WO2025204132A1 - Information processing device, operation method for information processing device, and operation program for information processing device - Google Patents

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

The technology disclosed herein relates to an information processing device, an operating method for an information processing device, and an operating program for an information processing device.

In the field of drug discovery, microelectrode arrays (MEAs) are used as a method for evaluating toxicity using cardiomyocytes generated from iPS (induced pluripotent stem) cells.
A technique using a microelectrode array has been developed (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-like cardiomyocyte is formed at the bottom of each well in contact with the multiple microelectrodes. Each microelectrode outputs waveform data representing an 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 that is compared with the drug-treated waveform data. The control waveform data is, for example, pre-administration waveform data obtained from cardiomyocytes before administering the drug candidate substance, and the drug-treated waveform data is, for example, post-administration waveform data obtained after administering the drug candidate substance to the same cardiomyocytes.

Evaluation items for toxicity assessment include, for example, items that evaluate 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 beat cycle of waveform data, and corresponds to the time interval between the Q wave and T wave in an electrocardiogram. The first peak corresponds to the time of depolarization in the action potential of myocardial cells, and the second peak corresponds to the time of repolarization in the action potential.

As detecting repolarization time is therefore important in toxicity assessment, JP 2022-505816 A and WO 2021/236535 A describe technology for detecting repolarization time by taking advantage of the correlation between the duration of extracellular potential and repolarization time.

Normally, the time of repolarization in an action potential coincides with the appearance of the second peak, which represents a maximum value, in waveform data that represents 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, there may be significant distortion in the waveform of the extracellular potential, and the extracellular potential at the time of repolarization may not reach a maximum value or maximum value. In such cases where the extracellular potential at the time of repolarization is not a maximum or maximum value, it can be difficult to detect the time of repolarization using conventional methods.

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 time of repolarization with greater accuracy than conventional methods, even when the extracellular potential at the time of repolarization is not at a maximum or maximum value.

In order to achieve the above object, the information processing device disclosed herein is an information processing device equipped with a processor, which obtains second-order derivative data by performing second-order differentiation on waveform data that represents changes in extracellular potential in response to the pulsation of cardiomyocytes, detects the repolarization time in the action potential of cardiomyocytes based on the second-order derivative data, and presents the detection results.

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

The second condition is preferably whether or not the negative drop in the extracellular potential in the waveform data is greater than or equal to a certain value.

If multiple candidates for the repolarization time are detected based on the second-order differential data, the processor preferably has the function of detecting the repolarization time from the latest candidate time within the pulsation period.

It is preferable that the waveform data include 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.

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

It is preferable that the processor has a function to prompt the user for confirmation if the detection accuracy of the repolarization time is below a certain standard.

It is preferable that the waveform data be obtained using an MEA plate that has multiple electrodes on the bottom and multiple wells in which cardiomyocytes can be placed.

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 obtains second-order derivative data by performing second-order differentiation on waveform data that represents 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 results.

The operating program for an information processing device according to the disclosed technology is an operating program for an information processing device equipped with a processor, and causes the processor to perform processes including obtaining second-order derivative data by performing second-order differentiation on waveform data that represents changes in extracellular potential in response to the pulsation of cardiomyocytes, detecting the repolarization time in the action potential of cardiomyocytes based on the second-order derivative data, and presenting the detection results.

The technology disclosed herein allows for more accurate detection of the second peak than conventional techniques that do not use second-order derivative data, even when the second peak is not the maximum value in the pulsation cycle.

FIG. 1 is a diagram schematically illustrating an electrical function evaluation system. FIG. 2 is a perspective view showing an example of an MEA plate. FIG. 1 is a diagram showing an example of a well. FIG. 1 shows an example of a microelectrode array. FIG. 2 is a block diagram illustrating an example of a hardware configuration of the electrical function evaluation system. FIG. 2 is a block diagram illustrating an example of a functional configuration of the information processing device. FIG. 1 is a diagram showing an example of a myocardial waveform. FIG. 10 is a diagram showing the variability of pre-administration waveform data. FIG. 10 is a diagram showing an example of waveform data output from a microelectrode array. FIG. 10 is a diagram showing an example of waveform data that changes upon administration of a drug candidate substance. FIG. 10 is a diagram showing an example of waveform data in which EAD occurs. FIG. 10 is a diagram showing an example of waveform data in which DAD occurs. FIG. 10 is a diagram showing an example of waveform data in which cardiac arrest occurs. FIG. 10 is a diagram showing an example of a case where the repolarization point is not a maximum value. FIG. 10 is an enlarged view showing an example in which the repolarization point is not a maximum value. 10 is a flowchart showing an example of a processing procedure for detecting repolarization time. FIG. 10 is a diagram illustrating an example of processing for removing unnecessary portions. FIG. 10 is a diagram illustrating an example of second-order differential data. FIG. 10 is a diagram showing an example of how to determine the repolarization time. FIG. 10 is a diagram showing an example of using different post-administration waveform data to detect repolarization time. FIG. 10 is a diagram illustrating a warning process for a user.

Embodiments of the technology disclosed herein will be described below with reference to the drawings.

Figure 1 shows a schematic diagram of an electrical function evaluation system 2 that measures the electrical activity of cells. The electrical function evaluation system 2 shown in Figure 1 is composed of a cell culture device 10 and an information processing device 20. The cell culture device 10 makes it possible to measure waveforms that indicate electrophysiological changes in cells (e.g., myocardial waveforms that indicate the pulsation of cardiomyocytes) while culturing the cells. The cell culture device 10 also controls the culture environment (e.g., temperature, carbon dioxide concentration).

An MEA plate 30 is used for cell culture. The cell culture device 10 is provided with a culture chamber 11 that houses the MEA plate 30. The cell culture device 10 also has a sliding lid 12 for opening and closing the culture chamber 11. The MEA plate 30 is attached to the culture chamber 11 with cells seeded on it. The culture chamber 11 functions as an incubator, allowing cells to be cultured for long periods of time.

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

The information processing device 20 is configured as a general-purpose 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, touchpad, or mouse. The information processing device 20 is connected to the cell culture device 10 via a wired or wireless connection. The display unit 21 and input unit 22 may be configured as external devices connected to the information processing device 20.

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 are substances such as compounds that are drug candidates created during the drug development process. Drug-treated waveform data in which the drug candidate substance is administered and control waveform data that is compared with the drug-treated waveform data can be used to evaluate the cardiotoxicity, which is the effect that the drug candidate substance has 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.

Control waveform data is, for example, pre-administration waveform data obtained from cardiomyocytes before the administration of a drug candidate substance, and drug-treated waveform data is, for example, post-administration waveform data obtained after the drug candidate substance is administered to the same cardiomyocytes. Alternatively, a negative control group of cardiomyocytes not administered the drug candidate substance and a drug-administered group of cardiomyocytes administered the drug candidate substance may be prepared, and waveform data obtained from the negative control group may be used as control waveform data, and waveform data obtained from the drug-administered group may be used as drug-treated waveform data. In the following, an example will be explained using post-administration waveform data as drug-treated waveform data and pre-administration waveform data as control waveform data.

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

Figure 3 shows an example of a well 32. The well 32 is a roughly 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 Figure 4) is provided on the bottom 34 of the well 32; for example, the microelectrode array 40 is embedded in the bottom 34.

Figure 4 shows an example of a microelectrode array 40. The microelectrode array 40 has a plurality of electrodes 41. In the example shown in Figure 4, the microelectrode array 40 has 16 microelectrodes (hereinafter simply referred to as electrodes) 41 arranged in a 4x4 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. Below, 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.

Figure 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 an 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 a microelectrode array 40 provided in each well 32. In other words, the potential measurement circuit 50 measures 16 myocardial waveforms for each well 32.

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.

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 the processing. The processor 23 is, for example, a CPU (Central Processing Unit).
is.

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, RAM (Random Access Memory), ROM (Read Only Memory), or 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 an HDD (Hard Disk Drive) or SSD (Solid State Drive), which stores the OS (Operating System), various data, etc. 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.

FIG. 6 shows an example of the functional configuration of the information processing device 20. The information processing device 20 realizes various functions by having the processor 23 execute processing based on the program 28. These various functions may also be realized by hardware. Note that the program 28 is an example of an "operation program" according to the technology disclosed herein.

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.

The output unit 62 performs output processing to output the analysis results of the analysis unit 61 to the display unit 21. The analysis results are presented to the user through the output processing. The output processing is an example of processing that realizes "presentation" according to the technology of the present disclosure. Note that in this example, the output processing shows an example of outputting to the display unit 21 of the information processing device 20, but the analysis results may also 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 can also be realized through such output processing.

FIG. 7 shows an example of a myocardial waveform. FIG. 7(A) shows a myocardial waveform representing the intracellular action potential of myocardial cells, and FIG. 7(B) shows a myocardial waveform representing changes in the extracellular potential of myocardial cells 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. 7(B).

As is well known, cardiomyocytes have corresponding ion channels that allow ions such as sodium ions (Na ⁺ ), calcium ions (Ca ²⁺ ), and potassium ions (K ⁺ ) to pass in and out of the cells. When the cell membrane is stimulated, the permeability of the ion channels changes, allowing ions to flow in and out through the ion channels. This causes contraction and expansion of the cardiomyocytes. Contraction and expansion occur periodically, resulting in pulsation. The action potential within the cardiomyocytes changes in response to this pulsation, as shown in Figure 7(A).

Specifically, when the cell membrane of a cardiac muscle cell is not excited, the intracellular potential is maintained at a negative level, while the extracellular potential is positive, resulting in a polarized state between the inside and outside of the cell. When the cell membrane is stimulated, the permeability of the sodium ion (Na ⁺ ) ion channel increases, allowing sodium ions (Na ⁺ ) to flow into the cell. As positive ions flow into the cell, the intracellular potential shifts to a positive state. This marks the beginning of an excited state for cardiac muscle cells. This state is called depolarization, as it transitions in a direction that eliminates the potential difference between the polarized cell and its outside. This change in potential increases the permeability of the calcium ion (Ca ²⁺ ) ion channel, allowing calcium ions (Ca ²⁺ ) to flow into the cell. This maintains a positive intracellular potential for a while. Subsequently, the permeability of the potassium ion (K ⁺ ) ion channel increases, allowing potassium ions (K ⁺ ) to flow out of the cell, returning the intracellular potential to a negative state. This results in polarization again inside and outside the cell. This is called repolarization. Repolarization terminates the excited state of cardiac muscle cells. Cardiomyocytes periodically repeat this excited state, which manifests as a pulsation.

In response to this pulsation, the extracellular potential measured by the MEA plate 30 changes as shown in Figure 7(B). First, when no action potential is generated in the cardiomyocyte, the extracellular potential maintains a reference potential of approximately "0." When depolarization occurs in the cardiomyocyte, 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 cardiomyocyte, the extracellular potential exhibits relatively steep rises and falls. 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.

In Figure 7 (B), FPD is the extracellular potential duration (FPD: Field Potential Duration), and ISI is the interspike interval (ISI: Interspike Interval), 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 will vary depending on the state of the cardiomyocytes or various factors at the time of measurement, even under the same measurement conditions.

Figure 8 shows waveform variability when measurement conditions are the same. 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 time of the first peak P1 aligned. As shown in Figure 8, the pre-administration waveform data varies in the time of the second peak P2, resulting in variability in the FPD. There is also variability in the ISI. There is also variability in the amplitude A2 of the second peak P2.

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

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 determined to be suitable for use in toxicity assessment based on pre-administration waveform data before the drug candidate substance is administered. Wells 32 that can output suitable waveform data are then used for toxicity assessment.

Furthermore, the waveforms shown in Figures 7(B) and 8 show the 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.

Figure 10 shows changes in the waveform when a drug candidate substance is administered to cardiomyocytes. Figure 10 shows pre-administration waveform data before administration and post-administration waveform data after administration, overlaid with the time of the first peak P1 aligned. The post-administration waveform data shows multiple post-administration waveform data for 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. This type of waveform disturbance is thought to occur when the toxicity of the drug candidate substance inhibits the ion channels in the cardiomyocytes mentioned above.

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

The toxicity assessment of a drug candidate substance is performed by analyzing pre-administration waveform data and multiple post-administration waveform data at different concentrations, as shown in Figure 10, and comparing the analysis results. For example, the FPD (see Figure 7) corresponds to the QT interval (the time from the start of the Q wave to the end of the T wave) in an electrocardiogram, and is therefore 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 the FPD, users can assess the cardiotoxicity of a drug candidate substance, which is its toxicity to the heart. In addition to FPD, other cardiotoxicity assessment items include EAD (Early After Depolarization), DAD (Delayed After Depolarization), and cardiac arrest.

As shown in Figure 11, EAD is a phenomenon in which depolarization occurs before the second peak P2. In the waveform data of the extracellular potential, EAD appears as an abnormal convex waveform with a minus peak, dropping between the first peak P1 and the second peak P2. As shown in Figure 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 Figure 13(A), in the case of cardiac arrest, signals such as peaks at the time of beating are not observed in the waveform data of the extracellular potential. Figure 13(A) shows a case in which beating has completely stopped, and is a typical example of cardiac arrest. In addition to Figure 13(A), cardiac arrest may also be evaluated when there is some amplitude indicating beating, but no peaks or other signals are observed, as shown in Figure 13(B). When assessing both Figure 13(A) and Figure 13(B) as cardiac arrest, cardiac arrest is determined based on the following two features. The first feature (feature 1 in Figure 13(B)) is that the first peak P1 does not drop much in the negative direction, and its absolute value is below a certain value (for example, the threshold THC). The second feature (feature 2 in Figure 13(B)) is that the second peak P2 cannot be confirmed. By determining an abnormal waveform based on these features, it is possible to assess cardiac arrest in Figure 13(B) in addition to Figure 13(A).

As shown in Figures 8 and 10, the repolarization time of an action potential typically coincides with the appearance time of the second peak P2, which indicates a 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 the drug candidate substance, there may be significant waveform distortion, and the extracellular potential at the repolarization time TP may not reach a maximum value or a maximum value. Here, PP indicates the extracellular potential at the repolarization time TP and is called the repolarization point in the extracellular potential.

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

Conventionally, the maximum value after a certain time after the first peak P1 is detected as the second peak P2, and the time at which the second peak P2 appears is taken as the repolarization time TP. With this conventional method, as shown in Figure 15, if the repolarization point PP is not a maximum value like the second peak P2, there is a risk that the repolarization time TP will be erroneously detected, making it impossible to accurately detect the repolarization time TP.

As mentioned above, when evaluating the toxicity of a drug candidate substance, it is necessary to read the FPD, EAD, and DAD from the waveform data. In order to read the FPD, EAD, and DAD, it is necessary to know where the repolarization time TP is in the waveform data being 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.

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

FIG. 16 is a flowchart showing an example of the processing procedure when the analysis unit 61 detects the repolarization time TP. Data such as conditions referenced by the analysis unit 61 to detect the repolarization time TP is stored in the memory 24 as reference information 29.

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 these 16 channels of waveform data, waveform data that meets the above-mentioned 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 beat period (corresponding to the beat interval ISI in Figure 7), which is the interval between multiple first peaks P1.

As waveform data, pre-administration waveform data before administration of the drug candidate substance and post-administration waveform data after administration are acquired. Furthermore, for 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 attached to each waveform data.

In step S2000, the analysis unit 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 pieces of data of, for example, two beats in length, and the resulting data of two beats is superimposed based on the first peak P1, and the average value is calculated. Next, the first peak P1, which is an unnecessary portion for detecting the repolarization time TP, is deleted from the waveform data whose average value has been calculated.

As shown in Figure 17, one example of deleting unnecessary parts is the process of deleting a certain amount of time TC before and after the first peak P1, which corresponds to the beginning and end of one beat. The value of the certain amount of time TC before and after the first peak P1 may be different.

Furthermore, as pre-processing, a process is performed to smooth the waveform data from which unnecessary portions have been removed. One example of smoothing processing is to calculate the moving average value in the time direction for the amplitude values of the post-administration waveform data and regenerate 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, making it possible to turn the waveform data into a smooth curve. After completing pre-processing, the analysis unit 61 proceeds to step S3000 shown in Figure 16.

In step S3000, the analysis unit 61 obtains second-order derivative data by performing second-order differentiation on the waveform data. Figure 18 shows the waveform data shown in Figure 15 and its second-order derivative data. The analysis unit 61 detects the repolarization time TP in the waveform data based on the obtained second-order derivative data.

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.

Specifically, as shown in FIG. 18, portions of the waveform data where the extracellular potential drops in the negative direction appear as negative peaks in the second-derivative data. In the example shown in FIG. 18, the portions of the waveform data where the extracellular potential drops in the negative direction are the waveform portion near the maximum value MP and the waveform portion including the change point XP. Therefore, negative peaks appear in the second-derivative data in portions corresponding to these waveform portions. The greater the drop in the negative direction in the waveform data, the greater the drop in the negative peak in the second-derivative data (i.e., the absolute value of the negative peak). In the example shown in FIG. 18, the drop in the negative direction is steeper in the waveform portion of the waveform corresponding to the change point XP than at the maximum value MP, and therefore the drop in the negative peak in the second-derivative data is also greater in the portion corresponding to the change point XP than in the portion corresponding to the maximum value MP.

The analysis unit 61 first searches the second-order derivative data for portions that indicate negative peaks, such as the maximum value MP and the change point XP. It then 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 derivative data. More specifically, the first condition is a condition that the negative drop (absolute value of the negative peak) in the second-order derivative 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 derivative 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.

In Figure 18, as an example, the constant value for 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 more than the constant value ("4"), satisfying the first condition. In contrast, the portion corresponding to the maximum value MP has a drop in the negative direction of less than the constant value ("4"), not satisfying the first condition. Furthermore, with regard to 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 is an example of a potential change of more than the constant value, while ΔAM is an example of a potential change less than the constant value. Therefore, the second condition is satisfied for the change point XP, but not for the maximum value MP.

In step S4000, the analysis unit 61 performs this determination and identifies waveform portions that include a change point XP that satisfies the conditions as candidate portions that include a repolarization point PP. In the example shown in FIG. 18, the waveform portion in the waveform data that includes the change point XP is identified as a candidate portion that includes a repolarization point PP.

Note that while the example shown in FIG. 18 is an example in which there is only one candidate portion that satisfies the first and second conditions, 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.

In step S5000, the analysis unit 61 detects the repolarization time TP from the candidate portion. First, in the example shown in FIG. 18, there is only one candidate portion that satisfies the first and second conditions, the waveform portion including the change point XP, so 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, as an example, detects the repolarization time TP from the candidate portion that is the latest within the beat period among the multiple candidate portions.

Candidate portions are extracted as portions with a temporal 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 there are other methods for detecting the repolarization time TP from the candidate portion besides the method shown in FIG. 19. For example, the time corresponding to the maximum amplitude in the candidate portion may be determined as the repolarization time TP. In this way, the method for detecting the repolarization time TP from the candidate portion may be determined appropriately, taking into account the correlation between the action potential and the extracellular potential.

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

As explained above, in the information processing device 20 according to the technology of the present disclosure, the processor 23 obtains second-order derivative data by performing second-order differentiation on waveform data that represents changes in the extracellular potential in response to the pulsation of cardiomyocytes, detects the repolarization time of the action potential of the cardiomyocytes based on the second-order derivative data, and presents the detection result. This makes it possible to detect the repolarization time with greater accuracy than conventional methods, even when the extracellular potential at the repolarization time is not a local maximum or maximum value.

In addition, the processor 23 uses two conditions to detect the repolarization time TP: a first condition related to the amplitude of the negative peak in the second 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 derivative data, the repolarization time TP can be detected with greater accuracy than when the second condition is not used. Furthermore, the second condition is a condition as to whether 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 does not complicate the process.

In addition, when multiple candidates for the repolarization time TP are detected based on the second-order differential data, the processor 23 has the function of detecting the repolarization time TP from the latest candidate within the pulsation cycle. Such a judgment 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 judgment condition can easily simplify processing.

Furthermore, the waveform data to be analyzed to detect repolarization time TP includes at least post-administration waveform data, which is pre-administration waveform data before a drug candidate substance is administered to cardiomyocytes, and post-administration waveform data after the drug candidate substance is administered. Furthermore, as shown in FIG. 14, detecting repolarization time TP is often more difficult with post-administration waveform data than with pre-administration waveform data. Therefore, the technology disclosed herein is more effective with post-administration waveform data.

Furthermore, as shown in FIG. 14, the post-administration waveform data includes multiple pieces of post-administration waveform data with different concentrations of the administered drug candidate substance. In this case, when detecting the repolarization time TP for one piece of target data among the multiple pieces of post-administration waveform data, the 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.

Specifically, as shown in FIG. 20, consider the case where there is a plurality of post-administration waveform data of different concentrations, and 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 the plurality of post-administration waveform data other than the post-administration waveform data of an ultra-high concentration is examined, the time of the second peak P2 tends to be later as the concentration increases, as indicated by the thick arrow in FIG. 20. Taking this tendency into consideration, it is thought that the repolarization time TP of the post-administration waveform data of an ultra-high concentration is later than that of the post-administration waveform data of a high concentration. Based on this tendency, processor 23 determines the change point XP, rather than the maximum value MP, to be the repolarization point PP, and detects the repolarization time TP.

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 can be improved by using information from post-administration waveform data other than the target data.

Furthermore, as shown in FIG. 21, the processor 23 may have a function to prompt the user for confirmation if the detection accuracy of the repolarization time TP is below a standard. The processor 23 calculates the detection accuracy. If the detection accuracy is below a preset standard, the processor 23 displays a warning on the display unit 21 to prompt the user for confirmation along with the detection result. The detection accuracy is determined to be below the standard if, for example, 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.

In the above embodiment, the hardware structure of the processing units that perform various processes, such as the data acquisition unit 60, analysis unit 61, and output unit 62, is the various processors shown below.

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 with a circuit configuration designed specifically to perform specific processing, such as an ASIC (Application Specific Integrated Circuit).

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 (for example, multiple FPGAs, or a combination of a CPU and an FPGA). Multiple processing units may also be configured with a single processor. Examples of multiple processing units configured with a single processor include, first, a form in which one or more CPUs are combined with software to form a single processor, and this processor functions as multiple processing units. Second, a form in which a processor is used to realize 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 a hardware structure using one or more of the various processors listed above.

Furthermore, the hardware structure of these various processors is, more specifically, an electrical circuit that combines circuit elements such as semiconductor devices.

The above explanation allows one to understand the following techniques.
[Additional note 1]
An information processing device including a processor,
The processor
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to the pulsation of cardiomyocytes;
Detecting a repolarization time in an action potential of a cardiac muscle cell based on the second-order differential data;
Presenting the detection results,
Information processing device.
[Additional note 2]
The processor uses two conditions, 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 waveform data corresponding to the peak, to detect the repolarization time.
Item 1. An information processing device according to item 1.
[Additional note 3]
The second condition is whether or not the waveform data has a negative drop in the extracellular potential of a certain value or more.
3. The information processing device according to claim 2.
[Additional note 4]
The processor
When multiple candidates for the repolarization time are detected based on the second-order differential data, the repolarization time is detected from the candidate with the latest time within the pulsation period.
4. The information processing device according to any one of claims 1 to 3.
[Additional note 5]
The waveform data includes at least post-administration waveform data out of pre-administration waveform data before administering the drug candidate substance to the cardiomyocytes and post-administration waveform data after administering the drug candidate substance.
5. The information processing device according to any one of claims 1 to 4.
[Additional note 6]
In the case where the post-administration waveform data includes a plurality of post-administration waveform data with different concentrations of the administered drug candidate substance, and the repolarization time is detected for one target data among the plurality of post-administration waveform data,
The processor uses information of the post-administration waveform data other than the target data to detect the repolarization time in the target data.
6. The information processing device according to claim 5.
[Additional note 7]
The processor has a function of prompting a user for confirmation when the detection accuracy of the repolarization time is below a standard.
7. The information processing device according to any one of claims 1 to 6.
[Additional Note 8]
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 cardiomyocytes can be placed.
8. An information processing device according to any one of claims 1 to 7.
[Additional Note 9]
A method for operating an information processing device having a processor, comprising:
The processor
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to the pulsation of cardiomyocytes;
Detecting a repolarization time in an action potential of a cardiac muscle cell based on the second-order differential data;
Presenting the detection results,
A method for operating an information processing device.
[Additional Note 10]
An operating program for an information processing device having a processor,
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to pulsation of cardiomyocytes;
Detecting a repolarization time in an action potential of a cardiomyocyte based on the second derivative data;
Presenting the detection results;
An operating program for an information processing device that causes a processor to execute processing including the steps of:

The technology of the present disclosure can be appropriately combined with the various embodiments and/or modified examples described above. Furthermore, it is not limited to the above embodiments, and various configurations can be adopted as long as they do not deviate from the gist of the technology. Furthermore, the technology of the present disclosure extends not only to programs but also to storage media that non-temporarily store programs. Storage media are, for example, computer-readable non-temporary storage media such as USB (Universal Serial Bus) memory, flexible disks, and CD-ROMs (Compact Disc Read Only Memory). Programs may also be provided online via a network such as the Internet. The technology of the present disclosure also extends not only to programs but also to program products. Program products include all forms of products for providing programs. Like programs, program products may be provided stored on computer-readable non-temporary storage media, or they may be provided online.

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.

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 (10)

An information processing device including a processor,
The processor:
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to the pulsation of cardiomyocytes;
detecting a repolarization time in an action potential of the cardiomyocyte based on the second-order differential data;
Presenting the detection results,
Information processing device. the processor uses two conditions, 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, to detect the repolarization time.
The information processing device according to claim 1 . The second condition is whether or not the waveform data has a negative drop of a certain value or more in the extracellular potential.
The information processing device according to claim 2 . The processor:
and when a plurality of candidates for the repolarization time are detected based on the second-order differential data, detecting the repolarization time from the candidate that is the latest time within the pulsation period.
The information processing device according to claim 1 . 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.
The information processing device according to claim 1 . In the case where the post-administration waveform data includes a plurality of post-administration waveform data in which the drug candidate substance is administered at different concentrations, and the repolarization time is detected for one target data among the plurality of post-administration waveform data,
The processor uses information of the post-administration waveform data other than the subject data to detect the repolarization time in the subject data.
The information processing device according to claim 5 . The processor has a function of prompting a user for confirmation when the detection accuracy of the repolarization time is below a standard.
The information processing device according to claim 1 . The waveform data is waveform data acquired using an MEA plate having a plurality of electrodes provided on the bottom thereof and a plurality of wells in which the cardiomyocytes can be placed.
The information processing device according to claim 1 . A method for operating an information processing device having a processor, comprising:
The processor:
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to the pulsation of cardiomyocytes;
detecting a repolarization time in an action potential of the cardiomyocyte based on the second-order differential data;
Presenting the detection results,
A method for operating an information processing device. An operating program for an information processing device having a processor,
obtaining second-order differential data by performing second-order differentiation on waveform data representing changes in extracellular potential according to pulsation of cardiomyocytes;
detecting a repolarization time of an action potential of the cardiomyocyte based on the second-order differential data;
Presenting the detection results;
An operating program for an information processing device that causes a processor to execute processing including the steps of: