JP2007222313A - Apparatus and program for determining biological parameter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To precisely and speedily acquire a biological parameter set including at least one appropriate biological parameter. <P>SOLUTION: An apparatus for determining a biological parameter is provided which comprises a simulation execution section that receives a biological parameter set, simulates heart activity, and acquires action potential information showing the action potential of the heart, a difference calculation section for calculating the difference between the acquired action potential information and experimental action potential information, a permissible parameter set determination section for determining whether the biological parameter set is within a permissible range or not using the difference calculated by the difference calculation section, and a permissible parameter output section for outputting a biological parameter set within the permissible range. Using the apparatus, a biological parameter set including at least one appropriate biological parameter is acquired precisely and speedily. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention is animal evaluation test data obtained at an early stage of drug development, using a biological parameter determination device for estimating animal biological parameters using data of cardiac action potential waveforms, and animal evaluation test data. Thus, the present invention relates to an apparatus for estimating the degree of risk of arrhythmia for a human heart of a target drug.

  There is a simulation method and apparatus for diffusion of a drug in a living tissue that can accurately analyze the diffusion phenomenon of the drug in the living tissue (see Patent Document 1). Such a simulation method is a method of simulating the diffusion of a specific substance in a living body using a finite element method, and using a part of tissue separated from a living body, without using the finite element method. A reference diffusion characteristic constant is determined, a reference diffusion characteristic is set based on the reference diffusion characteristic constant, a anatomy to be analyzed is determined based on a finite element method, and the determination is performed using the reference diffusion characteristic constant The diffusion in the living body structure is calculated based on the finite element method, and the calculation diffusion characteristic according to the calculation result based on the finite element method of diffusion in the living body is compared with the reference diffusion characteristic determined without using the finite element method. And calculating an optimum diffusion characteristic coefficient based on a finite element method by correcting a reference diffusion characteristic constant so that a deviation between the calculated diffusion characteristic and the reference diffusion characteristic is minimized. It is a simulation method for in vivo diffusion to.

  In addition, there is a technique regarding a method for determining the site of the electrical activity of the heart that can determine the site very accurately and at high speed (see Patent Document 2). In such a method for determining the site of electrical activity of the heart, a multi-channel measurement device is used to measure the body surface potential generated by the electrical activity of the heart at a plurality of measurement points, and the body surface potential at each measurement point is measured. A characteristic value is stored, and a body surface potential characteristic value is compared to a comparison value stored in the data bank, where the comparison value is an electrical value of a comparative heart whose location at the heart is known. Sites of comparative heart electrical activity, which show comparative surface potentials due to physical activity, and where the comparative values of cardiac electrical activity have very similarities with values that characterize body surface potentials In the method of sending out as a result of determining the site of the electrical activity of the heart, the comparison value is obtained by using a heart model provided in the thorax model. Is the method.

Further, as a related technique, there is a simulation apparatus that receives a biological parameter set as an input, simulates a cell, and acquires action potential waveform information (see Non-Patent Document 1).
JP 08-016551 (first page, FIG. 1 etc.) JP 08-280644 (first page, FIG. 1 etc.) Nobuaki Sarai, Akinori Noma “SimBio: Biological Dynamic Model Development Platform”, MME Japan Journal BME, vol. 18, no. 2, p. 3-11, 2004 (issued in February 2004)

  However, the conventional biological parameter determination device has a problem that it is impossible to obtain a biological parameter set including one or more appropriate biological parameters with high accuracy and high speed.

  Specifically, Patent Document 1 is a method for analyzing a diffusion phenomenon of a drug in a biological tissue, and a biological parameter set cannot be obtained from action potential information.

  Further, Patent Document 2 is a method of determining an electrical activity site of the heart using body surface potential, and a biological parameter set cannot be obtained from action potential information.

  Furthermore, the technique in the simulation apparatus of Non-Patent Document 1 is a technique that can be incorporated as a component of the biological parameter determination apparatus.

  The biological parameter determination device according to the first aspect of the present invention includes a biological parameter set storage unit that stores two or more biological parameter sets having one or more biological parameters that are biological parameters, and two or more biological parameter sets. Information indicating the action potential of the heart by simulating the activity of the heart by inputting the parameter set selection unit for selecting one of the biological parameter sets from the inside and the one biological parameter set selected by the parameter set selection unit A simulation execution unit that obtains action potential information at predetermined time intervals, and a steady state that determines whether or not the activity state of the heart to be simulated has become a steady state from a change in action potential information that is an output of the simulation execution unit The determination unit and the steady state determination unit are the activity states of the heart to be simulated An action potential information acquisition unit that acquires action potential information that is an output of the simulation execution unit when it is determined that a steady state has been reached, and an experiment that stores experimental action potential information that is action potential information as a result of an animal experiment The action potential information storage unit, the action potential information acquired by the action potential information acquisition unit, the difference calculation unit that calculates the difference between the experimental action potential information, and the difference calculated by the difference calculation unit And an allowable parameter set determining unit that determines whether or not the one biological parameter set is a biological parameter set within an allowable range, and the allowable parameter set determining unit has the one biological parameter set within an allowable range. When it is determined that it is not a biological parameter set, one of the biological parameter sets not selected by the parameter set selection unit is selected from the biological parameter sets. When the control unit for instructing to select a subset and the allowable parameter set determination unit determine that the one biological parameter set is a biological parameter set within an allowable range, the one biological parameter set is output. It is a biological parameter determination apparatus provided with an allowable parameter set output unit.

  With this configuration, a biological parameter set can be obtained with high accuracy.

  In addition, the biological parameter determination device according to the second aspect of the present invention is the biometric parameter determination device according to the first aspect, wherein the dissimilarity calculation unit includes the action potential value indicated by the action potential information acquired by the action potential information acquisition unit Absolute value difference information acquisition means for acquiring absolute value difference information, which is information relating to the difference between the action potential values indicated by the experimental action potential information, and the action potential change indicated by the action potential information acquired by the action potential information acquisition unit Change difference information acquisition means for acquiring change difference information that is information relating to a difference between the value of the action potential indicated by the experimental action potential information and the absolute value difference information and the change difference information. The biological parameter determination device includes a dissimilarity calculating means for calculating a dissimilarity between the action potential information acquired by the action potential information acquiring unit and the experimental action potential information.

  With this configuration, the difference between action potential information and experimental action potential information can be obtained with high accuracy, and as a result, a biological parameter set can be obtained with higher accuracy.

  In addition, the biological parameter determination device according to the third aspect of the present invention removes noise from the experimental action potential information stored in the experimental action potential information storage unit with respect to either the first or second invention. A pre-processing unit that performs pre-processing as a process and obtains new experimental action potential information, and the dissimilarity calculation unit obtains the action potential information acquired by the action potential information acquisition unit and the pre-processing unit. This is a biological parameter determination device that calculates the degree of difference from the experimental action potential information.

  With this configuration, a biological parameter set can be obtained with higher accuracy.

  Further, the biological parameter determination device according to the fourth aspect of the present invention is the biometric parameter determination device according to the third aspect of the present invention, wherein the preprocessing unit is configured such that the potential value indicated by the action potential information acquired by the action potential information acquisition unit The biological parameter determination device includes a scaling unit that scales the potential value indicated by the experimental action potential information so that the maximum potential value indicated by the potential information matches.

  With this configuration, a biological parameter set can be obtained with higher accuracy.

  In the biological parameter determination device according to the fifth aspect of the present invention, the preprocessing unit performs a moving average with respect to a potential value indicated by the experimental action potential information. It is a biological parameter determination device including a smoothing unit that calculates and uses the calculated moving average value as a potential value indicated by new experimental action potential information.

  With this configuration, a biological parameter set can be obtained with higher accuracy.

  Further, in the biological parameter determination device of the sixth aspect of the invention, in contrast to the first aspect of the invention, the parameter set selection unit determines a range of values of one or more parameters constituting the two or more biological parameter sets. A search range determining means for limiting the range of each of the one or more parameters and determining a search space having information on the limited range, and one or more sets existing in the search space determined by the search range determining means It is a biological parameter determination apparatus provided with the parameter set selection means which selects one parameter set from these parameter sets.

  With this configuration, a biological parameter set can be obtained at high speed and with high accuracy.

Further, in the biological parameter determination device of the seventh invention, in contrast to the sixth invention, the search range determination means divides the range of n parameter values constituting the previous search range into two, 2 ⁿ search ranges having a value range of n parameter combinations divided into two are acquired, and a parameter set having the smallest difference among the representative parameter sets of the 2 ⁿ search ranges. This is a biological parameter determination device that narrows the search range with the search range having a previous search range as the search range.

  With this configuration, a biological parameter set can be obtained at high speed and with high accuracy.

  Further, in the biological parameter determination device according to the eighth aspect of the present invention, in contrast to the sixth aspect, the search range determination means holds information on the value ranges of the parameters constituting the previous two or more parameter sets. A living body that narrows the search range with the range of half of the value range of each parameter as the next search range centering on the parameter set with the smallest difference among the two or more parameter sets in the previous time. It is a parameter determination device.

  With this configuration, a biological parameter set can be obtained at high speed and with high accuracy.

  Further, in the biological parameter determination device according to the ninth aspect of the present invention, in the first to eighth aspects of the invention, the allowable parameter set determination unit responds to the difference calculated by the difference calculation unit. The biological parameter determination apparatus determines whether or not the one biological parameter set is a biological parameter set within an allowable range by using a curved surface method.

  With this configuration, a biological parameter set can be obtained easily, at high speed, and with high accuracy without bothering people.

  According to the biological parameter determination device of the present invention, a biological parameter set can be obtained with high accuracy. Moreover, according to the arrhythmia risk evaluation apparatus of the present invention, the degree of arrhythmia risk of the target drug with respect to the human heart can be estimated using animal evaluation test data.

Hereinafter, embodiments of the biological parameter determination device and the like will be described with reference to the drawings. In addition, since the component which attached | subjected the same code | symbol in embodiment performs the same operation | movement, description may be abbreviate | omitted again.
(Embodiment)

  In the present embodiment, a biological parameter determination apparatus and the like that outputs biological parameters by inputting information on action potentials as a result of animal experiments will be described. Then, using this biological parameter determination device, if the biological parameter set is acquired from the action potential information before drug injection, and the biological parameter set is acquired from the action potential information after drug injection, the effect of drug injection Can be obtained quantitatively. Note that the effect of drug injection is obtained from the difference in biological parameter set before and after drug injection.

  FIG. 1 is a block diagram of the biological parameter determination apparatus in the present embodiment.

  The biological parameter determination apparatus includes a biological parameter set storage unit 101, a parameter set selection unit 102, a simulation execution unit 103, a steady state determination unit 104, an action potential information acquisition unit 105, an experimental action potential information storage unit 106, a preprocessing unit 107, A dissimilarity calculation unit 108, an allowable parameter set determination unit 109, a control unit 110, and an allowable parameter set output unit 111 are provided.

  The parameter set selection unit 102 includes search range determination means 1021 and parameter set selection means 1022.

  The preprocessing unit 107 includes scaling means 1071 and smoothing means 1072.

  The difference calculation unit 108 includes an absolute value difference information acquisition unit 1081, a change difference information acquisition unit 1082, and a difference calculation unit 1083.

The biological parameter set storage unit 101 stores two or more sets of biological parameter sets having one or more biological parameters that are biological parameters. Biological parameters include current flowing through various channels of cells (for example, Na channel, Ca channel, _KATP channel, Kr channel, K1 channel, Ks channel, etc.), opening / closing speed of each channel, ion affinity, intracellular and extracellular There are hundreds of parameters, such as the ion concentration. The biological parameter usually has a biological parameter identifier for identifying the biological parameter and a parameter value. However, if the enumeration order of the biometric parameters is determined in the biometric parameter set, the biometric parameters may be values alone. The biological parameter set may be stored in advance or may be calculated by means not shown. Holds information on the range of values that each biological parameter can take, and a means (not shown) determines one value of each biological parameter from the range of values that each biological parameter can take and builds a biological parameter set You may do it. The biological parameter set storage unit 101 is preferably a non-volatile recording medium, but can also be realized by a volatile recording medium.

  The parameter set selection unit 102 selects one biological parameter set from two or more biological parameter sets. There is no limitation on the algorithm for selecting one biological parameter set. One biological parameter set may be arbitrarily selected, or one biological parameter set may be selected by a predetermined algorithm. It is preferable that the parameter set selection unit 102 selects one biological parameter set by the processing of the search range determination unit 1021 and the parameter set selection unit 1022. An example of an algorithm for selecting one biological parameter set will be described later. The parameter set selection unit 102 can usually be realized by an MPU, a memory, or the like. The processing procedure of the parameter set selection unit 102 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

The search range determination unit 1021 limits the range of the one or more parameters using the range of the values of the one or more parameters constituting two or more biological parameter sets, and has information on the limited range. Determine the search space. Note that the range of parameter values is usually determined in advance, and information on the range is stored in the recording medium. Further, the search range determination unit 1021 divides the range of n parameter values (n is an integer equal to or greater than 1) that constitutes the previous search range into two, and the combination of the n parameters divided into two. 2 ⁿ search ranges having a value range are acquired, and a search range having a parameter set having the smallest difference among the representative parameter sets of the 2 ⁿ search ranges is set as the previous search range. The search range may be narrowed. The search range determination unit 1021 holds, for example, information on the value range of each parameter constituting the previous two or more parameter sets, and among the two or more parameter sets, the parameter set having the smallest difference in the previous time The search range may be narrowed by setting a half of the range of each parameter value as the next search range. The search range determination unit 1021 can usually be realized by an MPU, a memory, or the like. The processing procedure of the search range determination unit 1021 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The parameter set selection unit 1022 selects one parameter set from one or more parameter sets existing in the search space determined by the search range determination unit 1021. The parameter set selection unit 1022 can be usually realized by an MPU, a memory, or the like. The processing procedure of the parameter set selection means is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The simulation execution unit 103 receives the one biological parameter set selected by the parameter set selection unit 102, simulates the activity of the heart, and obtains action potential information that is information indicating the action potential of the heart at predetermined time intervals. . Since the simulation technique for inputting the biological parameter set and obtaining the action potential information at a predetermined time interval is a known technique, detailed description thereof is omitted. Note that the action potential information is, for example, a set of pairs of information indicating the potential of heart activity and information indicating time or time. Further, for example, the action potential information may include information on various ion concentrations (potassium ions, sodium ions, calcium ions, etc.) in the heart cells. For example, the action potential information may be information such as action potential duration (for example, APD 90, APD 60, APD 30). The data structure of action potential information is not limited. The “predetermined time interval” described above is not necessarily regular, and does not need to be determined in advance, and may be a random interval (an interval acquired by generating a random number). The simulation execution unit 103 can be usually realized by an MPU, a memory, or the like. The processing procedure of the simulation execution unit 103 is usually realized by software, and the software is recorded in a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

The steady state determination unit 104 changes the activity state of the heart to be simulated to a steady state from a change in action potential information (for example, a change in ion concentration such as potassium ion, sodium ion, calcium ion) output from the simulation execution unit 103. Judge whether or not. For example, the steady state determination unit 104 outputs the potassium ion concentration or / and sodium ion concentration or / and calcium ion concentration, which is the output of the simulation execution unit 103 at time t, and the output of the simulation execution unit 103 at time (t + 1). The potassium ion concentration or / and the sodium ion concentration or / and the calcium ion concentration are compared, and if the difference is less than a predetermined difference, it is determined that the activity state of the heart has become a steady state. Moreover, steady-state decision unit 104, for example, which is the output action potential information of the simulation execution portion 103 of the time t and _{(V t),} the time (t + 1) is the output of the simulation executing unit 103 is the action potential information _{(V t + 1} ) And if the difference is less than a predetermined difference, it is determined that the heart activity has become steady. The steady state determination unit 104 can usually be realized by an MPU, a memory, or the like. The processing procedure of the steady state determination unit 104 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The action potential information acquisition unit 105 acquires action potential information that is an output of the simulation execution unit 103 when the steady state determination unit 104 determines that the activity state of the heart to be simulated has become a steady state. The action potential information acquisition unit 105 normally obtains action potential information when it is determined that a steady state is reached and action potential information that is the final output result of the simulation execution unit 103. The action potential information acquisition unit 105 can be usually realized by an MPU, a memory, or the like. The processing procedure of the action potential information acquisition unit 105 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The experimental action potential information storage unit 106 stores experimental action potential information that is action potential information as a result of animal experiments. The experimental action potential information may be information that has received manual input or information received from an external device. The experimental action potential information storage unit 106 is preferably a non-volatile recording medium, but can also be realized by a volatile recording medium.

  The preprocessing unit 107 reads out the experimental action potential information stored in the experimental action potential information storage unit 106, performs preprocessing that is a process for removing noise on the experimental action potential information, and creates a new experimental action potential information. get information. There may be several types of preprocessing, and one or more processes may be combined. An example of the preprocessing is scaling or smoothing processing described later. The preprocessing unit 107 can usually be realized by an MPU, a memory, or the like. The processing procedure of the preprocessing unit 107 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit). Note that the preprocessing performed by the preprocessing unit 107 is necessary for improving the accuracy of calculating the degree of difference described later, but is not essential.

  The scaling means 1071 determines the potential value indicated by the experimental action potential information so that the maximum value indicated by the action potential information acquired by the action potential information acquisition unit 105 matches the maximum value indicated by the experimental action potential information. To change. Such processing is called scaling. The scaling means 1071 can be usually realized by an MPU, a memory, or the like. The processing procedure of the scaling means 1071 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The smoothing means 1072 calculates a moving average for the potential value indicated by the experimental action potential information, and sets the calculated moving average value as the potential value indicated by the new experimental action potential information. Such processing is called smoothing. Since the process of calculating the moving average is a known technique, detailed description thereof is omitted. The smoothing means 1072 can usually be realized by an MPU, a memory, or the like. The processing procedure of the smoothing means 1072 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The difference calculation unit 108 calculates the difference between the action potential information acquired by the action potential information acquisition unit 105 and the experimental action potential information. Here, the “difference” means a difference (difference) between the action potential information acquired by the action potential information acquisition unit 105 and the experimental action potential information, and may be a similarity. It goes without saying that “the degree of difference is small (low)” is equivalent to “the degree of similarity is high (high)”. The difference calculation unit 108 preferably calculates the difference between the action potential information acquired by the action potential information acquisition unit 105 and the experimental action potential information acquired by the preprocessing unit 107. The dissimilarity calculation unit 108 normally holds information on a calculation formula for calculating the dissimilarity on a recording medium (not shown), reads out the information on the calculation formula, and adds the action formula information acquisition unit 105 to the calculation formula. Substituting the action potential information acquired by, and the information obtained from the experimental action potential information as parameters, and performing calculations, the degree of difference is obtained. The difference calculation unit 108 uses the action potential information acquired by the action potential information acquisition unit 105 and the preprocessing unit 107 using only the absolute value difference described later, only the change difference information, or other information. The degree of difference from the experimental action potential information may be calculated. The dissimilarity calculation unit 108 can be usually realized by an MPU, a memory, or the like. The processing procedure of the difference calculation unit 108 is usually realized by software, and the software is recorded in a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The absolute value difference information acquisition unit 1081 is absolute value difference information that is information on the difference between the action potential value indicated by the action potential information acquired by the action potential information acquisition unit 105 and the action potential value indicated by the experimental action potential information. To get. It does not matter whether the absolute value difference information acquisition unit 1081 acquires the absolute value of the difference between the ranges of the values indicated by the two action potential information. The absolute value difference information acquisition unit 1081 may obtain, for example, the accumulation of absolute values of differences between two action potentials Vm (cell membrane potential) and RMP (resting membrane potential), or the difference between the two action potentials Vm. It is also possible to obtain only the accumulation of absolute values of. The absolute value difference information acquisition unit 1081 can be usually realized by an MPU, a memory, or the like. The processing procedure of the absolute value difference information acquisition unit 1081 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The change difference information acquisition unit 1082 is a change that is information regarding the difference between the action potential change value indicated by the action potential information acquired by the action potential information acquisition unit 105 and the action potential change value indicated by the experimental action potential information. Get difference information. This change is a change over time. A temporal change is a change that occurs over time. For example, the change difference information acquisition unit 1082 accumulates the difference between the value obtained by time differentiation of the action potential information acquired by the action potential information acquisition unit 105 and the value obtained by time differentiation of the action potential information indicated by the experimental action potential information. Calculate and get. The change difference information acquisition unit 1082 can be usually realized by an MPU, a memory, or the like. The processing procedure of the change difference information acquisition unit 1082 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The difference calculation means 1083 calculates the difference between the action potential information acquired by the action potential information acquisition unit and the experimental action potential information using the absolute value difference information and the change difference information. The difference degree calculation means 1083 weights the absolute value difference information and the change difference information, for example, and obtains the sum as the difference degree. The degree-of-difference calculation means 1083 can usually be realized by an MPU, a memory, or the like. The processing procedure of the dissimilarity calculation means 1083 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The allowable parameter set determination unit 109 determines whether one biological parameter set is a biological parameter set within an allowable range, using the difference calculated by the difference calculation unit 108. For example, the allowable parameter set determination unit 109 determines whether one biological parameter set is a biological parameter set within an allowable range using the response surface method for the difference calculated by the difference calculation unit 108. To do. Since the response surface method is a known technique, a description thereof will be omitted. In addition, for example, the allowable parameter set determination unit 109 outputs a difference parameter and one biological parameter set to the user, receives an input of an instruction indicating whether or not the user is within the allowable range, and receives information on the instruction (indicating the allowable range). Information or information indicating information outside the allowable range) may be performed. When accepting a user instruction, the user makes a substantial decision, and the allowable parameter set determination unit 109 performs a process of accepting and holding the user instruction. The allowable parameter set determination unit 109 can be usually realized by an MPU, a memory, or the like. The processing procedure of the allowable parameter set determination unit 109 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  When the allowable parameter set determination unit 109 determines that one biological parameter set is not within the allowable range, the control unit 110 determines one biological parameter set from among the biological parameter sets not selected by the parameter set selection unit 102. Instructs the user to select a parameter set. In addition, even when the allowable parameter set determination unit 109 determines that one biological parameter set is a biological parameter set within the allowable range, the control unit 110 obtains a biological parameter set within another allowable range. The parameter set selection unit 102 may be instructed to select one biological parameter set from among unselected biological parameter sets. In such a case, for example, it is determined whether or not all parameter sets in the biological parameter set storage unit 101 are within an allowable range. In such a case, for example, until a predetermined number (for example, “5”) of allowable parameter sets are found, the control unit 110 causes the parameter set selection unit 102 to select one biological parameter from unselected biological parameter sets. You will be prompted to select a set. The control unit 110 can usually be realized by an MPU, a memory, or the like. The processing procedure of the control unit 110 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

  The allowable parameter set output unit 111 outputs the one biological parameter set when the allowable parameter set determination unit 109 determines that the one biological parameter set is within the allowable range. Here, the output is a concept including display on a display, printing on a printer, sound output, transmission to an external device, accumulation in a recording medium, and the like. The allowable parameter set output unit 111 may be considered to include or not to include an output device such as a display or a speaker. The permissible parameter set output unit 111 may be realized by output device driver software, or output device driver software and an output device.

  Next, the operation of the biological parameter determination device will be described using the flowcharts of FIGS.

  (Step S201) The parameter set selection unit 102 selects one biological parameter set from two or more biological parameter sets. The parameter set selection unit 102 reads, for example, one biological parameter set in the stored order from the biological parameter sets stored in the biological parameter set storage unit 101.

  (Step S202) The simulation execution unit 103 receives one biological parameter set selected by the parameter set selection unit 102, simulates the activity of the heart, and obtains action potential information that is information indicating the action potential of the heart as a predetermined value. Obtain and output at time intervals. The predetermined time interval is not necessarily equal.

  (Step S203) The steady state determination unit 104 determines whether or not the activity state of the simulation target heart has become a steady state from the change in the two or more action potential information of the simulation result in Step S202. Normally, when there is no change between the immediately preceding action potential information and the current action potential information, or when there is a small difference within a predetermined difference, the steady state determination unit 104 determines that a steady state has been reached. If it is in a steady state, the process goes to step S204. If it is not in a steady state, the process returns to step S202, and the simulation by the simulation execution unit 103 is continued. Normally, when returning to step S202, the process of inputting one biological parameter set selected by the parameter set selection unit 102 is not performed again, and only the simulation by the simulation execution unit 103 is continued.

  (Step S204) The action potential information acquisition unit 105 acquires action potential information that is an output of the simulation execution unit 103 when the steady state determination unit 104 determines that the activity state of the simulation target heart has reached a steady state.

  (Step S205) The preprocessing unit 107 reads the experimental action potential information in the experimental action potential information storage unit 106 on the memory.

  (Step S206) The preprocessing unit 107 performs preprocessing on the experimental action potential information read in step S205. Details of the preprocessing will be described with reference to the flowchart of FIG.

  (Step S207) The dissimilarity calculation unit 108 calculates the dissimilarity between the action potential information acquired in step S204 and the experimental action potential information that is the result of the preprocessing in step S206. Details of the algorithm for calculating the degree of difference between the two action potential information will be described with reference to the flowchart of FIG.

  (Step S208) The difference calculation unit 108 stores the set of the selected biological parameter set and the difference calculated in step S207 in a recording medium (not shown) (may be a main memory).

  (Step S209) The allowable parameter set determination unit 109 determines whether or not the selected one biological parameter set is a biological parameter set within an allowable range, using the degree of difference calculated in step S207. Whether or not it is within the allowable range may be determined by the user and input by an input means (not shown) or may be automatically determined using the response surface method. If it is within the allowable range, go to Step S210, and if it is outside the allowable range, go to Step S212.

  (Step S210) The control unit 110 determines whether or not to end the process. Whether or not to end the process may be determined to end the process if a biological parameter set within one allowable range is found, or determined to end if a biological parameter set within a predetermined number of allowable ranges is found. Alternatively, it may be determined that the process is ended by inputting a user's end instruction. In addition, the algorithm which judges that a process is complete | finished does not matter. If it is determined that the process is to be terminated, the process proceeds to step S211. If it is determined that the process is not to be terminated, the process proceeds to step S213.

  (Step S211) The permissible parameter set output unit 111 reads out and outputs the biometric parameter set that the permissible parameter set determination unit 109 determines to be a biometric parameter set within the permissible range. The process ends.

  (Step S212) The control unit 110 deletes the biological parameter set that is not within the allowable range.

  (Step S213) The control unit 110 instructs the parameter set selection unit 102 to select the next biological parameter set. The process returns to step S201.

  In the flowchart of FIG. 2, another algorithm may be used as the selection algorithm for the biological parameter set.

  Next, preprocessing (step S206) of the biological parameter determination device will be described with reference to the flowchart of FIG.

(Step S301) The scaling means 1071 uses the average value (V _SRMP ) and the maximum value (V _SH ) of the resting membrane potential indicated by the action potential information of the simulation result acquired by the action potential information acquisition unit 105 as the action potential. Obtained from the values that make up the information. Note that the information constituting the action potential information includes, for example, voltage (mV) and time information in pairs.

(Step S302) The scaling means 1071 acquires the average value (V _ERMP ) and the maximum value (V _EH ) of the resting membrane potential among the information on the experimental action potential.

(Step S303) The scaling means 1071 changes the maximum value (V _EH ) of the experimental action potential information to the maximum value (V _SH ) and the minimum value (V _ERMP ) to the minimum value (V _SRMP ).

  (Step S304) The scaling means 1071 substitutes 1 for the counter i.

  (Step S305) The scaling means 1071 determines whether or not there is an i-th value in the experimental action potential information. If there is an i-th value, the process goes to step S306, and if there is no i-th value, the process goes to step S309.

(Step S306) The scaling means 1071 changes the i-th value (V _i ) using V _SL , V _SH , and V _ERMP V _SRMP . Specifically, the i-th value is determined by (V _i −V _ERMP ) × (V _SH −V _SRMP ) / (V _EH −V _ERMP ) + V _SRMP . Note that the scaling means 1071 holds information of the arithmetic expression (V _i −V _ERMP ) × (V _SH −V _SRMP ) / (V _EH −V _ERMP ) + V _SRMP , reads the information of the arithmetic expression, The acquired parameter is substituted into the arithmetic expression to obtain the scaled i-th value.

(Step S307) The scaling means 1071 stores the new i-th value (V _i ) obtained in step S306.

  (Step S308) The scaling means 1071 increments the counter i by 1. The process returns to step S305.

  (Step S309) The smoothing means 1072 substitutes 1 for the counter i.

  (Step S310) The smoothing means 1072 determines whether or not there is an i-th point (value) in the experimental action potential information. If there is an i-th point, the process goes to step S311, and if there is no i-th value, the process returns to the upper function.

  (Step S311) The smoothing means 1072 calculates the moving average of the i-th point.

  (Step S312) The smoothing means 1072 stores the moving average of the i-th point calculated at step S311.

  (Step S313) The smoothing means 1072 increments the counter i by 1. The process returns to step S310.

  In the flowchart of FIG. 3, the processing from step S301 to step S308 is scaling processing. Moreover, the process of step S309 to step S313 is a smoothing process.

  In the flowchart of FIG. 3, the arithmetic expression for the scaling process is not limited to the above expression.

  Next, the dissimilarity calculation process (step S207) of the biological parameter determination device will be described with reference to the flowchart of FIG.

  (Step S401) The dissimilarity calculation unit 108 reads out information on the arithmetic expression of the dissimilarity stored in a recording medium (not shown).

  (Step S402) The absolute value difference information acquisition unit 1081 performs an initialization process. The initialization process is a process for substituting 1 into the counter i. Further, this is a process of setting the value of the variable that is the basis for calculating the degree of difference to “0”. Here, there is an absolute value difference information variable that is a variable for storing absolute value difference information.

  (Step S403) The absolute value difference information acquisition unit 1081 determines whether or not the i-th value exists in the action potential information acquired by the action potential information acquisition unit 105 and / or the experimental action potential information. The action potential information or / and experimental action potential information acquired by the action potential information acquisition unit 105 is a set of pairs of action potential values and time or time information.

  (Step S404) The absolute value difference information acquisition unit 1081 acquires the i-th value (action potential) of two pieces of action potential information. The two action potential information is the action potential information acquired by the action potential information acquisition unit 105 and the experimental action potential information.

  (Step S405) The absolute value difference information acquisition unit 1081 determines whether or not the point corresponding to the i-th value acquired in step S404 is a point acquired as RMP. If it is a point acquired as RMP, go to step S406, and if it is not a point acquired as RMP, go to step S409.

  (Step S406) The absolute value difference information acquisition unit 1081 determines whether or not the point corresponding to the i-th value acquired in step S404 is the point acquired as the first RMP. If it is a point acquired as the first RMP, go to step S407, and if it is not a point acquired as the first RMP, go to step S409.

  Here, the absolute value difference information acquisition unit 1081 may calculate the difference between the two action potential information RMPs.

  (Step S407) The absolute value difference information acquisition unit 1081 calculates the absolute value of the difference between the i-th values of the two action potential information. Then, the absolute value difference information acquisition unit 1081 temporarily stores the calculated value.

  (Step S408) The absolute value difference information acquisition unit 1081 increments the counter i by 1. Return to step S403.

  (Step S409) The absolute value difference information acquisition unit 1081 acquires the absolute value of the difference between the i-th values of the two action potential information acquired in step S404.

  (Step S410) The absolute value difference information acquisition unit 1081 adds the values calculated in step S409. Go to step S408.

  (Step S411) The change difference information acquisition unit 1082 calculates time derivatives of two pieces of action potential information.

  (Step S412) The change difference information acquisition unit 1082 performs an initialization process. The initialization process is a process for substituting 1 into the counter i. Further, this is a process of setting the value of the variable that is the basis for calculating the degree of difference to “0”. Here, there is a change difference information variable, which is a variable for storing change difference information, as a variable for calculating the degree of difference.

  (Step S413) The change difference information acquisition unit 1082 determines whether or not the i-th value exists in the action potential information and / or the experimental action potential information acquired by the action potential information acquisition unit 105. If the i-th value exists, the process goes to step S414. If the i-th value does not exist, the process goes to step S417.

  (Step S414) The change difference information acquisition unit 1082 acquires time differential values of the two action potential information corresponding to the i-th value, and calculates information regarding the difference between the two time differential values. Information on the difference between the values of these two time derivatives is also called the rate of change.

  (Step S415) The change difference information acquisition unit 1082 adds the change rate (value) acquired in step S414.

  (Step S416) The change difference information acquisition unit 1082 increments the counter i by one. Return to step S412.

  (Step S417) The dissimilarity calculation unit 108 substitutes parameters for the arithmetic expression read in step S401, and calculates the dissimilarity. Here, the parameter is a value calculated in step S407, step S410, or step S415.

  (Step S418) The difference calculation unit 108 stores the difference calculated in step S417 in the recording medium.

  In the flowchart of FIG. 4, the processes in steps S402 to S410 are processes for calculating absolute value difference information. In the process of calculating the absolute value difference information, the processes of step S406 and step S407 are processes for acquiring RMP difference information (hereinafter, referred to as “static film distance information” as appropriate), and step S409. The process of step S410 is a process of obtaining information on the difference between the repolarization phases (hereinafter referred to as “repolarization phase distance information” as appropriate). Further, the processes in steps from step S411 to step S416 are processes for calculating change difference information. In the flowchart of FIG. 4, when calculating the difference degree, absolute value difference information and change difference information are calculated, and the difference degree is calculated based on these two pieces of information (values). However, the difference degree may be calculated by using only one of the absolute value difference information and the change difference information. Further, the absolute value difference information is calculated using the stationary membrane distance information and the repolarization phase distance information, but only the repolarization phase distance information may be used. Further, absolute value difference information may be calculated for all counters i without being separated into static membrane distance information and repolarization distance information.

In the flowchart of FIG. 4, in step S401, the parameter set selection unit 102 arbitrarily selects one biological parameter set from one or more biological parameter sets. However, the parameter set selection unit 102 may select one biological parameter set by the following algorithm. This algorithm is, for example, a simple bisection method described below. A conceptual diagram of the simple bisection method is shown in FIG. The simple two-division method divides each of n parameter value ranges constituting the previous search range into two parts, and 2 ⁿ search ranges each having a value range of a combination of the n parameter values divided into two. This is a method of acquiring and narrowing the search range with the search range having the smallest parameter set as the previous search range among the representative parameter sets of the 2 ⁿ search ranges. More specifically, the simple bisection algorithm will be described with reference to the flowcharts of FIGS.

  (Step S601) The search range determination means 1021 reads the search range information of each parameter. It is assumed that the initial value of the search range for each parameter is determined in advance and stored in a recording medium.

(Step S602) The search range determination unit 1021 acquires a value obtained by dividing the search range of each parameter into two from the search range information of the search range of each parameter read in step S601. For example, if the range of one parameter is “1 to 10”, the search range determination unit 1021 divides the range into “1 to 5” and “6 to 10”, for example. Search range determining means 1021 divides the range into two for all parameters (n). Then, the search range determination unit 1021 divides all n parameters into two, and obtains “2 ⁿ ” search ranges that are combinations thereof.

  (Step S603) The parameter set selection unit 1022 substitutes 1 for the counter i.

  (Step S604) The parameter set selection unit 1022 determines whether there is an i-th search range. If there is an i-th search range, go to step S605, and if there is no i-th search range, go to step S607.

  (Step S605) The parameter set selection unit 1022 obtains an optimal solution for the i-th search range. The optimal solution is a biological parameter set with the smallest difference. An algorithm for obtaining an optimal solution will be described with reference to the flowchart of FIG.

  (Step S606) The parameter set selection unit 1022 increments the counter i by 1. The process returns to step S604.

  (Step S607) The parameter set selection unit 1022 acquires a solution (biological parameter set) having the smallest difference among the optimal solutions obtained in the search range of (i-1).

  (Step S608) The parameter set selection unit 1022 acquires information on the search range of each parameter constituting the biological parameter set selected in Step S607.

(Step S609) The parameter set selection unit 1022 determines whether or not to end the process. If the process ends, the process goes to step S610, and if not, the process goes to step S611. Note that whether or not to end the process is a determination whether or not all the parameter sets in the 2 ⁿ search ranges have been acquired. If all the parameter sets have been acquired, the process ends. You may judge. Also, the user may determine whether to end the process. That is, the user may specify and select a parameter set for only the necessary search range, and the process may be completed when the parameter set for the selected search range is acquired. In such a case, there are provided means for prompting the user to select (means for displaying a menu or input screen for selection on the screen) and means for accepting the user's input.

  (Step S610) The parameter set selection unit 1022 outputs the biological parameter set (optimal solution) acquired in step S607. The process ends.

  (Step S611) The parameter set selection unit 1022 performs parameter selection processing recursively.

  Note that the flowchart of FIG. 6 is a recursive process.

  Next, an algorithm for obtaining an optimal solution will be described using the flowchart of FIG. In the flowchart of FIG. 7, the description of the same steps as those in the flowchart of FIG. 2 is omitted.

  (Step S701) The parameter set selection unit 1022 acquires n types of parameter sets for searching for an optimal solution within the search range. The n types of parameter sets may be input by the user or automatically determined within the search range. As an algorithm to be automatically determined, for example, when the search range of a certain parameter is “4 to 6”, an algorithm that acquires “4”, “5”, and “6” at equal intervals of “1” may be used.

  (Step S702) The parameter set selection unit 1022 substitutes 1 for a counter i.

  (Step S703) The parameter set selection unit 1022 determines whether or not “i <= n”. If “i <= n”, go to step S704, and if “i <= n”, go to step S706.

  (Step S704) The parameter set selection unit 1022 reads the i-th parameter set among the n types. Go to step S202.

  (Step S705) The parameter set selection unit 1022 increments the counter i by one.

  (Step S706) The parameter set selection unit 1022 acquires a parameter set having the smallest degree of difference among the n types of parameter sets. Return to upper function.

  Next, an algorithm for selecting another biological parameter set performed by the parameter set selection unit 102 will be described. This algorithm is called a range reduction method. A conceptual diagram of the range reduction method is shown in FIG. In FIG. 8, (1), (2), and (3) and the search range are narrowing in half. The range reduction method holds information on the range of values of each parameter constituting the previous two or more parameter sets, and among the two or more parameter sets, the parameter set with the smallest difference in the previous time is the center. This is a method of narrowing the search range by setting a half of the value range of each parameter as the next search range.

  A specific range reduction algorithm will be described with reference to the flowchart of FIG.

  (Step S901) The search range determination means 1021 reads the previous search range of each parameter. When there is no previous time (first time), the search range of each parameter stored in advance is read.

  (Step S902) The search range determination means 1021 reads an optimal solution. The optimum solution is information that is stored in the recording medium in advance or input by the user. The optimal solution is a biological parameter set.

  (Step S903) The search range determination unit 1021 calculates half of the width of the search range read out in step S901 for each parameter, and uses the optimum solution acquired in step S902 as the center point, and the width obtained by halving each parameter. Is calculated for each parameter. However, the range is calculated so as not to exceed the first stored range or the search range specified by the user. If the range stored first or the search range specified by the user is exceeded, the range including the center point of the optimal solution is calculated while maintaining the range of the width half of each parameter. Go to step S605.

  (Step S904) The parameter set selection unit 1022 determines whether or not to end the process. If the process is to end, the process goes to step S905, and if the process is not to end, the process goes to step S906. Whether or not to end the process may be determined in advance by the number of loops of this process, or by an instruction from the user.

  (Step S905) The parameter set selection unit 1022 outputs the optimum solution calculated in step S605. The process ends.

  (Step S906) The parameter set selection unit 1022 performs parameter set selection processing recursively.

  Hereinafter, a specific operation of the biological parameter determination apparatus in the present embodiment will be described.

  First, the biological parameter determination apparatus holds information on ranges and step sizes that can be taken by each biological parameter in FIG. 10 for each biological parameter by means not shown. Here, the biological parameters are exemplified by parameters identified by “IKr”, “IK1”, and “IKs”. Further, in FIG. 10, the biological parameter “IKr” indicates that “0.0, 0.1, 0.2,... 4.8, 4.9, 5.0” can be taken. “IKr” is a current flowing through a rapid activation delayed rectifier potassium channel (Kr channel), “IK1” is a current flowing through an inward rectifying potassium channel (K1 channel), and “IKs” is a slow activation delay. This is a current flowing through a rectifying potassium channel (Ks channel).

  Then, the biological parameter determination apparatus generates a biological parameter set based on the range of each biological parameter shown in FIG. 10 and the step size information by means not shown, and accumulates the biological parameter set in the biological parameter set storage unit 101. FIG. 11 shows a biological parameter set management table for managing such biological parameter sets. In FIG. 11, one or more biometric parameter sets (table records) including biometric parameter values such as “ID” and “IKr”, “IK1”, and “IKs” are managed. “ID” is information for identifying a record and exists for record management in the table.

  That is, the present biological parameter determination device is a device that acquires a biological parameter set within an allowable range from the biological parameter set of FIG.

  FIG. 12 is data representing the experimental action potential information stored in the experimental action potential information storage unit 106 as a graph. The experimental action potential information is a set of information having a pair of time (ms) and potential (mV), and is a set of action potential information as a result of animal experiments.

  First, the parameter set selection unit 102 first selects the biological parameter set “IKr: 0.0, IK1: 0.20, IKs: 1.00,. ... ”Is read out.

  Next, the simulation execution unit 103 receives one biological parameter set selected by the parameter set selection unit 102, simulates the heart activity, and sets action potential information, which is information indicating the heart action potential, for a predetermined time. Obtain and output at intervals.

  Next, the steady state determination unit 104 determines whether or not the activity state of the heart to be simulated has become a steady state from the change in two or more action potential information of the simulation result in the simulation execution unit 103, and enters the steady state. Action potential information in the case of becoming. The graph in which the action potential information in the steady state is displayed in a graph has a shape similar to that in FIG.

  Next, the action potential information acquisition unit 105 extracts action potential information that is an output of the simulation execution unit 103 when it is determined that the activity state of the heart to be simulated has become a steady state.

  FIG. 13 is a diagram in which a graph of experimental action potential information (Experiment data) and a graph of action potential information (Simulation) that is an output of the simulation execution unit 103 are overlapped. In FIG. 13, the vertical axis represents potential (mV) and the horizontal axis represents time (msec).

Next, the preprocessing unit 107 reads the experimental action potential information in the experimental action potential information storage unit 106 into the memory and performs preprocessing. That is, the scaling means 1071 of the preprocessing unit 107 calculates the average value (V _SRMP ) and the maximum value (V _SH ) of the potential of the resting membrane potential indicated by the action potential information of the simulation result acquired by the action potential information acquisition unit 105. The action potential information is acquired from the value. Then, the scaling means 1071 acquires the average value (V _ERMP ) and the maximum value (V _EH ) of the resting membrane potential among the information on the experimental action potential. Next, the scaling means 1071 sets the maximum value (V _EH ) of the experimental action potential information to the maximum value (V _SH ), and the average value (V _ERMP ) of the resting membrane potential (V _SRMP ). Change to The scaling means 1071 also scales the data at other points so that the maximum value, the resting membrane potential matches the value of the experimental action potential. As a result, as shown in FIG. 14, the potential width of the experimental action potential information becomes the same as the potential width of the action potential information of the simulation result. By the scaling process, the experimental data (Experiment data) can be scaled in the vertical direction so that the maximum amplitude of the action potential matches the simulation, and an appropriate difference can be calculated. In FIG. 14, the vertical axis represents potential (mV) and the horizontal axis represents time (msec).

  Next, the smoothing unit 1072 performs the following smoothing process on the experimental action potential information subjected to the scaling process and the action potential information obtained as a result of the simulation. That is, the smoothing means 1072 calculates a moving average value for all points (information consisting of potential (mV) and time (ms)) of the experimental action potential information subjected to the scaling process, and calculates the value. The point value of the experimental action potential information. Similarly, the smoothing means 1072 calculates a moving average value for all points (information consisting of potential (mV) and time (ms)) of action potential information as a simulation result, and calculates the value as a simulation. The resulting action potential information points. FIG. 15 shows action potential information after the smoothing process. The noise of the experimental data can be removed by the smoothing process. FIG. 15 shows the result of removing noise from experimental data by taking a moving average stepwise. The upper line (a) is a data group obtained by taking a moving average at intervals of 10.0 msec. The band (b) on the outer side of the line is a data group obtained by taking a moving average at intervals of 1.0 msec. Further, the outer band (c) is a data group obtained by taking a moving average at intervals of 0.1 msec. Further, (d) is raw data before taking a moving average.

  FIG. 16 shows the waveforms of the experimental action potential waveform before the drug administration (Before) and after the drug administration (After) when the above scaling process and smoothing process are completed. In FIG. 16, the vertical axis represents potential (mV) and the horizontal axis represents time (msec).

  Next, the dissimilarity calculation unit 108 calculates the dissimilarity between the acquired action potential information, which is a simulation result, and the experimental action potential information, which is the result of preprocessing, as follows.

First, the dissimilarity calculation unit 108 reads out information on the arithmetic expression for the dissimilarity stored in a recording medium (not shown). Here, it is assumed that the equation for calculating the degree of difference is, for example, Equation 1. FIG. 17 is a diagram showing the correspondence between the calculation formula for calculating the difference and the original information, and is a diagram showing the concept of the difference.

  In Equation 1, parameters A, B, and C are weighting coefficients, and are usually positive values. Also, the first and second terms to which the parameters A and B are applied are terms for calculating absolute value difference information, which is the distance between the action potential information of the simulation result and the experimental action potential information. The first term is a term for calculating resting membrane distance information which is a distance of resting membrane potential (RMP). The second term is a term for calculating repolarization phase distance information that is the distance of the repolarization phase. The third term on which C is applied is a term for calculating change difference information calculated by normalizing the distance between the action potential information of the simulation result and the experimental action potential information.

In Equation 1, RMP _model is an average value of resting membrane potential (RMP) in action potential information of simulation results, and RMP _exp is an average of resting membrane potential (RMP) in experimental action potential information. A value is preferred.
In Equation 1, Vm _model is the action potential of the simulation result, and Vm _exp is the action potential of the experimental action potential information. Phase 2 indicates the point (time and membrane potential) at which the membrane potential of the action potential reaches the maximum value. Phase 3 indicates a point (phase 3 end point) where repolarization (approaching the resting membrane potential) can be completed from the point where the membrane potential of the action potential reaches the maximum value (starting point of Phase 2) to the resting membrane potential. Therefore, calculating the sum of the absolute value difference information of Vm from Phase 2 to Phase 3 in the second term of Equation 1 means that the action potential information (time, membrane potential) included from the start point of Phase 2 to the end point of Phase 3 It means calculating absolute value difference information.
Furthermore, in Formula 1, dVm / dt _model is a value obtained by differentiating Vm _model with respect to time, and dVm / dt _exp is a value obtained by differentiating Vm _exp with respect to time.

  Then, the absolute value difference information acquisition means 1081 inputs the action potential information of the simulation result and the experimental action potential information into the first term and the second term of Equation 1, calculates the absolute value difference information, and the recording medium Temporarily store in. The details of this processing are as described in the flowchart of FIG. Next, the change difference information acquisition unit 1082 inputs the action potential information of the simulation result and the experimental action potential information into the third term of Formula 1, calculates the change difference information, and temporarily stores it in the recording medium.

  Then, the dissimilarity calculation unit 108 reads out the calculation results of the first term, the second term, and the third term of Equation 1 from the recording medium, calculates their sum, and obtains the dissimilarity. The smaller the difference is, the more similar the action potential information of the simulation result and the experimental action potential information are.

  Next, the allowable parameter set determination unit 109 is a biological parameter set in which the selected one biological parameter set (the biological parameter set of “ID = 1” in FIG. 11) is within the allowable range using the calculated degree of difference. Determine whether or not. Preferably, the allowable parameter set determination unit 109 calculates a determination coefficient using the response surface method, and determines whether the biological parameter set is within the allowable range based on whether the determination coefficient is within the allowable range. It is. When the response surface method is used, there are two or more pairs of the biological parameter set stored in the biological parameter set storage unit 101 and the degree of difference (difference calculated by the difference degree calculation unit 108). Necessary to calculate. Further, if the applied curved surface method is used, it is preferable that a biological parameter set predicted as an optimal solution can be calculated as a calculation result of the response curved surface method.

  Then, the allowable parameter set output unit 111 outputs a biological parameter set within the allowable range. Here, the output includes concepts such as display on a display, storage in a recording medium, and transmission to an external device.

  Next, the biological parameter determination apparatus performs the same process as described above on the biological parameter set after “ID = 2” in FIG. 11 to obtain a biological parameter set in an allowable range.

  In the above specific example, when selecting a biological parameter set within the allowable range, all candidate biological parameter sets are processed. However, the parameter selection method (simple bisection method or range reduction method shown in FIGS. 6 and 9) is used. ) To obtain an optimal biological parameter set efficiently.

  As described above, according to this embodiment, a biological parameter set can be obtained with high accuracy from experimental action potential information that is action potential information as a result of animal experiments.

  Further, according to the present embodiment, since it is determined whether or not one biological parameter set is an acceptable biological parameter set by using the response surface method, it is possible to easily and quickly perform the operation without bothering humans. In addition, a biological parameter set can be obtained with high accuracy.

  In the present embodiment, the time differentiation (dVm / dt) information of the action potential information is used when calculating the degree of difference. This is because the information of the time derivative (dVm / dt) of action potential information shows a characteristic change due to the change of each current system (FIG. 18). This is because it is possible to evaluate the direct influence on each current system. FIG. 18 shows changes in the dVm / dt waveform when the parameters of each channel are changed from 0 to 200%. Specifically, FIG. 18A shows the change in the dVm / dt waveform of the biological parameter “ICaL”, FIG. 18B shows the change in the dVm / dt waveform of the biological parameter “IKr”, and FIG. The dVm / dt waveform change of the biological parameter “IK1”, FIG. 18D shows the dVm / dt waveform change of the biological parameter “IKs”.

  Further, using the biological parameter determination device in the present embodiment, if the biological parameter set is obtained from the action potential information before drug injection, and the biological parameter set is obtained from the action potential information after drug injection, The effects and side effects of drug input can be obtained quantitatively. Note that the effect of drug injection is obtained from the difference in biological parameter set before and after drug injection.

  Furthermore, the processing in the present embodiment may be realized by software. Then, this software may be distributed by software download or the like. Further, this software may be recorded on a recording medium such as a CD-ROM and distributed. This also applies to other embodiments in this specification. In addition, the software which implement | achieves the biological parameter determination apparatus in this Embodiment is the following programs. That is, the program stores a parameter set selection step for selecting one biological parameter set from two or more biological parameter sets stored in the computer, and one biological parameter set selected in the parameter set selection step. From the simulation execution step of obtaining the action potential information, which is information indicating the action potential of the heart, and the change in the action potential information that is the output in the simulation execution step. Output in the simulation execution step when it is determined in the steady state determination step that the activity state of the heart to be simulated is in the steady state. Life Action potential information acquisition step for acquiring potential information, action potential information acquired in the action potential information acquisition step, difference calculation step for calculating a difference between stored experimental action potential information, and the difference Using the degree of difference calculated in the calculating step, an allowable parameter set determining step for determining whether or not the one biological parameter set is a biological parameter set in an allowable range; and A control step for instructing the parameter set selection unit to select one biological parameter set from unselected biological parameter sets when it is determined that the biological parameter set is not within an allowable range; and In the allowable parameter set determining step, the one biological parameter set is permitted. If it is determined that the biological parameter set in the range, a program, for executing the allowable parameter set output step of outputting the biological parameter set of the one.

  The difference calculation step in the program is information relating to a difference between an action potential value indicated by the action potential information acquired in the action potential information acquisition step and an action potential value indicated by the experimental action potential information. Absolute value difference information acquisition step for acquiring absolute value difference information, action potential change value indicated by action potential information acquired in action potential information acquisition step, and action potential change value indicated by experimental action potential information A change difference information acquisition step for acquiring change difference information that is information relating to a difference between the action potential information acquired by the action potential information acquisition unit using the absolute value difference information and the change difference information, and the experiment. It is preferable to include a difference degree calculating step for calculating a difference degree from the action potential information.

  The program further causes a computer to perform a preprocessing that is a process of removing noise from the experimental action potential information to obtain new experimental action potential information, and the difference degree calculating step includes: It is preferable to calculate the difference between the action potential information acquired in the action potential information acquisition step and the experimental action potential information acquired in the preprocessing step.

  In the preprocessing step in the program, the experimental action potential is set such that the maximum value of the potential indicated by the action potential information acquired in the action potential information acquisition step matches the maximum value of the potential indicated by the experimental action potential information. It is preferable to provide a scaling step for scaling the potential value indicated by the information.

  In the preprocessing step in the program, a moving average is calculated for the potential value indicated by the experimental action potential information, and the calculated moving average value is used as a potential value indicated by the new experimental action potential information. It is preferable to include a smoothing step.

  In addition, the parameter set selection step in the program limits the range of the one or more parameters using a range of values of the one or more parameters that constitute the two or more sets of biological parameter sets. A search range determining step for determining a search space having the information of the selected range, and a parameter set selecting step for selecting one parameter set from one or more parameter sets existing in the search space determined in the search range determination step It is suitable to have.

Further, the search range determining step in the above program divides the value range of n parameters constituting the previous search range into two, and 2 ⁿ having a value range of the combination of the n parameters divided into two. The search range is acquired and the search range having the parameter set with the smallest difference among the representative parameter sets of the 2 ⁿ search ranges is set as the previous search range, and the search range is narrowed. That is preferred.

  Further, the search range determination step in the program holds information on the value ranges of the parameters constituting the previous two or more parameter sets, and the most different degree of difference among the previous two or more parameter sets. Centering on a small parameter set, it is preferable to narrow the search range by setting a half of the range of each parameter value as the next search range.

  Further, in the program, whether the allowable parameter set determination step is a biological parameter set in which the one biological parameter set is within an allowable range using a response surface method with respect to the difference calculated in the difference calculation step. It is preferred to determine whether or not. Furthermore, an optimal solution calculated from the response surface method and a predicted biological parameter set may be selected.

  FIG. 19 shows the external appearance of a computer that executes the program described in this specification and realizes the biological parameter determination device according to various embodiments described above. The above-described embodiments can be realized by computer hardware and a computer program executed thereon. FIG. 19 is an overview diagram of the computer system 340, and FIG. 20 is a block diagram of the computer system 340.

  In FIG. 19, a computer system 340 includes a computer 341 including a FD (Flexible Disk) drive and a CD-ROM (Compact Disk Read Only Memory) drive, a keyboard 342, a mouse 343, a monitor 344, and a microphone 345. .

  In FIG. 20, in addition to the FD drive 3411 and the CD-ROM drive 3412, the computer 341 includes a CPU (Central Processing Unit) 3413, a bus 3414 connected to the CPU 3413, the CD-ROM drive 3412, and the FD drive 3411, and a boot. A ROM (Read-Only Memory) 3415 for storing a program such as an up program, and a RAM (Random Access Memory) connected to the CPU 3413 for temporarily storing instructions of an application program and providing a temporary storage space 3416 and a hard disk 3417 for storing application programs, system programs, and data. Although not shown here, the computer 341 may further include a network card that provides connection to the LAN.

  A program that causes the computer system 340 to execute the function of the biological parameter determination apparatus according to the above-described embodiment is stored in the CD-ROM 3501 or the FD 3502, inserted into the CD-ROM drive 3412 or the FD drive 3411, and further the hard disk 3417. May be transferred to. Alternatively, the program may be transmitted to the computer 341 via a network (not shown) and stored in the hard disk 3417. The program is loaded into the RAM 3416 at the time of execution. The program may be loaded directly from the CD-ROM 3501, the FD 3502, or the network.

  The program does not necessarily include an operating system (OS), a third-party program, or the like that causes the computer 341 to execute the function of the biological parameter determination device according to the above-described embodiment. The program only needs to include an instruction portion that calls an appropriate function (module) in a controlled manner and obtains a desired result. How the computer system 340 operates is well known and will not be described in detail.

  In each of the above embodiments, each process (each function) may be realized by centralized processing by a single device (system), or by distributed processing by a plurality of devices. May be.

  As described above, the biological parameter determination device according to the present invention has an effect that a biological parameter set can be obtained with high accuracy, and performs the preprocessing of the device for estimating the effect of drug injection and side effects. Useful as such.

Block diagram of biological parameter determination apparatus in embodiment A flowchart for explaining the operation of the biological parameter determination device Flow chart for explaining the operation of the pre-process Flow chart explaining the difference calculation processing Conceptual diagram of the simple bisection method Flow chart explaining the simple bisection method Flow chart explaining the algorithm for obtaining the optimal solution Conceptual diagram of the same range reduction method Flowchart explaining the same range reduction method The figure which shows the example of the information of the same body parameter The figure which shows the same body parameter set management table Figure showing a graph of the experimental action potential information The graph of the action potential information graph of the experiment and the action potential information graph of the simulation result The figure which shows the same scaling processing result The figure which shows the same smoothing processing result Diagram showing waveforms before and after the same preprocessing The figure which shows the calculation formula which calculates the difference degree, and the concept The figure which shows the dVm / dt waveform change when the parameter of each channel is changed from 0 to 200% External view of a computer realizing the same biological parameter determination device Block diagram of a computer system that implements the biological parameter determination device

Explanation of symbols

DESCRIPTION OF SYMBOLS 101 Biometric parameter set storage part 102 Parameter set selection part 103 Simulation execution part 104 Steady state judgment part 105 Action potential information acquisition part 106 Experimental action potential information storage part 107 Preprocessing part 108 Dissimilarity calculation part 109 Permissible parameter set determination part 110 Control Unit 111 allowable parameter set output unit 1021 search range determination unit 1022 parameter set selection unit 1071 scaling unit 1072 smoothing unit 1081 absolute value difference information acquisition unit 1082 change difference information acquisition unit 1083 difference degree calculation unit

Claims (15)

A biological parameter set storage unit that stores two or more biological parameter sets having one or more biological parameters that are biological parameters;
A parameter set selection unit for selecting one biological parameter set from the two or more biological parameter sets;
A simulation execution unit that inputs one biological parameter set selected by the parameter set selection unit, simulates the activity of the heart, and obtains action potential information that is information indicating the action potential of the heart;
An action potential information acquisition unit for acquiring the action potential information;
An experimental action potential information storage unit storing experimental action potential information which is action potential information of the result of animal experiments;
The difference calculation unit that calculates the difference between the action potential information acquired by the action potential information acquisition unit and the experimental action potential information;
An allowable parameter set determination unit that determines whether the one biological parameter set is a biological parameter set within an allowable range, using the difference calculated by the difference calculation unit;
When the allowable parameter set determination unit determines that the one biological parameter set is not a biological parameter set within an allowable range, the biological parameter set is selected from the unselected biological parameter sets by the parameter set selection unit. A control unit instructing to
When the allowable parameter set determining unit determines that the one biological parameter set is a biological parameter set within an allowable range, the biological parameter determining device includes an allowable parameter set output unit that outputs the one biological parameter set. . Further comprising a steady state determination unit that determines whether or not the activity state of the heart to be simulated has become a steady state from a change in action potential information that is an output of the simulation execution unit;
The action potential information acquisition unit
2. The biological parameter determination device according to claim 1, wherein the steady state determination unit acquires action potential information that is an output of the simulation execution unit when it is determined that the activity state of the heart to be simulated has become a steady state. The difference calculation unit
Absolute value difference information acquisition for acquiring absolute value difference information, which is information regarding the difference between the action potential value indicated by the action potential information acquired by the action potential information acquisition unit and the action potential value indicated by the experimental action potential information. Means,
A change difference for acquiring change difference information, which is information relating to a difference between an action potential change value indicated by the action potential information acquired by the action potential information acquisition unit and an action potential change value indicated by the experimental action potential information. Information acquisition means;
The dissimilarity calculating means for calculating a dissimilarity between the action potential information acquired by the action potential information acquiring unit and the experimental action potential information using the absolute value difference information and the change difference information. Or the biological parameter determination apparatus of Claim 2. A pre-processing unit that obtains new experimental action potential information by performing pre-processing that is a process for removing noise with respect to the experimental action potential information stored in the experimental action potential information storage unit;
The difference calculation unit
The biological parameter determination device according to any one of claims 1 to 3, wherein a degree of difference between the action potential information acquired by the action potential information acquisition unit and the experimental action potential information acquired by the preprocessing unit is calculated. The pre-processing unit is
Scaling that scales the value of the potential indicated by the experimental action potential information so that the maximum value of the potential indicated by the action potential information acquired by the action potential information acquisition unit matches the maximum value of the potential indicated by the experimental action potential information. The biological parameter determination apparatus according to claim 4, further comprising means. The pre-processing unit is
5. A smoothing unit is provided for calculating a moving average with respect to a potential value indicated by the experimental action potential information and setting the calculated moving average value as a potential value indicated by new experimental action potential information. Or the biological parameter determination apparatus of Claim 5. The parameter set selector is
A search for limiting a range of each of the one or more parameters using a range of values of the one or more parameters constituting the two or more sets of biological parameters, and determining a search space having information on the limited range A range determination means;
The biological parameter determination apparatus according to claim 1, further comprising parameter set selection means for selecting one parameter set from one or more parameter sets existing in the search space determined by the search range determination means. The search range determining means includes
The range of values of n parameters constituting the previous search range is divided into two, to get the 2 ⁿ pieces of search range having a range of values of the combination of the two split the n parameters, the 2 ⁿ pieces The biological parameter determination device according to claim 7, wherein the search range is narrowed by using, as a previous search range, a search range having a parameter set with the smallest difference among the representative parameter sets of each search range. The search range determining means includes
It holds information on the range of values of each parameter constituting the previous two or more parameter sets. Among the two or more parameter sets, the parameter set having the smallest degree of difference in the previous time is used as the center. The biological parameter determination apparatus according to claim 7, wherein the search range is narrowed by setting a half of the value range as a next search range. The allowable parameter set determination unit includes:
10. Any one of claims 1 to 9, wherein a response surface method is used to determine whether or not the one biological parameter set is a biological parameter set within an allowable range for the difference calculated by the difference calculation unit. Or a biological parameter determination device. On the computer,
A parameter set selection step for selecting one biological parameter set from two or more stored biological parameter sets;
A simulation execution step of inputting the one biological parameter set selected in the parameter set selection step, simulating the activity of the heart, and obtaining action potential information that is information indicating the action potential of the heart;
Action potential information acquisition step of acquiring action potential information which is an output in the simulation execution step;
A difference degree calculating step for calculating a difference degree between the action potential information acquired in the action potential information acquisition step and the stored experimental action potential information;
An allowable parameter set determining step for determining whether or not the one biological parameter set is a biological parameter set within an allowable range using the difference calculated in the difference calculating step;
When it is determined in the allowable parameter set determination step that the one biological parameter set is not a biological parameter set within an allowable range, one biological parameter set is selected from the unselected biological parameter sets in the parameter set selection unit A control step instructing to
A program for executing an allowable parameter set output step of outputting the one biological parameter set when the one biological parameter set is determined to be a biological parameter set within an allowable range in the allowable parameter set determination step. On the computer,
From the change in action potential information that is the output of the simulation execution unit, a steady state determination step for determining whether or not the activity state of the heart to be simulated has become a steady state is further executed,
The action potential information acquisition step includes
12. The program according to claim 11, wherein the steady state determination unit acquires action potential information that is an output of the simulation execution unit when it is determined that the activity state of the heart to be simulated has become a steady state. The difference calculation step includes
Absolute value difference information acquisition for acquiring absolute value difference information, which is information regarding the difference between the action potential value indicated by the action potential information acquired in the action potential information acquisition step and the action potential value indicated by the experimental action potential information. Steps,
A change difference for obtaining change difference information, which is information relating to a difference between the action potential change value indicated by the action potential information acquired in the action potential information acquisition step and the action potential change value indicated by the experimental action potential information. An information acquisition step;
The dissimilarity calculating step of calculating a dissimilarity between the action potential information acquired by the action potential information acquisition unit and the experimental action potential information using the absolute value difference information and the change difference information. Or the program of Claim 12. On the computer,
A pre-processing step for obtaining new experimental action potential information by performing pre-processing that is a process for removing noise with respect to the experimental action potential information;
The difference calculation step includes
The program according to any one of claims 11 to 13, wherein the degree of difference between the action potential information acquired in the action potential information acquisition step and the experimental action potential information acquired in the preprocessing step is calculated. The parameter set selection step includes:
A search for limiting a range of each of the one or more parameters using a range of values of the one or more parameters constituting the two or more sets of biological parameters, and determining a search space having information on the limited range A range determination step;
The program according to claim 11, further comprising a parameter set selection step of selecting one parameter set from one or more parameter sets existing in the search space determined in the search range determination step.