 uses the two conditions, the first and second conditions, of the second-order differential data to detect the repolarization time TP. After identifying the candidate portion, the analysis unit 61 proceeds to step S5000 shown in FIG. 16.

[0067] In step S5000, the analysis unit 61 detects the repolarization time TP from the candidate portion. First, in the example shown in Fig. 18, the only candidate portion that satisfies the first and second conditions is the waveform portion including the change point XP, and therefore the repolarization time TP is detected from this waveform portion. On the other hand, if there are multiple candidate portions that satisfy the first and second conditions, the analysis unit 61, for example, detects the repolarization time TP from the candidate portion that is the latest within the beat period among the multiple candidate portions.

[0068] The candidate portion is extracted as a portion having a time width. The analysis unit 61 detects the repolarization time TP from the candidate portion, as shown in FIG. 19 as an example. In FIG. 19, the point corresponding to the minimum value of the second-order differential data is determined as the repolarization point PP, and the time corresponding to the repolarization point PP is detected as the repolarization time TP. Note that methods for detecting the repolarization time TP from the candidate portion may be other than those shown in FIG. 19. For example, the time corresponding to the maximum amplitude of the candidate portion may be determined as the repolarization time TP. The method for detecting the repolarization time TP from the candidate portion in this manner may be determined appropriately, taking into account the correlation between the action potential and the extracellular potential.

[0069] 16 , after step S5000, the process proceeds to step S6000. In step S6000, the output unit 62 displays the detection results on the display unit 21. The detection results include, for example, waveform data as shown in FIG. 15 , repolarization points PP, and repolarization times TP, and a screen showing these is displayed on the display unit 21.

[0070] As described above, in the information processing device 20 according to the technology of the present disclosure, the processor 23 obtains second-order differential data by performing second-order differentiation on waveform data representing changes in the extracellular potential according to the pulsation of cardiomyocytes, detects the repolarization time of the action potential of the cardiomyocytes based on the second-order differential data, and presents the detection result. This makes it possible to detect the repolarization time more accurately than conventional methods, even when the extracellular potential at the repolarization time is not a local maximum or maximum value.

[0071] Furthermore, the processor 23 uses two conditions for detecting the repolarization time TP: a first condition related to the amplitude of the negative peak in the second-order derivative data, and a second condition related to the amplitude of the waveform data corresponding to the peak. By using the second condition related to the amplitude of the waveform data in addition to the first condition related to the second-order derivative data, the repolarization time TP can be detected more accurately than when the second condition is not used. Furthermore, the second condition is a condition as to whether or not the negative drop in the extracellular potential in the waveform data is equal to or greater than a certain value. The second condition is a simple process, and therefore does not complicate the process.

[0072] Furthermore, when multiple candidates for the repolarization time TP are detected based on the second-order differential data, the processor 23 has a function of detecting the repolarization time TP from the candidate with the latest time within the pulsation cycle. Such a determination condition is set based on the tendency that the repolarization point PP corresponding to the repolarization time TP in the pulsation cycle is often a negative drop that appears at the latest time. When there are multiple candidates for the repolarization time TP, detecting the repolarization time TP using such a determination condition can easily simplify the processing.

[0073] Furthermore, the waveform data to be analyzed for detecting the repolarization time TP includes at least post-administration waveform data, which is obtained from pre-administration waveform data obtained before a drug candidate substance is administered to cardiomyocytes and post-administration waveform data obtained after the drug candidate substance is administered. Furthermore, as shown in FIG. 14 , detecting the repolarization time TP is often more difficult with post-administration waveform data than with pre-administration waveform data. Therefore, the technology of the present disclosure is more effective with post-administration waveform data.

[0074] 14, the post-administration waveform data includes a plurality of post-administration waveform data in which the concentrations of the administered drug candidate substance are different. In this case, when detecting the repolarization time TP for one target data among the plurality of post-administration waveform data, processor 23 may use information on post-administration waveform data other than the target data to detect the repolarization time TP for the target data.

[0075] Specifically, as shown in FIG. 20 , when there are multiple post-administration waveform data of different concentrations, consider the case where the repolarization time TP is detected for the post-administration waveform data of an ultra-high concentration, which is an example of target data. In this case, information on post-administration waveform data other than the post-administration waveform data of an ultra-high concentration is used to detect the repolarization time TP in the post-administration waveform data of an ultra-high concentration. In the example of FIG. 20 , similar to the example of FIG. 18 , the post-administration waveform data of an ultra-high concentration has a maximum value MP and a change point XP. Furthermore, when the second peak P2 corresponding to the repolarization time TP of multiple post-administration waveform data other than the post-administration waveform data of an ultra-high concentration is examined, as indicated by the bold arrow in FIG. 20 , the time of the second peak P2 tends to be delayed as the concentration increases. Considering this tendency, it is considered that the repolarization time TP of the post-administration waveform data of an ultra-high concentration is delayed compared to the post-administration waveform data of a high concentration. Based on this tendency, the processor 23 determines the change point XP, rather than the maximum value MP, as the repolarization point PP and detects the repolarization time TP.

[0076] Note that, depending on the drug candidate, the repolarization time TP may become earlier as the concentration increases, contrary to the example in Figure 20. In such cases, the maximum value MP may be detected as the repolarization time TP. In this way, when detecting the repolarization time TP from the target data, the accuracy of detecting the repolarization time TP is improved by using information on post-administration waveform data other than the target data.

[0077] 21 , the processor 23 may have a function of prompting the user to check if the detection accuracy of the repolarization time TP is below a reference level. The processor 23 calculates the detection accuracy. If the detection accuracy is below a preset reference level, the processor 23 displays a warning on the display unit 21 to prompt the user to check along with the detection result. For example, the detection accuracy is determined to be below the reference level if the minimum value of the negative peak in the second-order differential data is below a certain value. In this way, if the detection accuracy is low, it is left to the user's visual confirmation, thereby reducing erroneous detection.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] The above description allows the understanding of the following technologies. [Supplementary Item 1] An information processing device including a processor, wherein the processor obtains second-order derivative data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to pulsation of cardiomyocytes, detects a repolarization time in the action potential of the cardiomyocytes based on the second-order derivative data, and presents the detection result. [Supplementary Item 2] The information processing device according to Supplementary Item 1, wherein the processor uses two conditions, a first condition related to the amplitude of a negative peak in the second-order derivative data, and a second condition related to the amplitude of waveform data corresponding to the peak, to detect the repolarization time. [Supplementary Item 3] The information processing device according to Supplementary Item 2, wherein the second condition is a condition as to whether or not the negative drop in the extracellular potential in the waveform data is equal to or greater than a certain value. [Supplementary Item 4] The information processing device of any one of Supplementary Items 1 to 3, wherein the processor has a function of detecting the repolarization time from the latest candidate time within the beat period when multiple candidates for the repolarization time are detected based on the second-order differential data. [Supplementary Item 5] The information processing device of any one of Supplementary Items 1 to 4, wherein the waveform data includes at least post-administration waveform data out of pre-administration waveform data before the drug candidate is administered to the cardiomyocytes and post-administration waveform data after the drug candidate is administered. [Supplementary Item 6] The information processing device of Supplementary Item 5, wherein the post-administration waveform data includes multiple post-administration waveform data with different concentrations of the administered drug candidate, and when detecting the repolarization time for one target data item among the multiple post-administration waveform data items, the processor uses information on the post-administration waveform data items other than the target data item to detect the repolarization time for the target data item. [Supplementary Item 7] The information processing device according to any one of Supplementary Items 1 to 6, wherein the processor has a function of prompting a user for confirmation when the detection accuracy of the repolarization time is below a standard. [Supplementary Item 8] The information processing device according to any one of Supplementary Items 1 to 7, wherein the waveform data is waveform data acquired using an MEA plate having a plurality of electrodes provided on a bottom thereof and a plurality of wells in which cardiomyocytes can be placed.[Supplementary Item 9] An operating method of an information processing device having a processor, wherein the processor obtains second-order derivative data by performing second-order differentiation on waveform data representing changes in extracellular potential according to pulsation of cardiomyocytes, detects a repolarization time in the action potential of cardiomyocytes based on the second-order derivative data, and presents the detection result. [Supplementary Item 10] An operating program of an information processing device having a processor, which causes the processor to execute processes including: obtaining second-order derivative data by performing second-order differentiation on waveform data representing changes in extracellular potential according to pulsation of cardiomyocytes, detecting a repolarization time in the action potential of cardiomyocytes based on the second-order derivative data, and presenting the detection result.

[0083] 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.

[0084] 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 elements may be replaced in the above-described description and illustrations, as long as they do not deviate from 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.

[0085] The disclosure of Japanese Patent Application No. 2024-051831, 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 obtains second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to the pulsation of cardiomyocytes, detects the repolarization time in the action potential of the cardiomyocytes based on the second-order differential data, and presents the detection result.

2. The information processing device according to claim 1, wherein the processor uses two conditions to detect the repolarization time: a first condition related to the amplitude of a negative peak in the second derivative data, and a second condition related to the amplitude of the waveform data corresponding to the peak.

3. The information processing device according to claim 2, wherein the second condition is whether or not the minus drop of the extracellular potential in the waveform data is equal to or greater than a certain value.

4. The information processing device according to claim 1, wherein the processor has a function of detecting the repolarization time from the latest candidate time within the pulsation period when multiple candidates for the repolarization time are detected based on the second-order differential data.

5. The information processing device according to claim 1, wherein the waveform data includes at least the post-administration waveform data of pre-administration waveform data before administering a drug candidate substance to the cardiomyocytes and post-administration waveform data after administering the drug candidate substance.

6. The information processing device of claim 5, wherein the post-administration waveform data includes multiple post-administration waveform data with different concentrations of the drug candidate substance to be administered, and when the repolarization time is detected for one target data among the multiple post-administration waveform data, the processor uses information on the post-administration waveform data other than the target data to detect the repolarization time in the target data.

7. The information processing device according to claim 1, wherein the processor has a function of prompting a user for confirmation when the detection accuracy of the repolarization time is below a standard.

8. The information processing device according to claim 1, wherein the 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 obtains second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to the pulsation of cardiomyocytes, detects the repolarization time in the action potential of the cardiomyocytes based on the second-order differential data, and presents the detection result.

10. An operating program for an information processing device having a processor, which causes the processor to execute processes including: obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential in response to the pulsation of cardiomyocytes; detecting the repolarization time in the action potential of the cardiomyocytes based on the second-order differential data; and presenting the detection results.

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