Drug responsiveness calculation apparatus, method for calculating drug responsiveness of gene expressed in organoid, and computer program

Abstract

The purpose of embodiments disclosed in the present specification is to provide an apparatus and a method for selecting, from among a large number of organoids, an organoid suitable for a drug experiment on a specific gene. In addition, the purpose of embodiments disclosed in the present specification is to provide an apparatus and a method for calculating a drug responsiveness value for a specific gene of organoids by utilizing RNAsep data, which is genetic data.

Description

Drug response determination device, method for determining drug response of genes expressed in organoids, and computer program

[0001] The present disclosure relates to a drug responsiveness calculation device, a method for calculating drug responsiveness of a gene expressed in an organoid, and a computer program, and more specifically, to extracting a gene expression level and calculating responsiveness to a given gene.

[0002] In cancer treatment, organoid models are widely used to verify the effectiveness of drugs that regulate specific genes. Organoids are cell bodies that can reproduce in vivo tissues in 3D, and are obtained from specific cancer tissues.

[0003] Organoids can be used not only to evaluate drug responsiveness, but also to fundamentally understand how drugs work on cancer.

[0004] To evaluate the efficacy of new drugs, experiments can be conducted using organoids to measure drug responsiveness. Each organoid is generated to represent a different cancer type, and its response to drugs varies accordingly. Therefore, it is necessary to select organoids with high drug responsiveness for experiments.

[0005] Therefore, there is an emerging need to select suitable organoids to evaluate the efficacy of novel drugs that regulate specific genes.

[0006] The embodiments disclosed herein are intended to provide a device and method for selecting an organoid suitable for drug testing on a specific gene from among a large number of organoids.

[0007] In addition, the embodiments disclosed in this specification aim to provide a device and method for calculating drug responsiveness values ​​for specific genes of organoids by utilizing RNAsep data, which is genetic data.

[0008] According to embodiments of the present disclosure, a method may include a step of inputting data including one or more first genes into a drug responsiveness calculation device; calculating a first-first expression level rank value and a first-second expression level rank value of the first gene for one or more first organoids derived from one or more first tissue cells in which the first gene is expressed; calculating a second-first expression level rank value and a second-second expression level rank value of the first gene for the first tissue cells; calculating a drug responsiveness value for each organoid using at least one of the first-first expression level rank value, the first-second expression level rank value, the second-first expression level rank value, and the second-second expression level rank value for each organoid and each tissue cell; detecting a first organoid having a drug responsiveness value equal to or greater than a reference responsiveness value; and generating information about the first organoid as output data and transmitting the information to an external device.

[0009] The above 1-1 expression level ranking value may be a value corresponding to the expression level ranking of the first gene in the first organoid compared to the expression levels of the first gene in other organoids, divided by the number of the first organoids.

[0010] The above 1-2 expression level ranking value may be a value corresponding to the expression level ranking of the first gene compared to the expression levels of other genes expressed in the first organoid, divided by the total number of genes in the first organoid.

[0011] The above 2-1 expression level ranking value may be a value corresponding to the expression level ranking of the first gene in the first tissue cell compared to the expression levels of the first gene in other tissue cells, divided by the number of the first tissue cells related to the first gene.

[0012] The above 2-2 expression level ranking value may be a value corresponding to the expression level ranking of the first gene compared to the expression levels of other genes expressed in the first tissue cell, divided by the number of all genes expressed in the first tissue cell.

[0013] The data for the first tissue cells or the data for the first organoid may be obtained from an external database.

[0014] According to embodiments of the present disclosure, a device may include: a data input unit that inputs data including one or more first genes; an organoid data processing unit that calculates a first-first expression level rank value and a first-second expression level rank value of the first gene for one or more first organoids derived from one or more first tissue cells in which the first gene is expressed; a tissue data processing unit that calculates a second-first expression level rank value and a second-second expression level rank value of the first gene for the first tissue cells; a reactivity value calculation unit that calculates a drug reactivity value for each organoid using at least one of the first-first expression level rank value, the first-second expression level rank value, the second-first expression level rank value, and the second-second expression level rank value for each organoid and each tissue cell; and a data output unit that detects a first organoid having a drug reactivity value equal to or greater than a reference reactivity value, generates information about the first organoid as output data, and transmits the output data to an external device.

[0015] A computer program according to an embodiment of the present invention can be stored in a medium to execute any one of the methods according to an embodiment of the present invention using a computer.

[0016] In addition, other methods for implementing the present invention, other systems, and computer-readable recording media recording a computer program for executing the above methods are further provided.

[0017] Other aspects, features and advantages other than those described above will become apparent from the following drawings, claims and detailed description of the invention.

[0018] According to any one of the aforementioned problem solving methods, among numerous organoids, an organoid suitable for drug testing on a specific gene can be selected.

[0019] Additionally, RNAsep data, which is genetic data, can be used to calculate drug responsiveness values ​​for specific genes in organoids.

[0020] FIG. 1 is a block diagram of a drug response calculation device according to embodiments of the present disclosure.

[0021] Figure 2 is a diagram schematically illustrating input data and output data of a drug response calculation method.

[0022] FIG. 3 is a diagram of a network environment of a drug response calculation device according to embodiments of the present disclosure.

[0023] Figure 4 is a flowchart of a method for calculating drug responsiveness according to embodiments of the present disclosure.

[0024] Figure 5 is a diagram illustrating the operation of a learning device that determines a reference reactivity value.

[0025] Figure 6A is an example table of expression levels for the gene SLC25A31, and Figure 6B is an example diagram of a graph of expression levels of the gene SLC25A31.

[0026] Figure 6C is an example graph of the expression level of the gene SLC25A31 in 15 organoids.

[0027] Figure 6D is an example diagram of the expression level ranking values ​​of genes expressed in lung cells.

[0028] Figure 6E is an example diagram of the expression level ranking values ​​of genes expressed in colon cells.

[0029] FIG. 6F is an example table of drug responsiveness values ​​of the gene SLC25A31 according to embodiments of the present disclosure.

[0030] The configuration and operation of the present invention will be described in detail with reference to embodiments of the present invention illustrated in the attached drawings below.

[0031] The present invention is capable of various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the detailed description. The effects and features of the present invention, as well as the methods for achieving them, will become clearer with reference to the embodiments described in detail below, along with the drawings. However, the present invention is not limited to the embodiments disclosed below and can be implemented in various forms.

[0032] Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. When describing with reference to the drawings, identical or corresponding components are given the same drawing reference numerals, and redundant descriptions thereof will be omitted.

[0033] Hereinafter, the term “upper” or “upper” may include not only things that are directly above in contact, but also things that are above in a non-contact manner.

[0034] In the following examples, the terms first, second, etc. are not used in a limiting sense, but are used for the purpose of distinguishing one component from another.

[0035] In the examples below, singular expressions include plural expressions unless the context clearly indicates otherwise.

[0036] In the following examples, terms such as “include” or “have” mean that a feature or component described in the specification is present, and do not preclude the possibility that one or more other features or components may be added.

[0037] For convenience of explanation, the sizes of components in the drawings may be exaggerated or reduced. For example, the sizes and thicknesses of each component shown in the drawings are arbitrarily indicated for convenience of explanation, and thus the present invention is not necessarily limited to what is shown.

[0038] Additionally, terms such as “…part”, “…area”, etc. described in this specification may mean a unit that processes at least one function or operation.

[0039] Here, organoids refer to three-dimensional cell aggregates formed through self-renewal and self-organization from adult stem cells, embryonic stem cells, or induced pluripotent stem cells. Organoids can contain specific cells of model organs by re-aggregating and recombining cells using three-dimensional culture techniques.

[0040] Here, tissue cells refer to cells present within an organ in biology. In this specification, tissue cells are collected from a subject (human, animal, plant, etc.) and may include cancer cells associated with disease.

[0041] FIG. 1 is a block diagram of a drug response calculation device according to embodiments of the present disclosure.

[0042] The drug responsiveness calculation device (100) can calculate a numerical value corresponding to the drug responsiveness of the organoid. The drug responsiveness calculation device (100) can calculate the drug responsiveness of the organoid for each gene. The drug responsiveness calculation device (100) can calculate the expression level ranking value of the first gene for the tissue cells and the organoid, thereby calculating the drug responsiveness of the organoid. If the degree of similarity between the information related to the expression level of the gene in the tissue cells and the information related to the expression level of the gene in the organoid is high, it can be determined that the drug responsiveness of the organoid is high.

[0043] The drug responsiveness calculation device (100) can calculate a drug responsiveness value in an organoid by considering at least one of the expression level ranking value of the first gene in the organoid and the expression level ranking value of the first gene in the tissue cell. The drug responsiveness calculation device (100) can output an organoid suitable for a drug test based on the drug responsiveness value calculated by a predetermined method. The drug responsiveness calculation device (100) can be designed to output an organoid having the highest drug responsiveness value or an organoid having a drug responsiveness value higher than a predetermined reference responsiveness value.

[0044] The drug responsiveness calculation device (100) can calculate a first expression level rank value of a first gene in an organoid. The first expression level rank value in an organoid refers to a first expression level rank value of the first gene among genes expressed in the organoid. The drug responsiveness calculation device (100) can calculate a second expression level rank value of the first gene in a tissue cell. The second expression level rank value in a tissue cell refers to a first expression level rank value of the first gene among genes expressed in the tissue cell. The first and / or second expression level rank values ​​can be set to have higher values ​​for genes with higher expression levels. The drug responsiveness calculation device (100) can calculate a responsiveness value of an organoid for the first gene based on the first expression level rank value and the second expression level rank value calculated for the first gene.

[0045] The drug reactivity calculation device (100) can calculate reactivity values ​​of the first gene for each of a plurality of organoids.

[0046] The drug responsiveness calculation device (100) can output information about a first organoid for a first gene. The drug responsiveness calculation device (100) can transmit the information to a terminal of a user who has requested information about the first organoid. The drug responsiveness calculation device (100) can request payment of a fee for providing information about the first organoid. The first organoid can include one or more organoids.

[0047] The fee for providing information on the first organoid may vary depending on the information provided.

[0048] In other words, the drug responsiveness calculation device (100) can detect a first organoid with a good drug responsiveness to a first gene requested by a user and generate information about the first organoid. The drug responsiveness calculation device (100) can transmit information about the first organoid to the user's account, terminal, etc. Through the information about the first organoid provided in this way, the user can obtain information about the organoid with a good responsiveness to a drug that acts on the gene. The user can use the organoid with a good responsiveness obtained in this way to perform a test on a drug that acts on the gene and treats diseases such as cancer. The user can perform a test on the drug and calculate the performance of the drug that acts on the gene.

[0049] The drug responsiveness calculation device (100) according to embodiments of the present disclosure predicts the responsiveness of an organoid to a specific drug, thereby enabling selection of a suitable organoid. The drug responsiveness calculation device (100) can reduce the time and cost required for selecting a suitable organoid. The drug responsiveness calculation device (100) can predict the responsiveness to a specific gene based on the genetic characteristics of the organoid. The drug responsiveness calculation device (100) can simplify the experiment and execution process for searching for an organoid with good drug responsiveness. Good drug responsiveness may mean having a drug responsiveness similar to that of tissue cells.

[0050] The drug reactivity calculation device (100) may include a data input unit (110), an organoid data processing unit (120), a tissue data processing unit (130), a reactivity value calculation unit (140), and / or a data output unit (150).

[0051] The data input unit (110) can input data including one or more first genes. The data input unit (110) can input data regarding a first drug to be tested. The data input unit (110) can determine a first gene that responds to the first drug. The data input unit (110) can search data regarding the first drug to determine a first gene that responds to the first drug.

[0052] The tissue cell in which the first gene is expressed is called a first tissue cell, and the organoid derived from the first tissue cell is called a first organoid. There may be one or more first tissue cells. There may also be one or more first organoids. For example, to determine drug responsiveness in relation to lung cancer, there may be 48 tissue cells and 48 organoids related to lung cancer. Information on the 48 tissue cells can be obtained from a database related to tissue cells. Information on the 48 organoids can be obtained from a database related to organoids.

[0053] The organoid data processing unit (120) can calculate a first expression level ranking value of a first gene for a first organoid derived from a first tissue cell.

[0054] The organoid data processing unit (120) can calculate the expression levels of genes included in the first organoid and list them in order of the magnitude of the expression levels of the genes to calculate the 1-1 expression level ranking value or the 1-2 expression level ranking value of the first gene. The 1-1 or 1-2 expression level ranking value can be calculated by one or more methods. The organoid data processing unit (120) can calculate the expression level of the first gene based on the number of reads of the first gene and the length of the transcript of the first gene in the genome data of the first organoid.

[0055] The first-1 or first-2 expression level rank value of the first gene may calculate the expression level of the first gene and include the rank value of the expression level of the first gene. Here, the genomic data may include an RNA sequence and / or a DNA sequence.

[0056] The 1-1 expression level rank value of the first gene may be set as a value obtained by dividing the expression level of the first gene by the total number of organoids. To be more specific, the 1-1 expression level rank value of the first gene may be a rank value of the average expression level of the first gene in the first organoid among the total t organoids. For example, when the first gene is expressed in 15 organoids, the organoid data processing unit (120) may calculate a rank value of the expression level of the first gene in the first organoid among the expression levels of the first gene in the 15 organoids.

[0057] In another embodiment, the first-second expression level ranking value of the first gene may be calculated based on whether the first gene is expressed, whether the first organoid corresponds to the first tissue cell, the total number of genes expressed in the first organoid, and the expression level ranking of the first gene among n genes expressed in the first organoid, according to the mathematical formula below.

[0058]

[0059] may be the overall expression ranking value of genes in the jth organoid. j is an index for the organoid, which is a natural number greater than or equal to 1, and may be a value less than or equal to the total number of organoids. i is an index for a gene, which is a natural number greater than or equal to 1, and may be a value less than or equal to the total number of genes. k is an index corresponding to a tissue cell, which is a natural number greater than or equal to 1, and may be a value less than or equal to the value of the total tissue cells.

[0060] indicates whether the i gene is expressed, and if i is 1, it can be 0 or 1, which is the expression of the first gene of the j organoid. If expressed, it can be 1, and if not expressed, it can be 0.

[0061] is whether the j-th organoid corresponds to the k-th tissue cell, and can be 0 if corresponding, and 1 if not corresponding. The correspondence can be determined by whether the organoid is derived from the k-th tissue cell.

[0062] is the total number of genes expressed in the i organoid.

[0063] may be an expression level ranking value of the i-th gene by comparing the expression levels of n genes expressed in the j-th organoid. For example, if 12,125 genes are expressed in an organoid of lung cells, the expression level ranking value of the 1000th gene may be calculated as the expression level ranking value by comparing the expression levels of the 12,125 genes. The rank value may be set to 12,125-1000=11,125. The rank function may be a function that outputs the order of the expression level of the first gene among the genes expressed in the j-th organoid. The rank function may be a function that outputs an expression level ranking value by a preset mathematical formula. The rank function may be designed to be changeable by an administrator. The reference reactivity value also changes in response to the output value of the rank function. The 1-1 and / or 1-2 expression level ranking values ​​of the first gene calculated by the above methods may be designed to have a larger value as the rank increases.

[0064] The tissue data processing unit (130) can calculate a second expression level value of a first gene based on the genetic data of a first tissue cell, and can calculate a second-1 or second-2 expression level ranking value of the first gene in the tissue cell.

[0065] The second expression level value of the first gene can be calculated based on the number of reads of the first gene and the length of the transcript of the first gene in the genomic data of the first tissue cell.

[0066] The 2-1 or 2-2 expression level rank value of the first gene refers to the expression level rank value of the first gene among the genes in the first tissue cell. The 2-1 expression level rank value of the first gene can be designed to have a larger value as the expression level rank increases.

[0067] The second-first expression level rank value of the first gene may be a rank value of the average expression level of the first gene in the first tissue by comparing the expression levels of the first gene in a total of t tissues. For example, the second-first expression level rank value may be calculated by comparing the expression levels of the first gene in 15 tissue cells and corresponding to the rank of the expression levels of the first gene in the first tissue cells. The second-first expression level rank value of the first gene may be a rank value of the average expression level of the first gene in the first tissue cells among a total of t tissues.

[0068]

[0069] i is a value representing the gene index, which can be increased by the number of expressed genes. Here, it will be calculated by setting it to 1.

[0070] t is the total number of tissue cells, Among the total t tissue cells, the rank value of the average expression level of the first gene in the k-th tissue cell may be used. For example, when comparing the average expression levels of the first gene in 15 tissue cells, if the rank of the average expression level of the first gene in the k-th tissue cell is 5th, the rank value may be 10 (= 15-5). The T value may be 10 / 15.

[0071] In an optional embodiment, the second-second expression level rank value of the ith gene in the kth tissue cell can be calculated by the mathematical formula below. Since the index of the gene is 1, i can be set to 1 for calculation.

[0072]

[0073] is the expression of the first gene in the k tissue cell, which can be 0 or 1.

[0074] is the total number of genes expressed in the k tissue cells, is a natural number, and can be a value less than or equal to the total number of tissue cells.

[0075] may be the expression level ranking value of the first gene among nk genes expressed in the k-th tissue cell. For example, if 1000 genes are expressed in the k-th tissue cell and the expression level of the first gene is ranked 200th when the rank of the expression levels of the genes is calculated, the rank value may be 800 (1000-200). The rank function may be a function that outputs the order of the expression level of the first gene among the genes expressed in the k-th tissue cell. The rank function may be a function that outputs the expression level ranking value by a preset mathematical formula. The rank function may be designed to be changeable by an administrator. The reference reactivity value also changes in response to the output value of the rank function.

[0076] The reactivity calculation unit (140) can calculate the reactivity value of the first organoid for the first gene based on the 1-1 or 1-2 expression level rank value of the first organoid and the 2-1 or 2-2 expression level rank value of the first tissue cell.

[0077] The 1-1 expression level ranking value may be the average of the expression level ranking values ​​of the first gene in organoids corresponding to the tissue. The 1-2 expression level ranking value may be the actual expression level ranking value considering all genes expressed in the first organoid.

[0078] The 2-1 expression level ranking value may be the average of the expression level ranking values ​​of the first gene in tissue cells corresponding to the tissue. The 2-2 expression level ranking value may be the actual expression level ranking value considering all genes expressed in the first tissue cells.

[0079] The reactivity value calculation unit (140) inputs the 1-1 and / or 1-2 expression level ranking values ​​of the first gene for the 1st to i-th organoids in which the first gene is expressed, as calculated by the organoid data processing unit (120), and inputs the 2-1 and / or 2-2 expression level ranking values ​​of the first gene for the 1st to k-th tissue cells in which the first gene is expressed, as calculated by the tissue data processing unit (130), so that the reactivity value of the first gene can be calculated for each organoid based on the 1-1 or 1-2 expression level ranking value and the 2-1 or 2-2 expression level ranking value.

[0080] The reactivity value calculation unit (140) can compare the reactivity values ​​of the first gene of each organoid to detect a first organoid having a reactivity similar to that of tissue cells for the first gene. The organoid having a reactivity similar to that of tissue cells may be an organoid having the highest ranked reactivity value, or one or more organoids having a reactivity value higher than a predetermined reference reactivity value.

[0081] More specifically, the reactivity value calculation unit (140) can calculate the reactivity value of the j organoid using the following mathematical formula.

[0082] It may be that the j organoid and the k tissue cells have a corresponding relationship.

[0083] In the above explanation, all i's are set to 1, but the i value can be any value within each maximum value.

[0084]

[0085] is the average expression level rank value of the i gene in the organoid, is the rank value of the average expression level of the i gene in the kth tissue cell among the total t tissues, is the overall expression level ranking value of the i gene in the k tissue cell, In the j organoid, it refers to the ranking value of the expression level of the i gene corresponding to the k tissue cell.

[0086] The data output unit (150) can generate information about the first organoid as output data. The information about the first organoid can include the name of the first organoid and the reactivity value for the first gene of the first organoid.

[0087] The data output unit (150) can transmit information about the first organoid to the terminal of the user who requested the information. The data output unit (150) can request payment of a fee for providing information about the first organoid. The data output unit (150) can transmit information about the first organoid to the terminal of the user who has completed payment of the fee.

[0088] Figure 2 is a diagram illustrating the input data and output data of the drug response calculation method. It refers to the ranking value of the expression level of the i gene corresponding to the k tissue cell in the j organoid.

[0089] The data output unit (150) can generate information about the first organoid as output data. The information about the first organoid can include the name of the first organoid and the reactivity value for the first gene of the first organoid.

[0090] The data output unit (150) can transmit information about the first organoid to the terminal of the user who requested the information. The data output unit (150) can request payment of a fee for providing information about the first organoid. The data output unit (150) can transmit information about the first organoid to the terminal of the user who has completed payment of the fee. This is a drawing.

[0091] As illustrated in FIG. 2, in order to calculate drug responsiveness according to embodiments of the present disclosure, a selected first gene (Gene i) can be input (D1).

[0092] The expression levels of genes can be calculated for tissue cells (D2).

[0093] For tissue cells, the average value (T) of the expression level ranking values ​​of the first gene can be calculated (D4). The overall expression ranking value (P) of the first gene in the tissue cells can be calculated (D5).

[0094] Expression levels of genes can be calculated for organoids (D3).

[0095] For organoids, the average value (E) of the expression level ranking values ​​of the first gene can be calculated (D6). For each organoid, the overall expression ranking value (Q) of the first gene can be calculated (D7).

[0096] Finally, the drug responsiveness value can be calculated based on the average value of the expression level ranking value of the first gene in the tissue cells (T), the overall expression level ranking value of the first gene (P), and, for organoids, the average value of the expression level ranking value of the first gene (E), and the overall expression level ranking value of the first gene (Q).

[0097] According to embodiments of the present disclosure, a drug responsiveness value (S(k, i, j)) can be calculated for a k-th tissue cell among tissues, a j-th organoid among organoids, and an i-th gene among genes (D8).

[0098] By changing the index of tissue cells, organoids, and genes, a drug responsiveness value can be calculated, and one or more organoids having a responsiveness value higher than a predetermined standard responsiveness value or having the highest responsiveness value can be detected (D9).

[0099] Information about one or more detected organoids can be generated and transmitted to other user terminals. The information about the organoids can be encrypted to allow disclosure by a designated user. The information about the organoids can be encrypted with a key value associated with the user. The key value associated with the user can be the output of a preset hash function. A fee may be charged for providing information about the organoids.

[0100] FIG. 3 is a diagram of a network environment of a drug response calculation device according to embodiments of the present disclosure.

[0101] The drug response calculation device (100) can communicate with a user terminal (200) connected to a network.

[0102] The user terminal (200) may be a terminal possessed by a user who wishes to determine drug responsiveness. For example, the user terminal may be a researcher conducting drug development or drug experiments. The user terminal (200) may request information on organoids that are highly responsive to genes or drugs. Using the requested and received information on organoids, the user terminal (200) may conduct experiments on the efficacy and effectiveness of drugs that act on the i gene to treat cancer, diseases, and other conditions.

[0103] The user terminal (200) can generate a report including information on the organoid and the reactivity value for the organoid received from the drug responsiveness calculation device (100). The user terminal (200) can transmit result data for experiments, tests, etc. performed using the received organoid information to the drug responsiveness calculation device (100).

[0104] The drug response calculation device (100) can update the drug response calculation process or reference response value using the experimental result data of the organoid obtained from the user terminal (200). Here, the user terminal (200) is expressed singularly, but may be plural.

[0105] Figure 4 is a flowchart of a method for calculating drug responsiveness according to embodiments of the present disclosure.

[0106] The drug responsiveness calculation device (100) can detect one or more organoids having a high drug responsiveness value for a second gene input by a user.

[0107] As illustrated in FIG. 4, the drug responsiveness calculation device (100) can select one or more organoids and one or more tissue cells in which a second gene is expressed. The index of each of one or more organoids can be set as j, and the index of each of one or more tissue cells can be set as k. j can be set to a value from 1 to the number of organoids. k can be set to a value from 1 to the number of tissue cells.

[0108] In S110, the drug responsiveness calculation device (100) can calculate the first-first expression level rank value or the first-second expression level rank value of the second gene in one or more organoids in which the second gene is expressed.

[0109] The 1-1 expression level rank value refers to the average expression level rank value of the ith gene in the organoid corresponding to the kth tissue cell among the total t organoids. The 1-1 expression level rank value can be calculated using the mathematical formula below. i is a value representing the gene index and can be increased by the number of expressed genes. Here, it is calculated by setting it to 1.

[0110]

[0111] The rank function may be a rank value of the expression level of the first gene of the j-th organoid, which is calculated by comparing the expression levels of the first gene of the total t organoids. For example, if the expression level of the first gene is the highest in the lung cell organoid among 15 tissue cells, the rank of the first gene in the lung cell organoid may be 15. The rank function may be a function that outputs the order of the expression level of the first gene in the j-th organoid among the total t organoids. The rank function may be a function that outputs the expression level rank value by a preset mathematical formula. The rank function may be designed to be changeable by an administrator. The reference reactivity value also changes in response to the output value of the rank function.

[0112] The first-second expression level ranking value may be the expression level ranking value of the second gene in each of one or more organoids. The first-second expression level ranking value can be calculated using the mathematical formula below. "i" represents the gene index and can be increased by the number of genes expressed. Here, it will be calculated by setting it to 1.

[0113]

[0114] may be the overall expression ranking value of genes in the jth organoid. j is an index for the organoid, which is a natural number greater than or equal to 1, and may be a value less than or equal to the total number of organoids. i is an index for a gene, which is a natural number greater than or equal to 1, and may be a value less than or equal to the total number of genes. k is an index corresponding to a tissue cell, which is a natural number greater than or equal to 1, and may be a value less than or equal to the value of the total tissue cells.

[0115] j is an index for the organoid, is a natural number greater than or equal to 1, and may be a value less than or equal to the total number of organoids.

[0116] i is an index for a gene, and is a natural number greater than or equal to 1, and can be a value less than or equal to the total number of genes.

[0117] k is an index corresponding to a tissue cell, is a natural number greater than or equal to 1, and may be less than or equal to the value of all tissue cells.

[0118] indicates whether the i gene is expressed, and if i is 1, it can be 0 or 1, which is the expression of the first gene of the j organoid. If expressed, it can be 1, and if not expressed, it can be 0.

[0119] is whether the j-th organoid corresponds to the k-th tissue cell, and can be 0 if corresponding, and 1 if not corresponding. The correspondence can be determined by whether the organoid is derived from the k-th tissue cell.

[0120] is the total number of genes expressed in the i organoid.

[0121] may be the expression level ranking value of the first gene among n genes expressed in the jth organoid. For example, in the jth organoid, if 100 genes are expressed and the expression level of the first gene is the second highest, the rank value may be output as 99=100-1. If the expression level ranking is 1st, the total number, 100, may be set as the rank value. The rank function may be a function that outputs the order of the expression level of the first gene among the genes expressed in the jth organoid. The rank function may be a function that outputs the expression level ranking value by a preset mathematical formula. The rank function may be designed to be changeable by an administrator. The reference reactivity value also changes in response to the output value of the rank function.

[0122] The 1-1 and / or 1-2 expression level ranking values ​​of the first gene produced by the above methods can be designed so that the higher the ranking, the larger the value.

[0123] In S120, the drug response calculation device (100) can calculate the second-1 and second-2 expression level ranking values ​​of the second gene in one or more tissue cells in which the second gene is expressed, respectively.

[0124] The second-1 expression level ranking value may be the rank value of the average expression level of the first gene in the k-th tissue by comparing the expression levels of the first gene in all t tissues. The second-1 expression level ranking value may be the rank value of the average expression level of the second gene in the cells of the k-th tissue among all t tissues.

[0125] The 2-1 expression level ranking value can be calculated using the mathematical formula below.

[0126]

[0127] i is a value representing the gene index, which can be increased by the number of expressed genes. Here, it will be calculated by setting it to 1.

[0128] t is the total number of tissue cells, may be the rank value of the average expression level of the first gene in the k-th tissue cell among the total t tissues. For example, when comparing the average expression levels of the first gene in 15 tissue cells, if the rank of the average expression level of the first gene in the k-th tissue cell is 5th, the rank value may be 10 = (15-5). The T value may be 10 / 15.

[0129] The second-second expression level rank value of the first gene in the kth tissue cell can be calculated using the mathematical formula below. Since the gene index is 1, i can be set to 1 for calculation.

[0130]

[0131] is the expression of the first gene in the k tissue cells, and can be 0 or 1.

[0132] is the total number of genes expressed in the k tissue cells, is a natural number, and may be less than or equal to the total number of tissue cells.

[0133] is expressed in the k tissue cells k It can be the expression level rank value of the first gene among the genes. For example, if 1000 genes are expressed in the k-th tissue cell and the expression level of the first gene is ranked 200th when the rank of the expression levels of the genes is calculated, the rank value can be 800 as 1000-200. The rank function can be a function that outputs the order of the expression level of the first gene among the genes expressed in the k-th tissue cell. The rank function can be a function that outputs the expression level rank value by a preset mathematical formula. The rank function can be designed to be changeable by the administrator. The reference reactivity value also changes in response to the output value of the rank function.

[0134] In S130, the drug responsiveness calculation device (100) can calculate a drug responsiveness value for each organoid by using at least one of the first-1 expression level ranking value, the first-2 expression level ranking value, the second-1 expression level ranking value, and the second-2 expression level ranking value for each organoid and each tissue cell.

[0135] In S130, the drug responsiveness calculation device (100) inputs the 1-1 and / or 1-2 expression level ranking values ​​of the second gene for the 1st to i-th organoids in which the second gene is expressed, calculated from the organoid data processing unit (120), and inputs the 2-1 and / or 2-2 expression level ranking values ​​of the second gene for the 1st to k-th tissue cells in which the second gene is expressed, calculated from the tissue data processing unit (130), so that the responsiveness value of the second gene can be calculated for each organoid based on the 1-1 expression level ranking value and the 2-1 or 2-2 expression level ranking value.

[0136] More specifically, the drug response calculation device (100) ranks the first and second expression levels according to the following mathematical formula: Ranking values ​​of expression levels 2-1 and 2-2 Based on this, drug responsiveness values ​​for each organoid can be calculated.

[0137]

[0138] is the average expression level rank value of the i gene in the organoid, is the rank value of the average expression level of the i gene in the kth tissue cell among the total t tissues, is the overall expression level ranking value of the gene I in the k tissue cells, In the j organoid, it refers to the ranking value of the expression level of the i gene corresponding to the k tissue cell.

[0139] In S140, the drug reactivity calculation device (100) can compare the reactivity values ​​of the second gene and detect a second organoid having a reactivity value higher than a predetermined reference reactivity value.

[0140] In S150, the drug responsiveness calculation device (100) can generate information about the second organoid as output data. The information about the second organoid can include the name of the second organoid and the responsiveness value for the second gene of the second organoid.

[0141] Figure 5 is a diagram illustrating the operation of a learning device that determines a reference reactivity value.

[0142] According to embodiments of the present disclosure, a learning device (300) for determining a reference reactivity value may be further provided. The learning device (300) may be trained using deep learning or machine learning, and may be trained by inputting a large amount of reactivity values ​​calculated for organoids for a gene. In this way, the reference reactivity value may be determined using a machine learning or deep learning method.

[0143] The learning device (300) can use machine learning and / or deep learning to calculate a reference reactivity value for a reactivity value. The learning device (300) can continuously input training data and determine a reference reactivity value as a result of learning.

[0144] The reference reactivity value produced as a result of learning is transmitted to the drug reactivity calculation device (100) and serves as a criterion for determining whether the drug reactivity value of the organoid is high or low. The drug reactivity calculation device (100) can output whether the drug reactivity value is high or low based on the reference reactivity value.

[0145] Figure 6A is an example table of expression levels for the gene SLC25A31, and Figure 6B is an example diagram of a graph of expression levels of the gene SLC25A31.

[0146] According to embodiments of the present disclosure, to calculate the drug responsiveness value of the SLC25A31 gene, tissue cells and organoids expressing the SLC25A31 gene are determined. Information on the organoids can be obtained from an external database, such as the PDO bank. Information on the tissue cells can be obtained from an external database, such as GTEx.

[0147] As shown in Figure 6A, the gene SLC25A31 can be expressed in 15 cells: brain, breast, colon, heart, kidney, lung, lymph node, ovary, pancreas, prostate, skeletal muscle, suprapublic skin, testis, thyroid, and uterus. The gene SLC25A31 can be expressed at different expression levels in the 15 cells and the 15 organoid cells.

[0148] Figure 6B is an example graph of the expression level of the gene SLC25A31 in 15 tissue cells.

[0149] The graph of the gene SLC25A31 can be expressed as the values ​​of the expression level on the Y-axis for the tissue cells on the X-axis. The graph can be expressed in order of the magnitude of the expression level of the gene SLC25A31. As shown in Figure 6B, the gene SLC25A31 is expressed most highly in lung cells among the tissue cells, with an expression level of 11.01465 (FPKM).

[0150] Figure 6C is an example graph of the expression level of the gene SLC25A31 in 15 organoids.

[0151] The graph of the gene SLC25A31 can be expressed as the values ​​of the expression level on the Y-axis for the organoids on the X-axis. The graph can be expressed in order of the magnitude of the expression level of the gene SLC25A31. As shown in Figure 6C, the gene SLC25A31 is expressed the most in lung cells among the organoids, with 11.03422 (FPKM).

[0152] When calculating the 1-1 expression level rank value of the gene SLC25A31 in the organoid of lung cells, t=15, rank is 15, and the 1-1 expression level rank value (T) can be calculated as 1.

[0153] When calculating the 1-1 expression level rank value of the gene SLC25A31 in the organoid of colon cells, t=15, rank is 10, so the 1-1 expression level rank value (T) can be 0.666.

[0154] According to the embodiments of the present disclosure, when calculating the 2-1 expression level rank value of the gene SLC25A31 in lung cells, t=15, rank can be calculated as 15 and the 2-1 expression level rank value (T) can be calculated as 1.

[0155] When calculating the 2-1 expression level rank value of the gene SLC25A31 in colon cells, t=15, rank is 13, so the 2-1 expression level rank value (T) can be 0.866.

[0156] Figure 6D is an example diagram of the expression level ranking values ​​of genes expressed in lung cells.

[0157] According to embodiments of the present disclosure, for each tissue cell in which the gene SLC25A31 is expressed, an expression level ranking value can be calculated again. As illustrated in Fig. 6D, considering lung cells in which the gene SLC25A31 is expressed, the expression level ranking value of the gene SLC25A31 in lung cells can be 0.956.

[0158] To be more specific, 12,125 genes are expressed in lung cells, and among these, the expression rank of the gene SLC25A31 is 11,591. Accordingly, the expression level of the 2-2 gene can be 11,591 / 12,125=0.956.

[0159] Figure 6E is an example diagram of the expression level ranking values ​​of genes expressed in colon cells.

[0160] As illustrated in Figure 6E, when describing colon cells in which the gene SLC25A31 is expressed, the expression level rank value of the gene SLC25A31 in colon cells may be 0.495. The gene SLC25A31 may have a rank value of 5899 among 11918 genes expressed in colon cells. The second-second gene expression level of the gene SLC25A31 in colon cells may be 0.495.

[0161] By a similar process as above, the expression level of the first and second genes of the SLC25A31 gene per organoid can be calculated to be 0.944.

[0162] According to the above description, the 1-1 and 2-1 gene expression levels can be calculated by comparing the expression levels of tissue cells in which the genes are expressed, thereby calculating a ranking value of the gene expression levels. The 1-2 and 2-2 gene expression levels can be calculated by comparing the expression levels of other genes in each tissue cell or organoid, thereby calculating a ranking value of the gene expression levels.

[0163] FIG. 6F is an example table of drug responsiveness values ​​of the gene SLC25A31 according to embodiments of the present disclosure.

[0164] As illustrated in Figure 6F, drug responsiveness values ​​such as 0.863849, 0.849629, etc. can be calculated for organoids and tissue cells expressing the gene SLC25A31. Among these, several, for example, five organoid cells having drug responsiveness values ​​higher than the reference responsiveness value or higher than the reference rank can be output for the gene SLC25A31.

[0165] In addition, although the preferred embodiments of the present invention have been illustrated and described above, the present invention is not limited to the specific embodiments described above, and various modifications can be made by a person having ordinary skill in the art to which the present invention pertains without departing from the gist of the present invention claimed in the claims, and such modifications should not be understood individually from the technical idea or prospect of the present invention.

[0166] Therefore, the spirit of the present invention should not be limited to the embodiments described above, and not only the scope of the patent claims described below, but also all scopes equivalent to or equivalently modified from the scope of the patent claims are considered to fall within the scope of the spirit of the present invention.

Claims

1. A drug response generation device inputs data including one or more first genes; A step of calculating a first-first expression level rank value and a first-second expression level rank value of the first gene for one or more first organoids derived from one or more first tissue cells in which the first gene is expressed; For the first tissue cell, a step of calculating the 2-1 expression level ranking value and the 2-2 expression level ranking value of the first gene; A step of calculating a drug responsiveness value for each organoid using at least one of the first-1 expression level rank value, the first-2 expression level rank value, the second-1 expression level rank value, and the second-2 expression level rank value for each organoid and each tissue cell; A step of detecting a first organoid having a drug reactivity value greater than or equal to a reference reactivity value; and A method for calculating drug responsiveness of a gene expressed in an organoid, comprising the step of generating information about the first organoid as output data and transmitting the information to an external device.

2. In paragraph 1, The above 1-1 expression level ranking value is, A method for calculating drug responsiveness of a gene expressed in an organoid, wherein the value corresponding to the rank of the expression level of the first gene in the first organoid is compared with the expression levels of the first gene in other organoids, and is divided by the number of the first organoids.

3. In paragraph 1, The above 1-2 expression level ranking values ​​are, A method for calculating drug responsiveness of a gene expressed in an organoid, wherein the value corresponding to the rank of the expression level of the first gene is compared with the expression levels of other genes expressed in the first organoid, and the value is divided by the total number of genes in the first organoid.

4. In paragraph 1, The above 2-1 expression level ranking value is, A method for calculating drug responsiveness of a gene expressed in an organoid, wherein the value corresponding to the rank of the expression level of the first gene in the first tissue cell is compared with the expression levels of the first gene in other tissue cells, and the value is divided by the number of the first tissue cells related to the first gene.

5. In paragraph 1, The above 2-2 expression level ranking value is, A method for calculating drug responsiveness of a gene expressed in an organoid, wherein the value corresponding to the rank of the expression level of the first gene is compared with the expression levels of other genes expressed in the first tissue cell, and the value is divided by the number of all genes expressed in the first tissue cell.

6. In paragraph 1, A method for calculating drug responsiveness of a gene expressed in an organoid, wherein the data for the first tissue cell or the data for the first organoid is obtained from an external database.

7. A data input unit for inputting data including one or more first genes; An organoid data processing unit that calculates a first-first expression level rank value and a first-second expression level rank value of the first gene for one or more first organoids derived from one or more first tissue cells in which the first gene is expressed; A tissue data processing unit that calculates a 2-1 expression level ranking value and a 2-2 expression level ranking value of the first gene for the first tissue cell; A responsiveness value calculation unit that calculates a drug responsiveness value for each organoid using at least one of the first-first expression level rank value, the first-second expression level rank value, the second-first expression level rank value, and the second-second expression level rank value for each organoid and each tissue cell; A drug responsiveness calculation device comprising a data output unit that detects a first organoid having a drug responsiveness value greater than or equal to a reference responsiveness value, generates information about the first organoid as output data, and transmits the output data to an external device.

8. In paragraph 7, The above 1-1 expression level ranking value is, A drug responsiveness calculation device, wherein the value corresponding to the rank of the expression level of the first gene in the first organoid is compared with the expression levels of the first gene in other organoids, and is divided by the number of the first organoids.

9. In paragraph 7, The above 1-2 expression level ranking values ​​are, A drug responsiveness calculation device, wherein the value corresponding to the rank of the expression level of the first gene compared to the expression levels of other genes expressed in the first organoid is divided by the total number of genes in the first organoid.

10. In paragraph 7, The above 2-1 expression level ranking value is, A drug responsiveness calculation device, wherein the value corresponding to the rank of the expression level of the first gene in the first tissue cell is compared with the expression levels of the first gene in other tissue cells, and the value is divided by the number of the first tissue cells related to the first gene.

11. In paragraph 7, The above 2-2 expression level ranking value is, A drug responsiveness calculation device, wherein the value corresponding to the rank of the expression level of the first gene is compared with the expression levels of other genes expressed in the first tissue cell, and the value is divided by the number of all genes expressed in the first tissue cell.

12. In paragraph 7, A drug responsiveness calculation device, wherein the data for the first tissue cells or the data for the first organoid are obtained from an external database.

13. A computer program stored in a computer-readable storage medium for executing any one of the methods of clauses 1 to 6 using a computer.

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