JP7141039B2 - DNA mutation screening device, DNA mutation screening system, DNA mutation screening method, and program - Google Patents

Description

The present invention relates to a DNA mutation narrowing-down device, a DNA mutation narrowing-down system, a DNA mutation narrowing-down method, and a program.

A technique is known in which DNA (DeoxyriboNucleic Acid) mutation data of a plurality of subjects is used to investigate the relationship between DNA mutations and specific diseases or quantitative traits (see, for example, Patent Document 1).

In addition, as a specific example of research, we conducted a genome-wide association analysis using the DNA information of about 160,000 Japanese people, and further conducted a meta-analysis conducted on 320,000 Westerners to determine the effects on body weight. There is an example of identifying 193 genomic regions that are thought to be (see, for example, Non-Patent Document 1).

Furthermore, exome analysis was performed using the genetic information of 50 people with hypertensive disorders of pregnancy (HDP: Hypertensive Disorders of Pregnancy) and the genetic information of 50 people who were not affected. Although there was a difference in the amount, there is an example in which the difference was not significant (see, for example, Non-Patent Document 2).

JP 2018-49472 A

Akiyama M, et.al, "Genome-wide association study identifies 112 loci for body mass index in the Japanese population.", Nature genetics, doi: 10.1038/ng.3951 Hansen, Anette Tarp, et al. "The Genetic Component of Preeclampsia: A Whole-Exome Sequencing Study.", Plos One, vol. 13, no. 5, 2018, doi:10.1371

For example, as in Non-Patent Document 1, when performing whole-genome association analysis, a huge number (for example, a number of thousands to hundreds of thousands) of DNA samples are required.

However, due to reasons such as lack of funding for research institutions and low prevalence of certain diseases, it is often not possible to obtain a sufficient number of samples. As such, it may not be possible to sufficiently narrow down the biomarkers associated with a given disease.

Also, depending on the disease, the definition of an affected group and a non-affected group may be ambiguous. For example, there are diagnostic guidelines for HDP, but in reality, blood pressure values like HDP may appear even if they are not classified as HDP. In such a case, there may not be a sufficient difference in genetic background between the affected group and the non-affected group, and DNA mutations associated with a given disease may not be sufficiently narrowed down.

As a method to solve these problems, in addition to the method of performing association analysis on the difference in the DNA sequence between the affected group and the non-affected group, quantitative traits related to a given disease such as body weight, BMI, blood pressure, body temperature, etc. , an association analysis using quantitative traits that evaluates the effect of DNA sequences on the magnitude of a quantitative trait. However, when performing association analysis using, for example, quantitative traits measured at the time of hospital visit, it is difficult to compare quantitative It is conceivable that the effect of visit time on traits cannot be removed and DNA mutations associated with a given disease cannot be sufficiently narrowed down.

As described above, with conventional techniques, it is difficult to narrow down DNA mutations associated with a given disease, for example, when there are few DNA samples of a specimen or when the definition of a disease is ambiguous. Furthermore, even when performing association analysis using quantitative traits, it can be assumed that it is difficult to narrow down DNA mutations associated with a given disease.

An embodiment of the present invention has been made in view of the above-mentioned problems, and facilitates identification of DNA mutations associated with a given disease when performing association analysis using quantitative traits associated with the given disease. To provide a DNA mutation narrowing down device capable of narrowing down.

In order to solve the above problems, a DNA mutation narrowing down apparatus according to one embodiment of the present invention provides a quantitative A feature of performing fitting to a predetermined polynomial on the continuous measured values of traits and extracting a feature amount from each subject using the coefficient of the polynomial, the intercept of the polynomial, or the coefficient and intercept of the polynomial an amount extraction unit, an acquisition unit that acquires information on DNA mutations in the plurality of subjects, an analysis unit that analyzes the relationship between the feature amount and the DNA mutations, and based on the analysis results of the analysis unit, the predetermined and a DNA mutation extraction unit for extracting DNA mutations related to the disease , wherein the analysis unit performs association analysis using the feature amount as an objective variable and the DNA mutation as an explanatory variable, and performs association analysis with the feature amount and each DNA A statistical index value indicating the degree of association with a mutation is calculated, and the DNA mutation extraction unit determines whether the statistical index value calculated by the analysis unit is equal to or greater than a predetermined reference value or equal to or less than a predetermined reference value. DNA mutations are extracted.

Quantitative traits related to a given disease include, for example, subject's blood pressure, weight, BMI (Body Mass Index), pulse, heart rate, body fat percentage, amount of activity, calorie consumption, sleep time, body temperature, and the like. includes continuously and quantitatively changing traits of Continuous measurements of quantitative traits are values that are measured and recorded continuously for a given period of time for those quantitative traits.

In this way, the use of continuous quantitative traits associated with a disease makes it possible to obtain more information about the disease than the binary information of diseased and non-diseased.

According to one embodiment of the present invention, there is provided a DNA mutation narrowing-down apparatus capable of easily narrowing down DNA mutations associated with a given disease when performing association analysis using quantitative traits associated with the given disease. can do.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram (1) showing a configuration example of a DNA mutation screening device according to an embodiment; FIG. 2 is a diagram (2) showing a configuration example of a DNA mutation screening device according to an embodiment. It is a figure which shows the example of the hardware constitutions of the DNA mutation narrowing-down apparatus which concerns on one Embodiment. 4 is a flowchart showing an overview of DNA mutation narrowing down processing according to an embodiment. 6 is a flowchart illustrating an example of feature amount extraction processing according to an embodiment; FIG. 4 is a diagram for explaining an example of feature amounts according to one embodiment; FIG. 4 is a flow chart showing an example of narrowing down processing for DNA mutations of the first specific example according to one embodiment. FIG. FIG. 10 is a flow chart showing an application example of the DNA mutation narrowing down process of the first specific example according to one embodiment. FIG. FIG. 10 is a flow chart showing an example of narrowing down processing for DNA mutations in a second specific example according to one embodiment. FIG. FIG. 11 is a flow chart showing an example of a diseased group and non-diseased group labeling process of the second specific example according to one embodiment. FIG.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described with reference to the drawings. In addition, the embodiment described below is an example, and the embodiment to which the present invention is applied is not limited to the following embodiment.

<Configuration of DNA mutation screening device>
The configuration of a DNA (DeoxyriboNucleic Acid) mutation screening device according to one embodiment will be described with reference to FIGS. The DNA mutation narrowing down device 110 is an information processing device having a computer configuration or a system including a plurality of information processing devices (DNA mutation narrowing down system 100). The DNA mutation narrowing down device 110 has, for example, a hardware configuration as shown in FIG.

The DNA mutation narrowing down apparatus 110 performs, for example, an association analysis (test) based on the input DNA mutation data of a plurality of subjects and continuous quantitative trait data, and the DNA mutation data is used to analyze continuous quantitative trait data. The effect on the change is calculated to narrow down the DNA mutations associated with a given disease, and the narrowed-down result (for example, a candidate list, etc.) is output.

Here, for the association analysis (test), linear regression, logistic regression, Fisher's exact test, chi-square test, Cochran-Amitage test, t-test, etc. can be used, but not limited thereto.

Note that the DNA mutation narrowing-down device 110 may be, for example, a device that narrows down candidates for DNA mutations such as single nucleotide polymorphisms related to a predetermined disease, and does not necessarily need to be the presence/absence of a predetermined disease, the degree of progression, etc. It does not have to specify a DNA mutation that directly indicates the .

FIG. 1 is a diagram (1) showing a configuration example of a DNA mutation screening device 110 according to an embodiment. The DNA mutation narrowing down apparatus 110 executes a predetermined program in the processor 301 of FIG. It implements a DNA mutation extraction unit 115, a storage unit 116, a result output unit 117, and the like. Note that at least some of the input reception unit 111, the feature amount extraction unit 112, the DNA mutation information acquisition unit 113, the association analysis unit 114, the DNA mutation extraction unit 115, the storage unit 116, and the result output unit 117 are implemented by hardware. It may be realized by

The input reception unit 111 is implemented by, for example, a program executed by the processor 301 in FIG. 3, and receives input data, input operations, and the like input from the input device 304, the communication device 306, and the like in FIG. For example, the input receiving unit 111 receives inputs of continuous measured values of quantitative traits related to a given disease, collected from a plurality of subjects including a subject suffering from the given disease.

The input receiving unit 111 can also receive inputs such as DNA sequence information (hereinafter referred to as DNA information) collected from a plurality of subjects including subjects suffering from a predetermined disease, DNA mutation information, and the like. .

DNA is a substance (deoxyribonucleic acid) that records genetic information, and is composed of about 3 billion pairs of bases. DNA includes genes, which are specific regions (nucleotide sequences) containing genetic information. In this embodiment, DNA mutations present in regions other than genes can also be narrowed down.

DNA mutations are structural (nucleotide sequence) mutations in DNA, and include, for example, single nucleotide polymorphisms (SNPs), copy number variations (CNVs), DNA deletions, insertions, and the like. can be included.

The feature quantity extraction unit 112 is implemented by, for example, a program executed by the processor 301 in FIG. Extract (determine).

Here, the feature amount is, for example, a polynomial coefficient, a polynomial intercept, or a polynomial coefficient and intercept obtained by fitting continuous measured values of quantitative traits related to a given disease to a given polynomial. is. A specific example of the method of extracting feature amounts by the feature amount extraction unit 112 will be described later.

The DNA mutation information acquisition unit (acquisition unit) 113 is implemented by, for example, a program executed by the processor 301 in FIG. 3, and acquires DNA mutation information in a plurality of subjects including subjects suffering from a predetermined disease. .

For example, the DNA mutation information acquisition unit 113 analyzes the DNA information received by the input reception unit 111 and extracts DNA mutation information.

Alternatively, as shown in FIG. 2, the DNA mutation information acquisition unit 113 acquires DNA mutation information of a plurality of subjects from a DNA mutation information acquisition device 210, which is an external device for acquiring DNA mutation information from DNA information. It can be anything. Furthermore, as shown in FIG. 2, the DNA mutation information acquisition unit 113 acquires DNA mutation information corresponding to a plurality of subjects from a DNA mutation information DB (database) 220 that stores pre-acquired DNA mutation information. It can be anything.

Preferably, the DNA mutation information acquired by the DNA mutation information acquiring unit 113 includes all single nucleotide polymorphism (SNP) information in the DNA sequence extracted from the DNA information (DNA sequence information) of a plurality of subjects. is included.

The association analysis unit (analysis unit) 114 is realized by, for example, a program executed by the processor 301 in FIG. Analyze the relationship with DNA mutations contained in the information. For example, the association analysis unit 114 performs association analysis (testing) using the feature amount as the objective variable and the DNA mutation as the explanatory variable, and expresses how much the DNA mutation affects the feature amount. Calculate the value of a statistical index that indicates the degree of association with

Here, the value of the statistical index indicating the degree of association between the feature quantity and the DNA mutation is included in the feature quantity extracted by the feature quantity extraction unit 112 and the DNA mutation information acquired by the DNA mutation information acquisition unit 113. Numerical values (eg, p-values, f-values, odds ratios, etc.) indicating significant differences from each DNA mutation are included.

For the association analysis (test), linear regression, logistic regression, Fisher's exact test, chi-square test, Cochran-Amitage test, t-test, etc. can be used, but not limited thereto.

Note that the association analysis unit 114 labels the feature amount extracted by the feature amount extraction unit 112 into a group affected by a predetermined disease and a group not affected by a predetermined disease using a predetermined reference value, and determines the significance of each DNA mutation. It is also possible to calculate the value of a statistical index indicating

The DNA mutation extraction unit 115 is implemented by, for example, a program executed by the processor 301 in FIG. For example, the DNA mutation extraction unit 115 extracts DNA mutations related to a predetermined disease based on the statistical index values calculated by the association analysis unit 114 .

The storage unit 116 is implemented by, for example, the program executed by the processor 301 in FIG. 3, the storage 303, the memory 302, and the like, and stores information received by the input receiving unit 111, information obtained by the DNA mutation information obtaining unit 113, and the like. memorize

The result output unit 117 is implemented by, for example, a program executed by the processor 301 in FIG. The result output unit 117 outputs the information of the DNA mutations related to the predetermined disease (for example, a DNA mutation candidate list, etc.) extracted by the DNA mutation extraction unit 115 to the hardware configuration shown in FIG. output device 305 or the like.

(Example of specific configuration)
As an example of a specific configuration of the DNA mutation narrowing down device 110, the input reception unit 111 shown in FIG. receive information on continuous blood pressure measurement values measured in the same period of time, etc.;

The feature amount extraction unit 112 fits the continuous blood pressure measurement values received by the input reception unit 111 to a polynomial (for example, a linear expression) to calculate the slope, intercept, and the like of the polynomial. As an example, the feature amount extraction unit 112 can use the slope of the polynomial as the feature amount.

The DNA mutation information acquisition unit 113, for example, extracts from the DNA information of a plurality of subjects including a subject suffering from a predetermined disease, and obtains information on each single nucleotide polymorphism (an example of DNA mutation) of all subjects. get.

The association analysis unit 114 uses the feature amount (slope of the polynomial) extracted by the feature amount extraction unit 112 as an objective variable, An association analysis (test) is performed as an explanatory variable. For example, the association analysis unit 114 performs a linear regression test, and p-value (statistical indicator value (an example of ) is calculated.

The DNA mutation extraction unit 115 determines that the p value of all the single nucleotide polymorphisms included in the nucleotide polymorphism information is below (or less than) a predetermined significance level (for example, 5×10 ⁻⁸ ). Extract single nucleotide polymorphisms.

Here, the significance level is a value indicating the level at which the p-value can be regarded as statistically significant, and 0.05 (5%) is used in general analysis. However, since thousands to tens of thousands of parameters are tested at once in genome analysis, the number of tests increases and the possibility of significant differences occurring by chance increases, so it is common to correct the significance level. 5 × 10 ^-8 (0.000005%) is often used as the level of the p-value after correction, but other values (for example, 5 × 10 ^-10 , 5 × 10 ^-12 , etc.) can be used as necessary. You can use it.

The storage unit 116 acquires continuous quantitative trait measurement values of a plurality of subjects including a subject suffering from a predetermined disease, and stores the acquired continuous quantitative trait measurement values.

The result output unit 117 outputs the single nucleotide polymorphism information extracted by the DNA mutation extraction unit 115 as a single nucleotide polymorphism related to a predetermined disease, for example, as a candidate list.

FIG. 2 is a diagram (2) showing a configuration example of a DNA mutation screening device according to an embodiment. As shown in FIG. 2, the DNA mutation narrowing-down device 110 may realize each function in cooperation with an external device such as the DNA mutation information acquisition device 210 and the DNA mutation information DB 220 . Further, the DNA mutation narrowing-down apparatus 110 may be the DNA mutation narrowing-down system 100 composed of a plurality of information processing apparatuses, as described above.

(Hardware configuration)
FIG. 3 is a diagram showing an example of the hardware configuration of the DNA mutation screening device 110 according to the embodiment shown in FIGS. 1 and 2. As shown in FIG. The DNA mutation narrowing down device 110 may be physically configured as a computer device including a processor 301, a memory 302, a storage 303, an input device 304, an output device 305, a communication device 306, a bus 307, and the like. In the following description, the term "apparatus" can be read as a circuit, device, unit, or the like.

The processor 301, for example, operates an operating system and controls the entire computer. The processor 301 may be configured with a central processing unit (CPU) including an interface with peripheral devices, a control device, an arithmetic device, registers, and the like.

The processor 301 also reads programs (program codes), software modules and data from the storage 303 and/or the communication device 306 to the memory 302 and executes various processes according to them. As the program, a program that causes a computer to execute at least part of the operation of the DNA mutation narrowing down apparatus 110 is used. Various processes performed in the DNA mutation narrowing down apparatus 110 may be performed by one processor 301, or may be performed by two or more processors 301 simultaneously or sequentially. Processor 301 may be implemented with one or more chips. Note that the program may be transmitted from a network via an electric communication line.

The memory 302 is a computer-readable storage medium, and is composed of at least one of, for example, ROM (Read Only Memory), EPROM (Erasable Programmable ROM), EEPROM (Electrically Erasable Programmable ROM), RAM (Random Access Memory), and the like. May be. The memory 302 may also be called a register, cache, main memory (main storage device), or the like. The memory 302 can store executable programs (program code), software modules, etc. for implementing the DNA mutation screening method according to one embodiment of the present invention.

The storage 303 is a computer-readable storage medium, for example, an optical disc such as a CD-ROM (Compact Disc ROM), a hard disk drive, a flexible disc, a magneto-optical disc (for example, a compact disc, a digital versatile disc, a Blu-ray disk), smart card, flash memory (eg, card, stick, key drive), floppy disk, magnetic strip, and/or the like. The storage 303 may also be called an auxiliary storage device. The storage medium described above may be, for example, a database, server, or other suitable medium including memory 302 and/or storage 303 .

The input device 304 is an input device (for example, keyboard, mouse, microphone, switch, button, sensor, etc.) that receives input from the outside. The output device 305 is an output device (for example, display, speaker, LED lamp, etc.) that outputs to the outside. Note that the input device 304 and the output device 305 may be integrated (for example, a touch panel display).

The communication device 306 is hardware (transmitting/receiving device) for communicating between computers via a wired and/or wireless network, and is also called a network device, network controller, network card, communication module, or the like. Also, the communication device 306 may have a function of directly communicating with an external device by short-range wireless communication.

Devices such as the processor 301 and the memory 302 are connected by a bus 307 for communicating information. The bus 307 may be composed of a single bus, or may be composed of different buses between devices.

<Process flow>
Next, the process flow of the method for narrowing down DNA mutations according to this embodiment will be described with reference to FIGS. 4 to 6. FIG.

FIG. 4 is a flowchart showing an overview of DNA mutation screening processing according to one embodiment. Here, the explanation will focus on the processing common to the first specific example and the second specific example, which will be described later.

In step S401, the input reception unit 111 of the DNA mutation narrowing down device 110 acquires continuous quantitative trait measurement values of a plurality of subjects including a subject suffering from a predetermined disease, Measured values of quantitative traits are stored in the storage unit 116 or the like.

In step S<b>402 , the feature quantity extraction unit 112 of the DNA mutation narrowing down device 110 extracts a feature quantity related to a predetermined disease from temporal changes in quantitative traits stored in the storage unit 116 . For example, the feature quantity extraction unit 112 executes a feature quantity extraction process as shown in FIG.

FIG. 5 is a flowchart illustrating an example of feature amount extraction processing according to an embodiment. This process shows an example of the feature amount extraction process executed in step S402 of FIG. 4, for example.

In step S<b>501 , the feature amount extraction unit 112 fits the continuous quantitative trait measurement values acquired by the input reception unit 111 to a polynomial, for example, as shown in FIG. 6 .

FIG. 6 is a diagram for explaining an example of feature amounts according to one embodiment. Here, as a specific example, the continuous quantitative trait is the measured value of the blood pressure of a pregnant woman (an example of a subject) measured at predetermined time intervals (eg, every day, the same time zone, etc.), and the polynomial is It is assumed to be a linear expression.

In FIG. 6 , the feature quantity extraction unit 112 fits the blood pressure measurement value 601 of the pregnant woman A to a linear expression “y=ax+b” by, for example, linear regression. Note that the linear expression "y=ax+b" is an example of a predetermined polynomial.

In step S502, the feature quantity extraction unit 112 calculates coefficients and intercepts of the fitted polynomial. For example, the feature quantity extraction unit 112 calculates the slope a1 and the intercept b1 of the straight line represented by the linear expression.

In step S503, the feature quantity extraction unit 112 extracts the calculated coefficient, intercept, or coefficient and intercept as feature quantities.

For example, it is assumed that the slope a2 and the intercept b2 are further calculated by performing fitting to the linear expression "y=ax+b" using the measured values of another pregnant woman B. In this case, as an example, the slopes a1 and a2 of the linear expressions can be used as feature amounts.

For example, as shown in FIG. 6, it is assumed that blood pressure increases with time (pregnancy progress). When each pregnant woman measures her blood pressure at each timing, for example, as shown in FIG. . When the blood pressures of pregnant women A and B are compared at different time points, the difference includes the influence of the difference in the time points of measurement.

On the other hand, as shown in FIG. 6, for example, the measured blood pressure values of pregnant woman A and pregnant woman B are fitted to a linear expression, and a regression line 602 for the blood pressure value of pregnancy A and a regression line 604 for the measured blood pressure value of pregnant woman B are obtained. is calculated. By also using the regression lines 602 and 604, it is possible to compare the difference in blood pressure transition between pregnancies A and B from the slopes of both. In addition, by using the predicted value of blood pressure at a predetermined time (t), it is possible to perform a comparison that eliminates the influence of the difference in measurement time points.

As another example, in FIG. 6, it is assumed that time t0 is the first day of pregnancy of the pregnant woman. It is also assumed that the presence or absence of the onset of a certain disease is related to the blood pressure value on the first day of pregnancy. In this case, even if there is no record of blood pressure values on the first day of pregnancy, such as pregnant women A, pregnant women B, and pregnant women C, by fitting the blood pressure values of each pregnant woman to the linear equation, the intercept b1 of the linear equation and the intercept b2, intercept 3 can be obtained and used as a feature quantity.

Similarly, for example, the blood pressure of each pregnant woman at the time when a predetermined number of days have passed since the first day of pregnancy can be calculated using a fitted linear expression and used as a feature amount.

In this way, the feature amount extraction unit 112 extracts a feature amount related to a predetermined disease from temporal changes in quantitative traits collected from a plurality of subjects.

Note that the slopes a1, a2, a3 and the intercepts b1, b2, b3 described above are examples of feature amounts extracted by the feature amount extraction unit 112. FIG. Also, the linear expression shown in FIG. 6 is an example of a predetermined polynomial, and the predetermined polynomial may be a polynomial of degree 2 or higher.

Here, returning to FIG. 4, the description of the flowchart showing an example of DNA mutation narrowing down processing is continued.

In step S403, the DNA mutation information acquiring unit 113 of the DNA mutation narrowing down apparatus 110, for example, in parallel with the processing of steps S401 and S402, detects DNA mutations in a plurality of subjects including a subject suffering from a predetermined disease. Get information.

As an example, the DNA mutation information acquiring unit 113 uses the DNA information of a plurality of subjects including a subject suffering from a predetermined disease, which is received by the input receiving unit 111, to obtain predetermined DNA mutation information ( For example, all single nucleotide polymorphisms, etc.) are extracted (obtained).

As another example, the DNA mutation information obtaining unit 113 may obtain a plurality of subjects including a subject suffering from a predetermined disease, which are extracted by the DNA mutation information obtaining apparatus 210 shown in FIG. It may be one that acquires the subject's DNA mutation information. Further, the DNA mutation information acquiring unit 113 obtains the DNA mutation information of a plurality of subjects including a subject suffering from a predetermined disease from the pre-registered DNA mutation information DB 220 shown in FIG. DNA mutation information of a plurality of subjects including a subject who is in the same group may be obtained.

It should be noted that the plurality of subjects for whom continuous quantitative trait measurement values are obtained in step S401 and the plurality of subjects for which single nucleotide polymorphism information is obtained in step S403 are the same subjects.

In step S404, the association analysis unit 114 of the DNA mutation narrowing down apparatus 110 analyzes the association between the feature amount extracted in step S402 and the DNA mutation included in the DNA mutation information acquired in step S403.

As an example, the association analysis unit 114 performs association analysis (testing) using the feature amount as the objective variable and the DNA mutation as the explanatory variable, and calculates a statistical index value indicating the degree of association between the feature amount and each DNA mutation ( first specific example). For example, the association analysis unit 114 may use the p-value calculated from the Wald statistic of the coefficient of each DNA mutation as the value of the statistical index in a regression equation in which the feature amount is the objective variable and the DNA mutation is the explanatory variable. can be done.

As another example, the association analysis unit 114 uses a predetermined reference value to label the feature quantity as a diseased group and a non-diseased group, and for each DNA mutation, in the diseased group and the non-diseased group A value of a statistical index indicating whether there is a difference in the number of possessions is calculated (second specific example). For example, the association analysis unit 114 can perform Fisher's exact test or chi-square test, and use the p-value representing the significance probability as the value of the statistical index.

The test (association analysis) when the association analysis unit 114 calculates the value of the statistical index includes, for example, linear regression, logistic regression, Fisher's exact test, chi-square test, Cochran-Amitage test, and t-test. etc. are used, but are not limited to these. Also, the value of the statistical index calculated by the association analysis unit 114 may be, for example, a p-value, an f-value, or an odds ratio, but is not limited to this.

In addition, the association analysis unit 114 may further consider dominant gene action, recessive gene action, genotype, etc. to calculate the value of the statistical index, or use information such as age, weight, BMI, etc. as the amount of co-editing. It can be anything.

In step S405, the DNA mutation extraction unit 115 of the DNA mutation narrowing down device 110 extracts DNA mutations related to a given disease based on the analysis results of the association analysis unit 114. FIG. For example, the DNA mutation extracting unit 115 extracts DNA related to a predetermined disease from among the DNA mutations included in the DNA mutation information acquired in step S403, using the value of the statistical index calculated in step S404 as a reference value. Extract mutations. For example, the DNA mutation extraction unit 115 extracts DNA mutations whose statistical index values are greater than or equal to a reference value or less than or equal to the reference value.

The information on the DNA mutation extracted by the above process is output by the result output unit 117 of the DNA mutation screening device 110 to the output device 305, the storage 303, etc., as a DNA mutation candidate related to a predetermined disease, for example. output to

Next, the processing flow of the DNA mutation narrowing-down method in the first specific example and the second specific example will be described.

[First specific example]
In a first specific example, the association analysis unit 114 of the DNA mutation narrowing down apparatus 110 performs association analysis using the feature amount as the objective variable and the DNA mutation as the explanatory variable, and obtains statistics indicating the degree of association between the feature amount and each DNA mutation. An example of processing for calculating a target index value (for example, a p-value) will be described.

FIG. 7 is a flowchart showing an example of narrowing down processing for DNA mutations according to the first specific example according to the embodiment.

In step S701, the input reception unit 111 of the DNA mutation narrowing down apparatus 110 acquires continuous quantitative trait measurement values of a plurality of subjects, and stores the acquired continuous quantitative trait measurement values in the storage unit 116 or the like. Save (memorize) to

In step S<b>702 , the feature quantity extraction unit 112 of the DNA mutation narrowing down device 110 extracts a feature quantity related to a given phenotype from temporal changes in quantitative traits stored in the storage unit 116 . For example, the feature quantity extraction unit 112 executes a feature quantity extraction process as shown in FIG.

A phenotype is, for example, a person's genotype expressed as a trait. and pre-determined diseases such as hypertension, diabetes, pregnancy-induced hypertension, and coronary artery disease. This embodiment can be applied not only to specific diseases but also to narrow down gene mutations associated with specific phenotypes.

In steps S703 and S704, the DNA mutation narrowing down apparatus 110 acquires information on DNA mutations in a plurality of subjects, for example, in parallel with the processing of steps S701 and S702. For example, in step S<b>703 , the input reception unit 111 of the DNA mutation narrowing down device 110 acquires DNA information of multiple subjects and stores it in the storage unit 116 . In step 704, the DNA mutation information acquiring unit 113 of the DNA mutation narrowing down device 110 analyzes the DNA information of the plurality of subjects stored in the storage unit 116 and extracts DNA mutation information.

In steps S703 and S704, the DNA mutation information acquisition unit 113 acquires information on DNA mutations in a plurality of subjects from the DNA mutation information acquisition device 210 shown in FIG. 2, the DNA mutation information DB 220, or the like. Also good.

In step S705, the association analysis unit 114 of the DNA mutation narrowing down apparatus 110 performs association analysis (test) using the feature amount as the objective variable and the DNA mutation as the explanatory variable, and obtains statistics indicating the degree of association between the feature amount and each DNA mutation. Calculate the value of the target index. For example, the association analysis unit 114 calculates a p-value, an f-value, an odds ratio, and the like as statistical index values indicating the degree of association between the feature amount and each DNA mutation.

In step S706, the DNA mutation extraction unit 115 of the DNA mutation narrowing down device 110 extracts DNA mutations for which the value of the statistical index calculated in step S705 is greater than or equal to the reference value or less than or equal to the reference value.

By the above processing, the DNA mutation narrowing down device 110 can extract DNA mutations associated with a predetermined phenotype from among the DNA mutations obtained in steps S703 and S704.

(Application example)
FIG. 8 is a flowchart showing an application example of the DNA mutation narrowing-down process of the first specific example according to one embodiment.

Here, using the above-described processing, even when there are few DNA information samples or when the definition of a given disease is ambiguous, DNA mutations associated with a given disease can be easily narrowed down. A method for narrowing down mutations will be described.

Here, as a specific example, the following description will be given assuming that the prescribed disease is hypertensive disorders of pregnancy (hereinafter referred to as HDP: Hypertensive Disorders of Pregnancy).

Although diagnostic guidelines are set for HDP, in practice, blood pressure values similar to HDP may appear even if they are not classified as HDP. In such cases, there may not be a sufficient difference in genetic background between the diseased group and the non-affected group, and DNA mutations associated with a given disease may not be sufficiently narrowed down. HDP is an example of a disease in which the definition of an affected group and a non-affected group is ambiguous.

Also, here, as shown in FIG. 6, the slope indicating the rate of change of the measured blood pressure value is related to the prevalence of HDP. , tend to be greater than the slope of blood pressure measurements in pregnant women without HDP. It should be noted that blood pressure measurements of pregnant women are an example of continuous measurements of quantitative traits associated with a given disease. Also, the slope of the blood pressure measurement value is an example of a normalized feature amount.

In step S801, the input reception unit 111 of the DNA mutation narrowing down device 110 acquires continuous quantitative trait measurement values including blood pressure measurement values in a plurality of subjects, including subjects suffering from HDP, Stored in storage unit 116 .

In step S802, the feature quantity extraction unit 112 of the DNA mutation narrowing down device 110 extracts the feature quantity related to HDP from the temporal change of the quantitative trait. For example, as shown in FIG. 6, the feature quantity extraction unit 112 fits a measured blood pressure value 601 of a pregnant woman to a linear expression "y=ax+b" and extracts the slope a of the linear expression as a feature quantity.

In step S803, the DNA mutation information acquisition unit 113 of the DNA mutation narrowing down device 110 acquires single nucleotide polymorphism information extracted from the DNA information of a plurality of subjects including subjects suffering from HDP. For example, the DNA mutation information acquisition apparatus 210 in FIG. 2 extracts information on all single nucleotide polymorphisms in a DNA sequence using DNA information of a plurality of subjects including subjects suffering from HDP. Further, the DNA mutation information acquisition unit 113 acquires information on the extracted single nucleotide polymorphism from the DNA mutation information acquisition device 210 . Information on single nucleotide polymorphisms is an example of information on DNA mutations.

In step S804, the association analysis unit 114 of the DNA mutation narrowing down device 110 uses the feature amount extracted in step S802 as the objective variable and the single nucleotide polymorphism included in the single nucleotide polymorphism information acquired in step S803 as the explanatory variable. Perform an association analysis (test). For example, the association analysis unit 114 calculates the p-value representing the significance probability from the Wald statistic of the coefficient of each single nucleotide polymorphism in a regression equation in which the feature amount is the objective variable and the single nucleotide polymorphism is the explanatory variable.

In step S805, the DNA mutation extraction unit 115 of the DNA mutation narrowing down apparatus 110 extracts the single nucleotide polymorphisms included in the single nucleotide polymorphism information acquired in step S803, and the p-value is at a predetermined significance level. Single nucleotide polymorphisms smaller than (eg, 5×10 ⁻⁸ ) are extracted.

This makes it possible to extract single nucleotide polymorphism information related to the slope a of the blood pressure measurement value, for example, single nucleotide polymorphism information related to HDP, as shown in FIG.

According to this embodiment, for example, in a disease such as HDP in which symptoms of the disease and quantitative traits such as blood pressure are involved, when performing association analysis using quantitative traits, multi-time information can be handled. , it is possible to improve the accuracy of association analysis (test) and easily extract (narrow down) single nucleotide polymorphisms associated with a predetermined disease.

Further, in this embodiment, for example, as shown in FIG. 6, association analysis is performed using feature amounts extracted from continuous measurement values of quantitative traits. Thereby, measured values of a plurality of subjects measured in mutually different periods can be similarly processed. In addition, estimating the measured values of quantitative traits at time points different from the measurement period and performing association analysis and perform related analysis, etc.).

As described above, according to the present embodiment, a DNA mutation narrowing-down device, a DNA mutation narrowing-down system, and a A method for narrowing down DNA mutations can be provided.

[Second example]
In a first specific example, the association analysis unit 114 performs association analysis using the feature amount as the objective variable and the DNA mutation as the explanatory variable, and a statistical index value (for example, (p-value, etc.) has been described.

In a second specific example, the association analysis unit 114 uses a predetermined reference value to label the feature quantity as a diseased group and a non-diseased group, and for each DNA mutation, the diseased group and the non-diseased group. An example of processing for calculating the value of a statistical index indicating whether there is a difference in the number of possessions between groups will be described.

FIG. 9 is a flow chart showing an example of narrowing down processing for DNA mutations in the second specific example according to one embodiment. A detailed description of the same processing as in the first specific example is omitted here.

In step S901, the input reception unit 111 of the DNA mutation narrowing down device 110 acquires continuous quantitative trait measurement values of a plurality of subjects, and stores the acquired continuous quantitative trait measurement values in the storage unit 116. Save (memorize).

In step S902, the DNA mutation narrowing down apparatus 110 extracts a feature amount related to a predetermined phenotype from changes in quantitative traits over time, and uses the extracted feature amount as a diseased group using a predetermined reference value. Unaffected and unaffected groups are labeled. For example, the DNA mutation narrowing down device 110 executes the labeling process for the diseased group and the non-diseased group as shown in FIG.

FIG. 10 is a flow chart showing an example of the process of labeling the diseased group and the non-diseased group in the second specific example according to one embodiment. This process shows an example of the diseased group and non-diseased group labeling process executed by the DNA mutation screening device 110 in step S902 of FIG.

In step S1001, the feature extraction unit 112 of the DNA mutation narrowing down apparatus 110 fits the continuous quantitative trait measurement values acquired by the input reception unit 111 to a polynomial.

In step S1002, the feature quantity extraction unit 112 calculates coefficients, intercepts, etc. of the fitted polynomial.

In step S1003, the feature quantity extraction unit 112 extracts a normalized feature quantity using the calculated coefficient, intercept, or coefficient and intercept.

As a specific example, when the predetermined phenotype is HDP, the feature quantity extraction unit 112, as described above with reference to FIG. , and the slope of the linear expression is extracted as a feature quantity.

In step S1004, the association analysis unit 114 of the DNA mutation narrowing down device 110 classifies (labels) the feature amount extracted by the feature amount extraction unit 112 into a diseased group and a non-diseased group using a predetermined reference value. do.

For example, as described above, the slope of blood pressure measurements in pregnant women with HDP tends to be greater than the slope of blood pressure measurements in pregnant women without HDP. (reference value) can be used to classify diseased and non-diseased groups. As a specific example, the association analysis unit 114 can label a feature quantity larger than a predetermined slope as a diseased group, and label a feature quantity less than or equal to a predetermined slope as a non-diseased group.

Here, returning to FIG. 9, the description of the flowchart showing an example of narrowing down processing for DNA mutations will be continued.

In steps S903 and S904, the DNA mutation narrowing down apparatus 110 acquires information on DNA mutations in a plurality of subjects, for example, in parallel with the processing of steps S901 and S902.

In step S905, the association analysis unit 114 of the DNA mutation narrowing down device 110 determines the number of possessions in the diseased group and the non-diseased group for each DNA mutation included in the DNA mutation information acquired by the DNA mutation information acquisition unit 113. Calculate the value of a statistical indicator that indicates whether there is a difference in

As a specific example, the association analysis unit 114 performs Fisher's exact test or chi-square test to calculate the p-value.

In step S906, the DNA mutation extraction unit 115 of the DNA mutation narrowing down device 110 extracts DNA mutations for which the value of the statistical index calculated by the association analysis unit 114 is equal to or greater than the reference value or equal to or less than the reference value.

As a specific example, the DNA mutation extraction unit 115 extracts DNA mutations whose p-values are equal to or less than a predetermined reference value (for example, 0.05).

In the above process, for example, by setting the predetermined phenotype as HDP, the measured value of the quantitative trait as the blood pressure measurement value of the pregnant woman, and the slope of the blood pressure measurement value as the feature quantity, the same as in the first specific example , DNA mutations (single nucleotide polymorphisms) associated with HDP can be extracted.

Also in the second specific example, even when there are few specimen samples or when the definition of a disease is ambiguous, DNA mutation narrowing down can easily narrow down DNA mutations associated with a given disease. Devices, DNA mutation screening systems, and DNA mutation screening methods can be provided.

As described above, according to the embodiments of the present invention, significant DNA mutations can be narrowed down even in cases where the number of samples is small, or the definition of a disease is ambiguous, and effective results cannot be obtained by ordinary genome-wide association analysis. can be included. As a result, it can be expected to identify disease-related DNA mutations that could not be identified by conventional techniques, and to utilize them for early detection and prevention of diseases.

<Supplement>
1 and 2 show blocks for each function. These functional blocks are realized by any combination of hardware and/or software. Further, means for realizing each functional block is not particularly limited. That is, each functional block may be implemented by one device physically and/or logically coupled, or may be implemented by two or more physically and/or logically separated devices directly and/or indirectly. These multiple devices may be connected together (eg, wired and/or wirelessly).

The hardware configuration of the DNA mutation screening device 110 shown in FIG. 3 may be configured to include one or more of each device shown in the figure, or may be configured without including some of the devices. Also good. In addition, the DNA mutation screening device 110 includes hardware such as a microprocessor, a digital signal processor (DSP), an ASIC (Application Specific Integrated Circuit), a PLD (Programmable Logic Device), and an FPGA (Field Programmable Gate Array). , and part or all of each functional block may be implemented by the hardware. For example, processor 301 may be implemented with at least one of these hardware.

The processing procedures, sequences, flowcharts, etc. of each aspect/embodiment described herein may be interchanged in order as long as there is no contradiction. For example, the methods described herein present elements of the various steps in a sample order, and are not limited to the specific order presented.

Input/output information and the like may be stored in a specific location (for example, memory), or may be managed in a management table. Input/output information and the like can be overwritten, updated, or appended. The output information and the like may be deleted. The entered information and the like may be transmitted to another device.

The determination may be made by a value represented by 1 bit (0 or 1), by a true/false value (Boolean: true or false), or by numerical comparison (for example, a predetermined value).

Each aspect/embodiment described herein may be used alone, may be used in combination, or may be used by switching between implementations. In addition, the notification of predetermined information (for example, notification of “being X”) is not limited to being performed explicitly, but may be performed implicitly (for example, not notifying the predetermined information). Also good.

Software, whether referred to as software, firmware, middleware, microcode, hardware description language or otherwise, includes instructions, instruction sets, code, code segments, program code, programs, subprograms, and software modules. , applications, software applications, software packages, routines, subroutines, objects, executables, threads of execution, procedures, functions, and the like.

Software, instructions, etc. may also be transmitted and received over a transmission medium. For example, the software can be used to access websites, servers, or other When transmitted from a remote source, these wired and/or wireless technologies are included within the definition of transmission media.

Information, signals, etc. described herein may be represented using any of a variety of different technologies. For example, data, instructions, commands, information, signals, bits, symbols, chips, etc. that may be referred to throughout the above description may refer to voltages, currents, electromagnetic waves, magnetic fields or magnetic particles, light fields or photons, or any of these. may be represented by a combination of

The terms explained in this specification and/or terms necessary for understanding this specification may be replaced with terms having the same or similar meanings.

In addition, the information, parameters, and the like described in this specification may be represented by absolute values, may be represented by relative values from a predetermined value, or may be represented by corresponding other information. . For example, radio resources may be indexed.

As used herein, the phrase "based on" does not mean "based only on," unless expressly specified otherwise. In other words, the phrase "based on" means both "based only on" and "based at least on."

To the extent that "including," "comprising," and variations thereof are used herein or in the claims, these terms, as well as the term "comprising," intended to be inclusive. Furthermore, the term "or" as used in this specification or the claims is not intended to be an exclusive OR.

Throughout this disclosure, where articles have been added by translation, e.g., a, an, and the in English, these articles are used unless the context clearly indicates otherwise. It shall include plural things.

Although the present invention has been described in detail above, it will be apparent to those skilled in the art that the present invention is not limited to the embodiments described herein. The present invention can be implemented with modifications and variations without departing from the spirit and scope of the invention defined by the claims. Accordingly, the descriptions herein are for illustrative purposes only and are not meant to be limiting of the present invention.

100 DNA mutation narrowing down system 110 DNA mutation narrowing down device 112 Feature quantity extraction unit 113 DNA mutation information acquisition unit (acquisition unit)
114 Association analysis part (analysis part)
115 DNA Mutation Extractor

Claims (10)

A continuous measure of a quantitative trait associated with a given disease collected from a plurality of subjects, including subjects with the given diseaseto a predetermined polynomial, and using the coefficient of the polynomial, the intercept of the polynomial, or the coefficient and intercept of the polynomial, for each subjecta feature quantity extraction unit that extracts a feature quantity;
an acquisition unit that acquires information on DNA mutations in the plurality of subjects;
an analysis unit that analyzes the relationship between the feature quantity and the DNA mutation;
a DNA mutation extraction unit that extracts a DNA mutation associated with the predetermined disease based on the analysis result of the analysis unit;
havedeath,
The analysis unit performs association analysis using the feature amount as an objective variable and the DNA mutation as an explanatory variable, and calculates a statistical index value indicating the degree of association between the feature amount and each DNA mutation,
The DNA mutation extraction unit extracts DNA mutations in which the value of the statistical index calculated by the analysis unit is a predetermined reference value or more or a reference value or less.
D.NA mutation screening device. Fitting a given polynomial to continuous measurements of a quantitative trait associated with the given disease, collected from a plurality of subjects, including subjects suffering from the given disease, the coefficients of the polynomial, A feature quantity extraction unit that extracts a feature quantity for each subject using the intercept of the polynomial, or the coefficient and intercept of the polynomial,
an acquisition unit that acquires information on DNA mutations in the plurality of subjects;
an analysis unit that analyzes the relationship between the feature quantity and the DNA mutation;
a DNA mutation extraction unit that extracts a DNA mutation associated with the predetermined disease based on the analysis result of the analysis unit;
has
The analysis unit is
Labeling the feature amount extracted by the feature amount extraction unit into a group affected by the predetermined disease and a group not affected by the predetermined disease using a predetermined reference value,
For each DNA mutation contained in the DNA mutation information acquired by the acquisition unit, calculate a statistical index value indicating whether there is a difference in the number of possession between the diseased group and the non-diseased group,
The DNA mutation extraction unit extracts DNA mutations in which the value of the statistical index calculated by the analysis unit is a predetermined reference value or more or a reference value or less.,
D.NA mutation screening device. The DNA mutation includes a single nucleotide polymorphism,
The statistical index includes a p-value representing a significance probability,
3. The DNA mutation narrowing down device according to claim 1, wherein said DNA mutation extracting unit extracts said single nucleotide polymorphisms whose p-value is smaller than a predetermined significance level. The predetermined disease includes gestational hypertension,
4. The DNA mutation narrowing down apparatus according to any one of claims 1 to 3 , wherein the continuous measured values of quantitative traits related to the predetermined disease include measured values of blood pressure measured at predetermined time intervals. . Continuous measurements of a quantitative trait associated with a given disease collected from a plurality of subjects, including subjects with the given diseaseis fitted to a predetermined polynomial, and using the coefficient of the polynomial, the intercept of the polynomial, or the coefficient and intercept of the polynomial, for each subjecta feature quantity extraction unit that extracts a feature quantity;
an acquisition unit that acquires information on DNA mutations in the plurality of subjects;
an analysis unit that analyzes the relationship between the feature quantity and the DNA mutation;
a DNA mutation extraction unit that extracts a DNA mutation associated with the predetermined disease based on the analysis result of the analysis unit;
havedeath,
The analysis unit performs association analysis using the feature amount as an objective variable and the DNA mutation as an explanatory variable, and calculates a statistical index value indicating the degree of association between the feature amount and each DNA mutation,
The DNA mutation extraction unit extracts DNA mutations in which the value of the statistical index calculated by the analysis unit is a predetermined reference value or more or a reference value or less.
D.NA mutation screening system. Fitting a predetermined polynomial to continuous measurements of a quantitative trait associated with the predetermined disease collected from a plurality of subjects, including subjects suffering from the predetermined disease, the coefficients of the polynomial, A feature quantity extraction unit that extracts a feature quantity for each subject using the intercept of the polynomial, or the coefficient and intercept of the polynomial,
an acquisition unit that acquires information on DNA mutations in the plurality of subjects;
an analysis unit that analyzes the relationship between the feature quantity and the DNA mutation;
a DNA mutation extraction unit that extracts a DNA mutation associated with the predetermined disease based on the analysis result of the analysis unit;
has
The analysis unit is
labeling the feature amount extracted by the feature amount extracting unit into a diseased group and a non-affected group of the predetermined disease using a predetermined reference value;
For each DNA mutation included in the DNA mutation information acquired by the acquisition unit, calculate a statistical index value indicating whether there is a difference in the number of possession between the diseased group and the non-diseased group,
The DNA mutation extraction unit extracts DNA mutations in which the value of the statistical index calculated by the analysis unit is a predetermined reference value or more or a reference value or less.
DNA mutation screening system. the computer
A continuous measure of a quantitative trait associated with a given disease collected from a plurality of subjects, including subjects with the given diseaseis fitted to a predetermined polynomial, and using the coefficient of the polynomial, the intercept of the polynomial, or the coefficient and intercept of the polynomial, for each subjecta process of extracting a feature quantity;
a process of obtaining information on DNA mutations in the plurality of subjects;
analyzing the relationship between the feature amount and the DNA mutationanalysisprocessing;
Saidanalysisextracting a DNA mutation associated with the predetermined disease based on the analysis result of the treatment;DNA mutation extractionprocessing;
rundeath,
In the analysis process, association analysis is performed using the feature amount as an objective variable and the DNA mutation as an explanatory variable, and a statistical index value indicating the degree of association between the feature amount and each DNA mutation is calculated;
The DNA mutation extraction process extracts DNA mutations in which the value of the statistical index calculated in the analysis process is a predetermined reference value or more or a reference value or less.
DNA mutation screening method. the computer
Fitting a predetermined polynomial to continuous measurements of a quantitative trait associated with the predetermined disease collected from a plurality of subjects, including subjects suffering from the predetermined disease, the coefficients of the polynomial, A feature quantity extraction process for extracting a feature quantity for each subject using the intercept of the polynomial, or the coefficient and intercept of the polynomial,
an acquisition process for acquiring information on DNA mutations in the plurality of subjects;
an analysis process for analyzing the relationship between the feature amount and the DNA mutation;
a DNA mutation extraction process for extracting a DNA mutation associated with the predetermined disease based on the analysis result of the analysis process;
and run
The analysis process includes
Labeling the feature amount extracted by the feature amount extraction process into the diseased group and the non-affected group of the predetermined disease using a predetermined reference value,
For each DNA mutation contained in the DNA mutation information acquired in the acquisition process, calculate a statistical index value indicating whether there is a difference in the number of carriers in the diseased group and the non-diseased group,
The DNA mutation extraction process extracts DNA mutations in which the value of the statistical index calculated in the analysis process is a predetermined reference value or more or a reference value or less.
DNA mutation screening method. to the computer,
A continuous measure of a quantitative trait associated with a given disease collected from a plurality of subjects, including subjects with the given diseaseto a predetermined polynomial, and using the coefficient of the polynomial, the intercept of the polynomial, or the coefficient and intercept of the polynomial, for each subjecta process of extracting a feature quantity;
a process of obtaining information on DNA mutations in the plurality of subjects;
analyzing the relationship between the feature amount and the DNA mutationanalysisprocessing;
extracting a DNA mutation associated with the predetermined disease based on the analysis result of the analyzing process;DNA mutation extractionprocessing;
run,
In the analysis process, association analysis is performed using the feature amount as an objective variable and the DNA mutation as an explanatory variable, and a statistical index value indicating the degree of association between the feature amount and each DNA mutation is calculated;
The DNA mutation extraction process extracts DNA mutations in which the value of the statistical index calculated in the analysis process is a predetermined reference value or more or a reference value or less.
program. to the computer,
Fitting a predetermined polynomial to continuous measurements of a quantitative trait associated with the predetermined disease collected from a plurality of subjects, including subjects suffering from the predetermined disease, the coefficients of the polynomial, A feature amount extraction process for extracting a feature amount for each subject using the intercept of the polynomial, or the coefficient and intercept of the polynomial,
an acquisition process for acquiring information on DNA mutations in the plurality of subjects;
an analysis process for analyzing the relationship between the feature amount and the DNA mutation;
a DNA mutation extraction process for extracting a DNA mutation associated with the predetermined disease based on the analysis result of the analysis process;
and
The analysis process includes
Labeling the feature amount extracted by the feature amount extraction process into the diseased group and the non-affected group of the predetermined disease using a predetermined reference value,
For each DNA mutation contained in the DNA mutation information acquired in the acquisition process, calculate a statistical index value indicating whether there is a difference in the number of carriers in the diseased group and the non-diseased group,
The DNA mutation extraction process extracts DNA mutations in which the value of the statistical index calculated in the analysis process is a predetermined reference value or more or a reference value or less.
program.

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