JP7646752B2 - Genetic analysis method and genetic analysis device - Google Patents

Description

The present invention relates to a genetic analysis method and a genetic analysis device implemented by a computer to analyze genetic mutations.

Amid recent advances in genetic testing technology, there are growing expectations for personalized medicine, in which a subject's genetic sequence is analyzed and appropriate treatments and drugs are selected according to the subject's characteristics. One known method of analyzing genetic sequences is panel testing, which uses next-generation sequencers to perform high-throughput analysis of abnormalities in specific genes related to specific diseases, or abnormalities in exon regions that are translated into proteins.

Patent Document 1 describes a system that compares genes, etc. with a reference sequence to determine whether they are abnormal, identifies drug therapies to be used in response to genes, etc. that show abnormalities, and determines a treatment method suited to the subject.

Special table 2015-200678 publication

In genetic testing, a different analysis is required for each gene to be analyzed. For example, in panel testing using a next-generation sequencer, fragmented genes are read simultaneously in parallel, and the read sequence information, which is the base sequence of each fragment, is mapped to a reference sequence to analyze the base sequence. Here, if the genes to be analyzed differ for each gene panel, a different analysis program may be required for each gene panel to be measured. Therefore, when conducting panel testing, it is troublesome to have to use different analysis programs for each gene panel.

Furthermore, when analyzing an entire exon region in genetic testing, many mutations are detected in the subject's genes. Among these mutations, the clinical significance and effective drugs for treatment have not been established, and some are not information that doctors can use in actual treatment. When doctors try to apply the results of genetic testing to the actual treatment of a subject, there is a demand for selectively identifying mutations that can be used in actual treatment from among the many detected mutations.

In this situation, users who conduct panel testing had to prepare dedicated analysis programs for gene analysis using a sequencer for each panel, depending on the genes to be tested and their needs, and then perform the gene analysis.

One aspect of the present invention aims to provide a genetic analysis method and device that are user-friendly and applicable to various genetic panels when analyzing target genes using a genetic panel.

In order to solve the above problems, a genetic analysis method according to one aspect of the present invention is a method for genetic analysis of multiple genes performed by a genetic analysis device that analyzes sequence information of multiple genes, which obtains lead sequence information read by a sequencer and information related to a gene panel for identifying a gene panel, analyzes the lead sequence information based on the obtained information related to the gene panel, and outputs an analysis result of the lead sequence information.

Analyzing the lead sequence information includes selecting reference sequence information to be compared with the lead sequence information from among multiple reference sequence information based on information about the acquired gene panel, and extracting mutations contained in the lead sequence information based on a comparison between the lead sequence information and the selected reference sequence information, and the analysis result of the lead sequence information may include information about the extracted mutations.

The information about the mutation may include information indicating the extracted position of the mutation and the base after the mutation.

Analyzing the lead sequence information includes extracting mutations contained in the lead sequence information and obtaining drug information related to the extracted mutations based on the obtained information on the gene panel, and the analysis result of the lead sequence information may include the obtained drug information.

The drug information may include information indicating the type of drug and the approval status of the drug.

The drug information may include information showing the approval status of the drug by country.

The method may further include displaying an input screen for inputting information about the gene panel.

In order to solve the above problems, a genetic analysis device according to one embodiment of the present invention is a genetic analysis device that analyzes sequence information of multiple genes, and includes a control unit that acquires lead sequence information read by a sequencer and information related to a gene panel for identifying a gene panel, and an output unit, and the control unit analyzes the lead sequence information based on the acquired information related to the gene panel, and outputs the analysis result of the lead sequence information to the output unit.

Analyzing the lead sequence information includes selecting reference sequence information to be compared with the lead sequence information from among multiple reference sequence information based on information about the acquired gene panel, and extracting mutations contained in the lead sequence information based on a comparison between the lead sequence information and the selected reference sequence information, and the analysis result of the lead sequence information may include information about the extracted mutations.

The information about the mutation may include information indicating the extracted position of the mutation and the base after the mutation.

Analyzing the lead sequence information includes extracting mutations contained in the lead sequence information and obtaining drug information related to the extracted mutations based on the obtained information on the gene panel, and the analysis result of the lead sequence information may include the obtained drug information.

The drug information may include information indicating the type of drug and the approval status of the drug.

The drug information may include information showing the approval status of the drug by country.

The device may further include an input unit that displays an input screen for inputting information about the gene panel.

The device may further include a storage unit that stores the plurality of pieces of reference sequence information, and the control unit may select, from the plurality of pieces of reference sequence information stored in the storage unit, reference sequence information to be compared with the lead sequence information.

The present invention can improve user convenience when measuring various combinations of target genes using various gene panels.

FIG. 1 is a diagram showing an application example of a gene analysis system according to an embodiment of the present invention. FIG. 2 is a sequence diagram showing an example of main processes performed in the gene analysis system. 10 is a diagram illustrating an example of a data structure of data stored in a management server. FIG. FIG. 1 is a diagram illustrating an example of the configuration of a gene analysis device. 13 is a flowchart showing an example of a process flow for accepting input of information related to a gene panel. FIG. 13 shows an example of a GUI used to input information regarding a gene panel. FIG. 2 is a diagram showing an example of a data structure of a gene panel related information database. FIG. 13 shows an example of a GUI used when a user updates information related to a gene panel. 1 is a flowchart illustrating an example of a procedure from pre-processing to sequencing for analyzing the base sequence of a sample DNA using a sequencer. FIG. 1 is a diagram illustrating an example of the step (a) of fragmenting a sample, and the step (b) of providing index sequences and adaptor sequences. FIG. 2 is a diagram illustrating an example of a hybridization process. FIG. 1 is a diagram illustrating an example of a process for recovering a DNA fragment to be analyzed. FIG. 1 is a diagram illustrating an example of a process for subjecting DNA fragments to a flow cell. FIG. 1 is a diagram illustrating an example of a process for amplifying a DNA fragment to be analyzed. FIG. 1 is a diagram illustrating an example of a sequencing process. 1 is a flowchart illustrating an example of a flow of analysis by a gene analysis device. FIG. 2 is a diagram showing an example of a file format of read sequence information. FIG. 4A is a diagram for explaining alignment by a data adjustment unit, and FIG. 4B is a diagram showing an example of a format of the alignment result by the data adjustment unit. FIG. 1 is a diagram showing an example of the structure of a reference sequence database. FIG. 1 shows examples of known mutations that are incorporated into reference sequences (that do not represent wild-type sequences) contained in a reference sequence database. 11 is a flowchart illustrating an example of a detailed alignment process. FIG. 13A is a diagram showing an example of score calculation, and FIG. 13B is a diagram showing another example of score calculation. FIG. 13 is a diagram showing an example of the format of a result file generated by a mutation identification unit. FIG. 2 is a diagram showing an example of the structure of a mutation database. FIG. 2 is a diagram showing a detailed example of the structure of mutation information in a mutation database. FIG. 13A is a table showing the correspondence between the genes to be analyzed and location information, and FIG. 13B is a diagram showing the state in which mutations that do not correspond to information on the gene panel have been excluded from the result file. FIG. 13 is a diagram showing another example of the configuration of a gene analysis device. 13 is a flowchart showing an example of a process in which a drug search unit generates a list of drugs related to mutations. FIG. 2 is a diagram illustrating an example of a data structure of a drug database. FIG. 2 is a diagram illustrating an example of a data structure of a drug database. 13 is a flowchart showing an example of a process in which a drug search unit generates a list including information about drugs related to mutations. 13 is a flowchart showing an example of a process for determining whether or not there is a drug that may be used off-label based on information obtained by a drug search unit searching a drug database, and generating a list including the determination results. FIG. 2 is a diagram illustrating an example of a data structure of a drug database. 13 is a flowchart showing an example of a process in which a drug search unit generates a list including information regarding clinical trials of drugs. FIG. 13 is a diagram showing another example of the configuration of a gene analysis device. FIG. 2 is a diagram illustrating an example of a data structure of a reference database. FIG. 13 is a diagram showing an example of a report to be created. FIG. 13 is a diagram showing another example of the configuration of a gene analysis device. FIG. 2 is a diagram showing an example of a data structure of a gene panel related information database. FIG. 13 shows another example of a GUI used to input information regarding a gene panel. FIG. 13 is a diagram showing another example of a GUI used for inputting information regarding a gene panel. 13 is a flowchart showing another example of the process flow for accepting input of information related to a gene panel. FIG. 13 is a diagram showing another example of a gene analysis device. 1 is a flowchart showing an example of a process flow for analyzing a gene sequence. FIG. 13 is a diagram illustrating an example of a quality evaluation index. FIG. 13 is a diagram showing an example of a report to be created.

[Embodiment 1]
Hereinafter, one embodiment of the present invention will be described in detail.

(Overview of gene analysis method)
A genetic analysis method according to one embodiment of the present invention acquires information about a gene panel, and outputs an analysis result of a read sequence read by a sequencer based on the acquired information about the gene panel. This makes it possible to obtain an appropriate analysis result according to the gene panel when analyzing various combinations of target genes using various gene panels, without having to use different analysis programs for each gene panel, thereby improving user convenience.

(Application example of gene analysis system 100)
First, an overview of a genetic analysis system 100 according to an embodiment of the present invention will be described with reference to Fig. 1. Fig. 1 is a diagram showing an application example of the genetic analysis system 100 according to an embodiment of the present invention. The genetic analysis system 100 is a system that analyzes gene sequence information, and includes at least a genetic analysis device 1 and a management server 3.

The genetic analysis system 100 shown in FIG. 1 is applied to an analysis system management institution 130 that manages all analyses performed at the testing institution 120, and to the testing institution 120 that analyzes samples provided in response to analysis requests from medical institutions 210 and provides the analysis results to the medical institutions 210. A genetic analysis device 1 is installed in the testing institution 120, and a management server 3 is installed in the analysis system management institution 130, and the genetic analysis system 100 is configured by the genetic analysis device 1 and the management server 3.

The testing institution 120 is an institution that tests and analyzes samples provided by the medical institution 210, creates a report based on the analysis results, and provides the report to the medical institution 210. The testing institution 120 is equipped with a sequencer 2, a genetic analysis device 1, and the like, but is not limited to these.

The analysis system management institution 130 is an institution that manages the overall analysis performed at each testing institution 120 that uses the genetic analysis system 100. For example, the analysis system management institution 130 is a business operator that installs the genetic analysis device 1 at the testing institution 120 and provides genetic analysis services corresponding to various gene panels. The analysis system management institution 130 updates the information stored in the database of the genetic analysis device 1, and manages the genetic analysis system 100 so that genetic analysis is performed based on the latest information. The analysis system management institution 130 obtains the status of genetic analysis in the genetic analysis device 1, and may receive remuneration from the testing institution 120 according to the results of the genetic analysis.

The medical institution 210 is an institution where doctors, nurses, pharmacists, etc. perform medical procedures such as diagnosis, treatment, and dispensing for patients, and examples of such institutions include hospitals, clinics, and pharmacies.

(Processing in an example of application of the gene analysis system 100)
Next, the process flow in an application example of the gene analysis system 100 shown in Fig. 1 will be described in more detail with reference to Fig. 2. Fig. 2 is a sequence diagram showing an example of main processes performed in the gene analysis system 100. Note that the processes shown in Fig. 2 are only a part of the processes performed at each institution.

<Application for and start of use of the gene analysis system>
First, a testing institution 120 that wishes to use the genetic analysis system 100 introduces the genetic analysis device 1. Then, the testing institution 120 applies for permission to use the genetic analysis system 100 to the analysis system management institution 130 (step S101).

The testing institution 120 and the analysis system management institution 130 can conclude a desired contract in advance for the use of the genetic analysis system 100 from among multiple contract types. For example, the contract type may be selected from multiple contract types that differ in the service content provided by the analysis system management institution 130 to the testing institution 120, the method of determining the system usage fee that the analysis system management institution 130 will charge to the testing institution 120, and the method of payment of the system usage fee. The management server 3 of the analysis system management institution 130 identifies the content of the contract concluded with the testing institution 120 in response to an application from the testing institution 120 (step S102).

Next, the management server 3 managed by the analysis system management institution 130 assigns a testing institution ID to the genetic analysis device 1 of the contracted testing institution 120, and starts providing various services (step S103).

The genetic analysis device 1 receives various services from the management server 3. The various services include the provision of programs and information for controlling gene sequence analysis results that can be output from the genetic analysis device 1, and reports based on the analysis results. This allows the genetic analysis device 1 to output analysis results and reports that match the input information about the gene panel.

<Analysis request to testing organization 120>
At the medical institution 210, a doctor or the like collects samples such as tissue and blood from the affected area of the subject as necessary. When requesting the testing institution 120 to analyze the collected samples, for example, an analysis request is transmitted from a communication terminal 5 provided at the medical institution 210 (step S105). When requesting the testing institution 120 to analyze the samples, the medical institution 210 provides the testing institution 120 with a sample ID assigned to each sample together with the analysis request. The sample ID assigned to each sample associates each sample with information on the subject from which the sample was collected.

As used herein, "subject" refers to human subjects as well as non-human subjects, such as mammals, invertebrates, vertebrates, fungi, yeast, bacteria, viruses, and plants. Although the examples herein relate to human subjects, the concepts of the present invention can be applied to genomes from any organism other than humans, such as animals or plants, and are useful in fields such as medicine, veterinary medicine, and animal science.

The following describes an example in which the medical institution 210 requests the testing institution 120 to analyze a panel test. Note that panel tests are not limited to clinical tests, but also include tests for research purposes.

When a genetic panel test is requested from the medical institution 210, the desired genetic panel may be specified. Therefore, the analysis request sent from the medical institution 210 in step S105 of FIG. 2 may include information related to the genetic panel. Here, the information related to the genetic panel may be any information that can be used to identify the genetic panel, and may be, for example, the name of the genetic panel and the names of the genes to be analyzed in the panel test.

<Analysis at the testing institution 120>
The genetic analysis device 1 receives an analysis request from the medical institution 210 (S106). Furthermore, the genetic analysis device 1 receives a sample from the medical institution 210 that is the sender of the analysis request.

There are multiple gene panels that can be used in the analysis requested by the medical institution 210 to the testing institution 120, and the gene group to be analyzed is determined for each gene panel. The testing institution 120 can also use multiple gene panels according to the purpose of the analysis. That is, a first gene panel can be used to analyze a first gene group to be analyzed for a first sample provided by the medical institution 210, and a second gene panel can be used to analyze a second gene group to be analyzed for a second sample.

The genetic analysis device 1 receives input from the user regarding information about the genetic panel to be used to analyze the sample (step S107).

At the testing facility 120, the received sample is pre-processed and sequenced using sequencer 2 (step S108).

Here, pre-processing can include processing from fragmenting genes such as DNA contained in the sample to recovering the fragmented genes. Furthermore, sequencing includes processing for reading the sequence of one or more DNA fragments to be analyzed that were recovered in pre-processing. Sequence information read by sequencing using the sequencer 2 is output to the genetic analysis device 1 as read sequence information.

Next, the genetic analysis device 1 acquires the read sequence information from the sequencer 2 and analyzes the genetic sequence (step S109).

The genetic analysis device 1 creates a report based on the analysis results in step S109 (step S110) and transmits the created report to the communication terminal 5 (step S111).

<Invoicing the medical institution 210 for analysis fee>
As described above, the testing institution 120 analyzes the sample in response to an analysis request from the medical institution 210, and creates a report based on the analysis results. The medical institution 210 receives the report from the testing institution 120 (step S112). The testing institution 120 may charge the medical institution 210 an analysis fee as compensation for analyzing the sample and providing the medical institution 210, which is the source of the analysis request, with a report based on the analysis results.

<System usage fee billing>
As described above, the analysis system management institution 130 provides various information and services according to the contents of the contract with the testing institution 120, and may charge each testing institution 120 a fee for using the system or the like.

The genetic analysis device 1 of the testing institution 120 that uses the genetic analysis system 100 notifies the management server 3 of information on the genetic panel used in the analysis, information on the analyzed genes, and analysis results, etc. (step S113). Specifically, the genetic analysis device 1 sends the testing institution ID, genetic panel ID, gene ID, and analysis results, etc. to the management server 3.

The management server 3 associates and stores the acquired testing institution ID, genetic panel ID, genetic ID, analysis results, etc. (step S114).

The testing institution ID is information that identifies the user performing the genetic sequence analysis, and may be a user ID, which is identification information assigned to each user who uses the genetic analysis device 1.

The gene panel ID is identification information assigned to identify the gene panel used to analyze the target gene. The gene panel ID assigned to the gene panel is associated with the gene panel name and the name of the company providing the gene panel, etc.

A gene ID is identification information assigned to each gene to identify the gene being analyzed.

The analysis results are information on the analysis status of gene sequence information. The analysis results may be, for example, the number of sequence analyses performed using a specified gene panel in the gene analysis device 1, the number of genes analyzed, or the cumulative number of identified mutations. Alternatively, the analysis results may be information on the amount of data processed in the analysis.

The management server 3 tally up the analysis results for each testing institution 120 for a specified period (e.g., any period such as a day, week, month, or year) and determines a system usage fee according to the tally up results and the contract type (step S115). The analysis system management institution 130 may invoice the testing institution 120 for the determined system usage fee and request that the system usage fee be paid to the analysis system management institution 130.

(Configuration of Genetic Analysis System 100)
The gene analysis system 100 is a system that analyzes gene sequence information, and includes at least a gene analysis device 1 and a management server 3. The gene analysis device 1 is connected to the management server 3 via a network 4 such as an intranet or the Internet.

(Sequencer 2)
The sequencer 2 is a base sequence analyzer used to read the base sequence of genes contained in a sample.

The sequencer 2 according to this embodiment is preferably a next-generation sequencer that performs sequencing using next-generation sequencing technology, or a third-generation sequencer. Next-generation sequencers are a group of base sequence analyzers that have been developed in recent years, and have dramatically improved analytical capabilities by performing massive parallel processing of clonally amplified DNA templates or single DNA molecules in a flow cell.

In addition, the sequencing technology that can be used in this embodiment can be a sequencing technology that obtains multiple reads by reading the same region in duplicate (deep sequencing).

Examples of sequencing techniques that can be used in this embodiment include ion semiconductor sequencing, pyrosequencing, sequencing-by-synthesis using reversible dye terminators, sequencing-by-ligation, and sequencing by oligonucleotide probe ligation, which are based on sequencing principles other than the Sanger method and can obtain a large number of reads per run.

The sequencing primers used for sequencing are not particularly limited, and are appropriately set based on a sequence suitable for amplifying the target region. In addition, the reagents used for sequencing may be selected appropriately depending on the sequencing technology and sequencer 2 used. The steps from pretreatment to sequencing will be explained later with specific examples.

(Management Server 3)
Next, the data stored in the management server 3 will be described with reference to Fig. 3. Fig. 3 is a diagram showing an example of the data structure of the data stored in the management server 3. The analysis system management institution 130 determines the system usage fee to be charged to each testing institution based on each data shown in Fig. 3. The management server 3 receives information including information identifying the user who performs gene sequence analysis (e.g., testing institution ID), information on the gene panel used, and information on the analysis status of the gene sequence (e.g., analysis results) from the gene analysis device 1 via the network 4.

In data 3A shown in FIG. 3, the names of the testing institutions using the genetic analysis system 100 are associated with the testing institution IDs assigned to each testing institution. In data 3B shown in FIG. 3, the types of contracts concluded between the analysis system management institution 130 and the testing institutions 120, the services (e.g., available gene panels) provided to the testing institutions that have concluded each contract, and the system usage fees are associated.

For example, if a testing institution "P Institution" has concluded a contract for "Plan 1" with the analysis system management institution 130, the analysis system management institution 130 will bill the testing institution P for a usage fee according to the number of operations. Note that the "number of operations" is, for example, the number of panel tests performed by the genetic analysis device 1.

Data 3C to 3E shown in FIG. 3 are analysis results relating to the number of operations performed, genes analyzed, and total number of mutations identified by the testing institutions using the genetic analysis system 100 from August 1, 2017 to August 31, 2017. These analysis results are transmitted from the genetic analysis device 1 to the management server 3 and stored in the management server 3. The analysis system management institution 130 determines the system usage fee to be charged to each testing institution based on this data on the analysis results. The period for tallying up the results is not limited to the above, and can be any period such as a day, a week, a month, or a year.

When the analysis system management institution 130 determines the system usage fee, the system usage fee may be changed depending on whether the gene panel used in the test was provided by a company that provides (e.g., manufactures or sells) the gene panel. In this case, the management server 3 may store data 3F shown in FIG. 3. Data 3F shown in FIG. 3 associates the name of the company providing the gene panel, such as "Company A" or "Company B," with the gene panel ID and an agreement regarding the system usage fee (e.g., whether or not a system usage fee is required).

Let us take as an example a case where "Institution P" has concluded a contract for "Plan 1" with the analysis system management institution 130, and the analysis results are as shown in Figure 3. Institution P has performed five tests using a gene panel provided by Company A (gene panel ID "AAA"), and ten tests using a gene panel provided by Company B (gene panel ID "BBB"). According to the data shown in Figure 3, no system usage fee is required for the five tests that used the gene panel provided by Company A. Therefore, the analysis system management institution 130 determines the system usage fee for Institution P, excluding the number of tests that used the gene panel provided by Company A.

(Configuration of Genetic Analysis Device 1)
4 shows an example of the configuration of the genetic analysis device 1. The genetic analysis device 1 is an apparatus including a control unit 11 that acquires lead sequence information read by the sequencer 2 and information on a gene panel including a plurality of genes to be analyzed, and an output unit 13 that outputs an analysis result of the lead sequence information based on the information on the gene panel acquired by the control unit 11. The genetic analysis device 1 can be configured using a computer. For example, the control unit 11 is a processor such as a CPU, and the storage unit 12 is a hard disk drive.

The memory unit 12 also stores a program for sequence analysis, a program for generating a single reference sequence, and the like. The output unit 13 includes a display, a printer, a speaker, and the like. The input unit 17 includes a keyboard, a mouse, a touch sensor, and the like. A device having the functions of both an input unit and an output unit, such as a touch panel in which a touch sensor and a display are integrated, may also be used. The communication unit 14 is an interface that allows the control unit 11 to communicate with an external device.

The genetic analysis device 1 includes a control unit 11 that controls each unit of the genetic analysis device 1, a first memory unit 12 that stores various data used by the analysis execution unit 110, an output unit 13, a communication unit 14, a display unit 16, and an input unit 17. The control unit 11 includes an analysis execution unit 110 and a management unit 116. Furthermore, the analysis execution unit 110 includes a sequence data reading unit 111, an information selection unit 112, a data adjustment unit 113, a mutation identification unit 114, and a report creation unit 115. The first memory unit 12 stores a gene panel related information database 121, a reference sequence database 122, a mutation database 123, and an analysis result log 151.

Even if a different gene panel is used for each analysis, the genetic analysis device 1 creates a report including analysis results corresponding to the gene panel used. A user of the genetic analysis system 100 can analyze the results of a panel test using a common analysis program regardless of the type of gene panel and create a report. This eliminates the hassle of having to use different analysis programs for each gene panel or make special settings for the analysis program for each gene panel used when conducting a panel test, improving user convenience.

When a user of the genetic analysis device 1 inputs information about a gene panel from the input unit 17, the information selection unit 112 refers to the gene panel related information database 121 and controls the algorithm of the analysis program so that the analysis program executes analysis of the genes to be analyzed according to the input information about the gene panel. In other words, the genetic analysis device 1 changes the analysis algorithm according to the input information about the gene panel.

Here, the information regarding the gene panel may be information that identifies the gene panel used in the measurement by sequencer 2, such as the gene panel name, the name of the gene being analyzed in the gene panel, and the gene panel ID.

Based on the information about the gene panel input from the input unit 17, the information selection unit 112 changes the analysis algorithm for performing an analysis corresponding to the genes that are the analysis targets of the gene panel indicated by the information about the gene panel. Specific changes to the analysis algorithm in this embodiment include (1) a change to the reference sequence, and (2) a change to the region of the mutation database 123 that is referenced to identify mutations.

The information selection unit 112 outputs instructions based on the information about the gene panel to at least one of the data adjustment unit 113, the mutation identification unit 114, and the report creation unit 115. By adopting this configuration, the genetic analysis device 1 can output the analysis results of the lead sequence information based on the input information about the gene panel.

In other words, the information selection unit 112 is a functional block that acquires information about a gene panel including multiple genes to be analyzed, and controls the output unit 13 to output the analysis results of the read sequence information based on the acquired information about the gene panel.

When a user performs a panel test to analyze genes contained in various samples, various gene panels are used depending on the group of genes to be analyzed for each sample.

That is, the genetic analysis device 1 can obtain first read sequence information read using a first gene panel for analyzing a first group of genes to be analyzed from a first sample, and second read sequence information read using a second gene panel for analyzing a second group of genes to be analyzed from a second sample.

Even when various combinations of target genes are analyzed using various gene panels, the genetic analysis device 1 is equipped with the information selection unit 112, so that it can appropriately output the analysis results of the read sequence information.

In other words, it is possible to appropriately output the analysis results of each lead sequence information by simply having the user select information related to the gene panel, without having to set an analysis program to be used in analyzing the lead sequence information for each gene to be analyzed or perform the analysis.

For example, when the information selection unit 112 outputs instructions to the data adjustment unit 113 based on information about a gene panel, the data adjustment unit 113 performs alignment processing that reflects the information about the gene panel.

Depending on the information on the gene panel, the information selection unit 112 instructs the data adjustment unit 113 to limit the reference sequences (reference sequences incorporating wild-type genomic sequences and mutant sequences) used for mapping the lead sequence information to only reference sequences related to genes that correspond to the information on the gene panel.

In this case, since the results of processing by the data adjustment unit 113 already reflect the information about the gene panel, the information selection unit 112 does not need to output instructions based on the information about the gene panel to the mutation identification unit 114, which performs processing following the processing by the data adjustment unit 113.

For example, when the information selection unit 112 outputs an instruction based on information about a gene panel to the mutation identification unit 114, the mutation identification unit 114 performs processing that reflects the information about the gene panel.

For example, the information selection unit 112 instructs the mutation identification unit 114 to limit the area of the mutation database 123 referenced by the mutation identification unit 114 to only mutations related to genes corresponding to the information on the gene panel, depending on the information on the gene panel. This causes the information on the gene panel to be reflected in the results of processing by the mutation identification unit 114.

(Enter gene panel information)
Here, the process of accepting input of information on a gene panel shown in step S107 of Fig. 2 will be described with reference to Fig. 5. Fig. 5 is a flow chart showing an example of the flow of the process of accepting input of information on a gene panel.

Here, we will explain an example of a configuration in which the control unit 11 displays a GUI for inputting information about a genetic panel on the display unit 16 and allows the user to input information about the genetic panel.

In this case, the input unit 17 may be a device (e.g., a mouse and a keyboard) capable of performing input operations on the GUI presented to the user. When a touch panel is superimposed on the display unit 16, the display unit 16 functions as the input unit 17. In other words, when a touch panel is used as the display unit 16, the display unit 16 also functions as the input unit 17.

First, the control unit 11 of the genetic analysis device 1 causes the display unit 16 to display a GUI that allows the user to select information about the genetic panel. Based on the user's input operation on the GUI, information about the genetic panel is acquired (step S201).

The information selection unit 112 searches the gene panel related information database 121 based on the information selected by the user from the information displayed as a GUI, and reads out information about the gene panel corresponding to the selected information.

The genetic analysis device 1 also reads out information about the genetic panel included in the analysis request received from the medical institution 210.

If the gene panel corresponding to the selected information is registered in the gene panel related information database 121 (YES in step S202) and the gene panel matches the gene panel included in the analysis request received from the medical institution 210 (YES in step S203), the information selection unit 112 accepts the input. Then, the information selection unit 112 displays a message on the display unit 16 indicating that the input gene panel is available (step S204).

On the other hand, if the gene panel corresponding to the selected information is not registered in the gene panel related information database 121, i.e., if an unregistered gene panel is selected (NO in step S202), the information selection unit 112 displays a message on the display unit 16 to the effect that the input gene panel cannot be used (step S205), and prohibits analysis by the genetic analysis device 1.

In this case, a message informing the user of the error may be displayed instead of a message indicating that the gene panel is unavailable. Such a message may be, for example, a message stating "The selected gene panel is not registered," or may further include a message urging the user to re-enter information regarding the gene panel, such as "Please re-enter information regarding the gene panel."

In addition, if the genetic panel corresponding to the selected information does not match the genetic panel included in the analysis request received from the medical institution 210 (NO in step S203), the information selection unit 112 displays a message on the display unit 16 to the effect that the input genetic panel cannot be used (step S205), and prohibits analysis by the genetic analysis device 1.

In this case, a message informing the user of the error may be displayed instead of a message indicating that the gene panel is unavailable. Such a message may be, for example, a message stating "The selected gene panel is different from the order," or may further include a message urging the user to re-enter information regarding the gene panel, such as "Please re-enter information regarding the gene panel."

This type of processing prevents sequencing using an inappropriate gene panel or performing unnecessary analysis operations, eliminating the wasteful use of gene panels and unnecessary operation of the genetic analysis system 100.

(Example of GUI used to input information about gene panel)
Next, some examples of input screens that allow a user to input information related to a gene panel will be described with reference to Fig. 6. Fig. 6 is a diagram showing an example of a GUI used for inputting information related to a gene panel.

As shown in FIG. 6, a list of gene panel names such as "xxxxx" and "yyyyy" may be displayed on the GUI as information related to the gene panel, and the user may select a desired gene panel from the gene panels shown in the list.

The list of gene panel names displayed on the GUI is based on the gene panel names of gene panels that have been assigned gene panel IDs and are registered in the gene panel related information database 121.

The GUI shown in FIG. 6 shows that "gene panel 2 (gene panel name: "yyyyy")" has been selected by the user. The information selection unit 112 uses the gene panel ID associated with the selected gene panel name "yyyyy" as a key to search the gene panel related information database 121 and obtains information about the gene panel corresponding to the input gene panel name.

(Gene panel related information database 121)
Next, data stored in the gene panel related information database 121 referred to by the information selection unit 112 when information related to a gene panel is input via the input unit 17 will be described with reference to Fig. 7. Fig. 7 is a diagram showing an example of the data structure of the gene panel related information database 121.

The gene panel related information database 121 stores, for each gene panel, the names of genes that can be analyzed and the gene IDs assigned to each gene, as shown in data 121A in FIG. 7.

The gene panel related information database 121 also stores, in association with each other, the names of selectable gene panels, the gene panel IDs assigned to each gene panel, and the gene IDs (related gene IDs) of the genes that each gene panel is intended to analyze, as shown in data 121B in FIG. 7. Each gene panel may also be associated with information regarding whether its use has been approved by a public institution (e.g., the Ministry of Health, Labor and Welfare of Japan, etc.).

As shown in FIG. 6, when the user is prompted to select a desired gene panel from among the gene panels presented in the GUI, the information selection unit 112 refers to the gene panel related information database 121 and extracts the gene panel ID and related gene ID associated with the selected gene panel name.

As shown in FIG. 40, when a gene to be analyzed is selected from among the gene names presented in the GUI, the information selection unit 112 refers to the gene panel related information database 121 to extract gene IDs associated with the selected gene name and gene panel IDs of gene panels that include these gene IDs in their related gene IDs.

In addition, the gene panel related information database 121 may store the names of gene panels related to a disease and the names of genes (or gene IDs) to be analyzed in each gene panel in association with each other, as shown in data 121C in FIG. 7.

When a gene panel related to a desired disease is selected from a list of gene panel names for each disease presented in the GUI (i.e., as shown in FIG. 41), the information selection unit 112 refers to the gene panel related information database 121 and extracts the gene IDs of the gene names associated with the gene panel name related to the selected disease, as well as the gene panel IDs of gene panels that include these gene IDs in their associated gene IDs.

<Update of gene panel related information database 121>
Here, updating of information stored in the genetic panel related information database 121 will be described with reference to Fig. 8. Fig. 8 is a diagram showing an example of a GUI used when a user updates the genetic panel related information database 121.

The information stored in the gene panel related information database 121 can be updated by an update patch provided to the testing institution 120 by the analysis system management institution 130. For example, when the genes to be analyzed in the gene panel are changed or a new gene panel is added, the information stored in the gene panel related information database 121 is updated to the latest information.

The analysis system management institution 130 may provide update patches to testing institutions 120 that have already paid the system usage fee. For example, the analysis system management institution 130 may notify the testing institution 120 that an update patch is available and that payment of the system usage fee is a condition for providing the update patch. By notifying the testing institution 120 in this manner, it is possible to appropriately encourage payment of the system usage fee.

When updating multiple genes at once, as shown in FIG. 8(a), a field for inputting a "Registered File Name" may be displayed, and a file name containing gene names, such as "Gene Panel Target Genes.csv", may be input into that field. In the example shown in FIG. 8(a), this "Gene Panel Target Genes.csv" contains multiple gene names, RET, CHEK2, PTEN, and MEK1.

When the "Register" button is pressed after the file name is entered, a request to update information on the gene corresponding to the gene name contained in the file is associated with the testing institution ID and transmitted to the management server 3 via the communication unit 14. The generation of this update request and the association with the testing institution ID may be configured to be performed, for example, by the control unit 11 in FIG. 4.

The analysis system management institution 130 allows the genetic analysis device 1 to download information including the gene ID assigned to the gene name included in the update request received by the management server 3 and the gene panel ID assigned to the gene panel that analyzes the gene.

Alternatively, if the user wishes to update the gene name by inputting it individually, a field for inputting the "gene name" may be displayed as shown in FIG. 8(b), and the user may input the gene name, such as "FBXW7", in that field.

When the "Register" button is pressed after the gene name is entered, a request to update information on the gene corresponding to the gene name is associated with the testing institution ID and sent to the management server 3 via the communication unit 14. The analysis system management institution 130 permits the genetic analysis device 1 to download information including the gene ID assigned to the gene name included in the update request received by the management server 3 and the gene panel ID assigned to the gene panel that analyzes the gene.

The field in FIG. 8(a) for inputting the "Registered file name" and the field in FIG. 8(b) for inputting the "Gene name" may be configured to display input candidates as suggestions.

For example, information on the input candidates to be displayed is provided in advance from the management server 3 to the genetic analysis device 1 and stored in the first storage unit 12. Then, when a click operation on the GUI of the input field is detected, all updatable gene names may be presented as input candidates and the user may select from among them, or updatable gene names that match the character string entered by the user may be presented as input candidates. Alternatively, for example, when the user enters "E" in the field for entering "gene name" in FIG. 8(b), a list of updatable gene names such as "EGFR" and "ESR" may be displayed and the user may select from the list. By presenting input candidates in this manner, input errors by the user can be prevented.

The gene panel related information database 121 may store the name of each gene, the gene ID of the gene, and the name of the protein that the gene encodes in association with each other.

In this case, even if the input character string is not a gene name but a protein encoded by the gene, the information selection unit 112 can refer to the gene panel related information database 121 to obtain the gene name and gene ID associated with the input protein name.

When a protein name is entered in the field for entering the "gene name" and the registration button is pressed, a GUI may be displayed that displays the gene name associated with the protein name and allows the user to confirm that the gene name is correct.

(Management Unit 116)
The management unit 116 associates the analysis results including the number of times the analysis execution unit 110 has operated, the number of genes analyzed, and the total number of identified genes with the gene panel ID and gene ID, and stores them in the analysis results log 151 as needed. The management unit 116 reads out data including the analysis results from the analysis results log 151 at any frequency (e.g., daily, weekly, or monthly), associates the data with the testing institution ID, and transmits the data to the management server via the communication unit 14.

(Communication unit 14)
The communication unit 14 enables the genetic analysis device 1 to communicate with the management server 3 via the network 4. Data transmitted from the communication unit 14 to the management server 3 may include a testing institution ID, a gene panel ID, a gene ID, analysis results, an update request, etc. Furthermore, data received from the management server 3 may include information related to the gene panel, names of genes that can be updated, etc.

(Reading of the lead sequence by sequencer 2)
Here, the sequencing procedure shown in S108 of Fig. 2 will be described along the flow shown in Fig. 9, with appropriate reference to Fig. 10 to Fig. 15. Fig. 9 is a flow chart for explaining an example of the procedure from pre-processing to sequencing for analyzing the base sequence of a sample DNA by the sequencer 2.

The type of sequencer 2 that can be used in this embodiment is not particularly limited, and a sequencer that can analyze multiple analysis targets in a single run can be suitably used. In the following, as an example, a sequencer (e.g., MySeq, HiSeq, NextSeq, etc.) from Illumina, Inc. (San Diego, CA) or a device that employs a method similar to that of an Illumina sequencer will be described.

Illumina's sequencers combine the Bridge PCR method with a technique called sequencing-by-synthesis, allowing them to amplify huge amounts of target DNA on a flow cell and sequence it while synthesizing it.

(a. Pretreatment)
First, as shown in (a) of FIG. 10, a sample (DNA) is fragmented to a length for reading the sequence with a sequencer 2 (step S301 of FIG. 9). The fragmentation of the sample DNA can be performed by a known method such as ultrasonic treatment or treatment with a reagent for fragmenting nucleic acid. The obtained DNA fragments (nucleic acid fragments) can be, for example, several tens to several hundreds of bp in length. Note that, although the following description will be given taking as an example a case where the gene to be analyzed is DNA, the gene to be analyzed may also be RNA.

Next, as shown in FIG. 10(b), adapter sequences corresponding to the type of sequencer 2 and sequencing protocol to be used are added to both ends (3' and 5' ends) of the DNA fragment obtained in step S301 (step S302 in FIG. 9). However, this step is essential when the sequencer 2 is an Illumina sequencer or a device that employs a similar method to an Illumina sequencer, but may be omitted when another type of sequencer 2 is used.

The adapter sequence is a sequence used to perform sequencing in a later step, and in one embodiment, it can be a sequence for hybridizing to an oligo DNA immobilized on a flow cell in the Bridge PCR method.

In one embodiment, as shown in the upper part of FIG. 10(b), adapter sequences (e.g., adapter 1 sequence and adapter 2 sequence in FIG. 10) may be added directly to both ends of a DNA fragment. The addition of adapter sequences to a DNA fragment can be achieved by a method known in the art. For example, the DNA sequence may be blunted and the adapter sequence may be ligated.

In another embodiment, as shown in the lower part of FIG. 10(b), index sequences may be inserted between both ends of the DNA fragment and the adapter sequence.

The index sequence is a unique sequence for each sample, each gene panel, and each company providing the gene panel, in order to distinguish the data of each sample. The base sequence used as the index sequence has a sequence pattern, such as, but not limited to, 10 to 14 consecutive adenines, 5 to 7 consecutive adenines followed by 5 to 7 consecutive guanines, and a given length.

Based on the sequence pattern and length, the index sequence can be used to identify information about the sequence of the DNA fragment to which the index sequence is added, such as which sample the lead sequence information is from, what gene panel was used, and which company provided the gene panel used. The configuration for identifying information about the panel using the index sequence will be described in detail later (see embodiment 4).

For example, the index sequence in the analysis using gene panel A may be a sequence pattern of 14 consecutive adenines, and the index sequence in the analysis using gene panel B may be a sequence pattern of 7 consecutive adenines followed by 7 consecutive guanines. Alternatively, the index sequence in the analysis using gene panel A may be a sequence of 14 consecutive adenines (i.e., the length of the index sequence is 14), and the index sequence in the analysis using gene panel C may be a sequence of 10 consecutive adenines (i.e., the length of the index sequence is 10).

The index sequence and the adapter sequence can be added to the DNA fragment by a method known in the art. For example, the DNA fragment may be blunted, the index sequence may be ligated, and then the adapter sequence may be ligated.

Next, as shown in FIG. 11, a biotinylated RNA bait library is hybridized to the DNA fragments to which the adapter sequences have been added (step S303 in FIG. 9). The biotinylated RNA bait library is composed of biotinylated RNA (hereinafter referred to as RNA bait) that hybridizes with the gene to be analyzed. The length of the RNA bait is arbitrary, but for example, a long oligo RNA bait of about 120 bp may be used to increase specificity.

In the panel test using the sequencer 2 in this embodiment, a large number of genes (e.g., 100 or more) are the genes to be analyzed. The reagent used in the panel test contains a set of RNA baits corresponding to each of the large number of genes. Since the number and types of genes to be tested differ depending on the panel, the set of RNA baits contained in the reagent used in the panel test also differs.

Then, as shown in FIG. 12, the DNA fragments to be analyzed are collected (step S304 in FIG. 9). In detail, as shown in the upper part of FIG. 12, the DNA fragments hybridized with the biotinylated RNA bait library are mixed with streptavidin magnetic beads, which are streptavidin-magnetic beads bound to streptavidin. This causes the streptavidin portion of the streptavidin magnetic beads to bind to the biotin portion of the RNA bait, as shown in the middle part of FIG. 12.

Then, as shown in the lower part of FIG. 12, the streptavidin magnetic beads are attracted by a magnet, and fragments that are not hybridized with the RNA bait (i.e., DNA fragments that are not the subject of analysis) are removed by washing. This makes it possible to select and concentrate DNA fragments that are hybridized with the RNA bait, i.e., DNA fragments that are the subject of analysis. The sequencer 2 obtains multiple read sequences by reading the nucleic acid sequences of the DNA fragments selected in this way using multiple RNA baits.

Furthermore, as shown in the left to center columns of Figure 13, the streptavidin magnetic beads and RNA bait are removed from the concentrated DNA fragments, and the fragments are amplified by PCR to complete the pretreatment.

(b. Sequencing)
First, as shown in the right column of Fig. 13, the sequence of the amplified DNA fragment is applied to a flow cell (step S305 in Fig. 9). Then, as shown in Fig. 14, the DNA fragment to be analyzed is amplified on the flow cell by Bridge PCR (step S306 in Fig. 9).

That is, the DNA fragment to be analyzed (for example, Template DNA in FIG. 14) has two different adapter sequences (for example, Adapter 1 sequence and Adapter 2 sequence in FIG. 14) added to both ends by the above-mentioned pretreatment ("1" in FIG. 14), and this DNA fragment is made into a single strand, and the Adapter 1 sequence on the 5' end side is fixed on the flow cell ("2" in FIG. 14). The Adapter 2 sequence on the 5' end side is fixed on the flow cell in advance, and the Adapter 2 sequence on the 3' end side of the DNA fragment is bound to the Adapter 2 sequence on the 5' end side on the flow cell, forming a bridge-like state ("3" in FIG. 14). In this state, a DNA extension reaction is performed by DNA polymerase ("4" in FIG. 14), and when denatured, two single-stranded DNA fragments are obtained ("5" in FIG. 14). By repeating this sequence of bridge formation, DNA extension reaction, and denaturation, multiple single-stranded DNA fragments can be locally amplified and fixed to form clusters ("6" to "10" in Figure 14).

Then, as shown in FIG. 15, the sequence is read by sequencing-by-synthesis using the single-stranded DNA that forms the cluster as a template (step S307 in FIG. 9).

First, DNA polymerase and fluorescently labeled dNTPs with blocked 3' ends are added to the single-stranded DNA immobilized on a flow cell (top left column of FIG. 15), and then a sequence primer is added (top right column of FIG. 15). The sequence primer may be designed to hybridize to a portion of the adapter sequence, for example. In other words, the sequence primer may be designed to amplify a DNA fragment derived from the sample DNA, and if an index sequence is added, it may be designed to further amplify the index sequence.

After adding the sequencing primer, a one-base extension reaction of the 3'-end blocked fluorescent dNTP is performed by DNA polymerase. Since a dNTP with a blocked 3' end is used, the polymerase reaction stops when the DNA is extended by one base. Then, the DNA polymerase is removed (middle right column of FIG. 15), and the fluorescent substance bound to the base is excited by laser light for the single-stranded DNA that has been extended by one base (lower right column of FIG. 15), and the light emission that occurs at that time is recorded as a photograph (lower left column of FIG. 15). The photographs are taken using a fluorescent microscope, with the wavelength filter changed to determine the four types of bases, and the fluorescent color corresponding to each of A, C, G, and T is taken. After all the photographs are imported, the base is determined from the photograph data. Then, the fluorescent substance and the protecting group blocking the 3' end are removed, and the next polymerase reaction proceeds. This flow is considered as one cycle, and by repeating the second and third cycles, the entire length can be sequenced.

Using the above method, the chain length that can be analyzed can reach up to 150 bases x 2, making it possible to analyze in units much smaller than a picotiter plate. By increasing the density, it is possible to obtain huge amounts of sequence information, 40 to 200 Gb, in a single analysis.

c. Gene Panels
The gene panel used to read the lead sequence by the sequencer 2 means, as described above, an analysis kit for analyzing multiple analysis targets in a single run, and in one embodiment, may be an analysis kit for analyzing multiple gene sequences related to a specific disease.

As used herein, the term "kit" refers to a package that includes containers (e.g., bottles, plates, tubes, dishes, etc.) that contain specific materials. Preferably, instructions for using each material are provided. When used herein in the context of a kit, "included" refers to a state in which the materials are contained in any of the individual containers that make up the kit. The kit may also be a package in which multiple different compositions are packaged together, and the composition may be in the form described above, or in the case of a solution form, may be contained in a container. The kit may include substance A and substance B mixed in the same container or in separate containers. The "instructions" show the procedure for applying each component of the kit to treatment and/or diagnosis. The "instructions" may be written or printed on paper or other media, or may be attached to electronic media such as magnetic tape, computer-readable disk or tape, CD-ROM, etc. The kit may also include containers that contain diluents, solvents, washing solutions, or other reagents. Additionally, the kit may also include equipment necessary for therapeutic and/or diagnostic applications.

In one embodiment, the gene panel may include one or more of the above-mentioned reagents for fragmenting nucleic acids, ligation reagents, cleaning solutions, PCR reagents (dNTPs, DNA polymerase, etc.), and magnetic beads. The gene panel may also include one or more of oligonucleotides for adding adapter sequences to the fragmented DNA, oligonucleotides for adding index sequences to the fragmented DNA, RNA bait libraries, etc.

In particular, the index sequence of each gene panel may be a sequence specific to the gene panel for identifying the gene panel. Furthermore, the RNA bait library of each gene panel may be a library specific to the gene panel, including RNA baits corresponding to each test gene of the gene panel.

(Sequence data reading unit 111, data adjustment unit 113, mutation identification unit 114)
Next, the processing of the sequence data reading unit 111, data adjusting unit 113, and mutation identifying unit 114 of the analysis execution unit 110 will be described along the processing flow shown in FIG. 16 with appropriate reference to FIGS.

Figure 16 is a flowchart explaining an example of the flow of analysis by the genetic analysis device 1. Note that the process shown in Figure 16 corresponds to step S109 shown in Figure 2.

<Sequence data reading unit 111>
First, in step S 11 of FIG. 16, the sequence data reading unit 111 reads the lead sequence information provided by the sequencer 2 .

The read sequence information is data indicating the base sequence read by the sequencer 2. The sequencer 2 sequences a large number of nucleic acid fragments obtained using a specific gene panel, reads their sequence information, and provides it to the genetic analysis device 1 as read sequence information.

In one embodiment, the lead sequence information may include the quality score of each base in the sequence together with the read sequence. In addition, both lead sequence information obtained by subjecting an FFPE sample collected from a lesion site of a subject to the sequencer 2 and lead sequence information obtained by subjecting a blood sample of the same subject to the sequencer 2 are input to the genetic analysis device 1.

Figure 17 is a diagram showing an example of a file format of read sequence information. In the example shown in Figure 17, the read sequence information includes a sequence name, a sequence, and a quality score. The sequence name may be a sequence ID or the like assigned to the read sequence information output by the sequencer 2. The sequence (sequence number 1) indicates the base sequence read by the sequencer 2. The quality score indicates the probability that base assignment by the sequencer 2 is not performed correctly. The sequence quality score (Q) of any base is expressed by the following formula:

Q=-10log _10E
In this formula, E represents an estimate of the probability that the base assignment is not performed correctly. A higher Q value means a lower probability of error. A lower Q value means that a larger portion of the read cannot be used. In addition, false positive mutation assignments also increase, which may reduce the accuracy of the results. Note that a "false positive" means that the lead sequence is determined to have a mutation even though it does not have the true mutation to be determined. Note that a "positive" means that the lead sequence has the true mutation to be determined, and a "negative" means that the lead sequence does not have the target mutation.

<Data Adjustment Unit 113>
Next, in step S12 of FIG. 16, the data adjusting unit 113 performs alignment of the read sequences of each nucleic acid fragment included in the read sequence information based on the read sequence information read by the sequence data reading unit 111.

(a) of FIG. 18 is a diagram explaining alignment by the data adjustment unit 113. The data adjustment unit 113 performs alignment by referring to the reference sequences stored in the reference sequence database 122 and mapping the read sequence of each nucleic acid fragment to the reference sequence to be compared with the read sequence information. In one embodiment, the reference sequence database 122 stores multiple types of reference sequences corresponding to each gene to be analyzed.

The data adjustment unit 113 also performs alignment on both the lead sequence information obtained by providing an FFPE sample taken from the lesion site of the subject to the sequencer 2 and the lead sequence information obtained by providing a blood sample from the same subject to the sequencer 2.

Figure 18 (b) is a diagram showing an example of the format of the alignment result of the data adjustment unit 113. The format of the alignment result is not particularly limited as long as it can identify the lead sequence, the reference sequence, and the mapping position, but may include reference sequence information, lead sequence name, position information, map quality, and sequence, as shown in Figure 18 (b).

The reference sequence information is information indicating the reference sequence name (reference sequence ID) in the reference sequence database 122, the sequence length of the reference sequence, etc. It is preferable that the reference sequence information can identify the reference sequence, and includes, for example, the reference sequence name and the reference sequence ID. The lead sequence name is information indicating the name (lead sequence ID) of each lead sequence that is the subject of alignment.

The position information is information indicating the position on the reference sequence to which the leftmost base of the read sequence is mapped (leftmost mapping position). The map quality is information indicating the mapping quality corresponding to the read sequence. The sequence is information indicating the base sequence corresponding to each read sequence (e.g. ...GTAAGGCACGTCATA...).

Figure 19 is a diagram showing an example of the structure of the reference sequence database 122. As shown in Figure 19, the reference sequence database 122 stores reference sequences that indicate wild-type sequences (e.g., genomic sequences of chromosomes #1 to #23) and reference sequences in which known mutations have been incorporated into the wild-type sequences.

Furthermore, metadata indicating information regarding the gene panel is attached to each reference sequence in the reference sequence database 122. The information regarding the gene panel attached to each reference sequence may, for example, directly or indirectly indicate the gene to be analyzed that corresponds to each reference sequence.

In one embodiment, the information selection unit 112 may control the data adjustment unit 113 to select a reference sequence corresponding to the information on the gene panel by referring to the input information on the gene panel and metadata of each reference sequence when the data adjustment unit 113 obtains a reference sequence from the reference sequence database 122. For example, in one aspect, the information selection unit 112 may control the data adjustment unit 113 to select a reference sequence corresponding to a gene to be analyzed that is identified by the input information on the gene panel. This allows the data adjustment unit 113 to perform mapping only to reference sequences related to the gene panel used, thereby improving the efficiency of analysis.

In other embodiments, the information selection unit 112 may not perform the above control. In that case, the information selection unit 112 may control the mutation identification unit 114 or the report creation unit 115, as described below.

Figure 20 shows examples of known mutations that are incorporated into reference sequences (not representing wild-type sequences) contained in the reference sequence database 122.

Known mutations are mutations registered in external databases (e.g., COSMIC, ClinVar, etc.) and have chromosomal location, gene name, and mutation identified, as shown in Figure 20.

In the example of FIG. 20, an amino acid mutation is specified, but a nucleic acid mutation may also be specified. The type of mutation is not particularly limited, and may be various mutations such as substitution, insertion, and deletion, or may be a mutation in which a part of the sequence of another chromosome or a reverse complementary sequence is bound.

Figure 21 is a flow chart illustrating an example of the detailed process of the alignment in step S12 in Figure 16. In one aspect, the alignment in step S12 in Figure 16 is performed by steps S401 to S405 shown in Figure 21.

In step S401 of FIG. 21, the data adjustment unit 113 selects unaligned read sequences from among the read sequences of each nucleic acid fragment included in the read sequence information acquired by the sequence data reading unit 111, and compares them with the reference sequence acquired from the reference sequence database 122. Then, in step S402, the data adjustment unit 113 identifies a position on the reference sequence where the degree of match with the read sequence satisfies a predetermined criterion. Here, the degree of match is a value indicating the degree to which the acquired read sequence information matches the reference sequence, and examples include the number or percentage of matching bases.

In one embodiment, the data adjustment unit 113 calculates a score indicating the degree of identity between the lead sequence and the reference sequence. The score indicating the degree of identity can be, for example, the percentage identity between the two sequences.

The data adjustment unit 113, for example, identifies the number of positions where the bases in the lead sequence and the bases in the reference sequence are identical, determines the number of matching positions, and calculates the percentage by dividing the number of matching positions by the number of bases in the lead sequence compared to the reference sequence (the number of bases in the comparison window).

Figure 22 (a) is a diagram showing an example of score calculation. In one embodiment, at the position shown in Figure 22 (a), the score of the degree of identity between the lead sequence R1 (sequence number 3) and the reference sequence (sequence number 2) is 100% because 13 out of 13 bases in the lead sequence match, and the score of the degree of identity between the lead sequence R2 (sequence number 4) and the reference sequence is 92.3% because 12 out of 13 bases in the lead sequence match.

In addition, when calculating the score indicating the degree of identity between the lead sequence and the reference sequence, the data adjustment unit 113 may calculate a score that is lower than the normal calculation if the lead sequence contains a specified mutation (e.g., an insertion/deletion (InDel)) compared to the reference sequence.

In one aspect, the data adjustment unit 113 may correct the score for a sequence in which the lead sequence contains at least one of an insertion and a deletion relative to the reference sequence, by multiplying the score calculated by the normal calculation as described above by a weighting coefficient according to the number of bases corresponding to the insertion/deletion. The weighting coefficient W may be calculated, for example, as W = {1 - (1/100) x (number of bases corresponding to the insertion/deletion)}.

Figure 22(b) is a diagram showing another example of score calculation. In one embodiment, at the position shown in Figure 22(b), the score of the degree of identity between the lead sequence R3 (sequence number 5) and the reference sequence (sequence number 2) is 88% in the normal calculation because 15 of the 17 bases in the lead sequence (the * indicating a deletion is also counted as one base) match, and the corrected score is 88% x 0.98 = 86%.

In addition, the score of the degree of identity between the lead sequence R4 (sequence number 6) and the reference sequence (sequence number 2) is calculated as 81% by normal calculation because 17 of the 21 bases in the lead sequence match, and the corrected score is 81% x 0.96 = 77.8%.

The data adjustment unit 113 calculates the score of the degree of match while changing the mapping position of the lead sequence for each reference sequence, thereby identifying the position on the reference sequence where the degree of match with the lead sequence satisfies a predetermined criterion. In this case, algorithms known in the field, such as dynamic programming, FASTA, and BLAST, may be used.

Returning to FIG. 21, next, if there is a single position on the reference sequence whose degree of match with the lead sequence satisfies a predetermined criterion (NO in step S403), the data adjustment unit 113 aligns the lead sequence to that position, and if there are multiple positions on the reference sequence whose degree of match with the lead sequence satisfies a predetermined criterion (YES in step S403), the data adjustment unit 113 aligns the lead sequence to the position with the highest degree of match (step S404).

Then, if the data adjustment unit 113 has not aligned all of the lead sequences included in the lead sequence information acquired by the sequence data reading unit 111 (NO in step S405), the data adjustment unit 113 returns to step S401, and if it has aligned all of the lead sequences included in the lead sequence information (YES in step S405), the data adjustment unit 113 completes the processing of step S12.

<Other Functions of Data Adjustment Unit 113>
In addition, the data adjustment unit 113 may output the result of comparing the lead sequence information with the sequence information of the genes to be analyzed by the gene panel associated with the acquired information on the gene panel as the analysis result of the lead sequence information.

The sequence information of the genes analyzed by the gene panel may include the sequence of the gene (e.g., exon) to be analyzed and an index sequence added to the sequence of the gene to be analyzed.

For example, in the cases shown in (1) and (2) below, the data adjustment unit 113 may cause the display unit 16 to display an error as a result of the analysis of the lead sequence information.

(1) When mapping a read sequence, the index sequence included in the read sequence information read by the sequence data reading unit 111 is different from the index sequence (e.g., see FIG. 39) corresponding to the information on the gene panel acquired by the information selecting unit 112.

(2) The lead sequence information contains a predetermined number or more of gene sequences that are not the subject of analysis by the gene panel corresponding to the information on the gene panel acquired by the information selection unit 112. Alternatively, the lead sequence information contains less than a predetermined number of gene sequences that are the subject of analysis by the gene panel indicated by the gene panel acquired by the information selection unit.

These are likely to occur due to errors in inputting information about the genetic panel by the user. Therefore, the data adjustment unit 113 may display errors such as "Analysis cannot be performed" and "There is an error in the information about the genetic panel" on the display unit 16.

Alternatively, the data adjustment unit 113 may further display a message such as "Please re-enter information about the gene panel" on the display unit 16 to prompt the user to re-enter the gene panel name and the name of the gene to be analyzed, etc.

The display unit 16 may be configured to display an error only when the number of lead sequence information including sequences of genes not targeted for analysis by the gene panel corresponding to the information on the gene panel is equal to or greater than a predetermined number. Alternatively, the display unit 16 may be configured to display an error only when the number of lead sequence information mapped to genes not targeted for analysis by the gene panel corresponding to the information on the gene panel is equal to or greater than a predetermined number.

Although an example has been described in which the display unit 16 is used as the output destination for outputting an error, the manner in which an error is output is not limited to this. For example, the error content may be output by voice from a speaker. Alternatively, a configuration may be adopted in which a lamp or the like is turned on or blinks to notify the user of the error.

<Mutation Identification Unit 114>
Next, returning to FIG. 16, in step S13, the mutation identification unit 114 compares the sequence of a reference sequence (alignment sequence) in which the lead sequence obtained by providing a sample collected from the lesion site of the subject is aligned with the sequence of a reference sequence in which the lead sequence obtained by providing a blood sample from the same subject is aligned.

Then, in step S14 of FIG. 16, the difference between the two alignment sequences is extracted as a mutation. For example, if the alignment sequence derived from a blood sample for the same position of the same gene to be analyzed is ATCGA and the alignment sequence derived from a tumor tissue is ATCCA, the mutation identification unit 114 extracts the difference between G and C as a mutation.

In one embodiment, the mutation identification unit 114 generates a result file based on the extracted mutations. FIG. 23 is a diagram showing an example of the format of the result file generated by the mutation identification unit 114. The format may be based on, for example, the Variant Call Format (VCF).

As shown in FIG. 23, the result file describes the position information, reference base, and mutated base for each extracted mutation. The position information indicates a position on the reference genome, and includes, for example, a chromosome number and a position on the chromosome. The reference base indicates a reference base (A, T, C, G, etc.) at the position indicated by the position information. The mutated base indicates a base after mutation of the reference base. The reference base is a base on an alignment sequence derived from a blood sample, and the mutated base is a base on an alignment sequence derived from a tumor tissue.

In FIG. 23, a mutation in which the reference base is C and the mutated base is G is an example of a substitution mutation, a mutation in which the reference base is C and the mutated base is CTAG is an example of an insertion mutation, and a mutation in which the reference base is TCG and the mutated base is T is an example of a deletion mutation. Also, a mutation in which the mutated base is G]17:198982], ]13:123456]T, C[2:321682[, or [17:198983[A] is an example of a mutation in which a part of a sequence of another chromosome or a reverse complementary sequence is attached.

Returning to FIG. 16, next, in step S15, the mutation identification unit 114 searches the mutation database 123. Then, in step S16, the mutation identification unit 114 refers to the mutation information in the mutation database 123 and identifies the mutations by annotating the mutations included in the result file.

Figure 24 is a diagram showing an example of the structure of the mutation database 123. The mutation database 123 is constructed based on an external database such as COSMIC or ClinVar. In one embodiment, each piece of mutation information in the database is provided with metadata related to information on the gene panel. In the example shown in Figure 24, each piece of mutation information in the database is provided with the gene ID of the gene to be analyzed as metadata.

Figure 25 is a diagram showing a detailed example of the structure of mutation information in the mutation database 123. As shown in Figure 25, in one embodiment, the mutation information included in the mutation database 123 may include a mutation ID, mutation position information (e.g., "CHROM" and "POS"), "REF", "ALT", and "Annotation". The mutation ID is an identifier for identifying a mutation. Of the mutation position information, "CHROM" indicates the chromosome number, and "POS" indicates the position on the chromosome number. "REF" indicates a base in the wild type, and "ALT" indicates a base after mutation.

"Annotation" indicates information about a mutation. "Annotation" may be information indicating an amino acid mutation, such as "EGFR C2573G" or "EGFR L858R." For example, "EGFR C2573G" indicates that the 2573rd residue of the protein "EGFR" is a mutation in which the cysteine has been replaced with glycine.

As in the above example, the "Annotation" of the mutation information may be information for converting a mutation based on base information into a mutation based on amino acid information. In this case, the mutation identification unit 114 can convert a mutation based on base information into a mutation based on amino acid information based on the referenced "Annotation" information.

The mutation identification unit 114 searches the mutation database 123 using information identifying the mutation included in the result file (e.g., the position information of the mutation and the base information corresponding to the mutation) as a key. For example, the mutation identification unit 114 may search the mutation database 123 using any of the information "CHROM", "POS", "REF", and "ALT" as a key. When a mutation extracted by comparing the alignment sequence derived from the blood sample with the alignment sequence derived from the lesion site is registered in the mutation database 123, the mutation identification unit 114 identifies the mutation as a mutation present in the sample and annotates the mutation included in the result file (e.g., "EGFR L858R", "BRAF V600E", etc.).

In one embodiment, the information selection unit 112 may mask (exclude) from the result file any mutations that do not correspond to the information about the gene panel input to the mutation identification unit 114 before the mutation identification unit 114 searches the mutation database 123 based on the result file.

For example, in one aspect, the mutation identification unit 114, which has been notified of information related to the gene panel from the information selection unit 112, may refer to a table showing the correspondence between the gene to be analyzed and position information (e.g., "CHROM" and "POS"), as shown in (a) of FIG. 26, to identify the position of a mutation corresponding to the gene to be analyzed identified by the notified information on the gene panel, and may mask (exclude) mutations at other positions from the result file, as shown in (b) of FIG. 26. This allows the mutation identification unit 114 to annotate only mutations in the result file that are related to the gene panel used, thereby improving the efficiency of mutation identification.

In addition, in one embodiment, the information selection unit 112 may control the mutation identification unit 114 to refer to the mutation information in the mutation database 123 in order to provide annotation, by referring to the input information about the gene panel and the metadata of each piece of mutation information, and to select and refer to the mutation information corresponding to the information about the gene panel.

For example, in one embodiment, the information selection unit 112 may control the mutation identification unit 114 to refer to mutation information corresponding to the gene to be analyzed that is identified by the input information on the gene panel. This allows the mutation identification unit 114 to refer only to mutation information in the mutation database 123 that is related to the used gene panel, thereby improving the efficiency of annotation.

In addition, from among all identified mutations, mutations corresponding to the input information on the gene panel may be selected based on the information on the gene panel, and information related to the selected mutation may be output as the analysis result of the lead sequence information.

In this case, for example, the metadata for each piece of mutation information stored in the mutation database may include, in addition to the gene ID of the gene to be analyzed, information regarding, for each mutation in the gene, whether or not the mutation is a target of analysis by the gene panel.

According to this configuration, the mutation identification unit 114 may refer to the information on the gene panel from the information selection unit 112 and the metadata of each piece of mutation information, and may be controlled to select only the mutation information corresponding to the information on the gene panel from among all the identified mutations. For example, there may be cases where different gene panels analyze genes with the same gene ID, but the mutations that are the subject of analysis are different from each other.

Even in such a case, by adopting the above configuration, the mutation identification unit 114 can output only the mutation information corresponding to the information on the gene panel input by the user to the report creation unit 115. Note that the configuration may be such that the mutation information is output from the output unit 13 or displayed on the display unit 16 as the analysis result of the lead sequence information.

(Report Creation Unit 115)
When the entire exon region is analyzed by panel testing, many mutations are detected in the subject's genes. Some of the mutations do not have established clinical significance or effective drugs for treatment, and contain information that is not useful for doctors in actual treatment. When doctors try to apply the results of genetic testing to the actual treatment of a subject, they want to selectively know the mutations that can be used in actual treatment from among the many detected mutations.

The report creation unit 115 creates a report based on the information output by the mutation identification unit 114 and the information on the gene panel provided by the information selection unit 112 (corresponding to step S110 in FIG. 2). The information included in the created report includes information on the gene panel and information on the identified mutations.

The report creation unit 115 selects what to include in the report based on the information on the gene panel from the information selection unit 112, and deletes the unselected information from the report. Alternatively, the information selection unit 112 may be configured to control the report creation unit 115 so that the information selection unit 112 selects information related to genes corresponding to the information on the gene panel input via the input unit 17 as the information to be included in the report, and deletes the unselected information from the report.

(Output unit 13)
The report created by the report creation unit 115 may be transmitted as an analysis result of the lead sequence information from the output unit 13 to the terminal device 5 installed in the medical institution 210 (corresponding to step S111 in FIG. 2 ), or may be transmitted to a printer (not shown) connected to the genetic analysis device 1, printed by the printer, and then sent as a paper medium from the testing institution 120 to the medical institution 210.

[Embodiment 2]
Other embodiments of the present invention will be described below. For ease of explanation, the same reference numerals are given to members having the same functions as those described in the above embodiment, and the description thereof will not be repeated.

(Configuration of Genetic Analysis Device 1a)
Here, a gene analyzer 1a capable of generating a report including information (drug information) related to a drug associated with a mutation identified by the mutation identifying unit 114 will be described with reference to FIG.

Figure 27 is a diagram showing another example of the configuration of the genetic analysis device 1a. The genetic analysis device 1a differs from the genetic analysis device 1 shown in Figure 4 in that the analysis execution unit 110a of the genetic analysis device 1a further includes a drug search unit 117, and the first storage unit 12a further includes a drug database 124.

(Drug search unit 117)
The flow of the process in which the drug search unit 117 generates a list including information about drugs will be described with reference to Fig. 28. Fig. 28 is a flowchart showing an example of the process in which the drug search unit 117 generates a list of drugs related to mutations.

The drug search unit 117 searches the drug database 124 using the mutation ID assigned to the mutation identified by the mutation identification unit 114 as a key (step S15a). Based on the search results, the drug search unit 117 generates a list including information about drugs related to the mutation (step S16a). The generated list is incorporated into the report created by the report creation unit 115.

(Drug Database 124)
When the drug search section 117 searches the drug database 124 to generate a drug list, data 124A stored in the drug database 124 will be described with reference to Fig. 29. Fig. 29 is a diagram showing an example of the data structure of the drug database 124.

As shown in FIG. 29, the drug database 124 stores a mutation ID assigned to each mutation, an associated drug name, and a drug ID assigned to each drug, which are associated with each other. Note that multiple associated drugs may be associated with each mutation ID, such as the mutation ID "#3" in FIG. 29 being associated with "Drug A" and "Drug B."

Each mutation ID in the drug database 124 may be assigned "metadata related to gene panel-related information," which is metadata related to information related to the gene panel. The drug search unit 117 refers to this "metadata related to gene panel-related information" in response to an instruction from the information selection unit 112.

Then, the drug search unit 117 changes the range in which to search the drug database 124 to the range indicated in the metadata. This allows the drug search unit 117 to narrow down the drugs to be referenced in the drug database according to the "metadata related to gene panel-related information" assigned to each drug and the information related to the input gene panel, and to generate a list including information related to drugs according to the information related to the gene panel.

<Modification 1>
The drug search unit 117 may search the drug database 124 having the data structure shown in Fig. 30 to generate a list including other information on drugs related to mutations. Specifically, in addition to the list of drugs related to mutations generated in the second embodiment, approval information of the drugs is added. This will be described with reference to Fig. 31. Fig. 31 is a flowchart showing an example of a process in which the drug search unit 117 generates a list including information on drugs related to mutations.

The drug search unit 117 searches the drug database 124, which stores the data shown in FIG. 30, to determine whether the related drug has been approved by an authority (FDA, PMDA, etc.). Specifically, the drug search unit 117 uses information about the mutation, such as a "mutation ID," as a key to search for an "approval status" that indicates whether the related drug corresponding to the mutation has been approved by an authority, and an "approved country" that indicates the country's authority by which the drug has been approved (step S15b).

Based on the search results, the drug search unit 117 generates a list including the mutation, related drugs corresponding to the mutation, and information regarding the approval of the related drugs (step S16b).

<Modification 2>
The drug search unit 117 may search the drug database 124 having the data structure shown in Fig. 30 to generate a list including further information on drugs related to the mutation. Specifically, in addition to the list of drugs related to the mutation generated in the second embodiment, information on drugs corresponding to the disease of the subject is added. This will be described with reference to Fig. 32. Fig. 32 is a flow chart showing an example of a process in which the drug search unit 117 determines the presence or absence of a drug that may be off-label use based on information obtained by searching the drug database 124, and generates a list including the determination result.

The drug search unit 117 searches the drug database 124, which stores the data 124B shown in FIG. 30, to determine whether the relevant drug has been approved by an authority (e.g., FDA, PMDA, etc.) (step S15b). If the searched drug is unapproved (NO in step S21), the drug search unit 117 associates the drug with the mutation as an unapproved drug (step S23) and generates a report on the drug related to the mutation (step S16a).

If the searched drug has been approved (YES in step S21), the drug search unit 117 determines whether the disease of the subject from whom the sample was collected matches the disease corresponding to the related drug searched from the drug database 124 (e.g., the "target disease" shown in Figure 30) (step S22).

If the subject's disease matches the "target disease" (YES in step S22), the search results are associated with the mutation as an approved drug (step S24), and a list is generated that includes the mutation, the associated drug corresponding to the mutation, and information regarding the approval of the associated drug (step S16a).

On the other hand, if the subject's disease is different from the "target disease" (NO in step S22), the searched related drug is determined to be a drug that may be off-label used, and the determination result is associated with the mutation (step S25), and a list is generated that includes the mutation, the related drug corresponding to the mutation, and information regarding the approval of the related drug (step S16a).

In addition, information regarding the subject's disease may be input from the input unit 17 by an operator or the like when performing genetic analysis, for example. In addition, for example, a disease ID, which is identification information corresponding to the subject's disease, may be included in the header area of the lead sequence information.

<Modification 3>
The drug search unit 117 may search the drug database 124 having the data structure shown in Fig. 33 to generate a list including information on clinical trials of drugs related to the mutation. Specifically, in addition to the list of drugs related to the mutation generated in the second embodiment, the drug clinical trial information is added. This will be described with reference to Fig. 34. Fig. 34 is a flowchart showing an example of a process in which the drug search unit 117 generates a list including information on clinical trials of drugs.

The drug search unit 117 searches for information such as the progress of clinical trials of related drugs from the drug database 124 that stores the data 124C shown in FIG. 33. Specifically, the drug search unit 117 searches for information related to clinical trials of the mutation, such as the "clinical trial/clinical trial status," the "country" where the clinical trial is being conducted, and the "institution" shown in FIG. 33, using the mutation ID as a key (step S15c in FIG. 34). Based on the search results, the drug search unit 117 generates a list that includes the mutation, the related drug corresponding to the mutation, and information related to the clinical trial of the related drug (step S16c in FIG. 34).

The data 124A shown in FIG. 29, the data 124B shown in FIG. 30, and the data 124C shown in FIG. 33 may be integrated into one and stored in the drug database 124, or may be distributed and stored in multiple databases including the drug database 124.

[Embodiment 3]
Other embodiments of the present invention will be described below. For ease of explanation, the same reference numerals are given to members having the same functions as those described in the above embodiment, and the description thereof will not be repeated.

(Configuration of Genetic Analysis Device 1b)
Here, a gene analysis device 1b capable of generating a report including various reference information related to the mutations identified by the mutation identification unit 114 will be described with reference to FIG.

Figure 35 is a diagram showing another example of the configuration of a genetic analysis device 1b. The genetic analysis device 1b differs from the genetic analysis device 1 shown in Figure 4 in that the analysis execution unit 110b of the genetic analysis device 1b further includes a reference search unit 118, and the first storage unit 12b further includes a reference database 125.

(Reference search unit 118)
The reference search unit 118 searches the reference database 125 using the mutation ID assigned to the mutation identified by the mutation identification unit 114 as a key. Based on the search result, the reference search unit 118 extracts reference information related to the mutation. The extracted reference information is incorporated into a report created by the report creation unit 115.

(Reference Database 125)
The data stored in the reference database 125 searched by the reference search unit 118 will be described with reference to Fig. 36. Fig. 36 is a diagram showing an example of the data structure of the reference database 125.

As shown in FIG. 36, the reference database 125 stores a mutation ID, information on the biological background of the mutation, molecular function information, clinical information, and literature information such as books and scientific papers related to the mutation, all of which are associated with each other.

Each mutation ID in the reference database 125 may be assigned "metadata related to gene panel-related information," which is metadata related to information related to the gene panel (not shown). In this case, the reference search unit 118 refers to this "metadata related to gene panel-related information" in response to an instruction from the information selection unit 112, and changes the range in which the reference database 125 is searched to the range indicated in the metadata. This allows the reference search unit 118 to narrow down the reference information to be referred to in the drug database according to the "metadata related to gene panel-related information" associated with each mutation and the input information related to the gene panel, and to extract reference information according to the information related to the gene panel.

(Report Creation Unit 115 of Genetic Analysis Apparatuses 1a and 1b)
The report creation unit 115 may create a report based on the information output by the drug search unit 117, or may create a report based on the information output by the reference search unit 118. Furthermore, the report creation unit 115 may create a report based on the information output by both the drug search unit 117 and the reference search unit 118.

The report created by the report creation unit 115 may include information about the identified mutation, information about drugs related to the mutation, references about the mutation (including, for example, molecular biological knowledge and literature information about each mutation), or any combination of these pieces of information.

The information selection unit 112, for example, selects information related to the target genes that correspond to the input information about the gene panel as the target to be included in the report, and controls the report creation unit 115 to create a report that includes the selected information.

Figure 37 is a diagram showing an example of a report created by the report creation unit 115. The upper left part of the report shown in this example lists "Patient ID" indicating the subject ID, "Patient's Gender", "Patient's Disease Name", "Name of Doctor in Charge" which is the name of the doctor in charge of the subject at the medical institution 210, and "Institution Name" indicating the name of the medical institution. In addition, the name of the gene panel "Panel A" is also included as information related to the gene panel. In this report, the column "Detected Gene Mutations and Related Drugs" contains information about the mutations identified by the mutation identification unit 114 and a list generated by the drug search unit 117 by searching the drug database 124 and based on the search results.

The "Clinical Trial List" column also contains a list of information about drug clinical trials that the drug search unit 117 has generated by searching the drug database 124 based on the search results.

[Embodiment 4]
Other embodiments of the present invention will be described below. For ease of explanation, the same reference numerals are given to members having the same functions as those described in the above embodiment, and the description thereof will not be repeated.

(Configuration of Genetic Analysis Device 1c)
Here, a genetic analysis device 1c having a function of allowing a user to input information about a genetic panel and a function of an information selection unit 112c acquiring information about the genetic panel based on an index sequence included in the lead sequence information will be described. In the following, the genetic panel related information database 121c, the data adjustment unit 113c, and the information selection unit 112c shown in FIG. 38 will be described with reference to FIG. 39.

Figure 38 is a functional block diagram showing another example of the configuration of the genetic analysis device 1c. Note that the read sequence information read by the sequence data reading unit 111 may include an index sequence for identifying the read sequence information for each sample or each type of gene panel, for example.

The index sequence may be inserted only into the sequence of a specific gene among the genes that are the subject of analysis by the gene panel. If the read sequence information does not have an index sequence inserted, the user can input information about the gene panel as shown in FIG. 6.

<Gene panel related information database 121c>
First, the data 121D stored in the gene panel related information database 121c referred to by the information selecting unit 112c will be described with reference to Fig. 39. Fig. 39 is a diagram showing an example of the data structure of the gene panel related information database 121c. The gene panel related information database 121c stores the names of selectable gene panels, the gene panel IDs assigned to each gene panel, and index sequence information to be inserted for each gene panel in association with each other.

In the example shown in FIG. 39, data is shown indicating that the lead sequence information analyzed using the gene panel "A panel" with the gene panel ID "AAA" contains the index sequence "pppppppppppp", and the lead sequence information analyzed using the gene panel "B panel" with the gene panel ID "BBB" contains the index sequence "qqqqqqqqqq." Note that "p" and "q" represent bases.

<Data Adjustment Unit 113c>
The data adjusting unit 113c analyzes the read sequence information read by the sequence data reading unit 111, and judges whether the sequence contains index sequences such as "pppppppppppp" and "qqqqqqqqq" stored in the gene panel related information database 121c. If an index sequence is not contained, the data adjusting unit 113c notifies the information selecting unit 112c accordingly. On the other hand, if an index sequence is contained, the data adjusting unit 113c outputs the detected index sequence (e.g., "pppppppppppp") to the information selecting unit 112c.

<Information Selection Unit 112c>
When the information selection unit 112c is notified by the data adjustment unit 113c that the index sequence is not included, the information selection unit 112c displays the GUI shown in FIG. 6 on the display unit 16 together with a message such as "Please enter information about the gene panel." On the other hand, when the information selection unit 112c receives an index sequence from the data adjustment unit 113c, the information selection unit 112c searches the gene panel related information database 121c using the index sequence as a key, and identifies gene panel related information such as a gene panel name and a gene panel ID corresponding to the index sequence. For example, when the index sequence received from the data adjustment unit 113c is "qqqqqqqqq", the information selection unit 112c searches the gene panel related information database 121c, identifies that "panel B" has been used as the gene panel, and acquires gene panel related information of the gene panel. The acquired gene panel related information is applied to control the data adjustment unit 113c, the mutation identification unit 114, the report creation unit 115, and the like, as described above.

When an index sequence is inserted into the lead sequence information in this way, it is possible to identify gene panel related information without requiring the user to input the gene panel related information. This provides further convenience to the user.

The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. The technical scope of the present invention also includes embodiments obtained by appropriately combining the technical means disclosed in different embodiments.

For example, FIG. 1 shows one medical institution 210 and one testing institution 120, but is not limited to this. That is, the medical institution 210 may request analysis from multiple testing institutions 120, and the testing institution 120 may accept analysis requests from multiple medical institutions 210. That is, there may be multiple medical institutions 210 and multiple testing institutions 120.

1 and 2, the testing facility 120 is shown with one sequencer 2 and one genetic analyzer 1, but is not limited to this. In other words, the testing facility 120 may be equipped with multiple sequencers 2 and multiple genetic analyzers 1.

The genetic analysis system 100 can also be suitably applied to institutions that have the functions of both the medical institution 210 and the testing institution 120 (for example, a research institute that combines clinical facilities and testing facilities, and a university hospital). This is not limited to the genetic analysis system 100, but the genetic analysis method executed by the genetic analysis device 1, the program for controlling the genetic analysis device 1 that realizes the genetic analysis method on a computer, and the computer-readable recording medium on which it is recorded can also be suitably applied to institutions that have the functions of both the medical institution 210 and the testing institution 120.

The analysis using the gene panel may be used to analyze polymorphisms such as single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNVs). The gene panel may also be used to output information on the amount of mutations in the entire gene being analyzed (also called tumor mutation burden) or to calculate methylation frequency.

Although an example of displaying an input GUI has been shown as a means for allowing a user to input information regarding a genetic panel, this is not limiting. For example, the input unit 17 may be a barcode reader, and the user may read the barcode. If a barcode is indicated on the label of the container of each reagent of each genetic panel, or on the surface of a box containing a set of reagents for a genetic panel, the barcode is read using a barcode reader, and information regarding the genetic panel is input.

When the control unit 11 causes the display unit 16 to display a GUI for inputting information about the gene panel, the control unit 11 may cause the user to select the genes to be analyzed. In this case, as shown in FIG. 40, the control unit 11 may cause the GUI to display a list of candidate genes, and cause the user to select the genes to be analyzed by the gene panel.

The gene names displayed on the GUI are based on the gene names of genes to which gene IDs have been assigned and registered in the gene panel related information database 121. The gene names in the list displayed as selection options are based on the information on gene panels registered in the gene panel related information database 121.

Figure 40 shows an example in which a list containing multiple gene names to be analyzed (e.g., "AKT1" and "APC") is provided with a check box to the left of each gene name. In the example shown in Figure 40, gene names such as "AKT1" and "APC" are selected, while gene names such as "EML4" and "JAK3" are not selected. The information selection unit 112 identifies the gene panel IDs associated with these gene names from the selected gene names, searches the gene panel related information database 121, and obtains information regarding the gene panel corresponding to the input gene panel name.

Alternatively, as shown in FIG. 41, a list of gene panel names for each disease, such as "lung cancer panel" and "colon cancer panel," may be displayed on the GUI, and the user may select a gene panel related to the desired disease from the gene panels shown in the list. A list of disease names, such as "lung cancer" and "colon cancer," may be displayed on the GUI, and the user may select a desired disease from the disease names shown in the list.

In this case, the information selection unit 112 identifies the gene panel ID associated with the selected disease name from the selected disease name, and searches the gene panel related information database 121 to obtain information about the gene panel corresponding to the selected disease name.

The gene names displayed in the GUI as options for selecting a gene panel related to the selected disease are displayed based on the information registered in the gene panel related information database 121.

The gene panel name of a disease-related gene panel may be the name of a reagent kit. The gene panel includes a set of reagents, such as various buffers, enzymes, and primers, used in target sequencing, which is performed to read the sequence of the gene to be analyzed by the sequencer 2. A reagent kit name or gene panel name is given to this set of reagents.

Here, another example of the process flow for accepting input of information related to a gene panel, shown in step S107 of FIG. 2, will be described with reference to FIG. 42. For ease of explanation, the same processes as those described in FIG. 5 are denoted by the same reference numerals, and the description thereof will not be repeated.

The process flow shown in FIG. 5 assumes, for example, a case where a testing institution 120 that receives an analysis request from a medical institution 210 performs a panel test using a gene panel specified by the medical institution 210. However, this is not limited to this, and analysis may also be performed using a gene panel other than the gene panel specified by the sample provider. For example, a research institution that searches for an optimal gene panel or seeks more effective ways to use gene panels may obtain samples from the medical institution 210 and perform panel tests using various gene panels in addition to analysis using the specified gene panel.

If the genetic panel corresponding to the selected information does not match the genetic panel included in the analysis request received from the medical institution 210 (NO in step S203), the information selection unit 112 displays a message on the display unit 16 notifying the user that the input genetic panel is different from the specified genetic panel and asking whether or not to use the input genetic panel (step S206). If an input requesting permission to use the input genetic panel is received (YES in step S207), the information selection unit 112 accepts the input. Then, the information selection unit 112 displays a message on the display unit 16 notifying the user that the input genetic panel is usable (step S204).

On the other hand, if an input is received requesting permission to use the input genetic panel (NO in step S207), the information selection unit 112 displays a message on the display unit 16 to the effect that the input genetic panel cannot be used (step S205), and prohibits analysis by the genetic analysis device 1.

The genetic analysis device 1 may be configured to be able to select either the input mode shown in FIG. 5 or the input mode shown in FIG. 42 when accepting input of information related to a genetic panel. For example, when performing a panel test using a genetic panel specified by the medical institution 210, it is preferable to select the input mode shown in FIG. 5, and when performing analysis using a genetic panel other than the specified genetic panel, it is preferable to select the input mode shown in FIG. 42. In this way, by providing multiple processing modes for accepting input of information related to a genetic panel, a user using the genetic analysis device 1 can select an input mode according to the application.

[Embodiment 5]
Other embodiments of the present invention will be described below. For ease of explanation, the same reference numerals are given to members having the same functions as those described in the above embodiment, and the description thereof will not be repeated.

The genetic analysis method according to this embodiment acquires information about a gene panel, and changes the analysis algorithm for evaluating the quality of the panel test based on the acquired information about the gene panel. This makes it possible to perform appropriate quality control according to the gene panel when analyzing various combinations of target genes using various gene panels.

Examples of quality evaluation processes that change depending on the genetic panel include (1) changing the quality evaluation index used in the quality evaluation of the panel test, (2) changing the criteria used to determine whether the same quality evaluation index is sufficiently reliable when used, and (3) changing the number of quality evaluation indexes used in the quality evaluation of the panel test.

Quality assessment indicators include, for example, the reading quality contained in the read sequence information output by sequencer 2, the proportion of bases read by sequencer 2 among the bases contained in the multiple genes to be analyzed, the reading depth of the read sequence information, the variance in the reading depth of the read sequence information, and whether or not all mutations in each standard gene contained in the quality control sample were detected.

(Configuration of Genetic Analysis Device 1d)
Here, a genetic analyzer 1d having a function of evaluating the quality of a panel test based on a quality evaluation index will be described with reference to Fig. 43. Fig. 43 is a diagram showing another example of the configuration of the genetic analyzer 1d. The genetic analyzer 1d is capable of creating a report including the evaluation result of the quality of the panel test. In Fig. 43, the flow of data is indicated by arrows.

The genetic analysis device 1d differs from the genetic analysis device 1 shown in FIG. 4 in that the analysis execution unit 110d further includes a quality control unit 119, and the memory unit 12d further includes a quality evaluation criteria database 126.

The quality evaluation criteria database 126 stores criteria values that define whether the reliability of the analysis results in the panel test reaches a certain standard. Here, the certain standard is used, for example, to determine whether the analysis results of the panel test have the reliability required for application to treatment or diagnosis.

(Quality Evaluation Index)
Quality evaluation indices generated by the quality control unit 119 for a measurement include, for example, the reading quality contained in the read sequence information output by the sequencer 2, the proportion of bases read by the sequencer 2 among the bases contained in the multiple genes to be analyzed, the reading depth of the read sequence information, the variance in the reading depth of the read sequence information, and whether or not all mutations in each standard gene contained in the quality control sample have been detected.

The above quality evaluation indicators are explained in detail below.

Quality Evaluation Index (1): Quality Score The quality score is an index that indicates the accuracy of each base in the gene sequence read by the sequencer 2.

For example, when the read sequence information is output from sequencer 2 in a FASTQ file, the quality score is included in the read sequence information (see FIG. 17). Note that details of the quality score are explained in embodiment 1, and therefore will not be explained here.

Quality evaluation index (2): Cluster concentration Cluster concentration is an index indicating the reading quality contained in the read sequence information output by the sequencer 2. The sequencer 2 locally amplifies and fixes a large number of single-stranded DNA fragments on the flow cell to form clusters (see 9 in FIG. 14). Then, the clusters on the flow cell are imaged using a fluorescent microscope, and the sequences are read by detecting the fluorescence of different wavelengths corresponding to A, C, G, and T. Cluster density is an index indicating how close the clusters of each gene formed on the flow cell are to each other.

For example, if the density of the clusters becomes too high, causing the clusters to be too close to each other or overlap, the contrast of the image of the flow cell, i.e., the signal-to-noise ratio, will be low, making it difficult to focus the fluorescence microscope. This will make it impossible to detect the fluorescence correctly, and as a result, there is a risk of a decrease in the accuracy of sequence reading.

Quality evaluation index (3): An index indicating the proportion of the base sequence of the target region read by sequencer 2 among the base sequences read by sequencer 2. This index indicates how many bases of the target region have been read out of the bases read by sequencer 2, including those outside the target region, and is calculated as the ratio of the total number of bases read to the total number of bases in the target region.

Quality assessment index (4) An index showing the reading depth of the read sequence information.

This index is based on the total number of read sequences that read each base contained in the gene being analyzed, and is calculated as the ratio of the total number of bases that have a depth equal to or greater than a specified value to the total number of bases that were read.

Read depth refers to the total number of read sequence information read for the same base, and is also called coverage rate, coverage, or depth of coverage.

Figure 45 shows a graph indicating the depth of each base when the total length of the gene being analyzed (the "target gene" in the figure) is L bases and the number of bases in the read region is t1 bases. The horizontal axis of the graph in Figure 45 is the position of the base, and the vertical axis is the depth of each base. In the example shown in Figure 45, of the t1 bases in the read region, the total number of bases in the region with a depth equal to or greater than a predetermined value (e.g., 100) is (t2 + t3) bases. In this case, the quality assessment index (4) is generated as the value of (t2 + t3)/t1.

Quality assessment index (5): An index showing the variation in the reading depth of the read sequence information.

This index indicates the uniformity of depth. If there is an extremely large amount of lead sequence information that is read only from a certain portion of the read area, the uniformity of depth will be low. On the other hand, if lead sequence information is present evenly throughout the entire read area, the uniformity of depth will be high. The uniformity of depth can be quantified, for example, using the interquartile range (IQR). A higher IQR indicates lower uniformity, and a lower IQR indicates higher uniformity.

Quality assessment index (6): An index showing whether all mutations in each standard gene contained in the quality control sample were detected.

This index indicates whether mutations in each standard gene contained in a quality control sample were detected and correctly identified when the quality control sample was measured together with a sample collected from a subject. For example, whether the position and type of known mutations in each standard gene contained in the quality control sample were correctly identified is used as a quality evaluation index. Quality control samples are prepared by mixing multiple standard genes.

The process flow for evaluating the quality of panel testing will be explained using Figure 44. Figure 44 is a flowchart showing an example of the process flow for analyzing gene sequences.

First, in step S31 of FIG. 44, pre-processing is performed to analyze the gene sequence. The pre-processing includes fragmenting genes such as DNA contained in the sample and recovering the fragmented genes. Here, the subject of analysis in the panel test for quality evaluation may be a sample collected from a subject, or a quality control sample prepared by mixing multiple standard genes.

The quality control sample contains at least two of the following standard genes: a standard gene containing an SNV, a standard gene containing an insertion, a standard gene containing a deletion, a standard gene containing a CNV, and a standard gene containing a fusion. For example, the quality control sample contains, as standard genes, a partial sequence of gene A that contains "SNV" relative to the wild type, and a partial sequence of gene B that contains "Insertion" relative to the wild type.

Next, in step S32, sequencer 2 reads the base sequence of the DNA contained in the pretreated sample.

Next, in step S33, the control unit 11d of the genetic analysis device 1d causes the input unit 17 to display a GUI for allowing the user to select information related to the genetic panel. Information related to the genetic panel is acquired based on the user's input operation on the GUI. Acquisition of information related to the genetic panel is not limited to user input via the GUI, and may be acquired, for example, by an identifier such as a barcode attached to the genetic panel, or identification may be performed by reading an index array.

The control unit 11d of the genetic analysis device 1d determines the type of genetic panel based on the acquired information about the genetic panel. The genetic analysis device 1d changes the analysis algorithm so as to perform quality control of the panel test according to the acquired type of genetic panel.

In S34, the genetic analysis device 1d analyzes the gene sequence according to the type of gene panel, and identifies the presence or absence of a mutation in the base sequence, the position of the mutation, the type of mutation, etc. The detected mutation is identified by analyzing the read gene sequence.

(Quality Control Department 119)
The genetic analysis device 1d evaluates the quality of the panel test based on the generated quality evaluation index. The quality control unit 119 acquires the quality score (quality evaluation index 1) and the cluster concentration (quality evaluation index 2) from the sequence data reading unit 111. In addition, the ratio of bases in the target region read by the sequencer 2 (quality evaluation index 3), the reading depth of the read sequence information (quality evaluation index 4), and the variation in the reading depth of the read sequence information (quality evaluation index 5) are acquired from the data adjustment unit 113. Furthermore, whether or not all mutations in each standard gene contained in the quality control sample have been detected (quality evaluation index 6) is acquired from the mutation identification unit 114. The quality control unit 119 does not need to acquire all of these quality evaluation indexes, and may acquire one or more arbitrary indexes.

The quality control unit 119 compares the acquired quality evaluation index with the reference value of the quality evaluation index stored in the quality evaluation standard database 126, and determines whether the analysis results are sufficiently reliable. Here, the quality evaluation standard database 126 stores the reference value of the quality evaluation index in association with information that identifies the gene panel.

If the type of gene panel in S35 is panel A, for example, quality evaluation index A is judged using standard value a, and quality evaluation index B is judged using standard value b. On the other hand, if the type of gene panel in S35 is panel B, quality evaluation index A is judged using standard value c, and quality evaluation index B is judged using standard value b. In this way, the same quality control index A is used in the analysis of panel A and the analysis of panel B, but different evaluation standards are used. Also, quality control indexes A and B are used in the analysis of panel A, while quality control indexes A and C are used in the analysis of panel B, so different quality control indexes are used.

Furthermore, if the type of gene panel is C panel in S35, the quality evaluation index D is judged using the reference value e. In this way, in the analysis of the A panel, the quality evaluation is performed based on two indexes, quality evaluation index A and B, but in the analysis of the C panel, the quality evaluation is performed using only quality evaluation index D. In this way, the number of quality evaluation indexes used may be changed depending on the gene panel.

Finally, in S36, the genetic analysis device 1d creates a report including the identified mutations and the evaluation results of the quality of the panel test determined in step S34.

Figure 46 is a diagram showing an example of a report created by the report creation unit 115. The upper left part of the report shown in this example lists a "Patient ID" indicating the subject ID, "Patient's Gender", "Patient's Disease Name", "Name of Doctor in Charge" which is the name of the doctor in charge of the subject at the medical institution 210, and "Institution Name" indicating the name of the medical institution.

Below that, the name of the gene panel, "Panel A," is included as information about the gene panel. In addition, the quality assessment index "QC index," which is information about the quality of the panel test, is output to the report.

If the quality assessment index falls below a certain standard, the detected gene mutation can be marked with an "*". In addition, a comment indicating low reliability can be added.

The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. The technical scope of the present invention also includes embodiments obtained by appropriately combining the technical means disclosed in different embodiments.

(Additional Note 1)
The present invention also includes the following aspects.

A genetic analysis method according to one aspect of the present invention is a genetic analysis method for analyzing gene sequence information, which obtains lead sequence information read by a sequencer (2) and information about a gene panel including a plurality of genes to be analyzed, and outputs an analysis result of the lead sequence information based on the obtained information about the gene panel.

According to this aspect, the analysis results of the read sequence information are output based on the information on the acquired gene panel. With this aspect, for example, a user who performs a panel test can obtain an output according to the gene panel when analyzing various combinations of target genes using various gene panels, thereby improving user convenience.

"Gene" includes the sequence on the genome from the start codon to the stop codon, the mRNA generated from the sequence on the genome, and the promoter region on the genome. Genes to be analyzed include mRNA transcribed from genes on the genome. mRNA includes pre-mRNA.

"Lead sequence" refers to the polynucleotide sequence obtained by sequencing, and "read sequence information" refers to the information of the lead sequence output by sequencer 2.

"Gene panel" means a reagent kit for analyzing multiple analysis targets by performing a series of analysis processes once (one run). In many cases, a gene panel includes a set of reagents such as primers and probes. Here, "multiple analysis targets" may be multiple gene sequences or multiple exons of a gene. For example, a reagent kit for analyzing the sequence of gene A and the sequence of gene B, a reagent kit for analyzing the sequence of exon 1 of gene A and the sequence of exon 2 of the same gene, etc. are included. A more specific example of a gene panel is a reagent kit for analyzing multiple gene sequences related to a specific disease. When using this gene panel, it is possible to analyze amplification, sequence substitution, deletion, insertion, methylation of promoter regions, fusion genes, etc. of one or multiple genes that are important in diagnosis. A gene panel includes multiple genes as analysis targets. For example, a large panel with 100 or more genes to be analyzed can be used as a gene panel.

"Information about the gene panel" may be any information that can be used to identify the gene panel, such as the name of the gene panel and the names of the genes to be analyzed in the panel test.

In one embodiment of the genetic analysis method of the present invention, the genes to be output as analysis results may be changed based on the information about the acquired gene panel.

This aspect allows the gene panel to output analysis results for the genes that it is analyzing.

The genetic analysis method according to one embodiment of the present invention may change the analysis algorithm for analyzing the genes for which the analysis results are to be output, based on the acquired information about the gene panel.

In this manner, when analyzing the genes targeted by the gene panel, it is not necessary to set an analysis program to be used for each gene.

The genetic analysis method according to one aspect of the present invention may display an input screen on the display unit (16) for inputting information in which multiple genes are associated with each other as information related to the genetic panel.

The genetic analysis method according to one embodiment of the present invention may display an input screen on the display unit (16) for selecting at least one piece of information from information relating to a plurality of gene panels.

The genetic analysis method according to one embodiment of the present invention may display an input screen on the display unit (16) for inputting the name of the reagent kit as information related to the genetic panel.

The genetic analysis method according to one embodiment of the present invention may display an input screen on the display unit (16) for inputting multiple genes to be analyzed as information related to the genetic panel.

The genetic analysis method according to one embodiment of the present invention may display an input screen on the display unit (16) for inputting the disease to be analyzed as information related to the genetic panel.

A genetic analysis method according to one aspect of the present invention may select reference sequence information to be compared with the lead sequence information based on information about the acquired gene panel, and output an analysis result based on a comparison between the lead sequence information and the selected reference sequence information.

A "reference sequence" is a sequence to which a read sequence is mapped in order to determine which region of a gene the read sequence corresponds to and which mutation in the gene the read sequence corresponds to. Also, "mapping" refers to the process of aligning each read sequence to the target reference sequence. Specifically, the intention is to find a region in the reference genome sequence that has a sequence identical or similar to the read read sequence, and to assign the read sequence to that region.

A genetic analysis method according to one aspect of the present invention may select reference sequence information to be compared with the lead sequence information from a plurality of reference sequence information including mutant sequences based on information related to the acquired gene panel, and output an analysis result based on the selected reference sequence.

"Mutation" refers to at least one of the following mutations: genetic polymorphism, substitution, and InDel. "InDel (insertion and/or deletion)" refers to a mutation that includes an insertion, deletion, or both an insertion and deletion. Genetic "polymorphism" includes SNV (Single Nucleotide Variant), VNTR (Variable Nucleotide of Tandem Repeat), and STRP (Short Tandem Repeat Polymorphism, microsatellite polymorphism).

The genetic analysis method according to one embodiment of the present invention may output the analysis results of the read sequence information using a genetic panel related information database (121) that stores, for each genetic panel, information on the genes to be analyzed in the genetic panel.

A genetic analysis method according to one aspect of the present invention may read a selected reference sequence from a reference sequence database (122) and perform alignment by mapping read sequence information to the read reference sequence.

A genetic analysis method according to one aspect of the present invention may read a selected reference sequence from a reference sequence database, determine the position of the read sequence information based on the degree of match between the reference sequence and the read sequence information, and identify mutations contained in the read sequence information.

The genetic analysis method according to one aspect of the present invention may output an analysis result including information about mutations identified by the analysis of the lead sequence information that are associated with information about the acquired gene panel.

The genetic analysis method according to one aspect of the present invention may output, based on the acquired information on the gene panel, drug information related to the mutation identified by the analysis of the lead sequence information as a result of the analysis of the lead sequence information.

The genetic analysis method according to one aspect of the present invention may search a drug database (124) that stores a correspondence between a mutation in a gene to be analyzed and a drug related to a gene panel, based on a mutation identified by analysis of lead sequence information.

The genetic analysis method according to one embodiment of the present invention may generate a list of drugs associated with the mutations identified by the analysis of the lead sequence information extracted in the search of the drug database (124).

The genetic analysis method according to one embodiment of the present invention may generate a list of drugs associated with the mutations identified by the analysis of the lead sequence information extracted in the search of the drug database (124).

The genetic analysis method according to one aspect of the present invention may output drug information including the approval status of the drug as a result of the analysis of the lead sequence information.

The genetic analysis method according to one aspect of the present invention may search a reference database (125) that stores the mutations of the gene to be analyzed in association with reference information related to the mutations, based on the mutations identified by the analysis of the lead sequence information.

A genetic analysis method according to one embodiment of the present invention creates a report based on the analysis results of the lead sequence information, and the report may include information regarding mutations identified by the analysis of the lead sequence information that correspond to information related to the obtained gene panel.

A genetic analysis method according to one aspect of the present invention may select, from among all identified mutations, a mutation that corresponds to the acquired information on the gene panel based on the information on the gene panel, and output information related to the selected mutation as an analysis result of the lead sequence information.

In a genetic analysis method according to one aspect of the present invention, the report may include information related to the genetic panel.

In a genetic analysis method according to one embodiment of the present invention, the report may include at least one of a list of drugs and reference information.

The genetic analysis method according to one aspect of the present invention may transmit information regarding the analysis status of the genetic sequence information to a management server (3).

The genetic analysis method according to one aspect of the present invention may transmit information regarding the analysis status of gene sequence information to a management server (3) for each piece of information related to a gene panel.

The genetic analysis method according to one embodiment of the present invention may transmit the number of gene sequence analyses to the management server (3) for each piece of information related to the genetic panel.

The genetic analysis method according to one embodiment of the present invention may transmit the number of analyzed genes for each piece of information related to the genetic panel to the management server (3).

The genetic analysis method according to one embodiment of the present invention may transmit information regarding the amount of data processed in the genetic sequence analysis to the management server (3) for each piece of information regarding the genetic panel.

The genetic analysis method according to one aspect of the present invention may output a comparison result between the lead sequence information and sequence information of the genes to be analyzed by the genetic panel associated with the acquired information on the genetic panel as an analysis result of the lead sequence information.

The genetic analysis method according to one embodiment of the present invention may display an error if the acquired information on the genetic panel is not registered.

For example, when information on an acquired gene panel is not registered in a gene panel related information database (121) or the like, performing an analysis using that gene panel may result in an inappropriate analysis result. According to this embodiment, it is possible to prevent the output of inappropriate results or the execution of unnecessary analysis using an unregistered gene panel.

The genetic analysis method according to one embodiment of the present invention may display an error if the acquired information on the genetic panel is not that specified by the medical institution (210).

A genetic analysis method according to one embodiment of the present invention may permit analysis of a genetic panel if, after an error is displayed, a user input is made requesting permission to use the genetic panel.

The genetic analysis method according to one embodiment of the present invention may prohibit analysis of the genetic panel if the acquired information on the genetic panel is not registered.

The genetic analysis method according to one embodiment of the present invention may prohibit analysis of the genetic panel if the acquired information on the genetic panel is not that specified by the medical institution (210).

In a genetic analysis method according to one embodiment of the present invention, the step of acquiring information about a gene panel may have multiple modes, and any one of the multiple modes may be selectable.

The genetic analysis method according to one aspect of the present invention may display an error if a predetermined number or more of the lead sequence information includes a gene sequence that is not the subject of analysis of the genetic panel indicated by the acquired information on the genetic panel.

In a genetic analysis method according to one aspect of the present invention, the lead sequence information may include an index sequence associated with information related to the gene panel.

In a genetic analysis method according to one embodiment of the present invention, the index sequence may be different for each piece of information related to the gene panel.

In a genetic analysis method according to one aspect of the present invention, an error may be displayed when information about a gene panel associated with an index sequence included in the lead sequence information differs from information about the acquired gene panel.

The first read sequence information read for the first sample using a first gene panel for analyzing a first group of genes to be analyzed may be analyzed, and the second read sequence information read for the second sample using a second gene panel for analyzing a second group of genes to be analyzed may be analyzed. Information regarding the gene panel may be obtained by accepting a selection of information identifying the gene panel, and the analysis results of the first read sequence information and the analysis results of the second read sequence information may be output based on the information regarding the selected gene panel.

The term "specimen" can be used interchangeably with specimen or sample, and is used synonymously with specimen and preparation in the art, and refers to any specimen or preparation obtained from a biological material source (e.g., an individual, a body fluid, a cell line, a tissue culture, or a tissue section).

The genetic analysis method according to one embodiment of the present invention further includes a step of evaluating the quality of the genetic panel test, and in the step of outputting the analysis results, the quality evaluation results may be output based on the acquired information about the genetic panel.

This aspect allows appropriate quality control to be performed according to the gene panel when analyzing various combinations of target genes using various gene panels.

"Quality assessment index" is an index for evaluating the quality of a gene panel test, and examples of such indexes include the reading quality contained in the read sequence information output by the sequencer (2), the proportion of bases read by the sequencer (2) among the bases contained in the multiple genes to be analyzed, the reading depth of the read sequence information, the variability of the reading depth of the read sequence information, and whether or not all mutations in each standard gene contained in the quality control sample were detected.

In one embodiment of the genetic analysis method of the present invention, in the step of evaluating the quality of a genetic panel test, a quality control index to be used in evaluating the quality may be selected based on the acquired information about the genetic panel.

In one embodiment of the genetic analysis method of the present invention, in the step of evaluating the quality of a genetic panel test, an evaluation criterion for the quality control index to be used in evaluating the quality may be selected based on the acquired information about the genetic panel.

In one embodiment of the genetic analysis method of the present invention, in the step of evaluating the quality of a genetic panel test, the number of quality control indicators to be used in evaluating the quality may be selected based on the acquired information about the genetic panel.

A genetic analysis device (1) according to one embodiment of the present invention is a genetic analysis device (1) that analyzes gene sequence information, and includes a control unit (11) that acquires lead sequence information read by a sequencer (2) and information about a gene panel including a plurality of genes to be analyzed, and an output unit (13), and the control unit (11) outputs the analysis result of the lead sequence information to the output unit (13) based on the acquired information about the gene panel.

According to this aspect, the genetic analysis device (1) outputs the analysis results of the read sequence information based on the information on the acquired genetic panel. With this aspect, a user who performs a panel test can obtain an output according to the genetic panel used when analyzing genes using various genetic panels, thereby improving user convenience.

In a genetic analysis device (1) according to one embodiment of the present invention, the control unit (11) may select reference sequence information to be compared with the lead sequence information based on the acquired information on the gene panel, and output an analysis result based on a comparison between the lead sequence information and the selected reference sequence information to the output unit (13).

In a genetic analysis device (1) according to one aspect of the present invention, the control unit (11) may output to the output unit (13) an analysis result including information on a mutation identified by the analysis of the lead sequence information and associated with information on the acquired gene panel.

In a genetic analysis device (1) according to one embodiment of the present invention, the control unit (11) may output, to the output unit (13), drug information related to the mutation identified by the analysis of the lead sequence information as a result of the analysis of the lead sequence information, based on the acquired information on the gene panel.

In a genetic analysis device (1) according to one embodiment of the present invention, the control unit (11) may output an evaluation result of the quality of the genetic panel test to the output unit (13) based on the acquired information about the genetic panel.

A management server (3) according to one embodiment of the present invention receives information from a genetic analysis device (1) including information identifying a user performing genetic sequence analysis, information regarding the genetic panel used, and information regarding the analysis status of the sequence information.

The "information on the analysis status of sequence information" may be, for example, the number of sequence analyses performed using a specified gene panel in the genetic analysis device 1, the number of genes analyzed, or the cumulative number of identified mutations. Alternatively, it may be information on the amount of data processed in the analysis.

The management server (3) according to one embodiment of the present invention may receive information regarding the analysis status of gene sequence information from the gene analysis device (1).

The management server (3) according to one embodiment of the present invention may receive information on the analysis status of gene sequence information from the gene analysis device (1) for each piece of information on a gene panel.

The management server (3) according to one embodiment of the present invention may receive the number of gene sequence analyses from the genetic analysis device (1) for each piece of information related to the gene panel.

The management server (3) according to one embodiment of the present invention may receive the number of analyzed genes for each piece of information related to the gene panel from the genetic analysis device (1).

The management server (3) according to one embodiment of the present invention may receive information regarding the amount of data processed in the gene sequence analysis from the gene analysis device (1) for each piece of information regarding a gene panel.

The management server (3) according to one embodiment of the present invention may calculate the fee when a user performs sequence analysis using the gene analysis device (1) based on information regarding the analysis status of the gene sequence information.

The management server (3) according to one embodiment of the present invention may receive a request to update information about a gene panel from the genetic analysis device (1).

A genetic analysis system (100) according to one embodiment of the present invention includes a genetic analysis device (1) including a control unit (11) that acquires lead sequence information read by a sequencer (2) and information on a genetic panel including a plurality of genes to be analyzed, and an output unit (13) that outputs an analysis result of the lead sequence information based on the information on the genetic panel acquired by the control unit (11), and a management server (3) that receives information including information identifying a user who performs genetic sequence analysis, information on the genetic panel used, and information on the analysis status of the genetic sequence from the genetic analysis device (1) via a network (4).

According to this aspect, the genetic analysis device (1) outputs the analysis results of the read sequence information based on the acquired information on the genetic panel. Meanwhile, the management server (3) receives information from the genetic analysis device (1) including information identifying the user performing the genetic sequence analysis, information on the genetic panel used, and information on the analysis status of the genetic sequence.

With this aspect, for example, a user who performs a panel test can obtain an output according to the gene panel used when analyzing various combinations of genes using various gene panels, thereby improving convenience. Furthermore, the management server (3) can confirm and manage the analysis results of the analysis performed by the user using the gene analysis device (1). Therefore, for example, the fee for using the gene analysis system (100) can be appropriately determined and charged to the user.

The genetic analysis system (100) according to one aspect of the present invention may calculate the fee when a user performs sequence analysis using the genetic analysis device based on information regarding the analysis status of the genetic sequence information.

The genetic analysis device (1) according to each aspect of the present invention may be realized by a computer. In this case, the present invention also includes a program for realizing the genetic analysis device (1) on a computer by making the computer operate as each unit (software element) of the genetic analysis device (1), and a computer-readable recording medium on which the program is recorded.

A program according to one aspect of the present invention is a program for analyzing gene sequence information, and causes a computer to execute the steps of acquiring lead sequence information read by a sequencer and information about a gene panel including a plurality of genes to be analyzed, and outputting an analysis result of the lead sequence information based on the acquired information about the gene panel.

This aspect provides the same effects as the genetic analysis method according to one aspect of the present invention.

A recording medium according to one aspect of the present invention is a computer-readable recording medium on which a program according to one aspect of the present invention is recorded.

A genetic analysis method according to one aspect of the present invention is a method for analyzing gene sequence information, which acquires lead sequence information read by a sequencer (2) and information on a gene panel including a plurality of genes to be analyzed, and outputs an analysis result of the lead sequence information based on the acquired information on the gene panel, and displays an error if the acquired information on the gene panel is not registered.

A genetic analysis method according to one aspect of the present invention is a method for analyzing gene sequence information, which acquires lead sequence information read by a sequencer (2) and information on a gene panel including a plurality of genes to be analyzed, and outputs an analysis result of the lead sequence information based on the acquired information on the gene panel, and displays an error if the acquired information on the gene panel is not that specified by a medical institution (210).

(Additional Note 2)
The present invention also includes the following aspects.

A genetic analysis method according to one aspect of the present invention is a genetic analysis method performed by a genetic analysis device that analyzes gene sequence information, the genetic analysis device being capable of analyzing multiple cancer gene panels, acquiring lead sequence information read by a sequencer and information about a cancer gene panel for selecting, from the multiple cancer gene panels, one analysis panel including multiple genes to be output as the analysis results, and outputting the analysis results of the lead sequence information using an analysis algorithm for analyzing the multiple genes to be output as the analysis results, based on the acquired information about the cancer gene panel.

A genetic analysis device according to one aspect of the present invention is a genetic analysis device that analyzes gene sequence information, is capable of analyzing multiple cancer gene panels, and includes a control unit that acquires lead sequence information read by a sequencer and information about a cancer gene panel for selecting, from the multiple cancer gene panels, one analysis panel including multiple genes to be output as the analysis results, and an output unit. The control unit outputs the analysis results of the lead sequence information to the output unit using an analysis algorithm for analyzing the multiple genes to be output as the analysis results, based on the acquired information about the cancer gene panel.

A genetic analysis system according to one aspect of the present invention includes a genetic analysis device including a control unit that acquires information about a cancer gene panel for selecting an analysis panel including a plurality of genes to be output from the lead sequence information read by a sequencer and a plurality of cancer gene panels, and an output unit that outputs an analysis result of the lead sequence information based on the information about the cancer gene panel acquired by the control unit, and a management server that receives information from the genetic analysis device including information identifying a user who performs gene sequence analysis, information about the cancer gene panel used, and information about the analysis status of the gene sequence, and the genetic analysis device is capable of analyzing the plurality of cancer gene panels, and the control unit outputs the analysis result of the lead sequence information to the output unit using an analysis algorithm for analyzing the plurality of genes to be output from the analysis result based on the information about the cancer gene panel acquired.

A program according to one aspect of the present invention is a program for analyzing gene sequence information, and causes a computer capable of analyzing multiple cancer gene panels to execute the steps of acquiring lead sequence information read by a sequencer and information about a cancer gene panel for selecting, from the multiple cancer gene panels, an analysis panel including multiple genes to be output as analysis results, and outputting an analysis result of the lead sequence information using an analysis algorithm for analyzing the multiple genes to be output as analysis results, based on the acquired information about the cancer gene panel.

A genetic analysis method according to one aspect of the present invention is a genetic analysis method performed by a genetic analysis device that analyzes gene sequence information, which acquires lead sequence information read by a sequencer and information on a cancer gene panel for selecting, from a plurality of cancer gene panels, one analysis panel including a plurality of genes for which analysis results are to be output, and outputs an analysis result of the lead sequence information using an analysis algorithm for analyzing the plurality of genes for which analysis results are to be output based on the acquired information on the cancer gene panel, and displays an error if the acquired information on the cancer gene panel is not registered.

A genetic analysis method according to one aspect of the present invention is a genetic analysis method performed by a genetic analysis device that analyzes gene sequence information, which acquires lead sequence information read by a sequencer and information on a cancer gene panel for selecting, from a plurality of cancer gene panels, one analysis panel including a plurality of genes for which analysis results are to be output, and outputs an analysis result of the lead sequence information using an analysis algorithm for analyzing the plurality of genes for which analysis results are to be output based on the acquired information on the cancer gene panel, and displays an error if the acquired information on the cancer gene panel is not that specified by a medical institution.

REFERENCE SIGNS LIST 1, 1a, 1b, 1c, 1d Genetic analysis device 2 Sequencer 3 Management server 4 Network 11, 11a, 11b, 11c, 11d Control unit 13 Output unit 16 Display unit 100 Genetic analysis system 121, 121c Gene panel related information database 122 Reference sequence database 124 Drug database 125 Reference database

Claims (11)

A method for analyzing a plurality of genes by a genetic analysis device that analyzes sequence information of a plurality of genes, comprising:
Obtaining read sequence information read by a sequencer and information on a gene panel for identifying a gene panel;
Based on the acquired information on the gene panel, one analysis panel including a plurality of genes to be output as analysis results is selected from the plurality of gene panels, and the read sequence information is analyzed;
outputting the analysis results of the read sequence information;
Analyzing the read sequence information includes:
selecting reference sequence information to be compared with the lead sequence information from among a plurality of reference sequence information based on the acquired information on the gene panel, and extracting mutations contained in the lead sequence information based on a comparison between the lead sequence information and the selected reference sequence information;
The analysis result of the lead sequence information includes information regarding the extracted mutation,
The information about the mutation includes information indicating the extracted position of the mutation and the base after the mutation.
A genetic analysis method comprising: Analyzing the read sequence information includes:
extracting a mutation contained in the lead sequence information, and obtaining drug information related to the extracted mutation based on the obtained information on the gene panel;
The gene analysis method according to claim 1 , wherein the analysis result of the lead sequence information includes the acquired drug information. The gene analysis method according to claim 2 , wherein the drug information includes information indicating a type of drug and an approval status of the drug. The gene analysis method according to claim 3 , wherein the drug information includes information indicating an approval status of the drug by country. The genetic analysis method according to claim 1 , further comprising displaying an input screen for inputting information regarding the gene panel. A gene analysis device that analyzes sequence information of a plurality of genes,
a control unit that acquires read sequence information read by the sequencer and information related to the gene panel for identifying the gene panel;
An output unit,
The control unit is
Selecting one analysis panel including a plurality of genes to be output as analysis results from the plurality of gene panels;
Analyzing the lead sequence information based on the acquired information on the gene panel, and outputting an analysis result of the lead sequence information to the output unit;
Analyzing the read sequence information includes:
selecting reference sequence information to be compared with the lead sequence information from among a plurality of reference sequence information based on the acquired information on the gene panel, and extracting mutations contained in the lead sequence information based on a comparison between the lead sequence information and the selected reference sequence information;
The analysis result of the lead sequence information includes information regarding the extracted mutation,
The information about the mutation includes information indicating the extracted position of the mutation and the base after the mutation.
A genetic analysis device characterized by: Analyzing the read sequence information includes:
extracting a mutation contained in the lead sequence information, and obtaining drug information related to the extracted mutation based on the obtained information on the gene panel;
The gene analysis device according to claim 6 , wherein the analysis result of the lead sequence information includes the acquired drug information. The genetic analysis device according to claim 7 , wherein the drug information includes information indicating a type of drug and an approval status of the drug. The genetic analysis device according to claim 8 , wherein the drug information includes information indicating an approval status of the drug by country. The genetic analysis device according to claim 6 , further comprising an input unit that displays an input screen for inputting information about the gene panel. Further comprising a storage unit for storing the plurality of reference sequence information,
The genetic analysis device according to claim 6 , wherein the control unit selects reference sequence information to be compared with the read sequence information from the plurality of pieces of reference sequence information stored in the storage unit.

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