WO2019083024A1 - Méthode d'analyse génétique, analyseur de gène, serveur de gestion, système, programme et support d'enregistrement d'analyse génétique - Google Patents

Méthode d'analyse génétique, analyseur de gène, serveur de gestion, système, programme et support d'enregistrement d'analyse génétique

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Publication number
WO2019083024A1
WO2019083024A1 PCT/JP2018/039963 JP2018039963W WO2019083024A1 WO 2019083024 A1 WO2019083024 A1 WO 2019083024A1 JP 2018039963 W JP2018039963 W JP 2018039963W WO 2019083024 A1 WO2019083024 A1 WO 2019083024A1
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WO
WIPO (PCT)
Prior art keywords
gene
information
analysis
panel
sequence
Prior art date
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PCT/JP2018/039963
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English (en)
Japanese (ja)
Inventor
二三夫 井上
誓吾 鈴木
鈴木　健一郎
Original Assignee
シスメックス株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2018201317A external-priority patent/JP7320345B2/ja
Application filed by シスメックス株式会社 filed Critical シスメックス株式会社
Priority to EP18869832.8A priority Critical patent/EP3702473A4/fr
Priority to CN201880069344.4A priority patent/CN111263964A/zh
Publication of WO2019083024A1 publication Critical patent/WO2019083024A1/fr
Priority to US16/855,239 priority patent/US20200350035A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B99/00—Subject matter not provided for in other groups of this subclass

Definitions

  • the present invention relates to a gene analysis method, a gene analysis device, a management server, a gene analysis system, a program, and a recording medium implemented by a computer to analyze gene mutations.
  • a panel test which analyzes an abnormality in a specific gene associated with a specific disease or an abnormality in an exon region translated into a protein at high throughput using a next-generation sequencer There is.
  • Patent Document 1 it is determined whether a gene or the like is abnormal as compared to a reference sequence, and a drug therapy used corresponding to the gene or the like showing an abnormality is identified, and treatment is performed according to the subject. A system for determining the method is described.
  • the user performing the panel test needs to prepare a dedicated analysis program to be used for gene analysis by the sequencer for each panel according to the gene to be tested and the request, and perform gene analysis.
  • One aspect of the present invention is a user-friendly gene analysis method, a gene analysis device, a management server, a gene analysis system, etc. which can be applied to various gene panels when analyzing genes to be analyzed using the gene panel Aims to achieve
  • a gene analysis method for analyzing sequence information of a gene, comprising: lead sequence information read by a sequencer (2); And information on a gene panel including a plurality of genes, and an analysis result of lead sequence information is output based on the acquired information on the gene panel.
  • the analysis result of the lead sequence information is output based on the acquired information on the gene panel.
  • the output according to the gene panel can be obtained, thereby improving user convenience. Do.
  • the “gene” includes a sequence on the genome from the start codon to the stop codon, an mRNA generated from the sequence on the genome, a promoter region on the genome, and the like. Genes to be analyzed include mRNA transcribed from genes on the genome. mRNA includes pre-mRNA.
  • the “lead sequence” means a polynucleotide sequence obtained by sequencing, and the “lead sequence information” refers to the information of the lead sequence outputted by the sequencer 2.
  • the "gene panel” means a reagent kit for analyzing a plurality of analysis objects by performing a series of analysis processes once (one run). Gene panels often contain a complete set of reagents such as primers and probes.
  • a plurality of analysis targets may be a plurality of gene sequences or a plurality of exons of a certain gene.
  • 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, and the like are included.
  • a more specific example of the gene panel includes a reagent kit for analyzing a plurality of gene sequences related to a specific disease.
  • the gene panel When this gene panel is used, amplification of one or more genes that are important for medical treatment, substitution of sequences, deletion, insertion, methylation of promoter region, fusion genes, and the like can be analyzed.
  • the gene panel contains a plurality of genes to be analyzed. As the gene panel, for example, a large panel of 100 or more genes to be analyzed can be used.
  • the “information on gene panel” may be any information that can be used to specify a gene panel, and may be, for example, a gene panel name and a name of a gene to be analyzed in panel inspection.
  • the target gene of the analysis result may be changed based on the information on the acquired gene panel.
  • an analysis algorithm for analyzing a gene as an output target of the analysis result may be changed.
  • an analysis program used for analysis may not be set for each gene.
  • An input screen for inputting information in which a plurality of genes are associated as information on a gene panel may be displayed on the display unit (16).
  • An input screen for selecting at least one piece of information from a plurality of gene panels may be displayed on the display unit (16).
  • An input screen for inputting the reagent kit name as information on the gene panel may be displayed on the display unit (16).
  • An input screen for inputting a plurality of genes to be analyzed as information on a gene panel may be displayed on the display unit (16).
  • An input screen for inputting a disease to be analyzed as information on a gene panel may be displayed on the display unit (16).
  • reference sequence information to be compared with the read sequence information may be selected, and an analysis result based on a comparison between the read sequence information and the selected reference sequence information may be output.
  • the “reference sequence” is a sequence to which the lead sequence is to be mapped in order to determine which region on the gene the lead sequence corresponds to, which mutation the lead sequence corresponds to the gene, etc. .
  • “mapping” means a process of aligning each read sequence to a target reference sequence. Specifically, it is intended to find a region having the same or similar sequence as the read sequence read in the genome sequence to be referred, and assign the read sequence to the region.
  • the reference sequence information to be compared with the lead sequence information is selected from a plurality of reference sequence information including the mutant sequence, and the analysis result based on the selected reference sequence is You may output it.
  • “Mutation” means polymorphism, substitution and / or mutation such as InDel of a gene.
  • InDel Insertion and / or Deletion
  • “Polymorphism” of a gene includes SNV (Single Nucleotide Variant, single nucleotide polymorphism), VNTR (Variable Nucleotide of Tandem Repeat, repeat sequence polymorphism), STRP (Short Tandem Repeat Polymorphism, microsatellite polymorphism), etc. .
  • the analysis result of the lead sequence information may be output using a gene panel related information database (121) that stores information on genes to be analyzed in the gene panel for each gene panel.
  • Alignment may be performed by reading the selected reference sequence from the reference sequence database (122) and mapping the read sequence information to the read reference sequence.
  • the selected reference sequence may be read from the reference sequence database, the position of the read sequence information may be determined based on the degree of matching between the reference sequence and the read sequence information, and the mutations included in the read sequence information may be identified.
  • an analysis result including information on the mutations associated with the acquired information on the gene panel may be output.
  • drug information related to the mutation identified by the analysis of the lead sequence information may be output as the analysis result of the lead sequence information.
  • a drug database (124) may be searched in which mutations of genes to be analyzed and drugs related to the gene panel are associated and stored.
  • a list of agents associated with the mutations identified by analysis of the lead sequence information, extracted in a search of the agent database (124) may be generated.
  • a list of agents associated with the mutations identified by analysis of the lead sequence information, extracted in a search of the agent database (124) may be generated.
  • drug information including the approval status of the drug may be output.
  • a reference database (125) may be searched, which stores the mutations of the gene to be analyzed and the reference information related to the mutations in association.
  • a report is prepared, and the report may include information on mutations among the mutations identified by the analysis of the lead sequence information, which correspond to the information related to the acquired gene panel. Good.
  • a mutation corresponding to the information on the acquired gene panel is selected based on the information on the gene panel, and information associated with the selected mutation is obtained as an analysis result of the lead sequence information. You may output it.
  • the report may include information related to the gene panel.
  • the report may include at least one of a drug list and reference information.
  • Information on the analysis status of gene sequence information may be transmitted to the management server (3).
  • Information on the analysis status of gene sequence information may be transmitted to the management server (3) for each information on the gene panel.
  • the number of gene sequence analyzes may be transmitted to the management server (3) for each information on the gene panel.
  • the number of analyzed genes may be transmitted to the management server (3) for each information on the gene panel.
  • Information on the amount of data processed in gene sequence analysis may be sent to the management server (3) for each information on the gene panel.
  • a comparison result of comparison between the lead sequence information and the sequence information of the gene to be analyzed by the gene panel associated with the acquired information on the gene panel may be output as an analysis result of the lead sequence information.
  • An error may be displayed if the acquired information on the gene panel is not registered.
  • An error may be displayed if the information on the acquired gene panel is not specified from the medical institution (210).
  • analysis of the gene panel may be permitted if the user inputs permission to use the gene panel.
  • Analysis of the gene panel may be prohibited if the acquired information on the gene panel is not registered.
  • the analysis of the gene panel may be prohibited if the information on the acquired gene panel is not specified from the medical institution (210).
  • any of the plurality of modes may be selectable.
  • An error may be displayed when the number of pieces of lead sequence information including the sequences of genes not to be analyzed among the pieces of lead sequence information indicated by the information on the acquired gene panel is equal to or more than a predetermined number.
  • the lead sequence information may include an index sequence associated with the information on the gene panel.
  • the index sequence may be different for each information on the gene panel.
  • An error may be displayed when the information on the gene panel associated with the index sequence included in the lead sequence information is different from the information on the acquired gene panel.
  • first read sequence information read using the first gene panel for analyzing the first analysis target gene group is analyzed
  • second analysis target gene group is analyzed
  • the result and the analysis result obtained by analyzing the second read sequence information may be output based on the information on the selected gene panel.
  • sample can also be used as a specimen or a sample, and is used in the same sense as a specimen or preparation in the art, and a biological material as a source (eg, an individual, a body fluid, a cell line, a tissue culture or a tissue section) Any preparations or preparations obtained from) are contemplated.
  • a biological material eg, an individual, a body fluid, a cell line, a tissue culture or a tissue section
  • the method may further include the step of evaluating the quality of the gene panel test, and in the step of outputting the analysis result, the evaluation result of quality may be output based on the information on the acquired gene panel.
  • the “quality evaluation index” is an index for evaluating the quality of gene panel test, and, for example, the reading quality included in the lead sequence information output by the sequencer (2) and the bases among the genes included in the plurality of genes to be analyzed was the ratio of bases read by the sequencer (2), the read depth of the read sequence information (depth), the variation of the read depth of the read sequence information (depth), or all mutations of each standard gene included in the quality control sample detected? Indicators such as whether or not.
  • a quality control index to be used in evaluating the quality may be selected based on the acquired information on the gene panel.
  • the evaluation criteria of the quality control index used in evaluating the quality may be selected.
  • the number of quality control indicators to be used in evaluating the quality may be selected based on the acquired information on the gene panel.
  • a gene analysis device (1) is a gene analysis device (1) for analyzing sequence information of a gene, and a read by a sequencer (2)
  • the gene analysis device (1) outputs the analysis result of the lead sequence information based on the acquired information on the gene panel. According to this aspect, when the user performing the panel test analyzes the gene using various gene panels, the output according to the gene panel to be used can be obtained, thereby improving the convenience of the user.
  • the control unit (11) selects reference sequence information to be compared with the read sequence information based on the acquired information on the gene panel, and analyzes based on comparison between the read sequence information and the selected reference sequence information. The result may be output to the output unit (13).
  • control unit (11) outputs, to the output unit (13), an analysis result including information on the mutations associated with the acquired information on the gene panel. Good.
  • the control unit (11) outputs the drug information related to the mutation identified by the analysis of the lead sequence information to the output unit (13) as an analysis result of the lead sequence information based on the acquired information on the gene panel. May be
  • the control unit (11) may output the evaluation result of the quality of the gene panel test to the output unit (13) based on the acquired information on the gene panel.
  • the management server (3) is information for specifying a user who performs gene sequence analysis, information on a gene panel used, and analysis status of the sequence information And information including the information on the information from the gene analysis device (1).
  • the “information regarding the analysis status of sequence information” may be, for example, the number of times of sequence analysis in which analysis using a predetermined gene panel is performed in the gene analysis device 1, or the number of analyzed genes. It may be a total such as the number of mutations identified. Alternatively, it may be information on the amount of data processed in the analysis.
  • the management server (3) may receive, from the gene analysis device (1), information on the analysis state of the sequence information of the gene.
  • the management server (3) may receive, from the gene analysis device (1), information on the analysis status of the sequence information of the gene for each information on the gene panel.
  • the management server (3) may receive the number of times of sequence analysis of the gene from the gene analysis device (1) for each information on the gene panel.
  • the management server (3) may receive the number of analyzed genes from the gene analysis device (1) for each information related to the gene panel.
  • the management server (3) may receive information on the amount of data processed in the sequence analysis of the gene from the gene analysis device (1) for each information on the gene panel.
  • the management server (3) may calculate the value when the user performs sequence analysis using the gene analysis device (1), based on the information on the analysis status of the gene sequence information.
  • the management server (3) may receive an update request for information on the gene panel from the gene analysis device (1).
  • a gene analysis system (100) comprises: information on a gene panel including lead sequence information read by a sequencer (2) and a plurality of genes to be analyzed
  • a gene analysis device (1) comprising: a control unit (11) for acquiring data; and an output unit (13) for outputting an analysis result of lead sequence information based on the information on the gene panel acquired by the control unit (11)
  • the information from the gene analyzer (1) to the network (4) including information specifying the user performing gene sequence analysis, information on the gene panel used, and information on the analysis status of gene sequences.
  • a management server (3) to receive the information.
  • the gene analysis device (1) outputs the analysis result of the lead sequence information based on the acquired information on the gene panel.
  • the management server (3) includes, from the gene analysis device (1), information specifying the user performing gene sequence analysis, information on the gene panel used, and information on the analysis status of the gene sequence Receive information
  • the management server (3) can confirm and manage the analysis result of the analysis performed by the user using the gene analysis device (1). Therefore, for example, consideration such as the fee for using the gene analysis system (100) can be appropriately determined and charged to the user.
  • the value when the user performs sequence analysis using the gene analysis device may be calculated based on the information on the analysis status of the sequence information of the gene.
  • the gene analysis device (1) may be realized by a computer, and in this case, the gene analysis is performed by operating the computer as each portion (software element) included in the gene analysis device (1).
  • a program for realizing the device (1) by a computer, and a computer readable recording medium recording the same also fall within the scope of the present invention.
  • a program is a program for analyzing sequence information of a gene, and a computer is provided with read sequence information read by a sequencer and a plurality of analysis targets. It is a program for executing a step of acquiring information on a gene panel including a gene and a step of outputting an analysis result of lead sequence information based on the acquired information on the gene panel.
  • a recording medium according to an aspect of the present invention is a computer readable recording medium on which a program according to an aspect of the present invention is recorded.
  • a gene analysis method acquires read sequence information read by a sequencer (2) and information on a gene panel including a plurality of genes to be analyzed, and the acquired information on the gene panel According to the gene analysis method for analyzing the sequence information of a gene, the analysis result of the lead sequence information is output, and an error is displayed when the acquired information on the gene panel is not registered.
  • a gene analysis method acquires read sequence information read by a sequencer (2) and information on a gene panel including a plurality of genes to be analyzed, and the acquired information on the gene panel It is a gene analysis method for analyzing sequence information of a gene which outputs analysis result of lead sequence information based on the case where information on the acquired gene panel is not designated from a medical institution (210), Display an error.
  • FIG. 1 is a view 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 processing performed in the gene analysis system.
  • FIG. 3 is a diagram showing an example of the data structure of data stored in the management server.
  • FIG. 4 is a diagram showing an example of the configuration of a gene analysis device.
  • FIG. 5 is a flow chart showing an example of the flow of processing for receiving input of information on a gene panel.
  • FIG. 6 is a diagram showing an example of a GUI used to input information on a gene panel.
  • FIG. 7 is a diagram showing an example of the data structure of a gene panel related information database.
  • FIG. 8 is a diagram showing an example of a GUI used when the user updates information on a gene panel.
  • FIG. 1 is a view 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 processing performed in the gene analysis system.
  • FIG. 9 is a flow chart for explaining an example of a procedure from pretreatment to sequencing for analyzing the base sequence of sample DNA by a sequencer.
  • FIG. 10 is a view for explaining an example of the step (a) of fragmentation of a sample, and the step (b) of application of an index sequence and an adapter sequence.
  • FIG. 11 is a view for explaining an example of the step of hybridization.
  • FIG. 12 is a diagram for explaining an example of a process of recovering a DNA fragment to be analyzed.
  • FIG. 13 is a figure explaining an example of the process of providing a DNA fragment to a flow cell.
  • FIG. 14 is a diagram for explaining an example of a process of amplifying a DNA fragment to be analyzed.
  • FIG. 15 is a diagram for explaining an example of the sequencing process.
  • FIG. 10 is a view for explaining an example of the step (a) of fragmentation of a sample, and the step (b) of application of an index sequence and an adapter sequence.
  • FIG. 11
  • FIG. 16 is a flow chart for explaining an example of the flow of analysis by the gene analysis device.
  • FIG. 17 is a diagram showing an example of a file format of read sequence information.
  • (A) of FIG. 18 is a figure explaining the alignment by a data adjustment part
  • (b) is a figure which shows an example of the format of the alignment result of a data adjustment part.
  • FIG. 19 shows an example of the structure of a reference sequence database.
  • FIG. 20 shows an example of a known mutation incorporated into a reference sequence (not showing a wild-type sequence) contained in a reference sequence database.
  • FIG. 21 is a flowchart for explaining an example of a detailed process of alignment. (A) of FIG.
  • FIG. 22 is a figure which shows an example of score calculation
  • (b) is a figure which shows the other example of score calculation.
  • FIG. 23 is a diagram showing an example of the format of the result file generated by the mutation identification unit.
  • FIG. 24 is a diagram showing an example of the structure of a mutation database.
  • FIG. 25 is a diagram showing a detailed example of the structure of mutation information in the mutation database.
  • (A) of FIG. 26 is a table showing the correspondence between a gene to be analyzed and position information
  • (b) is a diagram showing a state in which a mutation not corresponding to the information on the gene panel is excluded from the result file is there.
  • FIG. 27 is a diagram showing another example of the configuration of the gene analysis device.
  • FIG. 27 is a diagram showing another example of the configuration of the gene analysis device.
  • FIG. 28 is a flowchart showing an example of a process in which the drug search unit generates a list of drugs related to mutation.
  • FIG. 29 shows an example of the data structure of a drug database.
  • FIG. 30 shows an example of the data structure of a drug database.
  • FIG. 31 is a flowchart showing an example of a process in which the drug search unit generates a list including information on drugs related to mutation.
  • FIG. 32 is a flowchart showing an example of a process of determining the presence or absence of a drug that may be used outside the application based on the information obtained by searching the drug database by the drug search unit, and generating a list including the determination result. It is.
  • FIG. 33 is a diagram showing an example of the data structure of a drug database.
  • FIG. 34 is a flowchart showing an example of a process in which the drug search unit generates a list including information on drug trials.
  • FIG. 35 is a diagram showing another example of the configuration of the gene analysis device.
  • FIG. 36 shows an example of the data structure of the reference database.
  • FIG. 37 is a diagram showing an example of a created report.
  • FIG. 38 is a diagram showing another example of the configuration of the gene analysis device.
  • FIG. 39 is a diagram showing an example of the data structure of a gene panel related information database.
  • FIG. 40 is a diagram showing another example of a GUI used to input information on a gene panel.
  • FIG. 41 is a diagram showing another example of a GUI used to input information on a gene panel.
  • FIG. 40 is a diagram showing another example of a GUI used to input information on a gene panel.
  • FIG. 42 is a flowchart illustrating another example of the flow of processing for receiving input of information on a gene panel.
  • FIG. 43 is a diagram showing another example of the gene analysis device.
  • FIG. 44 is a flow chart showing an example of the flow of processing for analyzing gene sequences.
  • FIG. 45 is a diagram showing an example of the quality evaluation index.
  • FIG. 46 is a diagram showing an example of a report to be created.
  • Embodiment 1 Hereinafter, an embodiment of the present invention will be described in detail.
  • a gene analysis method acquires information on a gene panel, and outputs an analysis result of a lead sequence read by a sequencer based on the acquired information on the gene panel.
  • FIG. 1 is a view showing an application example of a gene analysis system 100 according to an embodiment of the present invention.
  • 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 system 100 shown in FIG. 1 analyzes and analyzes the provided sample in response to an analysis request from the analysis system management organization 130 that manages the entire analysis performed in the examination organization 120 and the medical institution 210. It is applied in the inspection organization 120 which provides the result to the medical institution 210.
  • the gene analysis device 1 is installed at the inspection organization 120, and the management server 3 is installed at the analysis system management organization 130.
  • the gene analysis device 100 and the management server 3 constitute a gene analysis system 100.
  • the inspection organization 120 is an organization which inspects and analyzes the sample provided from the medical institution 210, creates a report based on the analysis result, and provides the medical institution 210 with the report.
  • the sequencer 2 and the gene analyzer 1 and the like are installed in the inspection organization 120, the present invention is not limited to this.
  • the analysis system management organization 130 is an organization that manages the entire analysis performed in each inspection organization 120 using the gene analysis system 100.
  • the analysis system management organization 130 is an enterprise that installs the gene analysis device 1 at the inspection organization 120 and provides gene analysis services corresponding to various gene panels.
  • the analysis system management organization 130 updates the information stored in the database of the gene analyzer 1 and manages the gene analysis system 100 so that gene analysis is performed based on the latest information.
  • the analysis system management organization 130 may acquire the status of the gene analysis in the gene analysis device 1 and may receive a reward from the inspection organization 120 according to the result of the gene analysis.
  • the medical institution 210 is an institution where a doctor, a nurse, a pharmacist or the like performs medical operations such as diagnosis, treatment, dispensing for the patient, and examples thereof include a hospital, a clinic, a pharmacy and the like.
  • FIG. 2 is a sequence diagram showing an example of main processing performed in the gene analysis system 100.
  • the process shown in FIG. 2 is only a part of the process performed by each organization.
  • the inspection organization 120 that desires to use the gene analysis system 100 introduces the gene analysis device 1. Then, the application for use of the gene analysis system 100 is applied to the analysis system management organization 130 (step S101).
  • the inspection organization 120 and the analysis system management organization 130 can conclude a desired contract in advance regarding the use of the gene analysis system 100 among a plurality of contract types.
  • the service contents provided from the analysis system management organization 130 to the inspection organization 120, the method of determining the system usage fee charged to the inspection organization 120 by the analysis system management organization 130, and the method of paying the system usage fee differ. It may be selected from the contract types of
  • the management server 3 of the analysis system management organization 130 specifies the contents of the contract concluded with the inspection organization 120 in response to the application from the inspection organization 120 (step S102).
  • the management server 3 managed by the analysis system management organization 130 assigns an examination organization ID to the gene analysis device 1 of the examination organization 120 which has made a contract, and starts provision of various services (steps S103).
  • the gene analysis device 1 receives various services from the management server 3.
  • the various services include analysis results of gene sequences that can be output from the gene analysis device 1, and provision of programs and information for controlling reports based on the analysis results. Thereby, the gene analysis device 1 can output an analysis result, a report, and the like that conform to the information on the input gene panel.
  • a doctor or the like collects samples such as tissue and blood of a lesion site of a subject as needed.
  • an analysis request is transmitted from the communication terminal 5 provided in the medical institution 210 (step S105).
  • the medical institution 210 provides the examination organization 120 with the sample ID assigned to each sample together with the transmission of the analysis request.
  • the sample ID given to each sample is to associate information on the subject from which each sample is collected with each sample.
  • subject refers to human subjects as well as non-human subjects such as mammals, invertebrates, vertebrates, fungi, yeasts, bacteria, viruses and plants.
  • examples herein relate to human subjects, the concepts of the present invention are applicable to genomes from organisms other than humans, such as animals or plants, and are useful in the fields of medicine, veterinary medicine and animal science, etc. is there.
  • Panel inspection is not limited to clinical examinations, but includes examinations for research applications.
  • the analysis request transmitted from the medical institution 210 in step S105 of FIG. 2 may include information on the gene panel.
  • the information on the gene panel may be any information that can be used to specify the gene panel, and may be, for example, the gene panel name and the name of the gene to be analyzed in the panel test.
  • the gene analysis device 1 receives an analysis request from the medical institution 210 (S106). Furthermore, the gene analysis device 1 receives a sample from the medical institution 210 that is the transmission source of the analysis request.
  • the inspection organization 120 receives a request from the medical institution 210, and a gene group to be analyzed is determined for each gene panel.
  • the inspection organization 120 can also use a plurality of gene panels according to the purpose of analysis. That is, the first gene panel is used to analyze the first analysis target gene group for the first sample provided from the medical institution 210, and the second analysis target gene group is analyzed for the second sample. For this purpose, a second gene panel can be used.
  • the gene analysis device 1 receives an input of information on a gene panel used to analyze a sample from the user (step S107).
  • pretreatment of the received sample is performed, and sequencing using the sequencer 2 is performed (step S108).
  • the pretreatment may include a process of fragmenting a gene such as DNA contained in a sample and recovering the fragmented gene. Sequencing also includes a process of reading the sequence of one or more DNA fragments to be analyzed collected in the pretreatment. Sequence information read by sequencing by the sequencer 2 is output to the gene analysis device 1 as read sequence information.
  • the gene analysis device 1 acquires the read sequence information from the sequencer 2 and analyzes the gene sequence (step S109).
  • the gene analysis device 1 creates a report based on the analysis result in step S109 (step S110), and transmits the created report to the communication terminal 5 (step S111).
  • the sample in response to an analysis request from the medical institution 210, the sample is analyzed, and a report based on the analysis result is created.
  • the medical institution 210 receives a report from the inspection institution 120 (step S112).
  • the laboratory 120 may analyze the sample and charge the medical institution 210 for an analysis fee as a compensation for providing the medical institution 210 as the analysis request source with a report based on the analysis result.
  • the analysis system management organization 130 may, as described above, provide various information and services according to the contents of a contract with the inspection organization 120, and may also request each inspection organization 120 for compensation such as a system usage fee. .
  • the gene analysis device 1 of the inspection organization 120 using the gene analysis system 100 notifies the management server 3 of the information on the gene panel used for the analysis, the information on the analyzed gene, the analysis result and the like (step S113). Specifically, the gene analysis device 1 sends the inspection organization ID, the gene panel ID, the gene ID, the analysis result, and the like to the management server 3.
  • the management server 3 stores the acquired examination organization ID, the gene panel ID, the gene ID, the analysis result, and the like in association with each other (step S114).
  • the examination institution ID is information for specifying a user who performs sequence analysis of a gene, and may be a user ID which is identification information assigned to each user who uses the gene analysis device 1.
  • Gene panel ID is identification information provided to identify a gene panel used for analysis of a gene of interest.
  • 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.
  • the gene ID is identification information provided for each gene in order to specify the gene to be analyzed.
  • the analysis result is information on the analysis status of the gene sequence information.
  • the analysis result may be, for example, the number of times of sequence analysis for which analysis using a predetermined gene panel was performed in the gene analysis apparatus 1, or the number of analyzed genes, or the identified mutation It may be a total such as a number. Alternatively, it may be information on the amount of data processed in the analysis.
  • the management server 3 tabulates the analysis results in a predetermined period (for example, any period such as day, week, month, year) for each inspection organization 120, and determines the system usage fee according to the tabulation result and the contract type ( Step S115).
  • the analysis system management organization 130 may charge the determined system usage fee to the inspection organization 120 and request the analysis system management organization 130 to pay the system usage fee.
  • 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 and the Internet.
  • the sequencer 2 is a base sequence analyzer used to read the base sequence of a gene contained in a sample.
  • the sequencer 2 is preferably a next generation sequencer that performs sequencing using a next generation sequencing technology, or a third generation sequencer.
  • the next-generation sequencer is a group of base sequence analyzers that has been developed in recent years, and has dramatically improved by performing parallel processing of clonally amplified DNA templates or single DNA molecules in large quantities in a flow cell. It has analysis ability.
  • the sequencing technology that can be used in the present embodiment may be a sequencing technology that acquires multiple leads by reading the same region redundantly (deep sequencing).
  • sequencing techniques examples include ionic semiconductor sequencing, pyrosequencing, sequencing-by-synthesis using a reversible dye terminator, sequencing Sequencing technology that can obtain multiple reads per run based on sequencing principles other than the Sanger method, such as sequencing-by-ligation and sequencing by probe ligation of oligonucleotides .
  • the sequencing primer used for sequencing is not particularly limited, and is appropriately set based on a sequence suitable for amplifying a region of interest. Further, as a reagent used for sequencing, a suitable reagent may be selected according to the sequencing technology and sequencer 2 used. The procedure from pre-processing to sequencing will be described later with specific examples.
  • FIG. 3 is a view showing an example of the data structure of data stored in the management server 3.
  • the analysis system management organization 130 determines the system usage fee charged to each inspection organization based on each data shown in FIG. 3.
  • the management server 3 includes information (for example, a laboratory ID) for specifying a user who performs gene sequence analysis, information on a gene panel used, and information on analysis status of gene sequences (for example, analysis results). Information to be included is received from the gene analyzer 1 via the network 4.
  • the name of the testing organization using the gene analysis system 100 and the testing organization ID assigned to each testing organization are associated.
  • the type of contract that the analysis system management organization 130 concludes with the inspection organization 120 and the service provided to the inspection organization that has made each contract (for example, available gene panel ) And the system usage fee are associated.
  • the analysis system management organization 130 uses the inspection organization P according to the number of operations. Charge a fee.
  • the “number of operations” is, for example, the number of panel tests performed by the gene analyzer 1.
  • the data 3C to 3E shown in FIG. 3 were respectively identified by the number of operations performed by a laboratory using the gene analysis system 100 during the period from August 1, 2017 to August 31, 2017, the analyzed genes, and It is an analysis result about the total number of mutations. These analysis results are transmitted from the gene analyzer 1 to the management server 3 and stored in the management server 3.
  • the analysis system management organization 130 determines the system usage fee charged to each inspection organization based on the data of these analysis results.
  • the actual aggregation period is not limited to the above, and may be aggregated in any period such as day, week, month, year.
  • the system usage fee is determined depending on whether it is provided by a company that provides (for example, manufacturing or selling) the gene panel used for the test. You may change it.
  • data 3F shown in FIG. 3 may be stored in the management server 3.
  • the company name providing gene panels such as "company A” and "company B”, gene panel ID, and agreement on system usage fee (for example, necessity of system usage fee, etc.) And are associated.
  • the case where the “P organization” concludes a contract of “plan 1” with the analysis system management organization 130 and the analysis result is as shown in FIG. 3 will be described as an example.
  • the P organization conducts five tests using the gene panel (gene panel ID "AAA”) provided by company A, and tests using the gene panel (gene panel ID "BBB”) provided by company B. It has been done 10 times. According to the data shown in FIG. 3, no system fee is required for 5 batches using the gene panel provided by Company A. Therefore, the analysis system management organization 130 determines the system usage fee to the P organization excluding the number of examinations using the gene panel provided by the company A.
  • FIG. 4 is an example of the configuration of the gene analysis device 1.
  • the gene analysis device 1 is based on the control unit 11 for acquiring the read sequence information read by the sequencer 2 and the information on the gene panel including a plurality of genes to be analyzed, and the information on the gene panel acquired by the control unit 11 And an output unit 13 for outputting an analysis result of the lead arrangement information.
  • the gene analysis device 1 can be configured using a computer.
  • the control unit 11 is a processor such as a CPU
  • the storage unit 12 is a hard disk drive.
  • the storage 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. Alternatively, a device having both an input unit and an output unit function, such as a touch panel in which a touch sensor and a display are integrated, may be used.
  • the communication unit 14 is an interface for the control unit 11 to communicate with an external device.
  • the gene analysis device 1 controls the units included in the gene analysis device 1 to control all units, the first storage unit 12 that stores various data used by the analysis execution unit 110, the output unit 13, the communication unit 14, the display A unit 16 and an input unit 17 are provided.
  • the control unit 11 includes an analysis execution unit 110 and a management unit 116.
  • 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.
  • a gene panel related information database 121, a reference sequence database 122, a mutation database 123, and an analysis result log 151 are stored.
  • the gene analysis device 1 creates a report including analysis results corresponding to the used gene panel.
  • a user who uses the gene analysis system 100 can analyze the result of panel inspection with a common analysis program regardless of the type of gene panel, and create a report. Therefore, when performing panel inspection, the trouble that the analysis program used for every gene panel is properly used or special settings for each gene panel used for the analysis program are eliminated is eliminated. User convenience is improved.
  • the information selection unit 112 refers to the gene panel related information database 121, and the analysis program receives the information on the input gene panel.
  • An algorithm of an analysis program is controlled to execute analysis of a gene to be analyzed. That is, the gene analysis device 1 changes the analysis algorithm according to the input information on the gene panel.
  • the information on the gene panel may be any information that specifies the gene panel used for measurement by the sequencer 2.
  • gene panel name gene name targeted for analysis of gene panel, gene panel ID, etc. It is.
  • the information selection unit 112 changes the analysis algorithm for performing analysis corresponding to the gene to be analyzed of the gene panel indicated by the information on the gene panel based on the information on the gene panel input from the input unit 17.
  • the changes of the specific analysis algorithm in the present embodiment include (1) change of reference sequence, and (2) change of region of mutation database 123 which is referred to identify mutations.
  • the information selection unit 112 outputs an instruction based on the information on the gene panel to at least one of the data adjustment unit 113, the mutation identification unit 114, and the report creation unit 115.
  • the gene analysis device 1 can output the analysis result of the lead sequence information based on the input information on the gene panel.
  • the information selection unit 112 acquires information on a gene panel including a plurality of genes to be analyzed, and based on the acquired information on the gene panel, the analysis result of the lead sequence information is output from the output unit 13 Is a functional block to control the
  • genes contained in various samples are analyzed by the user performing panel inspection, various gene panels are used according to a group of genes to be analyzed for each sample.
  • the gene analysis device 1 reads the first read sequence information read from the first sample using the first gene panel for analyzing the first analysis target gene group, and the second analysis target from the second sample
  • a second gene panel for analyzing gene groups can be used to obtain second read sequence information read.
  • the gene analysis apparatus 1 includes the information selection unit 112 to appropriately analyze the analysis result of the lead sequence information. It can be output.
  • the user can select the information on the gene panel without setting the analysis program used for the analysis of the lead sequence information for each analysis target gene or performing the analysis, and It is possible to output an analysis result appropriately.
  • the data adjustment unit 113 performs an alignment process or the like reflecting the information on the gene panel.
  • the information selection unit 112 uses the reference sequence (the wild type genomic sequence and the reference sequence into which the mutant sequence is integrated) used by the data adjustment unit 113 to map the lead sequence information according to the information on the gene panel as information on the gene panel. It is instructed to limit only to the reference sequence for the gene corresponding to
  • the information selection unit 112 instructs the mutation identification unit 114 to perform processing after the processing by the data adjustment unit 113. It is not necessary to output an instruction based on information on the gene panel.
  • the mutation identification unit 114 performs a process reflecting the information on the gene panel.
  • the information selecting unit 112 instructs to limit the region of the mutation database 123 to which the mutation identifying unit 114 refers to only the mutation on the gene corresponding to the information on the gene panel. Thereby, the information on the gene panel is reflected in the result of the processing by the mutation identifying unit 114.
  • FIG. 5 is a flow chart showing an example of the flow of processing for receiving input of information on a gene panel.
  • control unit 11 causes the display unit 16 to display a GUI for inputting information related to the gene panel and allows the user to input information related to the gene panel.
  • the input unit 17 may be a device (for example, a mouse and a keyboard) capable of performing an input operation on the GUI presented to the user.
  • the display unit 16 has a function as the input unit 17. That is, when a touch panel is used as the display unit 16, the display unit 16 also functions as the input unit 17.
  • control unit 11 of the gene analysis device 1 causes the display unit 16 to display a GUI for causing the user to select information on a gene panel.
  • Information on the gene panel is acquired based on the user's input operation on the GUI (step S201).
  • the information selection unit 112 searches the gene panel related information database 121 based on the information selected by the user among the information displayed as a GUI, and reads out information on a gene panel corresponding to the selected information.
  • the gene analysis device 1 reads out information on the gene panel included in the analysis request received from the medical institution 210.
  • the gene panel corresponding to the selected information is registered in the gene panel related information database 121 (YES in step S 202), and the gene panel is one of the gene panels included in the analysis request received from the medical institution 210. If the user has made a decision (YES in step S203), the information selection unit 112 accepts the input. Then, the information selection unit 112 displays a message indicating that the gene panel input to the display unit 16 is usable (step S204).
  • information selector 112 causes the display unit 16 to display a message indicating that the input gene panel can not be used (step S205), and prohibits analysis by the gene analysis device 1.
  • a message indicating an error may be displayed instead of the message that the gene panel is not usable.
  • a message may be, for example, the message "The selected gene panel has not been registered.” Or "Please re-enter information on the gene panel”. It may be one that adds a prompting message.
  • the information selection unit 112 displays the display unit 16 A message indicating that the input gene panel is not available is displayed (step S205), and analysis by the gene analysis device 1 is prohibited.
  • a message may be displayed to notify an error.
  • a message may be, for example, a message such as "The selected gene panel is different from the order.”, Or "Re-enter information on the gene panel", etc. It may be a message.
  • Such processing prevents sequencing using an inappropriate gene panel and execution of unnecessary analysis operations, and wasteful use of the gene panel and useless movement of the gene analysis system 100. It can be eliminated.
  • FIG. 6 is a diagram showing an example of a GUI used to input information on a gene panel.
  • a list of gene panel names such as "xxxxx” and "yyyyy” is displayed on the GUI as information on the gene panel, and a desired gene panel for the user is selected from the gene panels shown in the list. You may
  • the list of gene panel names displayed on the GUI is displayed based on the gene panel name of the gene panel to which the gene panel ID is assigned, which is registered in the gene panel related information database 121.
  • the GUI shown in FIG. 6 shows that “gene panel 2 (gene panel name:“ yyyy ”)” is selected by the user.
  • the information selection unit 112 searches the gene panel related information database 121 using the gene panel ID associated with the selected gene panel name “yyyyy” as a key, and relates to the gene panel corresponding to the input gene panel name Get information.
  • FIG. 7 is a view showing an example of the data structure of the gene panel related information database 121. As shown in FIG.
  • the names of genes that can be analyzed and the gene ID assigned to each gene are stored for each gene panel.
  • genes related information database 121 as in the data 121B shown in FIG. 7, names of selectable gene panels, gene panel IDs assigned to each gene panel, and genes targeted by each gene panel are analyzed. Gene ID (related gene ID) is associated and stored. In addition, about each gene panel, the information regarding whether the use is approved by the public organization (for example, the Ministry of Health, etc. of Japan) may also be matched.
  • the information selection unit 112 refers to the gene panel related information database 121 to select the selected gene panel. Extract gene panel ID and related gene ID associated with the name.
  • the information selection unit 112 refers to the gene panel related information database 121 and associates it with the selected gene name.
  • the gene ID of the gene panel including the identified gene ID and the gene ID of the related gene ID is extracted.
  • the names of gene panels related to diseases and the gene names (or gene IDs) to be analyzed in each gene panel are stored in association with each other. May be
  • the information selection unit 112 selects the gene panel related information database 121.
  • the gene panel ID of the gene panel including those gene IDs and their gene IDs in the related gene ID is extracted from the gene name associated with the gene panel name for the selected disease, with reference to FIG.
  • FIG. 8 is a diagram showing an example of a GUI used when the user updates the gene panel related information database 121. As shown in FIG.
  • the update of the information stored in the gene panel related information database 121 may be performed by an update patch provided from the analysis system management organization 130 to the inspection organization 120. For example, when a gene to be analyzed in the gene panel is changed, or a new gene panel is added, the information stored in the gene panel related information database 121 is updated to the latest one.
  • the provision of the update patch from the analysis system management organization 130 may be performed on the inspection organization 120 for which the system usage fee has been paid.
  • the analysis system management organization 130 may notify the inspection organization 120 that there is an available update patch and that it is a condition of providing the update patch that the system usage fee is paid. By notifying in this manner, payment of the system usage fee can be appropriately urged to the inspection agency 120.
  • a field for inputting "registered file name” is displayed, and in that field, genes such as "gene panel target gene .csv", etc. You may enter a file name in which the name is written.
  • the “gene panel target gene. Csv” includes a plurality of gene names such as RET, CHEK2, PTEN and MEK1.
  • an update request for information on the gene corresponding to the gene name contained in the file is associated with the examination organization ID, and the communication unit 14 And sent to the management server 3.
  • the generation of the update request and the association with the inspection organization ID may be performed by, for example, the control unit 11 in FIG. 4.
  • the analysis system management organization 130 includes information including the gene ID given to the gene name included in the update request received by the management server 3 and the gene panel ID given to the gene panel for analysis of the gene.
  • the gene analyzer 1 permits downloading.
  • an update request for information on the gene corresponding to the gene name is associated with the examination organization ID, and is transmitted to the management server 3 via the communication unit 14 Be done.
  • the analysis system management organization 130 includes information including the gene ID given to the gene name included in the update request received by the management server 3 and the gene panel ID given to the gene panel for analysis of the gene.
  • the gene analyzer 1 permits downloading.
  • information of input candidates to be displayed is provided in advance from the management server 3 to the gene analysis device 1 and stored in the first storage unit 12. Then, when a click operation on the GUI of the field to be input is detected, all updatable gene names are presented as input candidates, allowing the user to select from among them, or updating possible matching the character string input by the user
  • the gene name may be presented as an input candidate.
  • a list of updatable gene names such as “EGFR” and “ESR” is displayed. Alternatively, the user may select one from the list.
  • each gene name, the gene ID of the gene, and the protein name encoded by the gene may be stored in association with each other.
  • the information selection unit 112 refers to the gene panel related information database 121 and the input protein name.
  • the gene name and gene ID associated with can be obtained.
  • the management unit 116 associates the analysis record including the number of times the analysis execution unit 110 has been operated, the number of analyzed genes, the total number of identified authorities, etc. with the gene panel ID and the gene ID, and analyzes the analysis record log 151 as needed.
  • the management unit 116 reads data including analysis results from the analysis result log 151 at an arbitrary frequency (for example, every day, every week, every month), associates the data with the inspection organization ID, and communicates the communication unit 14 Send to the management server via
  • the communication unit 14 is for the gene analysis device 1 to communicate with the management server 3 via the network 4.
  • the data transmitted from the communication unit 14 to the management server 3 may include a laboratory ID, a gene panel ID, a gene ID, an analysis record, an update request, and the like.
  • the data received from the management server 3 may include information on gene panels, gene names that can be updated, and the like.
  • FIG. 9 is a flow chart for explaining an example of a procedure from pretreatment to sequencing for analyzing the base sequence of sample DNA by the sequencer 2.
  • sequencer 2 that can be used in the present embodiment is not particularly limited, and a sequencer that can analyze a plurality of analysis targets in a single run can be suitably used.
  • a device for example, MySeq, HiSeq, NextSeq, etc.
  • Illumina San Diego, Calif.
  • a device adopting the same system as Illumina's sequencer is used.
  • Illumina's sequencer can perform sequencing while synthesizing and synthesizing a large number of target DNAs on a flow cell by a combination of Bridge PCR method and a technique called Sequencing-by-synthesis.
  • the sample (DNA) is fragmented into a length for reading the sequence by the sequencer 2 (step S301 of FIG. 9).
  • Fragmentation of sample DNA can be performed by known methods such as, for example, ultrasonication, and treatment with a reagent that fragments nucleic acid.
  • the resulting DNA fragment (nucleic acid fragment) may be, for example, tens to hundreds of bp in length.
  • the gene to be analyzed is DNA is described as an example, but the gene to be analyzed may be RNA.
  • step S302 in FIG. 9 adapter sequences corresponding to the type of sequencer 2 and the sequencing protocol to be used at both ends (3 'end and 5' end) of the DNA fragment obtained in step S301.
  • Step S302 in FIG. 9 this step is an essential step when the sequencer 2 is a device that adopts the same method as Illumina's sequencer or Illumina's sequencer, but when using other types of sequencer 2 May be omitted.
  • the adapter sequence is a sequence used to perform sequencing in a later step, and in one embodiment may be a sequence for hybridizing to oligo DNA immobilized on a flow cell in Bridge PCR method.
  • adapter sequences may be added directly to both ends of the DNA fragment. Addition of adapter sequences to DNA fragments can be carried out using techniques known in the art. For example, DNA sequences may be blunted and adapter sequences may be ligated.
  • an index sequence may be inserted between both ends of the DNA fragment and the adapter sequence.
  • the index sequence is a sequence unique to each sample, each gene panel, and each company providing a gene panel to distinguish data of each sample.
  • the base sequence used as the index sequence is not limited to this, for example, a sequence in which 10 to 14 consecutive adenine, 5 to 7 consecutive adenine and 5 to 7 consecutive guanine, etc. And have a given length.
  • the index sequence is based on the sequence pattern and length, and for which sequence of the DNA fragment the DNA sequence to which the index sequence is added, what sample lead sequence information, what gene panel was used, the gene panel used It can be used to identify information on which company providing the company, etc. A configuration for identifying information on a panel using an index array will be described in detail later (see Embodiment 4).
  • the index sequence in analysis using gene panel A is a sequence pattern in which adenine is 14 consecutive
  • the index sequence in analysis using gene panel B is a sequence pattern in which guanine is 7 consecutive after 7 adenine is continuous Good.
  • the index sequence in analysis using gene panel A is a sequence in which adenine is 14 consecutive (that is, the length of the index sequence is 14)
  • the index sequence in analysis using gene panel C is 10 consecutive adenines It may be an array (ie, the length of the index array is 10).
  • index sequences and adapter sequences can be carried out using techniques known in the art. For example, after blunting a DNA fragment and ligating an index sequence, an adapter sequence may be further ligated.
  • RNA bait library is hybridized to the DNA fragment to which the adapter sequence is attached (Step S303 in FIG. 9).
  • the biotinylated RNA bait library is composed of biotinylated RNA (hereinafter referred to as RNA bait) that hybridizes to a gene to be analyzed.
  • RNA bait biotinylated RNA
  • the length of the RNA bait is arbitrary, for example, a long oligo RNA bait of about 120 bp may be used to enhance the specificity.
  • a large number of genes (for example, 100 or more) are genes to be analyzed.
  • the reagents used in the panel test include a set of RNA bait corresponding to each of the large number of genes. Since different panels have different numbers and types of genes to be tested, the set of RNA bait contained in the reagent used in the panel test is also different.
  • the DNA fragment to be analyzed is recovered (step S304 in FIG. 9). Specifically, as shown in the upper part of FIG. 12, Streptavidin magnetic beads in which streptavidin and magnetic beads are bound are mixed with the DNA fragment hybridized with the biotinylated RNA bait library. As a result, as shown in the middle of FIG. 12, the streptavidin portion of the streptavidin magnetic beads and the biotin portion of the RNA bait are bound.
  • the streptavidin magnetic beads are collected with a magnet, and fragments not hybridized with the RNA bait (ie, DNA fragments not to be analyzed) are removed by washing.
  • the DNA fragment hybridized with the RNA bait that is, the DNA fragment to be analyzed can be selected and concentrated.
  • the sequencer 2 obtains a plurality of lead sequences by reading the nucleic acid sequence of the DNA fragment thus selected using a plurality of RNA baits.
  • the streptavidin magnetic beads and RNA bait are removed from the concentrated DNA fragment, and the pretreatment is completed by amplification by the PCR method.
  • the DNA fragment to be analyzed has two different adapter sequences (for example, adapter 1 sequence and adapter 2 sequence in FIG. 14) at both ends by the above-described pretreatment. Is added (“1” in FIG. 14), this DNA fragment is rendered single stranded, and the adapter 1 sequence on the 5 ′ end side is immobilized on the flow cell (“2” in FIG. 14).
  • the adapter 2 sequence at the 5 'end is fixed in advance on the flow cell, and the adapter 2 sequence at the 3' end of the DNA fragment is bridged by binding to the adapter 2 sequence at the 5 'end on the flow cell.
  • the bridge is formed (“3” in FIG. 14).
  • the DNA elongation reaction is carried out by DNA polymerase ("4" in FIG. 14), and when it is denatured, two single-stranded DNA fragments are obtained ("5" in FIG. 14).
  • DNA polymerase DNA polymerase
  • two single-stranded DNA fragments are obtained ("5" in FIG. 14).
  • a large number of single-stranded DNA fragments can be locally amplified and fixed to form clusters (FIG. 14 “6” to "10").
  • the sequence is read by sequencing-by-synthesis using single-stranded DNA forming a cluster as a template (step S307 in FIG. 9).
  • sequence primer may be designed, for example, to hybridize to a portion of the adapter sequence.
  • the sequence primer may be designed to amplify the DNA fragment derived from the sample DNA, and may be designed to further amplify the index sequence when the index sequence is added.
  • DNA polymerase After addition of the sequence primer, DNA polymerase performs single base extension reaction of 3 'end-blocked fluorescent dNTP. In order to use dNTP blocked at the 3 'end side, the polymerase reaction is stopped when it is extended by one base. Then, the DNA polymerase is removed (the middle right column in FIG. 15) and the fluorescent substance bound to the base is excited by laser light to the single-stranded extended single-stranded DNA (lower right column in FIG. 15). The light emission occurring at that time is recorded as a picture (lower left column in FIG. 15). Photographs are taken for each of the fluorescent colors corresponding to A, C, G, and T, respectively, while changing the wavelength filter in order to determine four types of bases using a fluorescence microscope.
  • the fluorescent substance and the protecting group blocking the 3 'end are removed to proceed to the next polymerase reaction.
  • the entire length can be sequenced by repeating this flow as one cycle and the second cycle and the third cycle.
  • the chain length that can be analyzed is up to 150 bases ⁇ 2, and analysis is possible in units much smaller than the picotiter plate, so by densifying, in one analysis A huge amount of sequence information of 40 to 200 Gb can be obtained.
  • the gene panel used for reading a lead sequence by the sequencer 2 means an analysis kit for analyzing a plurality of analysis objects in a single run, as described above, and in one embodiment, a plurality of genes related to a specific disease It can be an analysis kit for analyzing sequences.
  • kit is intended for packaging comprising a container (eg, a bottle, a plate, a tube, a dish, etc.) containing the particular material. Preferably, instructions for using each material are provided.
  • a container eg, a bottle, a plate, a tube, a dish, etc.
  • instructions for using each material are provided.
  • "provided” is intended to be contained within any of the individual containers that make up the kit.
  • the kit may be a package in which a plurality of different compositions are packaged together, wherein the form of the composition may be as described above, and in the case of a solution form it may be enclosed in a container It is also good.
  • the kit may be prepared by mixing substance A and substance B in the same container or in separate containers.
  • the "instructions” indicate procedures for applying each component in the kit to treatment and / or diagnosis.
  • the “instruction manual” may be written or printed on paper or other medium, or attached to an electronic medium such as magnetic tape, computer readable disc or tape, CD-ROM, etc. It is also good.
  • the kit can also include a container containing a diluent, solvent, wash solution or other reagent. Furthermore, the kit may be provided with the necessary equipment for therapeutic and / or diagnostic applications.
  • the gene panel comprises one or more of the above-described reagents for fragmenting nucleic acids, reagents for ligation, reagents for washing, reagents such as PCR reagents (dNTP, DNA polymerase etc.), and magnetic beads. It is also good. Also, the gene panel may be provided with one or more of an oligonucleotide for adding an adapter sequence to fragmented DNA, an oligonucleotide for adding an index sequence to fragmented DNA, an RNA bait library, etc. Good.
  • each gene panel may be a sequence unique to the gene panel for identifying the gene panel.
  • the RNA bait library provided in each gene panel may be a library unique to the gene panel, including RNA bait corresponding to each test gene of the gene panel.
  • sequence data reading unit 111 (Sequence data reading unit 111, data adjustment unit 113, mutation identification unit 114) Subsequently, the processing of sequence data reading unit 111, data adjustment unit 113, and mutation identification unit 114 of analysis execution unit 110 will be described along the flow of processing shown in FIG. 16 with reference to FIGS. 17 to 26 as appropriate. Do.
  • FIG. 16 is a flow chart for explaining an example of the flow of analysis by the gene analysis device 1. The process shown in FIG. 16 corresponds to step S109 shown in FIG.
  • step S11 of FIG. 16 the array data reading unit 111 reads the read array information provided from 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 the information to the gene analyzer 1 as lead sequence information.
  • the read sequence information may include the quality score of each base in the sequence, as well as the read sequence. Further, both of the lead sequence information obtained by applying the FFPE sample collected from the lesion site of the subject to the sequencer 2 and the lead sequence information obtained by applying the blood sample of the subject to the sequencer 2 are It is input to the gene analyzer 1.
  • FIG. 17 is a diagram showing an example of a file format of read sequence information.
  • the read sequence information includes the sequence name, the sequence, and the quality score.
  • the sequence name may be a sequence ID assigned to the read sequence information output from the sequencer 2 or the like.
  • the sequence shows the base sequence read by sequencer 2.
  • the quality score indicates the probability that the base 2 assignment by the sequencer 2 is not correctly performed.
  • E represents an estimated value of the probability that base assignment is not correctly performed.
  • the higher the Q value the lower the probability of error.
  • the lower the Q value the larger the unusable part of the lead.
  • false positive mutation assignments may also increase, which may reduce the accuracy of the results.
  • False positive means that although the lead sequence has no true mutation to be judged, it is judged to have a mutation.
  • “Positive” means that the lead sequence has a true mutation to be determined, and “negative” means that the lead sequence does not have a targeted mutation.
  • step S12 of FIG. 16 the data adjustment unit 113 executes alignment of the lead sequence of each of the nucleic acid fragments contained 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 for explaining alignment by the data adjustment unit 113.
  • the data adjustment unit 113 executes alignment by referring to the reference sequence stored in the reference sequence database 122 and mapping the lead sequence of each nucleic acid fragment to the reference sequence to be compared with the read sequence information. Do.
  • the reference sequence database 122 stores a plurality of types of reference sequences corresponding to the genes to be analyzed.
  • the data adjustment unit 113 also provides the read sequence information obtained by applying the FFPE sample collected from the lesion site of the subject to the sequencer 2 and the read sequence obtained by applying the blood sample of the subject to the sequencer 2 Perform an alignment, both with the information.
  • FIG. 18 is a diagram illustrating 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 read sequence, reference sequence and mapping position, but as shown in FIG. 18 (b), reference sequence information, read sequence name, position information, map It may include quality and alignment.
  • 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, and the like.
  • the reference sequence information is preferably capable of identifying the reference sequence, and includes, for example, a reference sequence name and a reference sequence ID.
  • the read sequence name is information indicating the name (read sequence ID) of each read sequence that has become the alignment target.
  • the position information is information indicating a position (Leftmost mapping position) on the reference sequence to which the leftmost base of the read sequence is mapped.
  • the map quality is information indicating the mapping quality corresponding to the lead arrangement.
  • the sequence is information indicating a nucleotide sequence (eg, ... GTAAGGCACGTCATA ...) corresponding to each read sequence.
  • FIG. 19 shows an example of the structure of the reference sequence database 122.
  • the reference sequence database 122 incorporates a reference sequence (for example, the genomic sequence of chromosomes # 1 to 23) representing a wild-type sequence and a known displacement relative to the wild-type sequence.
  • a reference sequence is stored.
  • each reference sequence in the reference sequence database 122 is provided with metadata indicating information on a gene panel.
  • the information on the gene panel provided to each reference sequence may be, for example, one directly or indirectly indicating the gene to be analyzed to which each reference sequence corresponds.
  • the information selection unit 112 when the data adjustment unit 113 acquires the reference sequence from the reference sequence database 122, the information selection unit 112 refers to the input information on the gene panel and the metadata of each reference sequence. Control may be performed to select a reference sequence corresponding to the information on the gene panel. 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 identified by the input information on the gene panel. As a result, the data adjustment unit 113 may perform mapping only to the reference sequences related to the used gene panel, so that the analysis efficiency can be improved.
  • 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 later.
  • FIG. 20 shows an example of a known mutation incorporated into the reference sequence (not showing the wild-type sequence) contained in the reference sequence database 122.
  • Known mutations are mutations registered in an external database (for example, COSMIC, ClinVar, etc.), and as shown in FIG. 20, chromosomal positions, gene names and mutations are identified.
  • mutations of amino acids are identified, but mutations of nucleic acids may be identified.
  • the type of mutation is not particularly limited, and may be various mutations such as substitution, insertion, deletion and the like, or may be a mutation to which a partial sequence of another chromosome or a reverse complementary sequence is bound.
  • FIG. 21 is a flow chart for explaining an example of a detailed process of alignment in step S12 of FIG.
  • the alignment in step S12 of FIG. 16 is performed by steps S401 to S405 shown in FIG.
  • step S401 in FIG. 21 the data adjustment unit 113 selects one of the read sequences of each of the nucleic acid fragments contained in the read sequence information acquired by the sequence data reading unit 111 that has not been aligned, and uses the reference sequence database. Compare with the reference sequence obtained from 122. Then, in step S402, the data adjustment unit 113 identifies the position on the reference array where the degree of coincidence with the read array satisfies a predetermined reference.
  • the degree of coincidence is a value indicating how much the acquired read sequence information and the reference sequence are in agreement, and, for example, the number and ratio of coincident bases can be mentioned as an example.
  • the data adjustment unit 113 calculates a score indicating the degree of matching between the read 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 identifies the number of positions where the base of the read sequence and the base of the reference sequence are identical, obtains the number of matched positions, and reads the number of matched positions compared with the reference sequence. The percentage is calculated by dividing by the number of bases in the sequence (number of bases in comparison window).
  • (A) of FIG. 22 is a figure which shows an example of score calculation.
  • the score of the degree of coincidence between the lead sequence R1 and the reference sequence is 100% because 13 bases out of the 13 bases of the lead sequence are identical, and The score of the degree of coincidence with the reference sequence is 92.3% because 12 bases out of the 13 bases of the lead sequence are coincident.
  • the data adjustment unit 113 determines that the lead sequence has a predetermined mutation (for example, insertion / deletion (InDel: Insertion / Deletion)) with respect to the reference sequence. If it is included, it may be calculated to have a lower score than the normal calculation.
  • a predetermined mutation for example, insertion / deletion (InDel: Insertion / Deletion)
  • the data adjustment unit 113 inserts or deletes, for example, a score calculated by the usual calculation as described above, for a sequence in which the lead sequence includes at least one of an insertion and a deletion relative to the reference sequence.
  • the score may be corrected by multiplying by a weighting factor according to the corresponding number of bases.
  • FIG. 22 (B) of FIG. 22 is a figure which shows the other example of score calculation.
  • the data adjustment unit 113 specifies the position on the reference sequence that satisfies the predetermined criteria by calculating the score of the matching degree while changing the mapping position of the reading sequence to each reference sequence.
  • algorithms known in the art such as dynamic programming, FASTA, BLAST may be used.
  • step S403 when the position on the reference array where the degree of coincidence with the read array satisfies the predetermined reference is a single position (NO in step S403), the data adjustment unit 113 If the read sequence is aligned at the corresponding position, and the position on the reference sequence at which the degree of coincidence with the read sequence satisfies the predetermined reference is a plurality of positions (YES in step S403), the data adjustment unit 113 The lead array is aligned at the position with the highest degree of coincidence (step S404).
  • step S405 when the data adjustment unit 113 does not align all the read sequences included in the read sequence information acquired by the sequence data reading unit 111 (NO in step S405), the process returns to step S401, and If all the included read sequences are aligned (YES in step S405), the process of step S12 is completed.
  • the data adjustment unit 113 outputs, as an analysis result of the lead sequence information, a comparison result of comparison between the lead sequence information and the sequence information of the gene to be analyzed by the gene panel associated with the acquired information about the gene panel. You may
  • the sequence information of the gene to be analyzed by the gene panel may include the sequence of the gene (eg, exon) to be analyzed and the index sequence added to the sequence of the gene to be analyzed.
  • the data adjustment unit 113 may cause the display unit 16 to display an error as an analysis result of the lead arrangement information.
  • the index sequence included in the read sequence information read by the sequence data reading unit 111 corresponds to the information corresponding to the information on the gene panel acquired by the information selection unit 112 (for example, FIG. (See 39).
  • the gene array corresponding to the information on the gene panel acquired by the information selection unit 112 includes a predetermined number or more of sequences of genes that are not to be analyzed.
  • the lead sequence information contains less than a predetermined number of sequences of genes to be analyzed by the gene panel indicated by the gene panel acquired by the information selection unit.
  • the data adjustment unit 113 may display on the display unit 16 errors such as “the analysis can not be performed” and “the information on the gene panel is incorrect”.
  • the data adjustment unit 113 further displays a message such as “Please enter information on the gene panel again” on the display unit 16, and the user may input the gene panel name and the gene name to be analyzed again. You may
  • the error may be displayed on the display unit 16 only when the number of pieces of lead sequence information including sequences of genes not to be analyzed is equal to or more than a predetermined number.
  • an error is displayed only when the number of pieces of lead sequence information mapped to genes not to be analyzed by the gene panel corresponding to the information on the gene panel among the lead sequence information is a predetermined number or more. May be
  • the aspect which outputs an error is not limited to this.
  • the error content may be output by voice from a speaker.
  • the user may be notified of an error by lighting or blinking a lamp or the like.
  • step S13 the mutation identification unit 114 supplies the sample obtained from the lesion site of the subject and the sequence of the reference sequence to which the lead sequence obtained is aligned (alignment sequence); A blood sample of the same subject is provided, and the lead sequence obtained is compared with the sequence of the aligned reference sequence.
  • step S14 of FIG. 16 the difference between both alignment sequences is extracted as a mutation.
  • the mutation identification unit 114 extracts the difference between G and C as a mutation. Do.
  • 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 identifying unit 114. As shown in FIG. The format may be based on, for example, Variant Call Format (VCF).
  • VCF Variant Call Format
  • the positional information indicates the position on the reference genome, and includes, for example, the chromosome number and the 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 the base after mutation of the reference base.
  • the reference base is a base on the alignment sequence derived from the blood sample, and the variant base is a base on the alignment sequence derived from the tumor tissue.
  • a mutation in which the reference base is C and the mutant base is G is an example of substitution mutation
  • a mutation in which the reference base is C and the mutant base is CTAG is an example of insertion mutation
  • a mutation in which the reference base is TCG and the mutant base is T is an example of a deletion mutation.
  • mutations whose mutant bases are G! 17: 198982], 13: 123456] T, C [2: 321682 [or, [17: 198983 [A] are sequences of other parts of chromosomes or reverse complements It is an example of a mutation bound to a sequence.
  • step S15 the mutation identification unit 114 searches the mutation database 123. Then, in step S16, the mutation identifying unit 114 refers to the mutation information in the mutation database 123, and annotates the mutation included in the result file to identify the mutation.
  • FIG. 24 shows an example of the structure of mutation database 123.
  • the mutation database 123 is constructed, for example, based on an external database such as COSMIC or ClinVar.
  • each mutation information in the database is provided with metadata about information on a gene panel.
  • the gene ID of the gene to be analyzed is attached as metadata to each piece of mutation information in the database.
  • FIG. 25 is a diagram showing a detailed example of the structure of mutation information in the mutation database 123.
  • mutation information included in mutation database 123 includes mutation ID, positional information of mutation (eg, “CHROM” and “POS”), “REF”, “ALT”, “Annotation” may be included.
  • Mutation ID is an identifier for identifying a mutation.
  • positional information of mutations "CHROM” indicates a chromosome number
  • POS indicates a position on the chromosome number
  • REF indicates a base in wild type (Wild type)
  • ALT indicates a base after mutation.
  • “Annotation” indicates information on mutation. “Annotation” may be information indicating a mutation of an amino acid such as “EGFR C2573G” or “EGFR L858R”, for example.
  • EGFR C2573G indicates that the cysteine at residue 2573 of the protein "EGFR” is a mutation substituted with glycine.
  • "Annotation" of mutation information may be information for converting a mutation based on base information into a mutation based on amino acid information.
  • 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 (for example, positional information on the mutation and base information corresponding to the mutation) specifying the mutation included in the result file as a key. For example, the mutation identification unit 114 may search the mutation database 123 using any of the information of “CHROM”, “POS”, “REF” and “ALT” as a key.
  • the mutation identification unit 114 detects the mutation existing in the sample. And assign annotations (eg, “EGFR L858R”, “BRAF V600E”, etc.) to the mutations included in the result file.
  • the information selection unit 112 causes the mutation identification unit 114 to search for mutations that do not correspond to the information on the gene panel input to the mutation identification unit 114 before searching the mutation database 123 based on the result file. You may mask (exclude) from the result file.
  • the mutation identification unit 114 notified of the information on the gene panel from the information selection unit 112 is a gene to be analyzed and position information (for example, “CHROM” and “ The position of the mutation corresponding to the gene to be analyzed identified by the information on the notified gene panel is identified with reference to the table showing the correspondence with “POS”), and as shown in FIG. The mutation at the position of may be masked (excluded) from the result file.
  • the mutation identification unit 114 only needs to annotate the mutations associated with the used gene panel in the result file, so that the efficiency of mutation identification can be improved.
  • the information identifying unit 114 when the information identifying unit 114 refers to the mutation information in the mutation database 123 in order to add the annotation, the information identifying unit 114 receives information on the input gene panel and each mutation.
  • the mutation identification unit 114 may control to select and refer to mutation information corresponding to information on the gene panel with reference to information metadata.
  • the information selection unit 112 may control the mutation identification unit 114 to refer to mutation information corresponding to the gene to be analyzed identified by the information on the input gene panel.
  • the mutation identification unit 114 only needs to refer to the mutation information related to the used gene panel in the mutation database 123, so that the efficiency of the annotation can be improved.
  • a mutation corresponding to the information on the input gene panel is selected based on the information on the gene panel, and as a result of analysis of the lead sequence information, a mutation associated with the selected mutation is selected.
  • Information may be output.
  • the mutation identification unit 114 refers to the information on the gene panel from the information selection unit 112 and the metadata of each mutation information, and among all the mutations identified, the information on the gene panel It may be controlled to select only mutation information corresponding to For example, although different gene panels analyze genes of the same gene ID, there may be cases where mutations to be analyzed are different from one another.
  • 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 generation unit 115.
  • the mutation information may be output from the output unit 13 or displayed on the display unit 16 as the analysis result of the lead sequence information.
  • the report creation unit 115 creates a report based on the information output from the mutation identification unit 114 and the information on the gene panel provided from the information selection unit 112 (corresponding to step S110 in FIG. 2).
  • the information contained in the generated report includes information on the gene panel and information on the identified mutations.
  • the report creation unit 115 causes the information selection unit 112 to select the target to be included in the report based on the information on the gene panel from the information selection unit 112, and deletes the information not selected from the report.
  • the information selection unit 112 selects the information related to the gene corresponding to the information on the gene panel input through the input unit 17 as a target to be included in the report, and the information not selected is deleted from the report. May be configured to control the report generation unit 115.
  • the report created by the report creation unit 115 may be data transmitted from the output unit 13 to the terminal device 5 installed in the medical institution 210 as an analysis result of the lead arrangement information (corresponding to step S111 in FIG. 2) . Alternatively, it may be sent to a printer (not shown) connected to the gene analysis device 1 and printed by the printer, and then sent from the examination institution 120 to the medical institution 210 as a paper medium.
  • FIG. 27 is a diagram showing another example of the configuration of the gene analysis device 1a.
  • the analysis execution unit 110a of the gene analysis apparatus 1a further includes a drug search unit 117, and the first storage unit 12a is different from the gene analysis apparatus 1 illustrated in FIG. 4 in that the first storage unit 12a further includes a drug database 124.
  • FIG. 28 is a flowchart showing an example of a process in which the drug search unit 117 generates a drug list related to mutation.
  • 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 on drugs related to mutation (step S16a). The generated list is incorporated into the report generated by the report generation unit 115.
  • FIG. 29 shows an example of the data structure of the medicine database 124. As shown in FIG.
  • a mutation ID given for each mutation is stored in association with each other. It should be noted that a plurality of related drugs may be associated with each mutation ID so that “drug A” and “drug B” are associated with the mutation ID “# 3” in FIG.
  • each mutation ID of the drug database 124 may be provided with “metadata related to gene panel related information” which is metadata related to information related to a gene panel.
  • the drug search unit 117 refers to the "metadata related to gene panel related information”.
  • the drug search unit 117 changes the range in which the drug database 124 is searched to the range indicated in the metadata.
  • the drug search unit 117 can narrow down the drugs to be referred to in the drug database according to the information on the gene panel input as "metadata on gene panel related information" given to each drug.
  • a list can be generated that contains information about the drug depending on the information about the gene panel.
  • the drug search unit 117 may search the drug database 124 having the data structure shown in FIG. 30 and generate a list including other information on the drug related to the mutation. Specifically, in addition to the list of drugs associated with mutations generated in Embodiment 2, drug approval information is added. This will be described with reference to FIG. 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 mutation.
  • the drug search unit 117 searches the drug database 124 storing the data shown in FIG. 30 to see if the relevant drug has been approved by the authority (FDA, PMDA, etc.). Specifically, the drug search unit 117 uses, for example, information on a mutation such as a “mutation ID” as a key, and indicates “approval status” indicating whether the related drug corresponding to the mutation is approved by the authority, Search for "approved country” indicating whether or not it is approved in (step S15b).
  • the drug search unit 117 generates a list including the mutation, the related drug corresponding to the mutation, information on approval of the related drug, and the like based on the search result (step S16b).
  • the drug search unit 117 may search the drug database 124 having the data structure shown in FIG. 30 and generate a list including further information on drugs related to the mutation. Specifically, in addition to the list of agents associated with mutations generated in Embodiment 2, information of agents corresponding to the disease of the subject is added. This will be described with reference to FIG. FIG. 32 determines the presence or absence of a drug having a possibility of Off-label use based on the information obtained by the drug search unit 117 searching the drug database 124, and a list including the determination result is displayed. It is a flow chart which shows an example of processing to generate.
  • the drug search unit 117 searches the drug database 124 storing the data 124B shown in FIG. 30 to see if the relevant drug is approved by the authority (FDA, PMDA, etc.) (step S15 b). If the searched drug is unapproved (NO in step S21), the drug search unit 117 associates the drug as a non-approved drug with the mutation (step S23), and generates a report of the drug related to the mutation (step S23). Step S16a).
  • the drug retrieval unit 117 determines the disease of the subject from which the sample was collected and the disease corresponding to the related drug retrieved from the drug database 124 (for example, It is determined whether or not “the target disease” shown in FIG. 30 matches (step S22).
  • step S22 When the disease of the subject and the "target disease” coincide (YES in step S22), the drug of the search result is associated with the mutation as an approved drug (step S24), the mutation, the related drug corresponding to the mutation, And a list including information related to the approval of the related drug (step S16a).
  • Step S22 when the disease of the subject and the "target disease" are different (NO in step S22), it is determined that the related drug retrieved is a drug having the possibility of off-label use (use outside application), The determination result is associated with the mutation (Step S25), and a list including the mutation, the related drug corresponding to the mutation, and information on approval of the related drug is generated (Step S16a).
  • the information on the disease of the subject may be input from the input unit 17 by the operator or the like, for example, when performing the gene analysis.
  • the header area of the lead arrangement information may include a disease ID which is identification information corresponding to a disease of a subject.
  • the drug search unit 117 may search the drug database 124 having the data structure shown in FIG. 33 and generate a list including information on trials of drugs related to mutation. Specifically, in addition to the list of drugs related to mutations generated in Embodiment 2, drug trial information is added. This will be described with reference to FIG. 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 the drug database 124 storing the data 124C shown in FIG. 33 for information such as the progress of the clinical trial of the related drug. Specifically, the drug search unit 117 uses the mutation ID or the like as a key, and information on the trial of the mutation, for example, the “trial / clinical test status” shown in FIG. 33, the “implementation country” performing the trial, Search for "implementing agency” and the like (step S15c in FIG. 34). The drug search unit 117 generates a list including the mutation, the related drug corresponding to the mutation, information on the trial of the related drug, and the like based on the search result (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 medicine database 124, and a plurality of medicine databases 124 are included. It may be distributed and stored in a database.
  • FIG. 35 is a diagram showing another example of the configuration of the gene analysis device 1b.
  • the analysis execution unit 110b of the gene analysis apparatus 1b further includes a reference search unit 118, and the first storage unit 12b is different from the gene analysis apparatus 1 illustrated in FIG. 4 in that the first storage unit 12b further includes a reference database 125.
  • 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 on the mutation. The extracted reference information is incorporated into the report created by the report creation unit 115.
  • FIG. 36 is a diagram showing an example of the data structure of the reference database 125. As shown in FIG.
  • a mutation ID information on the biological background of the mutation, molecular function information, clinical information, and literature information such as a book and a scientific article on the mutation are mutually associated. Are stored.
  • each mutation ID of the reference database 125 may be provided with “metadata related to gene panel related information” which is metadata related to information related to a gene panel (not shown).
  • the reference search unit 118 refers to the “metadata related to gene panel related information” according to the instruction from the information selection unit 112, and the range for searching the reference database 125 is indicated by the metadata. Change to a range.
  • the reference search unit 118 narrows 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 information related to the input gene panel. It is possible to extract reference information according to the information on the gene panel.
  • 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 from both the drug search unit 117 and the reference search unit 118.
  • the report created by the report creation unit 115 includes information on the identified mutation, information on the drug related to the mutation, a reference on the mutation (for example, information on molecular biological knowledge and documents on each mutation, etc. Or any combination of these information may be posted.
  • the information selection unit 112 selects, for example, information related to the target gene corresponding to the input information on the gene panel as a target to be included in the report, and the report generation unit 115 creates a report on which the selected information is posted. Control to
  • FIG. 37 is a diagram showing an example of a report created by the report creation unit 115.
  • “patient ID” indicating “subject ID”, “patient's gender”, “patient's disease name”, and the name of the doctor in charge of the subject at the medical institution 210 “ The name of the doctor in charge and the name of the institution showing the name of the medical institution are described.
  • the gene panel name "A panel” is also included as information on the gene panel.
  • information on the mutation identified by the mutation identification unit 114 and the drug search unit 117 search the drug database 124 in the column of “Detected gene mutation and related drug”, and are generated based on the search result. List is included.
  • the column of “clinical test list” includes a list of information on clinical trials of drugs generated by the drug search unit 117 by searching the drug database 124 and based on the search results.
  • Embodiment 4 Other embodiments of the present invention are described below. In addition, about the member which has the same function as the member demonstrated in the said embodiment for convenience of explanation, the same code
  • FIG. 38 is a functional block diagram showing another example of the configuration of the gene analysis device 1c.
  • an index sequence for identifying the read sequence information may be inserted for each sample or each type of gene panel.
  • the index sequence may be inserted only into the sequence of a specific gene among the genes to be analyzed by the gene panel. If it is the read sequence information in which the index sequence is not inserted, it is sufficient to allow the user to input information on the gene panel as shown in FIG.
  • FIG. 39 is a diagram showing an example of the data structure of the gene panel related information database 121 c.
  • names of selectable gene panels, gene panel IDs assigned to the respective gene panels, and index sequence information to be inserted are stored in association with each other.
  • the lead sequence information analyzed using the gene panel "A panel” having the gene panel ID "AAA” includes the index sequence "ppppppppppp", and the gene panel ID is "
  • the reading sequence information analyzed using the gene panel "B panel” which is BBB indicates data indicating that the index sequence” qqqqqqqqqqqq "is included.
  • "p" and "q” have shown the base.
  • the data adjustment unit 113c analyzes the read sequence information read by the sequence data reading unit 111, and the sequence includes the index sequences “ppppppppppp”, “qqqqqqqqq”, etc. stored in the gene panel related information database 121c. It is determined whether the If the index array is not included, the data adjustment unit 113c notifies the information selection unit 112c to that effect. On the other hand, when the index arrangement is included, the data adjustment unit 113 c outputs the detected index arrangement (for example, “ppppppppppp”) to the information selection unit 112 c.
  • the information selection unit 112c when notified by the data adjustment unit 113c that the index array is not included, displays the GUI shown in FIG. 6 together with a message such as "Please enter information about gene panel". Display on 16
  • the gene panel related information database 121c is searched using the index sequence as a key, and gene panel related information such as gene panel name and gene panel ID corresponding to the index sequence. Identify For example, when the index sequence received from the data adjustment unit 113c is "qqqqqqqqqqqqqqqqqq", the information selection unit 112c searches the gene panel related information database 121c, and specifies that "B panel” is used as a gene panel. And obtain gene panel related information of the gene panel. The acquired gene panel related information is applied to control of the data adjustment unit 113c, the mutation identification unit 114, the report creation unit 115, and the like as described above.
  • the index sequence when the index sequence is inserted into the read sequence information, it is possible to specify the gene panel related information without having the user input the gene panel related information. Thus, further convenience can be provided to the user.
  • FIG. 1 shows one medical institution 210 and one laboratory 120, it is not limited thereto. That is, the medical institution 210 may request the analysis to a plurality of inspection institutions 120, and the inspection institution 120 may receive an analysis request from a plurality of medical institutions 210. That is, each of the medical institution 210 and the examination institution 120 may be plural.
  • FIG. 1 and FIG. 2 show the sequencer 2 and the gene analysis device 1 of the inspection organization 120 one by one, it is not limited thereto. That is, the inspection organization 120 may be provided with a plurality of sequencers 2 and a plurality of gene analysis devices 1.
  • the genetic analysis system 100 should preferably be applied also to an institution having functions of both the medical institution 210 and the examination institution 120 (for example, a research institute which combines a clinical institution and an examination institution, and a university hospital). Is possible.
  • the present invention is not limited to the gene analysis system 100, and a gene analysis method executed by the gene analysis device 1, a program for controlling the gene analysis device 1 having a computer realized the gene analysis method, and a computer reading the same
  • a possible recording medium may also be suitably applied to an organization having the functions of both the medical institution 210 and the inspection institution 120.
  • Analysis using a gene panel may be used for analysis of polymorphisms such as single nucleotide polymorphism (SNP, Single Nucleotide Polymorphism) and copy number polymorphism (CNV, Copy Number Polymorphism).
  • the gene panel may be used for the output of information (also referred to as Tumor Mutation Burden etc.) regarding the amount of mutation or the like of the entire analysis target gene, and for calculation of the methylation frequency.
  • 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 gene panel and on the surface of a box containing a set of reagents of the gene panel, the barcode is read using a barcode reader. Thus, information on the gene panel is input.
  • the control unit 11 When the control unit 11 causes the display unit 16 to display a GUI for inputting information related to the gene panel, the user may select a gene to be analyzed. In this case, as shown in FIG. 40, a list of candidate genes may be displayed on the GUI, and the user may select a gene to be analyzed by the gene panel.
  • the gene name displayed on the GUI is displayed based on the gene name of the gene assigned with the gene ID registered in the gene panel related information database 121.
  • the gene name in the list displayed as a selection branch is displayed based on the information regarding the gene panel registered in the gene panel related information database 121.
  • FIG. 40 shows a list including a plurality of gene names (for example, “AKT1” and “APC” etc.) to be analyzed, and an example in which a check box is provided on the left side of each gene name is shown .
  • gene names such as “AKT1” and “APC” are selected, and gene names such as “EML4” and “JAK3” are not selected.
  • the information selection unit 112 specifies gene panel IDs associated with the selected gene names from the selected gene names, searches the gene panel related information database 121, and selects a gene panel corresponding to the input gene panel name. Get information about
  • a list of gene panel names is displayed on the GUI for each disease such as “lung cancer panel” or “colorectal cancer panel”, and a desired disease for the user from among the gene panels shown in the list. You may select the gene panel regarding.
  • a list of disease names such as “lung cancer” and “colorectal cancer” may be displayed on the GUI, and the user may select a desired disease from among the disease names shown in the list.
  • the information selection unit 112 specifies the gene panel ID associated with the disease name from the selected disease name, searches the gene panel related information database 121, and selects the gene corresponding to the selected disease name. Get information about the panel.
  • the gene name displayed on the GUI as a selection branch for selecting a gene panel associated with the selected disease is displayed based on the information registered in the gene panel related information database 121.
  • the gene panel name of the gene panel regarding disease may be a reagent kit name.
  • the gene panel includes a set of reagents such as various buffers, enzymes, and primers used for target sequencing, which are performed to read the sequence of the gene to be analyzed by the sequencer 2.
  • the reagent kit name or gene panel name is given to the entire set of reagents.
  • the flow of the process shown in FIG. 5 assumes, for example, a case where a panel inspection using a gene panel designated from the medical institution 210 is performed in the inspection institution 120 which has received an analysis request from the medical institution 210.
  • the present invention is not limited to this, and analysis may be performed using a gene panel other than the gene panel designated by the sample provider.
  • samples are obtained from medical institution 210 and, in addition to analysis using a designated gene panel, Panel testing with different gene panels may also be performed.
  • the information selection unit 112 causes the display unit 16 to Along with the fact that the input gene panel is different from the designated gene panel, a message is displayed asking whether to use the input gene panel (step S206).
  • the information selection unit 112 receives the input. Then, the information selection unit 112 displays a message indicating that the gene panel input to the display unit 16 is usable (step S204).
  • the information selection unit 112 causes the information selection unit 112 to display the input gene in the display unit 16. A message indicating that the panel can not be used is displayed (step S205), and analysis by the gene analysis device 1 is prohibited.
  • the gene analyzer 1 when the gene analyzer 1 receives the input of the information regarding a gene panel, it may be the structure which can select either the input mode shown in FIG. 5 or the input mode shown in FIG.
  • the input mode shown in FIG. 5 in the case of performing a panel test using a gene panel designated by the medical institution 210, it is preferable to select the input mode shown in FIG. 5, and analysis is performed using a gene panel other than the designated gene panel
  • the user using the gene analysis apparatus 1 can select the input mode according to the application.
  • the gene analysis method acquires information on a gene panel, and changes an analysis algorithm for evaluating the quality of panel inspection based on the acquired information on the gene panel.
  • an analysis algorithm for evaluating the quality of panel inspection based on the acquired information on the gene panel.
  • the quality evaluation index for example, the reading quality included in the read sequence information output by the sequencer 2, the ratio of the bases read by the sequencer 2 to the bases included in the plurality of genes to be analyzed, the reading of the read sequence information There are indicators such as the depth (depth), the variation in the reading depth of the lead sequence information (depth), and whether or not all mutations of each standard gene contained in the quality control sample are detected.
  • FIG. 43 is a view showing another example of the configuration of the gene analysis device 1d.
  • the gene analysis device 1d can create a report including the evaluation result of the quality of the panel test.
  • the flow of data is indicated by arrows.
  • the analysis execution unit 110 d of the gene analysis apparatus 1 d further includes a quality control unit 119, and the storage unit 12 d is different from the gene analysis apparatus 1 illustrated in FIG. 4 in that the storage unit 12 d further includes a quality evaluation reference database 126.
  • the quality evaluation standard database 126 stores reference values that define whether the reliability of the analysis result in the panel inspection has reached a certain standard.
  • the certain standard is used, for example, to determine whether or not it has the reliability required to apply the analysis result of the panel test to treatment or diagnosis.
  • the information selection unit 112 changes the reference value of the quality evaluation index based on the information on the gene panel input from the input unit 17.
  • Quality evaluation index As a quality evaluation index generated by the quality control unit 119 for measurement, for example, read quality included in the read sequence information output by the sequencer 2, read by the sequencer 2 among bases contained in a plurality of genes to be analyzed
  • the index such as the ratio of the identified bases, the reading depth of the read sequence information (depth), the variation in the reading depth of the read sequence information (depth), and whether all mutations of each standard gene contained in the quality control sample were detected It can be mentioned.
  • Quality Evaluation Index (1) Quality Score The quality score is an index indicating the accuracy of each base in the gene sequence read by sequencer 2.
  • the quality score is included in the read sequence information (see FIG. 17).
  • the details of the quality score are described in the first embodiment, and thus the description thereof is omitted here.
  • the cluster concentration is an indicator indicating the read quality included 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 a cluster (see 9 in FIG. 14). Then, the cluster group on the flow cell is imaged using a fluorescence microscope, and the sequence is read by detecting fluorescence of different wavelengths corresponding to A, C, G, and T, respectively.
  • the cluster density is an index showing how closely the clusters of each gene formed on the flow cell are close to each other.
  • Quality evaluation index (3) an index indicating the ratio of the base sequence of the target area read by the sequencer 2 to the base sequence read by the sequencer 2 This index is a base of other than the target area read by the sequencer 2 Among them, it is an index indicating how many bases in the target area have been read, and is calculated as the ratio between the total number of bases read and the total number of bases in the target area.
  • Quality evaluation index (4) index indicating the reading depth (depth) of lead sequence information This index is an index based on the total number of lead sequences from which the bases have been read for each base contained in the gene to be analyzed, Of the read bases, the ratio is calculated as the ratio between the total number of bases whose depth is greater than or equal to a predetermined value and the total number of read bases.
  • the reading depth (depth) means the total number of pieces of read sequence information read for the same base, and is also called coverage, coverage, or depth of coverage.
  • FIG. 45 shows a graph showing the depth of each base when the full length of the gene to be analyzed (“target gene” in the figure) is L bases and the base of the read region is t1 base. ing.
  • the horizontal axis of the graph in FIG. 45 is the position of the base, and the vertical axis is the depth of each base.
  • the total number of bases in the area having a depth of a predetermined value (for example, 100) or more is (t2 + t3) bases.
  • the quality evaluation index (4) is generated as a value of (t2 + t3) / t1.
  • Quality evaluation index (5) index showing variation in reading depth (depth) of lead arrangement information This index is an index showing uniformity of depth. If the read sequence information obtained by reading a part of the read area is extremely large, the uniformity of the depth is low. On the other hand, when the read arrangement information is present all over the read area, the uniformity of the depth is high. Depth uniformity can be quantified, for example, using the interquartile range (IQR). The higher the IQR, the lower the uniformity, and the lower the IQR, the higher the uniformity.
  • IQR interquartile range
  • Quality evaluation index (6) Index indicating whether or not all mutations possessed by each standard gene contained in the quality control sample have been detected This index is used when the quality control sample is measured in combination with the sample collected from the subject , An indicator showing whether mutations possessed by each standard gene contained in the quality control sample were detected and correctly identified. For example, it is used as a quality evaluation index whether or not the position of a known mutation possessed by each standard gene contained in the quality control sample, the type of mutation, etc. were correctly identified. Quality control samples are prepared by mixing multiple standard genes.
  • FIG. 44 is a flow chart showing an example of the flow of processing for analyzing gene sequences.
  • preprocessing for analyzing gene sequences is performed.
  • the pretreatment includes a process of fragmenting a gene such as DNA contained in the sample and recovering the fragmented gene.
  • the analysis target in the panel inspection for quality evaluation may be a sample collected from a subject, or a quality control sample prepared by mixing a plurality of standard genes.
  • the quality control sample contains at least two of a standard gene including SNV, a standard gene including Insertion, a standard gene including Deletion, a standard gene including CNV, and a standard gene including Fusion.
  • the quality control sample contains, as standard genes, a partial sequence of gene A containing "SNV" to wild type and a partial sequence of gene B containing "Insertion" to wild type.
  • step S32 the sequencer 2 reads the base sequence of DNA contained in the pretreated sample.
  • step S33 the control unit 11d of the gene analysis device 1d causes the input unit 17 to display a GUI for causing the user to select information on the gene panel.
  • Information on the gene panel is acquired based on the user's input operation to the GUI.
  • the acquisition of the information on the gene panel is not limited to the user's input by the GUI, but may be acquired by an identifier such as a barcode attached to the gene panel, or may be identified by reading the index sequence.
  • the control unit 11 d of the gene analysis device 1 d determines the type of gene panel based on the acquired information on the gene panel.
  • the gene analysis device 1 d changes the analysis algorithm so as to execute the quality control of the panel inspection according to the type of the acquired gene panel.
  • the gene analysis device 1d analyzes the gene sequence according to the type of gene panel, and specifies the presence or absence of a mutation in the base sequence, the position of the mutation, the type of mutation, and the like. By analyzing the read gene sequences, the detected mutations are identified.
  • the gene analysis device 1d evaluates the quality of the panel inspection based on the generated quality evaluation index.
  • the quality management unit 119 acquires the quality score (quality evaluation index 1) and the cluster concentration (quality evaluation index 2) from the array data reading unit 111.
  • quality evaluation index 3 the ratio of bases in the target area read by the sequencer 2
  • quality evaluation index 4 the reading depth of the read sequence information
  • quality evaluation index 5 the variation of the reading depth of the read sequence information
  • the quality control unit 119 does not need to acquire all of these quality evaluation indicators, and may acquire one or more arbitrary indicators.
  • the quality management 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 result has sufficient reliability.
  • the quality evaluation standard database 126 stores the standard value of the quality evaluation index in association with the information specifying the gene panel.
  • the quality evaluation index A is determined using the reference value a
  • the quality evaluation index B is determined using the reference value b.
  • the quality evaluation index A is determined using the reference value c
  • the quality evaluation index B is determined using the reference value b.
  • the quality evaluation index D is determined using the reference value e.
  • the quality evaluation is performed based on the two indexes of the quality evaluation indicators A and B, but in the analysis of the C panel, the quality evaluation is performed using only the quality evaluation indicator D. Is going.
  • the number of quality evaluation indexes to be used may be changed.
  • the gene analysis device 1d creates a report including the evaluation result of the identified mutation and the quality of the panel test determined in step S34.
  • FIG. 46 is a diagram showing an example of a report created by the report creation unit 115. As shown in FIG. In the upper left part of the report shown in this example, “patient ID” indicating “subject ID”, “patient's gender”, “patient's disease name”, and the name of the doctor in charge of the subject at the medical institution 210 “ The name of the doctor in charge and the name of the institution showing the name of the medical institution are described.
  • the gene panel name "A panel” is also included as information on the gene panel. Furthermore, a quality evaluation index "QC index”, which is information on the quality of panel inspection, is output in the report.

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Abstract

Le but de l'invention est d'améliorer la commodité de l'utilisateur dans l'analyse de séquences de gène à l'aide de divers panels de gènes. Un analyseur génétique (1) pour analyser des informations de séquence de gènes comprend : une unité de contrôle (11) acquérant des informations de séquence de lecture lues par un séquenceur (2) et des informations concernant une pluralité de panels contenant un gène d'analyte ; et une unité de sortie (13) délivrant des résultats d'analyse des informations de séquence de lecture sur la base des informations relatives aux panels acquises par l'unité de commande (11).
PCT/JP2018/039963 2017-10-27 2018-10-26 Méthode d'analyse génétique, analyseur de gène, serveur de gestion, système, programme et support d'enregistrement d'analyse génétique WO2019083024A1 (fr)

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EP18869832.8A EP3702473A4 (fr) 2017-10-27 2018-10-26 Méthode d'analyse génétique, analyseur de gène, serveur de gestion, système, programme et support d'enregistrement d'analyse génétique
CN201880069344.4A CN111263964A (zh) 2017-10-27 2018-10-26 基因解析方法、基因解析装置、管理服务器、基因解析系统、程序、及记录介质
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