A method for generating a report that reports the level of pathogenicity of gene mutations, and a report generation apparatus.

Abstract

To provide appropriate information even if a level of determined pathogenesis may be changed later.SOLUTION: A report creation method creates a report that reports a level of pathogenesis of gene mutation. The report creation method acquires information on the gene mutation detected in gene panel inspection, for a plurality of evaluation items, creates evaluation results on the basis of, a first standard for evaluating the evaluation items and at least the information on the gene mutation, determines the level of the pathogenesis on the basis of, a second standard for determining the level of the pathogenesis and the evaluation results, determines, of the plurality of evaluation items, an unsettled item in which the evaluation result is unsettled and determines whether the level of the pathogenesis is temporary on the basis of, a result of determination of the unsettled item, and according to a result of determination as to whether the level is temporary, creates a report that reports the level of the pathogenesis.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to a report generation method for generating a report that reports the pathogenicity level of a gene mutation. The present invention also relates to a report generation apparatus that generates a report that reports the pathogenicity level of a gene mutation. [Background Art]

[0002] Gene panel testing, which enables comprehensive examination of multiple gene abnormalities using a next-generation sequencer (NGS), has emerged and has begun to be utilized in fields such as oncology as a technology that plays an important role in personalized medicine. Furthermore, for genetic diseases, which are mostly intractable diseases, clarification of causative genes and research and development of therapeutic drugs are being advanced through gene analysis using NGS, and expectations for gene panel testing loaded with causative gene candidates are increasing.

[0003] When a gene mutation related to a genetic disease is detected in testing, it is recommended that the pathogenicity level of the gene mutation be determined based on predetermined guidelines. As a guideline for determining the pathogenicity level of a gene mutation, for example, the ACMG / AMP guideline can be mentioned. According to this guideline, (1) evaluation items applicable to the target gene mutation are determined based on the criteria of 28 multiple evaluation items related to pathogenicity, and (2) the pathogenicity level of the gene mutation is determined based on the applicable evaluation items.

[0004] Non-Patent Document 1 discloses the results of whole-exome sequence analysis performed using samples obtained from subjects at high risk of breast cancer or ovarian cancer, comparing the pathogenicity level determination results based on the ACMG / AMP guideline with the pathogenicity level determination results based on an existing database. Furthermore, in the pathogenicity level determination based on the ACMG / AMP guideline, a method for automatically determining whether some of the plurality of evaluation items related to pathogenicity are applicable or not applicable is disclosed. [Prior Art Documents] [Non-Patent Documents]

[0005] [Non-Patent Document 1] Am J Hum Genet, 2016 May 5;98(5):801-817, “Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer” [Overview of the project] [Problems that the invention aims to solve]

[0006] In gene panel testing, specialists such as physicians and genetic counselors comprehensively interpret the test results, including the assessment of the pathogenicity level of each gene mutation, to identify the causative gene and formulate a treatment plan. Therefore, it is important to appropriately determine the pathogenicity level in accordance with guidelines. However, among the multiple evaluation items used to determine the pathogenicity level, there are some items for which it is difficult to obtain the information necessary to distinguish between applicable and non-applicable cases in a short period of time.

[0007] For example, some of the evaluation criteria in the ACMG / AMP guidelines require information on genetic mutations and medical history of blood relatives, but obtaining this information in a short period of time can be difficult. Also, some of the evaluation criteria require data from a disease patient cohort, but obtaining cohort data with a sufficient number of patients can take a long time, especially for rare diseases.

[0008] Therefore, it is possible that the level of pathogenicity of a gene mutation may be determined based only on the confirmed evaluation items, while there are evaluation items whose applicability or non-applicability is still undetermined. However, some or all of the undetermined evaluation items may be determined through subsequent additional analyses or investigations, and in such cases, the previously obtained determination of the level of pathogenicity may change as the number of confirmed evaluation items increases. However, Non-Patent Literature 1 does not mention the possibility that the determination of the level of pathogenicity may be changed later.

[0009] Therefore, the object of the present invention is to provide a report generation method and a report generation apparatus that can provide appropriate information even when the determined level of pathogenicity may be changed later. [Means for solving the problem]

[0010] The present invention provides a report generation method for generating a report that reports the level of pathogenicity of a gene mutation, comprising: obtaining information on gene mutations detected by a gene panel test; generating evaluation results for a plurality of evaluation items based on a first criterion for evaluating each evaluation item and at least the information on the gene mutation; determining the level of pathogenicity based on a second criterion for determining the level of pathogenicity and the evaluation results; determining the undetermined items among the plurality of evaluation items for which the evaluation results are not yet determined; determining whether the level of pathogenicity is provisional based on the determination of the undetermined items; and generating a report that reports the level of pathogenicity according to the determination result of whether it is provisional or not.

[0011] Furthermore, the report generation device of the present invention is a report generation device that generates a report reporting the level of pathogenicity of a gene mutation, comprising a control unit and an output unit, wherein the control unit acquires information on gene mutations detected by a gene panel test, generates evaluation results for a plurality of evaluation items based on a first criterion for evaluating each evaluation item and at least the information on the gene mutation, determines the level of pathogenicity based on a second criterion for determining the level of pathogenicity and the evaluation results, determines the undetermined items among the plurality of evaluation items for which the evaluation results are not yet determined, determines whether the level of pathogenicity is provisional or not based on the determination result of the undetermined items, generates a report reporting the level of pathogenicity according to the determination result of whether it is provisional or not, and the output unit outputs the report. [Effects of the Invention]

[0012] According to the present invention, it is possible to provide a report generation method and a report generation apparatus that can provide appropriate information even when the determined level of pathogenicity may change later. [Brief explanation of the drawing]

[0013] [Figure 1] This is a schematic diagram of the report generation system according to the first embodiment. [Figure 2] This figure shows an example of the inspection request information input screen displayed on the display unit of a data transmission device. [Figure 3] This flowchart illustrates an example of the processing procedure performed by the control units of the data transmission device, the second report generation device, and the first report generation device. [Figure 4] This flowchart shows an example of the processing procedure when the control unit of the first report generation device determines the level of pathogenicity of gene mutation 1. [Figure 5] (a) and (b) are diagrams illustrating the content of the 28 evaluation items specified in the ACMG / AMP guidelines. [Figure 6] (a) and (b) are diagrams showing gene region information tables. [Figure 7] It is a diagram showing pathogenicity levels. [Figure 8] It is a diagram showing a second criterion for determining the pathogenicity level of a gene mutation using 28 evaluation items defined in the ACMG / AMP guidelines. [Figure 9] It is a flowchart showing an example of a processing procedure when a control unit of a first report generation device assigns a pathogenicity level in step S46. [Figure 10] It is a diagram showing an example of a master table stored in a storage unit of the first report generation device when an affirmative determination is made in step S28. [Figure 11] It is a diagram illustrating a case where the pathogenicity level is changed when an evaluation result is finalized. [Figure 12a] It is a diagram showing a first result report of Embodiment 1. [Figure 12b] It is a diagram showing a second result report of Embodiment 1. [Figure 13] It is a diagram partially showing a second region of the first result report or the second result report of Modification 1. [Figure 14] It is a diagram partially showing a second region of the first result report or the second result report of Modification 2. [Figure 15] It is a diagram partially showing a second region of the first result report or the second result report of Modification 3. [Figure 16] (a) is a diagram showing a summary report of Modification 4, and (b) is a diagram showing a detailed report of Modification 4. [Figure 17] It is a diagram showing a summary report of Modification 5. [Figure 18] It is a diagram showing a detailed report of Modification 5. [Figure 19] It is a diagram showing a summary report of Modification 6. [Figure 20] It is a diagram showing an input screen for inputting an evaluation result of an undetermined item, which is displayed on a display unit of a data transmission device in step S3. [Figure 21] It is a diagram showing an input screen according to a modification. [Figure 22] This figure illustrates the rules for determining the level of pathogenicity adopted in the second embodiment. [Figure 23] This is a flowchart corresponding to Figure 9 in the second embodiment. [Figure 24] This is a schematic diagram of the report generation system 101 according to the third embodiment. [Figure 25] This flowchart illustrates an example of a processing procedure performed by the control units of the data transmission device and the report generation device in the third embodiment. [Figure 26] This flowchart illustrates an example of a processing procedure performed by the control units of the data transmission device and the report generation device in the fourth embodiment. [Figure 27] This figure shows an example of an inspection request information input screen displayed on the display unit of the data transmission device in the fourth embodiment. [Modes for carrying out the invention]

[0014] Hereinafter, with reference to the drawings, examples of embodiments of the report generation method and report generation system according to the present invention will be described in detail. The embodiments described below are merely examples, and the present invention is not limited to these embodiments. In addition, in each of the following embodiments, the same components are denoted by the same reference numerals in the drawings, and redundant explanations are omitted.

[0015] (First Embodiment) Figure 1 is a schematic diagram of the report generation system 1 according to the first embodiment. As shown in Figure 1, the report generation system 1 comprises a data transmission device 2, a second report generation device 3, a first report generation device 4, a sequencer 5, and a storage device 9. The data transmission device 2, the second report generation device 3, and the first report generation device 4 are connected to each other via a network 6, which is the Internet. A mutation information database 8 is connected to the network 6. The first report generation device 4, the sequencer 5, and the storage device 9 are connected to each other via a local area network 7. The first report generation device 4 is a device that generates evaluation results for each evaluation item specified in the ACMG / AMP guidelines based on gene mutation information, determines the level of pathogenicity based on the generated evaluation results, and generates a report reporting the determined level of pathogenicity. The second report generation device 3 is a device that determines the level of pathogenicity based on the evaluation results for each evaluation item generated by the first report generation device 4 and additional evaluation results for undetermined items, and generates a report reporting the determined level of pathogenicity.

[0016] The data transmission device 2 is installed at the analysis requesting facility 10, for example, a hospital (medical facility), a testing center, or a biomedical science research institute. The data transmission device 2 is a computer. The data transmission device 2 comprises an input unit 2a, a display unit 2b, a transmitting / receiving unit 2c, a control unit 2f, and a storage unit 2g. The input unit 2a is used for data input and consists of a keyboard and a mouse. The display unit 2b consists of a liquid crystal panel and displays images. The display unit 2b may also consist of an organic EL panel. The input unit 2a and the display unit 2b may be configured as a touch panel in which a touch sensor and a display are integrated. The transmitting / receiving unit 2c is an interface for sending and receiving data with external devices via a network 6 connected to the data transmission device 2, and is configured as an interface compatible with Ethernet, for example. The control unit 2f is a CPU, and the storage unit 2g consists of a solid-state drive (SSD) and memory. The test request information for gene panel testing, entered by the user of the data transmission device 2 using the input unit 2a, is transmitted from the transmitting / receiving unit 2c to the second report generation device 3 via the network 6. I will explain the details of the inspection request information later.

[0017] The second report generation device 3 is installed in a data processing facility 20, for example, a server center. In this embodiment 1, the data processing facility 20 is a different facility from the analysis requesting facility 10, but it may be the same facility as the analysis requesting facility 10. The data processing facility 20 may be a facility of a cloud service provider, or a facility of a company that provides nucleic acid sequence analysis services. The second report generation device 3 may be a computer that constitutes a cloud system. The second report generation device 3 comprises an input unit 3a, a display unit 3b, a transmission / reception unit 3c, a control unit 3f, and a storage unit 3g. The hardware configuration of the input unit 3a, display unit 3b, transmission / reception unit 3c, control unit 3f, and storage unit 3g is the same as that of the input unit 2a, display unit 2b, transmission / reception unit 2c, control unit 2f, and storage unit 2g, respectively. The storage unit 3g stores a first criterion for evaluating each of a plurality of evaluation items used to determine the level of pathogenicity, and a second criterion for determining the level of pathogenicity based on the evaluation results of the plurality of evaluation items. The first and second criteria may be obtained by the control unit 3f from the mutation information database 8. The second report generation device 3 transmits the test request information received from the data transmission device 2 to the first report generation device 4 via the network 6 from the transmitting / receiving unit 3c. The second report generation device 3 also generates a second result report reporting the level of pathogenicity based on the additional evaluation results received from the data transmission device 2 and the information from the first result report reporting the level of pathogenicity received from the first report generation device 4, and transmits the second result report via the network 6 from the transmitting / receiving unit 3c to the data transmission device 2. The first and second criteria, additional evaluation results, first result report, and second report will be explained in detail later.

[0018] The first report generation device 4 is installed at the analysis request destination facility 30, for example, a data analysis facility. In this embodiment 1, the analysis request destination facility 30 is a different facility from both the analysis request source facility 10 and the data processing facility 20, but it may be the same facility as the analysis request source facility 10, or the same facility as the data processing facility 20. The first report generation device 4 may be a computer that constitutes a cloud system. The first report generation device 4 is able to access the mutation information database 8.

[0019] The first report generation device 4 comprises an input unit 4a, a display unit 4b, a transmitting / receiving unit 4c, a control unit 4f, and a storage unit 4g. The hardware configuration of the input unit 4a, display unit 4b, transmitting / receiving unit 4c, control unit 4f, and storage unit 4g is the same as that of the input unit 2a, display unit 2b, transmitting / receiving unit 2c, control unit 2f, and storage unit 2g, respectively. The storage unit 4g stores, similar to the storage unit 3g, a first criterion for evaluating each of the multiple evaluation items used to determine the level of pathogenicity, and a second criterion for determining the level of pathogenicity based on the evaluation results of the multiple evaluation items. The first and second criteria may be obtained by the control unit 4f from the mutation information database 8. The first report generation device 4 receives test request information from the second report generation device 3. The first report generation device 4 also generates a first result report based on the nucleic acid sequence data read from the storage 9, the reference sequence data obtained from the mutation information database 8, and the first and second criteria.

[0020] Sequencer 5 is a next-generation sequencer (NGS). Hereafter, when "sequencer" is mentioned, it refers to a next-generation sequencer. Sequencer 5 is a device that reads the base sequence information of nucleic acids, and can use systems such as the MiSeq system (Illumina, Inc.), NextSeq550 system (Illumina, Inc.), Ion GeneStudio S5 system (Thermo Fisher Scientific, Inc.), or Ion Torrent Genexus system (Thermo Fisher Scientific, Inc.). Sequencer 5 can read the nucleic acid sequences of multiple library samples in a single sequencing run. Storage 9 is Network Attached Storage (NAS). NAS is configured as a storage device that can be directly connected to a network.

[0021] When reading nucleic acid sequences using Sequencer 5, Sequencer 5 accepts a Sequence Run ID, Sample ID, and Index ID. The Sequence Run ID is the identification information for the Sequence Run data. In a single Sequence Run, i.e., with one cartridge, Sequencer 5 reads the nucleic acid sequences of multiple library samples and generates multiple nucleic acid sequence data corresponding to each library sample.

[0022] A library sample is a sample prepared for reading nucleic acid sequences, and is also called a library. Multiple library samples can be prepared, for example, by pre-treating multiple samples prepared from multiple subjects with reagents and attaching different index sequences to each sample. Library samples can be prepared, for example, using the Onco Guide® NCC OncoPanel Kit (manufactured by Sysmex Corporation). The sample ID is information that identifies each library sample. The index ID is information that identifies the index sequence attached to each library sample.

[0023] The user of Sequencer 5 dispenses multiple pre-prepared library samples into a single cartridge, sets the cartridge in Sequencer 5, and instructs it to start sequence reading. Upon receiving the instruction from the user to start sequence reading, Sequencer 5 reads the nucleic acid sequence for each of the multiple library samples, generates sequence run data, and records it in Storage 9. The sequence run data for each library sample includes the sample ID, index ID, and nucleic acid sequence data with the index sequence attached.

[0024] The mutation information database 8 consists of, for example, an external public sequence information database or a public known mutation information database. The control unit 4f of the first report generation device 4 compares each nucleic acid sequence data contained in the sequence run data read from the storage 9 with the reference sequence data stored in the mutation information database 8, and generates gene mutation information for each nucleic acid sequence data.

[0025] Variation information database 8 includes external publicly available sequence databases and publicly available known variant databases. Examples of publicly available sequence databases include NCBI RefSeq (web page, www.ncbi.nlm.nih.gov / refseq / ), NCBI GenBank (web page, www.ncbi.nlm.nih.gov / genbank / ), and UCSC Genome Browser. Examples of publicly available known variant databases include the COSMIC database (web page, www.sanger.ac.uk / genetics / CGP / cosmic / ), the ClinVar database (web page, www.ncbi.nlm.nih.gov / clinvar / ), and dbSNP (web page, www.ncbi.nlm.nih.gov / SNP / ). Variation information database 8 may also include publicly available known variant databases that include frequency information for each race or animal species regarding publicly available known variants. Examples of publicly available known variant information databases containing such information include HapMap Genome Browser release #28, Human Genetic Variation Browser (web page, www.genome.med.kyoto-u.ac.jp / SnpDB / index.html), and 1000 Genomes (web page, www.1000genomes.org / ). Furthermore, variant information database 8 may also be other public and / or commercial databases, such as UniProt and HGMD.

[0026] Next, the report generation method by the report generation system 1 will be described. Figure 3 is a flowchart illustrating the processes performed by the control units 2f, 3f, and 4f of the data transmission device 2, the second report generation device 3, and the first report generation device 4, respectively. Referring to Figure 3, in step S1, the control unit 2f of the data transmission device 2 displays the inspection request information input screen 40 (see Figure 2) on the display unit 2b, accepts the input of inspection request information, and transmits the accepted inspection request information to the second report generation device 3.

[0027] Figure 2 shows an example of the inspection request information input screen 40 displayed on the display unit 2b in step S1. As shown in Figure 2, the inspection request information input screen 40 displays a requesting facility information registration unit 41, an inspection request information registration unit 42, a request operation unit 43, and a cancellation operation unit 44. The requesting facility information registration unit 41 includes an input area 41a for entering the facility name, a display area 41b for the facility ID, and an input area 41c for entering contact information. Input areas 41a and 41c are configured so that the user can input numbers, characters, or symbols by operating the input unit 2a of the data transmission device 2. Input area 41a is an area for entering the name of the requesting facility, and for example, "xxx Hospital" is entered in input area 41a.

[0028] The display area 41b automatically displays the facility ID corresponding to the facility entered in the input area 41a. This display is performed by the control unit 2f searching for the facility ID corresponding to the facility name. The storage unit 2g stores a facility table showing the correspondence between facility IDs and the facility names corresponding to those facility IDs. By referring to this facility table, the control unit 2f displays the facility ID corresponding to the entered facility name in the display area 41b. For example, F01 is displayed in the display area 41b. If there is no facility ID corresponding to the entered facility name, an automatically generated facility ID is displayed. If there is no facility ID corresponding to the entered facility name, information indicating that there is no corresponding facility ID may be displayed on the inspection request information input screen 40.

[0029] Input field 41c is for entering the representative contact information of the requesting facility, and is set to accept the requesting facility's representative telephone number. Input field 41c may also be set to accept an email address, address, etc.

[0030] The inspection request information registration unit 42 includes an input area 42a for inputting the type of inspection, an input area 42b for inputting the attending physician, a display area 42c for displaying the attending physician's user ID, a display area 42d for displaying the inspection request ID, a display area 42e for displaying the specimen ID, a display area 42f for displaying the inspection request date, an input area 42g for inputting the inspection facility, a display area 42h for displaying the patient ID, an input area 42i for inputting the gender of the patient (subject), an input area 42j for inputting the disease name, and an input area 42k for inputting whether or not the patient has given consent. Input areas 42a, 42b, 42g, 42i, 42j, and 42k are configured so that the user can input numbers, characters, or symbols by operating the input unit 2a of the data transmission device 2.

[0031] Input area 42a is for entering the name of the panel test used for gene panel testing. Input area 42a is configured as a pull-down list containing panel test types accepted by the report generation system 1, and the user selects the panel test type from the pull-down list by operating the input unit 2a. Input area 42b is for entering the name of the patient's attending physician. Display area 42c displays the user ID corresponding to the attending physician's name information. This display is performed by the control unit 2f searching for the user ID corresponding to the attending physician. The storage unit 2g stores a facility table showing the correspondence between the attending physician's user ID and the attending physician's name corresponding to the user ID. By referring to this facility table, the control unit 2f displays the user ID corresponding to the entered attending physician's name in the display area 42c. If a user ID corresponding to the entered name does not exist, an automatically generated user ID may be displayed. Alternatively, if a user ID corresponding to the entered name does not exist, information indicating that a corresponding user ID does not exist may be displayed on the test request information input screen 40.

[0032] Display area 42d automatically displays the test request ID, which is an ID used to identify each individual test. Alternatively, an input area may be provided for entering the test request ID individually assigned by the requesting medical facility. Display area 42e automatically displays the specimen ID, which is an ID used to identify each individual specimen. Alternatively, an area may be provided for entering the test ID individually assigned by the requesting medical facility. Display area 42f automatically registers the date the test request was made.

[0033] Input area 42g is for entering the facility that will perform the genetic information testing. The patient ID is automatically displayed in display area 42h. Alternatively, an input area may be provided for entering a patient ID individually assigned by the requesting medical facility instead of display area 42h. Input area 42i is for entering the patient's gender, and input area 42j is for entering the patient's disease name. Input area 42k is for entering whether or not the patient has given consent. Patient consent includes consent to the test, consent to providing anonymized test results to a third-party organization, and combinations thereof. However, the content of patient consent is not limited to these. Information regarding "patient consent" may be displayed as a pull-down menu or radio buttons for selection, or as a list from which any combination can be selected.

[0034] The request operation unit 43 is operated, for example, by aligning the cursor with the image of the request operation unit 43 and clicking or double-clicking with the mouse. When the request operation unit 43 is operated, the information displayed in the input area / display area 41a~41c and input area / display area 42a~42k is sent to the second report generation device 3 as inspection request information. The cancellation operation unit 44 is operated, for example, by aligning the cursor with the image of the request operation unit 43 and clicking or double-clicking with the mouse. When the cancellation operation unit 44 is operated, the information that has been entered and displayed on the inspection request information input screen 40 up to that point is erased. Note that the inspection request information only needs to include the information necessary to request an inspection, and some of the information displayed in the input area / display area 41a~41c and input area / display area 42a~42k may be omitted.

[0035] Referring again to Figure 3, in step S11, the control unit 3f of the second report generation device 3 receives the inspection request information received from the data transmission device 2, that is, the information displayed in the input area / display area 41a~41c and the input area 42a~42k / display area of ​​the inspection request information input screen 40, and stores it in the storage unit 3g. In step S12, the control unit 3f transmits the inspection request information to the first report generation device 4. Next, in step S21, the control unit 4f of the first report generation device 4 receives the inspection request information transmitted from the second report generation device 3, stores it in the storage unit 4g, and displays on the display unit 4b that the inspection request information has been received.

[0036] When the user of the first report generator 4 or the user of the sequencer 5 recognizes that the test request information has been received based on the information displayed on the display unit 4b, they prepare a library sample from the sample identified by the sample ID displayed in the input area 42e of the test request information input screen 40 and have the sequencer 5 read the nucleic acid sequence data. The sequencer 5 records the sequence run data, including the read nucleic acid sequence data, in the storage 9. When the sequencer 5 has finished reading the nucleic acid sequence data, the user of the first report generator 4 operates the input unit 4a of the first report generator 4 to instruct it to read the nucleic acid sequence data. In response to this instruction, the control unit 4f receives the instruction from the user of the first report generator 4 to read the nucleic acid sequence data in step S22.

[0037] In step S23, the control unit 4f reads nucleic acid sequence data (hereinafter referred to as acquired sequence data) identified by the sample ID displayed in the input area 42e of the test request information input screen 40 from the sequence run data stored in the storage 9. In step S24, the control unit 4f detects all gene mutations contained in the acquired sequence data and acquires gene mutation information based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8. Gene mutation detection can be performed by the following known method. First, the position on the reference sequence where the degree of agreement between the acquired sequence data and the reference sequence data satisfies a predetermined standard is identified, and the corresponding bases of the acquired sequence data and the reference sequence data are compared. If there is no mismatch in the corresponding bases, it is determined that there are no gene mutations. On the other hand, if there is a mismatch in the corresponding bases, the mismatched bases are detected as gene mutations. Also in step S24, the control unit 4f determines the inheritance mode, mutation allele frequency, homozygous or heterozygous, mutation site (base), and mutation site (amino acid) based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8.

[0038] In step S25, the control unit 4f determines the pathogenicity level of one of the gene mutations detected in step S24. The details of the pathogenicity level determination process will be explained with reference to Figure 4. In step S45, the control unit 4f determines whether each of the 28 evaluation items specified in the ACMG / AMP guidelines (Richards et al., Genetics in Medicine volume 17, pages 405-423 (2015)) is applicable, based on the first criterion stored in the memory unit 4g and one of the gene mutations detected in step S24, and generates an evaluation result.

[0039] The processing of step S45 will be described in detail below with reference to Figures 5 and 6. Figure 5 is a diagram illustrating the contents of the 28 evaluation items specified in the ACMG / AMP guidelines. As shown in Figure 5, the evaluation items include 16 items related to pathogenicity shown in Figure 5(a) and 12 items related to benignity shown in Figure 5(b). Next, some of the evaluation items will be described in detail.

[0040] PVS1, one of the 16 items related to pathogenicity, is an evaluation item that, if present, suggests a very high probability of pathogenicity. PVS1 can be determined by determining whether or not there are coarse nonsense mutations, frameshifts, deletions of multiple exons, etc., in diseases caused by loss of function. The memory unit 4g of the first report generation device 4 and the memory unit 3g of the second report generation device 3 store nucleic acid sequence data with gene mutations that are judged to correspond to PVS1 according to the ACMG / AMP guidelines as the first criterion. In step S45 (Figure 4), the control unit 4f refers to the nucleic acid sequence data with gene mutations stored in the memory unit 4g and determines whether one of the gene mutations detected in step S24 is the same as the gene mutation in the nucleic acid sequence data stored in the memory unit 4g. If they are the same, it is determined to correspond to PVS1; otherwise, it is determined not to correspond to PVS1.

[0041] PS1 is an evaluation item that, if it is met, suggests a high probability of pathogenicity. Whether or not a gene meets PS1 can be determined by determining whether or not a similar amino acid mutation has already been identified as causing a disease. The memory unit 4g of the first report generation device 4 and the memory unit 3g of the second report generation device 3 store nucleic acid sequence data containing gene mutations that are judged to correspond to PS1 according to the ACMG / AMP guidelines as the first criterion. In step S45 (Figure 4), the control unit 4f refers to the nucleic acid sequence data containing gene mutations stored in the memory unit 4g and determines whether or not one of the gene mutations detected in step S24 is the same as a gene mutation in the nucleic acid sequence data stored in the memory unit 4g. If they are the same, it is determined to correspond to PS1; otherwise, it is determined not to correspond to PS1.

[0042] PM1 is an evaluation criterion that, if present, indicates a slightly higher likelihood of pathogenicity. Whether or not a mutation is present can be determined by examining whether it exists in a hotspot or functional domain region and whether or not it meets the criteria for benignity.

[0043] Figure 6 is a diagram showing gene region information, illustrating hotspot regions (Figure 6(a)) and functional domain regions (Figure 6(b)). In the hotspot region table shown in Figure 6(a), each gene on chromosome 1 has three hotspots. For example, the first hotspot is the nucleic acid sequence portion from base 67108753 to base 67109046 on chromosome 1. Each hotspot region is stored in memory units 4g and 3g as a first criterion. In step S45 (Figure 4), the control unit 4f determines whether one of the gene mutations detected in step S24 exists in a hotspot region stored in memory unit 4g. If it exists, it is determined to be PM1; otherwise, it is determined not to be PM1.

[0044] In the functional domain region table shown in Figure 6(b), there are three functional domain regions in a gene located on chromosome 1. For example, the first functional domain region is the nucleic acid sequence portion from base 8388315 to base 8388618 on chromosome 1. Each functional domain region is stored in memory units 4g and 3g as the first criterion. In step S45 (Figure 4), the control unit 4f determines whether one of the gene mutations detected in step S24 exists in a functional domain region stored in memory unit 4g. If it exists, it is determined to be PM1; otherwise, it is determined not to be PM1.

[0045] The first criterion is not limited to the examples above, but includes, for example, at least one of the following (1) to (7): (1) Disease name, (2) Information on the type and location of the gene mutation, and at least one of the amino acids and / or bases that have been altered by the mutation, (3) Information including at least one of the genetic information or medical history of a blood relative, (4) Information regarding the relationship between disease and gene mutations, (5) Frequency of gene mutations in the control population and / or disease population, (6) Regional information of each gene, (7) Information obtained by the prediction algorithm.

[0046] Examples of "types of mutations" include nonsense mutations, frameshift mutations, deletions of multiple exons, and missense mutations. Examples of "location of mutations" include the position of the mutation from the beginning of the genome or the transcript of the gene. Examples of "information on the relationship between disease and gene mutations" include, for example, the level of pathogenicity of known gene mutations in the disease and the information supporting that level, and information on amino acid substitutions and inheritance patterns of gene mutations that have been identified as pathogenic (likely pathogenic) in the disease.

[0047] Examples of "gene region information" include gene mutation information such as hotspot regions, functional domain regions, and repetitive regions.

[0048] The "information obtained by the prediction algorithm" includes information on the interpretation of mutations obtained through computer simulation calculations, such as predicted values ​​of the impact of mutations on protein function using SIFT. This information can be obtained using the prediction algorithm in Table 2 of the following reference: S. Richards et al., “Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology,” Genetics in Medicine 2015 17:5, vol. 17, no. 5, pp. 405-423, Mar. 2015, doi: 10.1038 / gim.2015.30.

[0049] Referring again to Figure 4, in step S46, the control unit 4f assigns a pathogenicity level to one of the gene mutations detected in step S24, based on a second criterion for determining the level of pathogenicity and the results of whether each evaluation item in step S45 is applicable (evaluation result).

[0050] Figure 7 shows the level of pathogenicity. As shown in Figure 7, the level of pathogenicity is indicated on a five-point scale. A pathogenicity ID of P, "pathogenic," is the highest level of pathogenicity and indicates that the substance is pathogenic. A pathogenicity ID of LP, "likely pathogenic," is the second highest level of pathogenicity and indicates that the substance may be pathogenic. A pathogenicity ID of B, "benign," is the lowest level of pathogenicity and indicates that the substance is benign. A pathogenicity ID of LB, "likely benign," is the second lowest level of pathogenicity and indicates that the substance is likely to be benign. A pathogenicity ID of US, "uncertain significance," indicates that the presence or absence of pathogenicity is unknown, and the level of pathogenicity is lower than "likely pathogenic" but higher than "likely benign."

[0051] Figure 8 shows the second criterion for determining the level of pathogenicity. The second criterion is set in accordance with the ACMG / AMP guidelines. For example, if at least one of the criteria P(i), P(ii), and P(iii) for determining "pathogenic" is met, it is determined to be "pathogenic". Criterion P(i) indicates that if the evaluation result in step S45 corresponds to PVS1 and at least one of criteria P(i)(a) to P(i)(d) is met, it is determined to be "pathogenic". P(i)(a) is satisfied if the evaluation result in step S45 corresponds to at least one of PS1-PS4, P(i)(b) is satisfied if the evaluation result in step S45 corresponds to two or more of PM1-PM6, P(i)(c) is satisfied if the evaluation result in step S45 corresponds to one of PM1-PM6 and one of PP1-PP5, and P(d) is satisfied if the evaluation result in step S45 corresponds to two or more of PP1-PP5.

[0052] Criterion P(ii) indicates that if the evaluation result in step S45 corresponds to two or more of PS1-PS4, the patient is determined to be "pathogenic". Criterion P(iii) indicates that if the evaluation result in step S45 corresponds to one of PS1-PS4 and at least one of criteria P(iii)(a) to P(iii)(c) is met, the patient is determined to be "pathogenic". P(iii)(a) is satisfied if the evaluation result in step S45 corresponds to three or more of PM1-PM6, P(iii)(b) is satisfied if the evaluation result in step S45 corresponds to two of PM1-PM6 and two or more of PP1-PP5, and P(iii)(c) is satisfied if the evaluation result in step S45 corresponds to one of PM1-PM6 and four or more of PP1-PP5.

[0053] Referring again to Figure 4, in step S46, the control unit 4f assigns one of the following classifications to one of the gene mutations detected in step S24, based on the second criterion and the evaluation result in step S45: “pathogenic,” “likely pathogenic,” “benign,” “likely benign,” and “uncertain significance.” This process will be described in detail below. Figure 9 is a flowchart showing an example of the processing procedure in which the control unit 4f of the first report generation device 4 assigns a level of pathogenicity in step S46. Referring to Figure 9, in step S51, the control unit 4f determines whether one of the gene mutations detected in step S24 meets the criteria for pathogenicity, based on the second criteria P(i) to P(iii) corresponding to pathogenicity shown in Figure 8. If the determination is positive in step S51, in step S52, the classification for pathogenicity is assigned to the gene mutation, and the process proceeds to step S55.

[0054] On the other hand, if a negative determination is made in step S51, the process proceeds to step S53, where the control unit 4f determines whether the gene mutation meets the criteria for likely pathogenic based on the second criteria LP(i) to LP(vi) corresponding to likely pathogenic shown in Figure 8. If a positive determination is made in step S53, the gene mutation is designated as likely pathogenic, and the process proceeds to step S55. On the other hand, if a negative determination is made in step S53, the control unit 4f proceeds to step S55.

[0055] In step S55, the control unit 4f determines whether the gene mutation meets the criteria for benign, based on the second criteria B(i) to B(ii) corresponding to benign shown in Figure 8. If the determination in step S55 is positive, the control unit 4f assigns benign to the gene mutation in step S56 and proceeds to step S59.

[0056] On the other hand, if a negative determination is made in step S55, the process proceeds to step S57, where the control unit 4f determines whether the gene mutation meets the criteria for likely benign based on the second criteria LB(i) to LB(ii) corresponding to likely benign shown in Figure 8. If a positive determination is made in step S57, the control unit 4f assigns likely benign to the gene mutation in step S58 and proceeds to step S59. On the other hand, if a negative determination is made in step S57, the control unit 4f proceeds to step S59.

[0057] In step S59, the control unit 4f determines whether the gene mutation falls under the second criterion US(i) to US(ii) corresponding to the uncertain significance shown in Figure 8. Specifically, the control unit 4f determines that the mutation falls under the uncertain significance criterion if it does not fall under any of the criteria for pathogenic, likely pathogenic, benign, or likely benign. In rare cases, both pathogenic and benign mutations may occur. In this case as well, the control unit 4f determines that the mutation falls under the uncertain significance criterion.

[0058] If the determination in step S59 is positive, in step S60 the control unit 4f assigns uncertain significance to the gene mutation and proceeds to step S61. On the other hand, if the determination in step S59 is negative, the control unit 4f returns the process to step S26 (Figure 3). In step S61, the control unit 4f determines whether both pathogenic and benign are assigned. If the determination in step S61 is positive, the control unit 4f removes pathogenic and benign in step S62 and returns the process to step S26 (Figure 3). Also, if the determination in step S61 is negative, the control unit 4f returns the process to step S26 (Figure 3) without executing step S62.

[0059] The pathogenicity level assigned in step S46 (Figures 4 and 9) may be changed by subsequent additional evaluations. This is explained below. The first criterion includes criteria other than the subject's genetic mutations, such as criteria regarding genetic mutations of the subject's relatives and criteria regarding the medical history of the subject's relatives. Therefore, in determining the applicability of each evaluation item in step S45 (Figure 4), there may be evaluation items that cannot be determined solely from the subject's genetic mutation information detected in step S24, i.e., evaluation items for which the evaluation result is uncertain. In such cases, the pathogenicity level assigned in step S46 may be changed later and is provisional information.

[0060] Figure 11 illustrates an example where the level of pathogenicity changes due to the addition or modification of evaluation results (applicability) of evaluation items after the fact. In the example shown in Figure 11(a), for the gene mutation "aaa", the evaluation result in step S45 corresponds to evaluation items PVS1, PS1, and BS2, and as a result, the level of pathogenicity is determined to be pathogenic. Also, for the gene mutation "bbb", the evaluation result in step S45 corresponds to evaluation items PS1 and PM3, and as a result, the level of pathogenicity is determined to be likely pathogenic. Furthermore, for the gene mutation "ccc", the evaluation result in step S45 corresponds to evaluation items PS1 and PM1, and as a result, the level of pathogenicity is determined to be likely pathogenic.

[0061] Furthermore, in this example, as shown in Figure 11(b), the pathogenicity determination result in Figure 11(a) was determined without finalizing the evaluation results for evaluation items PS2, PM6, PP1, PP4, and BS4 because there was insufficient information to determine whether evaluation items PS2, PM6, PP1, PP4, and BS4 were applicable in step S45. In this example, if additional analysis or investigation provides information to determine whether evaluation items PS2, PM6, PP1, PP4, and BS4 are applicable, as shown in Figure 11(c), for example, the gene mutation "aaa" may newly qualify as evaluation item BS4. In this case, applying the evaluation results of each evaluation item to the second criterion, the pathogenicity level of the gene mutation "aaa" changes from pathogenic to uncertain significance. Similarly, for example, the gene mutation "bbb" may newly qualify as evaluation item PS2. In this case, the pathogenicity level of the gene mutation "bbb" changes from likely pathogenic to pathogenic. It should be noted that even if a new gene mutation, such as "ccc," is identified as a PM6 evaluation criterion, the level of pathogenicity may not change.

[0062] Thus, if there are evaluation items for which the evaluation results are not yet determined, the level of pathogenicity may change, and the level of pathogenicity in question may be provisional rather than finalized. Therefore, in step S26 shown in Figure 3, the control unit 4f determines the evaluation items that are not yet determined (undetermined items) from among the evaluation items evaluated in step S45. Specifically, the control unit 4f determines whether each of the first criteria corresponding to each evaluation item is a criterion that relates only to the information of the gene mutation detected in step S24, or information that relates to other information as well. For example, evaluation item PVS1 is a criterion that relates only to the subject's genetic test results, and whether or not it applies can be determined by the information of the gene mutation detected in step S24, so the control unit 4f determines that the evaluation result of evaluation item PVS1 is finalized. On the other hand, evaluation item PS2 is a criterion that relates to the gene mutations of the subject's parents, and whether or not it applies cannot be determined by the information of the gene mutation detected in step S24 alone, so the control unit 4f determines that the evaluation result of evaluation item PS2 is not yet determined, that is, evaluation item PS2 is an undetermined item. The control unit performs the same determination for 28 evaluation items and determines the items that remain undetermined.

[0063] Next, in step S27, the control unit 4f determines whether the pathogenicity level determined in step S25 is provisional or not. Specifically, the control unit 4f determines whether the pathogenicity level changes when the evaluation result of the undetermined items determined in step S26 is changed from the evaluation result when the pathogenicity level was assigned in step S46, and the pathogenicity level is determined again. If changing the evaluation result of at least one undetermined item changes the pathogenicity level, the control unit 4f determines that the pathogenicity level is provisional. If changing the evaluation result of the undetermined items does not change the pathogenicity level, the control unit 4f determines that the pathogenicity level is not provisional. The control unit 4f also determines that the pathogenicity level is not provisional if it is determined in step S26 that there are no undetermined items.

[0064] Next, in step S28, the control unit 4f determines whether or not the pathogenicity level has been determined for all gene mutations detected in step S24. If the determination in step S28 is positive, the control unit 4f proceeds to step S29. If the determination in step S28 is negative, the control unit 4f returns to step S25 and repeats the process from steps S25 to S27 until the pathogenicity level has been determined for all gene mutations.

[0065] Figure 10 shows an example of a master table stored in memory unit 4g at the time of a positive determination in step S28. As shown in Figure 10, the master table stores the patient ID, specimen ID, test request ID, panel ID, disease, physician ID, medical facility ID, detected gene mutation, inheritance mode, mutation allele frequency, homozygous or heterozygous, mutation site (base), mutation site (amino acid), applicable evaluation item, pathogenicity ID, undetermined evaluation item, provisional flag, and potentially changeable pathogenicity ID, all linked together.

[0066] The patient ID, specimen ID, test request ID, panel ID, disease, physician ID, and medical facility ID are information based on the test request information received in step S21. The detected gene mutation, inheritance pattern, mutation allele frequency, homozygous or heterozygous, mutation site (base), and mutation site (amino acid) are information based on the gene mutation information obtained in step S24. In addition, the information on applicable evaluation items, pathogenicity ID, and undetermined evaluation items is information on the evaluation items evaluated in step S45, the pathogenicity level assigned in step S46, and the undetermined items determined in step S26. Specifically, applicable evaluation items are the evaluation items determined to be applicable in step S45. The pathogenicity ID is the pathogenicity ID (Figure 7) corresponding to the pathogenicity level assigned in step S46. Undetermined evaluation items are the undetermined items determined in step S26. Furthermore, the provisional flag and the modifiable pathogenicity ID are provisional information regarding the level of pathogenicity. The provisional flag will be "present" if the level of pathogenicity is determined to be provisional in step S27, and "absent" if it is determined not to be provisional. The modifiable pathogenicity ID is the pathogenicity ID that indicates the changed level of pathogenicity when the evaluation result of the undetermined items is changed for a level of pathogenicity that has been determined to be provisional.

[0067] For example, the first row of the master table contains data where the patient ID is PA01, the specimen ID is SA01, the test request ID is T01, the panel ID is P01, the disease is XXX, the physician ID is U01, the medical facility ID is F01, the detected gene mutation is aaa, the corresponding evaluation items are PVS1, PS1, BS2, the pathogenicity ID is P (pathogenic), the undetermined evaluation items are PS2, PM6, PP1, PP4, BS4, the provisional flag is "yes", and the potentially changeable pathogenicity ID is US (uncertain significance). The provisional flag is "yes" and the potentially changeable pathogenicity ID is US, indicating that the pathogenicity ID (P) for the gene mutation aaa is provisional and may be changed to US later. Note that in this example master table, the specimen IDs for the data in rows 1 through 4 are the same, but the detected mutations are different. Therefore, it can be seen that four gene mutations (aaa, bbb, ccc, ddd) were detected in the sample (library sample) with the corresponding sample ID.

[0068] Referring again to Figure 3, in step S29, the control unit 4f generates the first result report.

[0069] Figure 12a shows an example of a first result report 51 of the first embodiment. The first result report 51 is a report generated based on the information of the same sample in the master table shown in Figure 10 (the information from the first to fourth rows in the example in Figure 10). As shown in Figure 12a, the first result report 51 includes a first area 51a showing bibliographic information, a second area 51b showing the level of pathogenicity, and a third area 51c showing undetermined evaluation items (undetermined items). The first area 51a includes the test ID, medical facility, patient ID, attending physician, patient name, and gene panel name.

[0070] Area 2, 51b, is presented in tabular format. In this table, each row contains information on gene mutation, mode of inheritance, mutation allele frequency, homozygous or heterozygous, mutation site (base), mutation site (amino acid), pathogenicity, and ACMC category. The ACMC category is an evaluation item that has been determined to be applicable and confirmed, and is listed in the "Applicable Evaluation Items" column of the master table.

[0071] Pathogenicity is the determined level of pathogenicity, and the level corresponding to the pathogenicity ID listed in the "Pathogenicity ID" column of the master table is written in text. If the "Provisional Flag" in the master table is "Yes", the symbol "*" is added, as indicated by arrow k. The symbol "*" means that the level of pathogenicity listed in the pathogenicity column may change, and that the level of pathogenicity is provisional.

[0072] In the example shown in Figure 12a, the symbols "*" are placed to the right of the pathogenicity levels corresponding to the gene mutation "aaa", "likely pathogenic" corresponding to the gene mutation "bbb", and "likely pathogenic" corresponding to the gene mutation "ccc". Therefore, it can be seen that the pathogenicity levels for these three gene mutations are provisional. On the other hand, the symbol "*" is not placed to the right of the pathogenicity level corresponding to the gene mutation "ddd". Therefore, it can be seen that the pathogenicity level for the gene mutation "ccc" has been confirmed as uncertain significance.

[0073] Area 31c contains evaluation items that have not yet been determined. In the example shown in Figure 12a, all evaluation items listed in the first to fourth rows of the "Evaluation Items that Have Not Yet Been Determined" section of the master table are listed. Therefore, in the example shown in Figure 12a, PS2, PM6, PP1, PP4, and BS4 are listed in Area 31c. This makes it easy to see that evaluation items PS2, PM6, PP1, PP4, and BS4 were not used to determine the pathogenicity level of the gene mutations "aaa", "bbb", "ccc", and "ddd" reported in the first result report 51. Referring again to Figure 3, in step S30, the control unit 4f transmits the first result report generated in step S29 as an electronic file to the second report generation device 3 via the transmission / reception unit 4c.

[0074] In step S13, the control unit 3f of the second report generation device 3 receives the first result report transmitted from the first report generation device 4. In step S14, the control unit 3f transmits the first result report as an electronic file to the data transmission device 2 via the transmitting / receiving unit 3c.

[0075] In step S2, the control unit 2f of the data transmission device 2 receives the first result report from the second report generation device 3 and stores it in the storage unit 2g. This allows the patient's doctor to view the first result report stored in the storage unit 2g on the display unit 2b at any time. In step S3, the control unit 2f receives input of evaluation results for evaluation items (evaluation items listed in the third domain 51c) that are indicated as undetermined in the first result report, and transmits the received evaluation results (additional evaluation results) to the second report generation device 3 via the transmitting / receiving unit 2c.

[0076] Figure 20 shows the input screen 70 for inputting evaluation results of undetermined items, which is displayed on the display unit 2b of the data transmission device 2 in step S3.

[0077] The input screen 70 includes a display area 76 for displaying gene mutations and an evaluation result input area 77 for inputting evaluation results for evaluation items that are indicated as undetermined in the first result report. The input screen 70 is displayed for each detected gene mutation. The display area 76 displays one of the gene mutations listed in the first result report (Figure 12). The evaluation result input area 77 displays all of the undetermined evaluation items listed in area 3 51c of the first result report 51 (Figure 12). For each evaluation item, a checkbox 71 is displayed for inputting a "YES" result indicating that the evaluation item applies, a checkbox 72 is displayed for inputting a "NO" result indicating that the evaluation item does not apply, and a checkbox 73 is displayed for inputting "Unknown" indicating that it is unclear whether or not the evaluation item applies. The user of the data transmission device 2 separately obtains information on the subject's relatives, such as the parents' genetic information and medical history, and based on the obtained information, determines whether each evaluation item listed in the evaluation result input area 77 applies, and uses the mouse to check one of the checkboxes 71, 72, or 73. In the example in Figure 20, regarding evaluation item PS2, the user determined that PS2 does not apply even after considering the information separately obtained by the user, so the checkbox 72 indicating "NO" was checked. Regarding evaluation item PM6, the user determined that PM6 applies after considering the information separately obtained by the user, so the checkbox 71 indicating "YES" was checked.

[0078] The input screen 70 further includes a display operation unit 78, a setting operation unit 74, and a cancel operation unit 75. The display operation unit 78 is operated, for example, by aligning the cursor with the image of the display operation unit 78 and clicking or double-clicking with the mouse. When the user has finished checking all evaluation items and operates the display operation unit 78, the gene mutation displayed in the display area 76 is changed to a different gene mutation, the checks entered in checkboxes 71, 72, and 73 are cleared, and the screen switches to a screen for entering evaluation results for the new gene mutation. The display operation unit 78 is disabled when the evaluation results have been entered for all detected gene mutations. The setting operation unit 74 is disabled on the initial screen, but is enabled when the display operation unit 78 is disabled. The setting operation unit 74 is operated, for example, by aligning the cursor with the image of the setting operation unit 74 and clicking or double-clicking with the mouse. When the user has finished checking the evaluation items for all gene mutations and operates the setting operation unit 74, the control unit 2f transmits information on whether each evaluation item is applicable or unclear to the second report generation device 3 via the transmission / reception unit 2b. The cancel operation unit 75 is operated, for example, by aligning the cursor with the image of the cancel operation unit 75 and clicking or double-clicking with the mouse. When the cancel operation unit 75 is operated, the information entered on the input screen 70 up to that point is erased. The user enters information on whether each evaluation item is applicable or unclear for each gene mutation listed in the first result report into the input screen 70 and operates the setting operation unit 74.

[0079] According to Embodiment 1, since undetermined items are displayed in the first result report 51 and the input screen 70, the user can easily understand the information that needs to be obtained separately and easily determine the action to take. In addition, the user can input the evaluation results into the input screen 70 at any time after obtaining the additional information, so even if it takes a long time to obtain the additional information, the level of pathogenicity can be determined after obtaining the additional information.

[0080] Figure 21 shows an example of an input screen 80. The input screen 80 displays not only the evaluation items that are shown as undetermined in the first results report, but also the evaluation items that are shown as confirmed (evaluation items listed in the "ACMG Category" of Domain 2 51b). By adopting the input screen 80, users can reconfirm evaluation items that have been confirmed and change their evaluation results as needed.

[0081] Referring again to Figure 3, in step S15, the control unit 3f of the second report generation device 3 receives from the data transmission device 2, for each of the gene mutations described in the first result report, the gene mutations (the gene mutations displayed in the display area 76 of the input screen 80 (Figure 20)) and the evaluation results of the evaluation items that were not yet determined (information on whether each evaluation item is applicable or unknown, entered in the evaluation result display area 77 of the input screen 80 (Figure 20)).

[0082] In step S16, the control unit 3f determines, for one of the received gene mutations, the confirmed evaluation items listed in the ACMG category of the first result report 51 and the evaluation items received in step S15 for which the "YES" checkbox 71 was checked, as the applicable evaluation items. Similar to the process in step S46 (Figure 4), the control unit 3f determines the pathogenicity level based on the determined applicable evaluation items and the second criterion. If no evaluation items have the "YES" checkbox 71 checked, the control unit 3f may use the pathogenicity level listed in the first result report 51 as the pathogenicity level for the gene mutation.

[0083] In step S17, the control unit 3f determines whether the pathogenicity level generated in step S16 is provisional, similar to the process in step S27. Specifically, the control unit 3f changes the evaluation result received in step S15 that is "unknown" to "YES," and then determines whether the pathogenicity level changes from the level determined in step S16. If the pathogenicity level changes, the control unit 3f determines that the pathogenicity level is provisional. If the pathogenicity level does not change, the control unit 3f determines that the pathogenicity level is not provisional. The control unit 3f also determines that the pathogenicity level is not provisional if there are no undetermined items.

[0084] In step S18, the control unit 3f determines whether the level of pathogenicity has been determined for all gene mutations received in step S15 by the processing in step S16. If the determination in step S18 is negative, the control unit 3f repeats the processing from step S16 to step S17 until the level of pathogenicity has been determined for all gene mutations. If the determination in step S18 is positive, in step S19, the control unit 3f generates a second result report based on the level of pathogenicity determined in step S16 and the information on whether it is provisional or not determined in step S17. The format of the second result report can be the same as the format of the first result report 51 explained with reference to Figure 12a. In step S20, the control unit 3f transmits the second result report as an electronic file to the data transmission device 2 via the transmission / reception unit 3c. When step S20 is completed, the processing of the control unit 3f is completed.

[0085] In step S4, the control unit 2f of the data transmission device 2 receives the second result report from the second report generation device 3 and stores it in the storage unit 2g. This allows the patient's attending physician to view the second result report stored in the storage unit 2g on the display unit 2b at any time.

[0086] Figure 12b shows an example of the second results report 51' of the first embodiment. In this example, the evaluation results for PS2, PM6, PP4, and BS4, which were undetermined in the first results report 51, have been determined. In step S16 (Figure 3), the pathogenicity level for gene mutation aaa has changed from Pathogenic (Figure 12a) to uncertain significance, and for gene mutation aaa, the pathogenicity level has changed from Likely Pathogenic (Figure 12a) to Pathogenic. In this example, in step S17 (Figure 3), the pathogenicity level for gene mutation aaa and gene mutation bbb has been determined to be non-provisional, and the pathogenicity level for gene mutation ccc has been determined to be provisional. Furthermore, after the data transmission device 2 receives the second results report, the user may be able to obtain additional information such as information on the subject's relatives and disease patient cohort data. In this case, the control unit 2f of the data transmission device 2 executes the processes in steps S3 to S4, and the control unit 3f of the second report generation device 3 executes the processes in steps S15 to S20, thereby generating a second results report that reflects the newly obtained information.

[0087] [Effects of the First Embodiment] As described above, according to the report generation method of the first embodiment, the first result report and the second result report are generated according to the determination result of whether or not the pathogenicity level is provisional. Therefore, it is possible to generate reports that can provide appropriate information even if the determined pathogenicity level may change later. This makes it easy for users to understand that the pathogenicity level may change.

[0088] <Example 1> Figure 13 is a diagram partially showing the second area 52b of the first result report 52 (or second result report) of Modification Example 1. The format of the first and third areas of the first result report 52 of Modification Example 1 is the same as that of the first result reports 51 and 51' of Embodiment 1, so no explanation is provided.

[0089] As shown in Figure 13, in the first results report 52, when the pathogenicity level is provisional, the revised pathogenicity level is indicated instead of a symbol indicating that it is provisional. In the first results report 52, the revised pathogenicity level is shown in parentheses in the space indicated by reference number L in cell 52d where the pathogenicity level is shown.

[0090] In the example shown in Figure 13, the pathogenicity level corresponding to the gene mutation "aaa" is listed as pathogenic, with "(possible uncertain significance)" written below it. From this description, readers of the first results report 52 can recognize that the pathogenicity level for the gene mutation "aaa," currently listed as pathogenic, may be later changed to uncertain significance. In the example shown in Figure 13, the pathogenicity levels for the gene mutations "bbb" and "ccc," currently listed as likely pathogenic, are shown to be potentially changed to pathogenic later. Furthermore, the pathogenicity level for the gene mutation "eee," currently listed as uncertain significance, is shown to be potentially changed to likely pathogenic or likely benign. In addition, since there is no pathogenicity level in parentheses below the pathogenicity level for the gene mutation "ddd," it can be seen that the pathogenicity level for the gene mutation "ddd" is confirmed as uncertain significance.

[0091] <Modification 2> Figure 14 is a diagram partially showing the second area 53b of the first result report 53 (or second result report) of Modified Example 2. The format of the first and third areas of the first result report 52 of Modified Example 2 is the same as that of the first result reports 51 and 51' of Embodiment 1, so no explanation is provided.

[0092] In the modified version of the first results report 53, if the pathogenicity level is provisional and the changed pathogenicity level is higher than the original level, the changed pathogenicity level is shown in parentheses within the cell where the pathogenicity level is shown. Specifically, as shown in Figure 13, the pathogenicity level of the gene mutation "aaa," which is pathogenic, may later be changed to uncertain significance, but uncertain significance is not a higher pathogenicity level than pathogenic. Therefore, in this case, in the first results report 53, uncertain significance is not shown below pathogenic in the pathogenicity column for the gene mutation "aaa."

[0093] In contrast, as shown in Figure 13, the pathogenicity level of the gene mutations "bbb" and "ccc," which is likely pathogenic, may later be changed to pathogenic. Since pathogenic has a higher pathogenicity level than likely pathogenic, in the first results report 53, "(possibly pathogenic)" is written below likely pathogenic in the pathogenicity column for the gene mutation "aaa." Also, in cases where the pathogenicity level, uncertain significance, can be changed to likely pathogenic or likely benign, such as with the gene mutation "eee," only likely pathogenic, which has a higher pathogenicity level than the previous uncertain significance, is written in parentheses as "(possibly pathogenic)," while likely benign, which has a lower pathogenicity level than the previous uncertain significance, is not written.

[0094] In this way, when the pathogenicity level after the change is higher than before the change, indicating that the pathogenicity level is provisional makes it easy to grasp the possibility that the pathogenicity level may later change to a higher level, which is particularly important in clinical practice.

[0095] Furthermore, in the first result report 53 of the modified example 2, a column 53d titled "Conditions for Change in Pathogenicity" is added to the right of the "ACMG Category" column in the second area 53b. This column 53d shows the conditions under which the level of pathogenicity changes to a higher level. In the example shown in Figure 14, the "Conditions for Change in Pathogenicity" column for the gene mutation "bbb" states "PS2 is applicable." This allows viewers of the first result report 53 to recognize that if PS2 is newly applicable to the gene mutation "bbb," it changes from likely pathogenic to pathogenic, and they can easily decide on actions to take, for example, to conduct tests or investigations to confirm whether or not PS2 is applicable.

[0096] The conditions for a change in pathogenicity may involve multiple evaluation criteria, as described in the section for conditions for a change in pathogenicity of the gene mutation "eee," such as "PS2 is present and PM6 is present OR PS2 is present and both PP1 and PP4 are present." Even in this case, viewers can easily determine the necessary actions.

[0097] <Variation 3> Figure 15 is a diagram partially showing the second area 54b of the first result report 54 (or second result report) of Modification 3. The format of the first and third areas of the first result report 54 of Modification 3 is the same as that of the first result reports 51 and 51' of Embodiment 1, so no explanation is provided.

[0098] As shown in Figure 15, the first results report 54 includes "(provisional)" to the right of "pathogenicity" in the "pathogenicity" column 54d. This allows us to indicate that the level of pathogenicity is provisional in a smaller space compared to writing "(provisional)" for each gene mutation.

[0099] <Modification 4> Figure 16 shows the first result report 55 (or second result report) of Modification 4. As shown in Figure 16, the first result report 55 of Modification 4 includes a summary report 56 as the first report and a detailed report 57 as the second report. The summary report 56 is a report that reports information on the detected gene mutations and the evaluation results regarding the level of pathogenicity corresponding to those gene mutations, and is mainly viewed by the patient's attending physician. The detailed report 57 is a report that reports information on the detected gene mutations and the evaluation results regarding the level of pathogenicity corresponding to those gene mutations, and is mainly viewed by each member of the expert panel that interprets the results of the gene panel test. The detailed report 57 reports information on the detected gene mutations in more detail than the summary report 56.

[0100] The summary report 56 can adopt the format of the first result report 51 of Embodiment 1, or the formats of the first result reports 52, 53, and 54 of Modification 1-3. The summary report 56 includes a first area 56a in which some of the test request information is described, a second area 56b in which gene mutation information and pathogenicity levels are described, and a third area 56c in which undetermined items are described.

[0101] Detailed report 57 includes a first section 57a, which contains some or all of the test request information, and a second section 57b, which contains more detailed information on gene mutations and pathogenicity levels than the second section 56b. The second section 57b contains information that shows the details of each mutation, including the gene name of each mutation, the pathogenicity level, identified evaluation items, inheritance mode, mutation allele frequency, mutation type (homozygous or heterozygous, etc.), and information on the bases and / or amino acids changed by the mutation.

[0102] Furthermore, in at least one of the summary report 56 and the detailed report 57, a region describing information on gene mutations whose pathogenicity level has been determined to be provisional and the pathogenicity level corresponding to that gene mutation, and a region describing information on gene mutations whose pathogenicity level has been determined not to be provisional and the pathogenicity level corresponding to that gene mutation, may be clearly distinguishable. For example, the region describing information on gene mutations whose pathogenicity level has been determined to be provisional and the pathogenicity level corresponding to that gene mutation, and the region describing information on gene mutations whose pathogenicity level has been determined not to be provisional and the pathogenicity level corresponding to that gene mutation, may be described in separate tables.

[0103] <Modification 5> (Summary Report) Figure 17 shows the summary report 58 of Modification Example 5. The summary report 58 has the following characteristics, and is otherwise identical to the summary report 56. As shown in Figure 17, in the summary report 58, the second area 58b only includes information on gene mutations whose pathogenicity level has been determined to be non-provisional and the pathogenicity level corresponding to that gene mutation, while it does not include information on gene mutations whose pathogenicity level has been determined to be provisional and the pathogenicity level corresponding to that gene mutation. If there is a provisional pathogenicity level, the fourth area 58d includes a statement such as "For pathogenicity levels of other gene mutations, please refer to the detailed report," indicating that there is a provisional pathogenicity level and providing a link to that information. This allows users to quickly grasp the confirmed pathogenicity level and also refer to the provisional pathogenicity level as needed.

[0104] (Detailed report) Figure 18 shows the detailed report 59 of modified example 5. Detailed report 59 differs from detailed report 57 only in the description of the second region 59b. The explanation of the first region 59a of detailed report 59 is omitted. The second region 59b of detailed report 59 is divided into region 59c, which describes gene mutation information, and region 59d, which indicates the level of pathogenicity. The information described in regions 59c and 59d and the manner in which that information is described may be the same as the information described in region 57b of detailed report 57, or it may be changed as appropriate.

[0105] <Variation 6> Among the levels of pathogenicity, those with relatively high pathogenicity may be described in a way that distinguishes them from other levels of pathogenicity. Examples of relatively high pathogenicity levels include "pathogenic" and "likely patyogenic," with "pathogenic" being particularly high. For example, the summary report may only include information on "pathogenic" and "likely patyogenic," or "pathogenic" and their corresponding gene mutations, while not displaying information on other levels of pathogenicity and their corresponding gene mutations. The detailed report may then display information on all levels of pathogenicity and their corresponding gene mutations. This allows for easy identification of high pathogenicity levels, which are particularly important in clinical practice, through the summary report, and enables confirmation of all levels of pathogenicity in the detailed report as needed.

[0106] (Summary Report) Figure 19 shows the summary report 60 of modified example 6. As shown in Figure 19, the summary report 60 displays "pathogenic" and "likely patyogenic," which have relatively high levels of pathogenicity, in the second area 60b, and does not display other levels of pathogenicity. Alternatively, only "pathogenic" may be displayed in the second area 60b, and other levels of pathogenicity, including "likely patyogenic," may not be displayed.

[0107] Furthermore, like Summary Report 58, Summary Report 60 does not include provisional levels of pathogenicity, even if they are classified as "pathogenic" or "likely patyogenic." This allows users to easily understand relatively high and established levels of pathogenicity. Note that the format of the Summary Report is not limited to the above; for example, Summary Report 60 may include provisional levels of pathogenicity.

[0108] (Detailed report) The detailed report for Modification 6 can be the same as the detailed report 59 for Modification 5, so its explanation is omitted. Note that the format of the detailed report is not limited to those described above. For example, in addition to the subject's genetic mutation information, the detailed report may include clinical information including the subject's disease name, genetic information of the subject's relatives, and medical history information of the subject's relatives.

[0109] (Second Embodiment) As explained in the processing procedure for assigning pathogenicity levels (Figure 9), as shown in Figure 22(a), the ACMG / AMP guidelines may assign pathogenicity levels to both "pathogenic" and "benign," in which case the pathogenicity level is determined to be "uncertain significance."

[0110] Therefore, for example, even if a gene mutation meets a high level of "pathogenicity" based on the evaluation results of the 16 pathogenicity items (Figure 5a), it may also meet the "benign" evaluation results of the 12 benignity items, resulting in a final judgment of "uncertain significance." In this case, although the final judgment is "uncertain significance," it also meets the "pathogenic" criteria, so the gene mutation may be important in the disease the subject has. For these reasons, in the second embodiment, as shown in Figure 22(b), a gene mutation that meets the "pathogenic" criteria is judged as "pathogenic" even if it also meets the "benign" criteria.

[0111] The schematic configuration of the report generation system in the second embodiment is the same as the configuration shown in Figure 1. Furthermore, the schematic of the processing performed by the control units of the data transmission device 2, the second report generation device 3, and the first report generation device 4 is the same as the processing performed in the first embodiment, except for the processing of assigning pathogenicity levels as explained using Figure 9.

[0112] Figure 23 is a flowchart corresponding to Figure 9 in the second embodiment, and is a flowchart of the processing procedure for assigning a pathogenicity level in the second embodiment. Referring to Figure 23, when step S45 in Figure 4 is completed, in step S71, the control unit 4f determines whether the gene mutation 1 detected in step S24 meets the criteria for pathogenicity, based on the second criteria P(i) to P(iii) (Figure 8). If the determination in step S71 is positive, in step S72, the control unit 4f assigns pathogenicity to the gene mutation 1 detected in step S24, and returns the process to step S26 (Figure 3).

[0113] On the other hand, if a negative determination is made in step S71, the process proceeds to step S73, where the control unit 4f determines whether one of the gene mutations detected in step S24 meets the criteria for likely pathogenicity, based on the second criteria LP(i) to LP(vi) for likely pathogenicity. If a positive determination is made in step S73, the control unit 4f assigns the designation likely pathogenic to the gene mutation in step S74 and returns the process to step S26. On the other hand, if a negative determination is made in step S73, the control unit 4f proceeds to step S75.

[0114] In step S75, the control unit 4f determines whether the gene mutation meets the criteria for benign based on the second criteria B(i) to B(ii) of benign. If the determination in step S75 is positive, the control unit 4f assigns benign to the gene mutation in step S76 and returns the process to step S26.

[0115] On the other hand, if a negative determination is made in step S75, the process proceeds to step S77, where the control unit 4f determines whether the gene mutation meets the criteria for likely benign based on the second criteria LB(i) to LB(ii) for likely benign. If a positive determination is made in step S77, the control unit 4f assigns likely benign to the gene mutation in step S78 and returns the process to step S26. On the other hand, if a negative determination is made in step S75, the control unit 4f proceeds to step S79, where it assigns uncertain significance to the gene mutation and returns the process to step S26.

[0116] [Effects of the second embodiment] According to the second embodiment, the user can easily recognize that the detected gene mutation may be an important gene mutation in the disease the subject has.

[0117] (Third embodiment) Figure 24 is a schematic diagram of the report generation system 101 according to the third embodiment. The report generation system 101 comprises a data transmission device 2, a report generation device 14, a sequencer 5, and storage 9. The data transmission device 2 and the report generation device 14 are connected to each other via a network 6, which is the Internet. A mutation information database 8 is also connected to the network 6. The report generation device 14, the sequencer 5, and the storage 9 are also connected to each other via a local area network 7. The hardware configurations of the data transmission device 2, the report generation device 14, the sequencer 5, and the storage 9 are the same as those of the data transmission device 2, the first report generation device 4, the sequencer 5, and the storage 9 in the first embodiment. The data transmission device 2 sends and receives data to and from the report generation device 14 via the network 6.

[0118] The data transmission device 2 is installed at the facility requesting the analysis 10, for example, a hospital (medical facility), a testing center, or a biomedical science research institute. The report generation device 14 is installed at the facility receiving the analysis 30, for example, a data analysis facility. The facility requesting the analysis 10 and the facility receiving the analysis 30 are different facilities. However, the facility requesting the analysis 10 and the facility receiving the analysis 30 may be the same facility. The report generation device 14 may also be a computer that constitutes a cloud system. The facility receiving the analysis 30 may be a facility of a cloud service provider or a facility of a company that provides nucleic acid sequence analysis services. The report generation device 14 is able to access the mutation information database 8 via the network 6.

[0119] Figure 25 is a flowchart illustrating the processes performed by the control units of the data transmission device 2 and the report generation device 14 in the third embodiment. Referring to Figure 25, in step S101, the control unit 2f of the data transmission device 2 displays the inspection request information input screen 40 (see Figure 2) on the display unit 2b, accepts the input of inspection request information, and transmits the accepted inspection request information to the report generation device 14. Next, in step S121, the control unit 14f of the report generation device 14 receives the inspection request information transmitted from the data transmission device 2, stores it in the storage unit 14g, and displays on the display unit 14b that the inspection request information has been received.

[0120] When the user of the report generation device 14 or the user of the sequencer 5 recognizes that the test request information has been received based on the information displayed on the display unit 14b, they prepare a library sample from the sample identified by the sample ID displayed in the input area 42e of the test request information input screen 40 and have the sequencer 5 read the nucleic acid sequence data. The sequencer 5 records the sequence run data, including the read nucleic acid sequence data, in the storage 9. When the user of the report generation device 14 has finished reading the nucleic acid sequence data by the sequencer 5, they operate the input unit 14a of the report generation device 14 to instruct it to read the nucleic acid sequence data. In response to this instruction, the control unit 14f receives the instruction from the user of the report generation device 14 to read the nucleic acid sequence data in step S122.

[0121] In step S123, the control unit 14f reads nucleic acid sequence data (hereinafter referred to as acquired sequence data) identified by the sample ID displayed in the input area 42e of the test request information input screen 40 from the sequence run data stored in the storage 9. In step S124, the control unit 14f detects all gene mutations contained in the acquired sequence data and acquires gene mutation information based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8. Also in step S124, the control unit 14f determines the inheritance mode, mutation allele frequency, homozygous or heterozygous, mutation site (base), and mutation site (amino acid) based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8.

[0122] In step S125, the control unit 14f, using the same processing as in step S45 (Figure 4) of the first embodiment, determines whether each of the 28 evaluation items specified in the ACMG / AMP guidelines is applicable based on the first criterion stored in the memory unit 14g and one of the gene mutations detected in step S124, and generates an evaluation result. In step S126, the control unit 14f determines the undetermined items from among the evaluation items evaluated in step S125, using the same processing as in step S26 (Figure 3) of the first embodiment. In step S127, the control unit 14f determines whether the process for determining undetermined items has been performed for all gene mutations detected in step S124. If the determination in step S127 is positive, the control unit 14f proceeds to step S128. If a negative result is obtained in step S127, the control unit 14f returns to step S125 and repeats steps S125 to S126 until the determination process for all undetermined items has been performed for all gene mutations. In step S128, the control unit 14f transmits the information of the determined undetermined items to the data transmission device 2.

[0123] In step S102, the control unit 2f of the data transmission device 2 receives the unconfirmed items transmitted from the report generation device 14. In step S103, the control unit 2f displays the input screen 80 (Figure 20 or Figure 21) on the display unit 2b based on the unconfirmed items received in step S102, using the same processing as in step S3 of the first embodiment (Figure 3), receives the evaluation results (additional evaluation results) of the unconfirmed items, and transmits the received evaluation results to the report generation device 14. In step S129, the control unit 14f of the report generation device 14 receives the evaluation results of the unconfirmed items transmitted from the data transmission device 2. In step S130, the control unit 14f determines the level of pathogenicity for one of the gene mutations detected in step S124 using the same processing as in step S25 of the first embodiment (Figure 3).

[0124] In step S131, the control unit 14f determines whether the level of pathogenicity determined in step S130 is provisional, similar to the processing in steps S17 and S27 (Figure 3). In step S132, the control unit 14f determines whether the level of pathogenicity has been determined for all gene mutations detected in step S124 by the processing in step S130. If the determination in step S132 is negative, the control unit 14f repeats the processing from step S130 to step S131 until the level of pathogenicity has been determined for all gene mutations. If the determination in step S132 is positive, the control unit 14f generates a result report in step S133 according to the level of pathogenicity determined in step S130 and the information on whether it is provisional or not determined in step S131. The format of the result report can be the same as the format of the first result report or the second result report described using Figures 12a to 19. In step S134, the control unit 14f transmits the result report as an electronic file to the data transmission device 2 via the transmission / reception unit 14c. When step S134 is completed, the processing of the control unit 14f is finished.

[0125] In step S104, the control unit 2f of the data transmission device 2 receives the result report from the report generation device 14 and stores it in the storage unit 2g. This allows the patient's attending physician to view the result report stored in the storage unit 2g on the display unit 2b at any time. After the data transmission device 2 receives the result report, additional information such as information on the patient's relatives and disease patient cohort data may become available to the user. In this case, the control unit 2f of the data transmission device 2 executes the processes in steps S102 to S104, and the control unit 14f of the report generation device 14 executes the processes in steps S129 to S134, thereby generating a new result report that reflects the newly acquired information.

[0126] [Effects of the Third Embodiment] As described above, according to the report generation method of the third embodiment, the first result report and the second result report are generated according to the determination result of whether or not the pathogenicity level is provisional. Therefore, it is possible to generate reports that can provide appropriate information even if the determined pathogenicity level may change later. This makes it easy for users to understand that the pathogenicity level may change. Furthermore, according to the third embodiment, the second report generation device 3 does not exist compared to the first embodiment, so the hardware configuration of the system can be simplified.

[0127] (Fourth Embodiment) In the first to third embodiments described above, the report generation devices 3, 4, and 14 determined undetermined items (preliminary undetermined items) based on gene mutation information derived from nucleic acid sequence data read from storage 9, and then received evaluation results for these preliminary undetermined items. However, in the fourth embodiment, the test request information includes information for evaluating undetermined items, and the result report is generated without determining preliminary undetermined items. The hardware configuration of the report generation system in the fourth embodiment is the same as that of the report generation system 101 in the third embodiment, but it may also be the same as that of the report generation system 1 in the first embodiment.

[0128] Figure 26 is a flowchart illustrating the processes performed by the control units of the data transmission device 2 and the report generation device 14 in the fourth embodiment. Referring to Figure 26, in step S201, the control unit 2f of the data transmission device 2 displays the test request information input screen 140 (see Figure 27) on the display unit 2b, accepts the input of test request information, and transmits the accepted test request information to the report generation device 14. As shown in Figure 27, the test request information input screen 140 has an input area 42l for inputting gene mutations of blood relatives and an input area 42m for inputting the medical history of blood relatives added to the test request information input screen 40 (Figure 2). The input area 42l is configured in a pull-down list format, and the pull-down list displays a list of gene mutations of blood relatives related to the first criterion. The input area 42m is configured in a pull-down list format, and the pull-down list displays a list of medical history of blood relatives related to the first criterion. Therefore, the test request information in the fourth embodiment includes information on gene mutations of the subject's blood relatives and information on the medical history of the subject's blood relatives. Note that at least one of the input region 42l and the input region 42m can be omitted.

[0129] When the user of the report generation device 14 or the user of the sequencer 5 recognizes that the test request information has been received based on the information displayed on the display unit 14b, they prepare a library sample from the sample identified by the sample ID displayed in the input area 42e of the test request information input screen 140 and have the sequencer 5 read the nucleic acid sequence data. The sequencer 5 records the sequence run data, including the read nucleic acid sequence data, in the storage 9. Once the reading of the nucleic acid sequence data is complete, the user of the report generation device 14 operates the input unit 14a of the report generation device 14 to instruct it to read the nucleic acid sequence data. In response to this instruction, the control unit 14f receives the instruction from the user of the report generation device 14 to read the nucleic acid sequence data in step S222.

[0130] Referring again to Figure 26, in step S223, the control unit 14f reads nucleic acid sequence data (hereinafter referred to as acquired sequence data) identified by the sample ID displayed in the input area 42e of the test request information input screen 140 from the sequence run data stored in storage 9. In step S224, the control unit 14f detects all gene mutations contained in the acquired sequence data based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8, and obtains information on gene mutations. Also in step S224, the control unit 14f determines the inheritance mode, mutation allele frequency, homozygous or heterozygous, mutation site (base), and mutation site (amino acid) based on the acquired sequence data and the reference sequence data obtained from the mutation information database 8.

[0131] In step S225, the control unit 14f, using the same processing as in step S45 of the first embodiment (Figure 4), determines whether each of the 28 evaluation items specified by the ACMG / AMP guidelines applies to one of the gene mutations detected in step S224, based on the first criterion stored in the memory unit 14g, the information on the gene mutation, the information on gene mutations of the subject's relatives included in the test request information received in step S221, and the medical history information of the subject's relatives, and generates an evaluation result. In step S226, the control unit 14f determines the level of pathogenicity using the same processing as in step S46 of the first embodiment (Figure 4). In step S227, the control unit 14f determines the undetermined items from among the evaluation items evaluated in step S225, using the same processing as in step S26 of the first embodiment (Figure 3). In step S228, the control unit 14f determines whether the level of pathogenicity determined in step S226 is provisional, similar to the processing in steps S17 and S27 (Figure 3). In step S229, the control unit 14f determines whether the level of pathogenicity has been determined for all gene mutations detected in step S224. If the determination in step S229 is positive, the control unit 14f proceeds to step S230. If the determination in step S229 is negative, the control unit 14f returns to step S225 and repeats the processing in steps S225 to S228 until the level of pathogenicity has been determined for all gene mutations.

[0132] In step S230, the control unit 14f generates a result report based on the level of pathogenicity determined in step S226 and the information on whether the result is provisional or not determined in step S228. The format of the result report can be the same as that of the first result report or the second result report described using Figures 12a to 19. In step S231, the control unit 14f transmits the result report as an electronic file to the data transmission device 2 via the transmission / reception unit 14c. When step S231 is completed, the processing of the control unit 14f is completed.

[0133] In step S202, the control unit 2f of the data transmission device 2 receives the result report from the report generation device 14 and stores it in the storage unit 2g. This allows the patient's attending physician to view the second result report stored in the storage unit 2g on the display unit 2b at any time. Furthermore, after the data transmission device 2 receives the results report, the user may be able to obtain additional information such as information on the subject's relatives and disease patient cohort data. In this case, the control unit 2f of the data transmission device 2 transmits the additionally obtained information to the report generation device 14, and the control unit 14f of the report generation device 14 executes the processing in steps S225 to S231 based on the additional information received from the data transmission device 2, thereby generating a new results report that reflects the additionally obtained information.

[0134] [Effects of the fourth embodiment] As described above, according to the report generation method of the fourth embodiment, the first result report and the second result report are generated according to the determination result of whether or not the pathogenicity level is provisional. Therefore, it is possible to generate reports that can provide appropriate information even if the determined pathogenicity level may change later. This makes it easy for users to understand that the pathogenicity level may change. Furthermore, according to the fourth embodiment, compared to the first and third embodiments, there is no process to determine preliminary undetermined items, so the software processing can be simplified.

[0135] Furthermore, the present invention is not limited to the embodiments and their modifications described above, and various improvements and modifications are possible within the scope of the claims of this application and their equivalents. In addition, the report generation method and report generation apparatus of the present invention may be used to generate reports that report the level of pathogenicity for any disease, for example, reports that report the level of pathogenicity for hereditary tumors or reports that report the level of pathogenicity for hereditary retinal dystrophy.

[0136] For example, in the first to third embodiments, in steps S45 (Figure 4) and S125 (Figure 25), each evaluation item is evaluated based on the subject's gene mutation information. However, in addition to the subject's gene mutation information, each evaluation item may also be evaluated based on information included in the test request information, such as the subject's disease information.

[0137] Furthermore, in the first to third embodiments, the condition for determining that the pathogenicity level is provisional was that there is at least one undetermined item whose pathogenicity level changes when the evaluation results are added or modified. However, the condition for determining that the pathogenicity level is provisional may also be that there is a predetermined number of undetermined items (for example, one), regardless of whether the pathogenicity level changes or not.

[0138] Furthermore, in the first to third embodiments, the second report generation device 3 or report generation device 14 receives evaluation results of undetermined items from the data transmission device 2. However, the data transmission device 2 may also receive additional information such as information on gene mutations of the subject's relatives and information on the medical history of the subject's relatives, and the control unit of the second report generation device 3 or report generation device 14 may determine whether or not the undetermined items apply based on the received additional information and the first criterion.

[0139] Furthermore, in the first to third embodiments, the first result report 51 and the second result report 51' include the pathogenicity level and information indicating that the pathogenicity level is provisional, if the pathogenicity level is determined to be provisional. However, the first result report 51 and / or the second result report 51' may omit the pathogenicity level if the pathogenicity level is determined to be provisional. This allows the viewer of the report to easily grasp the non-provisional pathogenicity level, even if the determined pathogenicity level may change later.

[0140] Furthermore, in the first to third embodiments, the first result report 51 and the second result report 51' include the pathogenicity level and information indicating that the pathogenicity level is provisional, if the pathogenicity level is determined to be provisional. However, the first result report 51 and / or the second result report 51' may also include information indicating that the pathogenicity level is definitive, for pathogenicity levels that have been determined not to be provisional, i.e., definitive pathogenicity levels. In this way, it is possible to indicate whether each pathogenicity level displayed in the first result report 51 and / or the second result report 51' is provisional or not.

[0141] Furthermore, while the first to third embodiments use the first and second criteria based on the ACMG / AMP guidelines or rules that modify those guidelines, the first and second criteria based on other guidelines may also be used. [Explanation of Symbols]

[0142] 1,101 Report generation system, 2 Data transmission device, 3 Second report generation device, 4 First report generation device, 5 Sequencer, 6 Network, 7 Local area network, 8 Mutation information database, 9 Storage, 10 Facility requesting analysis, 20 Data processing facility, 30 Recipient facility, 40 Inspection request information input screen, 51,52,53,54,55 First result report or second result report, 56,58,60,62 Summary report, 57,59,61,63 Detailed report, 70,80 Input screen.

Claims

1. A report generation method comprising an information processing device that generates a report reporting the level of pathogenicity of a gene mutation, The aforementioned information processing device acquires information on gene mutations detected by gene panel testing, The information processing device generates evaluation results for multiple evaluation items based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The information processing device determines the level of pathogenicity based on the second criterion for determining the level of pathogenicity and the evaluation result. The information processing device determines, among the plurality of evaluation items, the items for which the evaluation result is not yet determined, and based on the determination result of the undetermined items, determines whether or not the level of pathogenicity is provisional. The information processing device generates a report reporting the level of pathogenicity according to the determination result of whether or not it is provisional. A report generation method in which, in determining whether or not something is provisional, if the determination result of the undetermined item meets predetermined conditions, the pathogenicity level is determined to be provisional.

2. The report generation method according to claim 1, wherein the predetermined condition is that the level of pathogenicity is changed by adding the evaluation result of at least one of the undetermined items to the evaluation result.

3. The report generation method according to claim 1, wherein the predetermined condition is that there are at least a predetermined number of undetermined items.

4. A report generation method comprising an information processing device that generates a report reporting the level of pathogenicity of a gene mutation, The aforementioned information processing device acquires information on gene mutations detected by gene panel testing, The information processing device generates evaluation results for multiple evaluation items based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The information processing device determines the level of pathogenicity based on the second criterion for determining the level of pathogenicity and the evaluation result. The information processing device determines, among the plurality of evaluation items, the items for which the evaluation result is not yet determined, and based on the determination result of the undetermined items, determines whether or not the level of pathogenicity is provisional. The information processing device generates a report reporting the level of pathogenicity according to the determination result of whether or not it is provisional. A report generation method comprising a first and a second report that report information on the gene mutation and information on the level of pathogenicity corresponding to the gene mutation, wherein the second report reports the information on the gene mutation in more detail than the first report.

5. The report generation method according to claim 4, wherein in generating the first report, the first report is generated according to the determination result of whether or not it is provisional and the level of pathogenicity.

6. The report generation method according to claim 5, wherein if the level of pathogenicity corresponding to the information on the gene mutation is higher than a predetermined level, the first report includes the information on the gene mutation and the level of pathogenicity, and if the level of pathogenicity corresponding to the information on the gene mutation is less than or equal to the predetermined level, the first report does not include the information on the gene mutation and the level of pathogenicity.

7. A method for generating a report according to any one of claims 4 to 6, wherein if the level of pathogenicity corresponding to the information on the gene mutation is determined to be provisional, the first report does not include the information on the gene mutation and the level of pathogenicity determined to be provisional, and the second report includes the information on the gene mutation, the level of pathogenicity determined to be provisional, and information indicating whether or not the level of pathogenicity is provisional.

8. A report generation method comprising an information processing device that generates a report reporting the level of pathogenicity of a gene mutation, The aforementioned information processing device acquires information on gene mutations detected by gene panel testing, The information processing device generates evaluation results for multiple evaluation items based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The information processing device determines the level of pathogenicity based on the second criterion for determining the level of pathogenicity and the evaluation result. The information processing device determines, among the plurality of evaluation items, the items for which the evaluation result is not yet determined, and based on the determination result of the undetermined items, determines whether or not the level of pathogenicity is provisional. The information processing device generates a report reporting the level of pathogenicity according to the determination result of whether or not it is provisional. A report generation method wherein, if the level of pathogenicity corresponding to the information of the gene mutation is determined to be provisional, the report does not include the information of the gene mutation and the level of pathogenicity determined to be provisional.

9. A report generation method comprising an information processing device that generates a report reporting the level of pathogenicity of a gene mutation, The aforementioned information processing device acquires information on gene mutations detected by gene panel testing, The information processing device generates evaluation results for multiple evaluation items based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The information processing device determines the level of pathogenicity based on the second criterion for determining the level of pathogenicity and the evaluation result. The information processing device determines, among the plurality of evaluation items, the items for which the evaluation result is not yet determined, and based on the determination result of the undetermined items, determines whether or not the level of pathogenicity is provisional. The information processing device generates a report reporting the level of pathogenicity according to the determination result of whether or not it is provisional. In determining the aforementioned undetermined items, Based on the information including the gene mutation information, the preliminary undetermined items are determined from the multiple evaluation items. The evaluation results are generated for the aforementioned preliminary undetermined items. A report generation method for determining the undetermined items from the preliminary undetermined items based on the evaluation results for the preliminary undetermined items.

10. In generating the evaluation results for the aforementioned preliminary undetermined items, The report generation method according to claim 9, further comprising providing the user with a screen for receiving evaluation results for the preliminary undetermined items, and receiving input of the evaluation results for the preliminary undetermined items via the screen.

11. In generating the evaluation results for the aforementioned preliminary undetermined items, To obtain additional information for evaluating the aforementioned preliminary undetermined items, A report generation method according to claim 9, which determines the evaluation result for the preliminary undetermined items based on the acquired additional information and the first criterion.

12. A report generating device that generates a report reporting the level of pathogenicity of gene mutations, Control unit and It includes an output section, The control unit, We obtain information on gene mutations detected by gene panel testing. For multiple evaluation items, evaluation results are generated based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The level of pathogenicity is determined based on the second criterion for determining the level of pathogenicity and the evaluation result. Among the aforementioned multiple evaluation items, determine the items for which the evaluation results are not yet determined, and based on the determination of the aforementioned items for which the results are not yet determined, determine whether the level of pathogenicity is provisional or not. Depending on the determination result of whether it is provisional or not, a report reporting the level of pathogenicity is generated. The output unit outputs the report, A report generating device that, in determining whether or not something is provisional, determines that the level of pathogenicity is provisional if the determination result of the undetermined item meets predetermined conditions.

13. A report generating device that generates a report reporting the level of pathogenicity of gene mutations, Control unit and It includes an output section, The control unit, We obtain information on gene mutations detected by gene panel testing. For multiple evaluation items, evaluation results are generated based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The level of pathogenicity is determined based on the second criterion for determining the level of pathogenicity and the evaluation result. Among the aforementioned multiple evaluation items, determine the items for which the evaluation results are not yet determined, and based on the determination of the aforementioned items for which the results are not yet determined, determine whether the level of pathogenicity is provisional or not. Depending on the determination result of whether it is provisional or not, a report reporting the level of pathogenicity is generated. The output unit outputs the report, The report generation device comprises a first and a second report that report information on the gene mutation and information on the level of pathogenicity corresponding to the gene mutation, wherein the second report reports the information on the gene mutation in more detail than the first report.

14. A report generating device that generates a report reporting the level of pathogenicity of gene mutations, Control unit and It includes an output section, The control unit, We obtain information on gene mutations detected by gene panel testing. For multiple evaluation items, evaluation results are generated based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The level of pathogenicity is determined based on the second criterion for determining the level of pathogenicity and the evaluation result. Among the aforementioned multiple evaluation items, determine the items for which the evaluation results are not yet determined, and based on the determination of the aforementioned items for which the results are not yet determined, determine whether the level of pathogenicity is provisional or not. Depending on the determination result of whether it is provisional or not, a report reporting the level of pathogenicity is generated. The output unit outputs the report, A report generating device in which, if it is determined that the level of pathogenicity corresponding to the information of the gene mutation is provisional, the report does not include the information of the gene mutation and the level of pathogenicity determined to be provisional.

15. A report generating device that generates a report reporting the level of pathogenicity of gene mutations, Control unit and It includes an output section, The control unit, We obtain information on gene mutations detected by gene panel testing. For multiple evaluation items, evaluation results are generated based on a first criterion for evaluating each evaluation item and at least the gene mutation information. The level of pathogenicity is determined based on the second criterion for determining the level of pathogenicity and the evaluation result. Among the aforementioned multiple evaluation items, determine the items for which the evaluation results are not yet determined, and based on the determination of the aforementioned items for which the results are not yet determined, determine whether the level of pathogenicity is provisional or not. Depending on the determination result of whether it is provisional or not, a report reporting the level of pathogenicity is generated. The output unit outputs the report, In determining the aforementioned undetermined items, Based on the information including the gene mutation information, the preliminary undetermined items are determined from the multiple evaluation items. The evaluation results are generated for the aforementioned preliminary undetermined items. A report generating device that determines the undetermined items from the preliminary undetermined items based on the evaluation results for the preliminary undetermined items.

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