Dosage regimen decision support system, dosage regimen decision support method, and dosage regimen decision support program

Abstract

To provide a support system, a method and a program capable of supporting determination of a medicine administration plan suitable for a patient, on the basis of a genotype unique to the patient.SOLUTION: There is provided an administration plan determination support system 1. The system comprises an information acquisition part configured so that: the information acquisition part acquires medicine information which indicates a planned medicine and an amount for its administration; the information acquisition part acquires at least one of inhibition factor information on a locus on a genome for which administration of the medicine is inhibited, and essential factor information on the locus on the genome which is required for administration of the medicine; the information acquisition part acquires information of a patient's genotype including at least one genotypic information out of a first genotype of the patient on the locus of the genome corresponding to the inhibition factor, and a second genotype of the patient on the locus on the genome corresponding to the essential factor. On the basis of at least one of a comparison result between the inhibition factor information and first genotype information and a comparison result between the essential factor information and the second genotype information, the system determines the propriety of the medicine information for the patient.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a system for assisting in determining a drug administration regimen, and more particularly to a system for assisting in determining a drug administration regimen suitable for a patient based on the patient's unique genotype. [Background technology]

[0002] The relationship between gene function and the effectiveness of medicines has been pointed out for some time, and there have been proposals to prescribe medicines tailored to specific patients by utilizing information on those patients (e.g., Patent Document 1).

[0003] However, no system has yet been proposed that uses a patient's genetic information to determine whether a drug thought to be effective against a certain disease is actually safe and effective for a particular patient. This is because there are multiple drugs known to be effective against a single disease, there are multiple genes that affect the efficacy or side effects of a single drug, and it is well known that the expression of the function of a single gene is related to multiple other genes.

[0004] Therefore, current outpatient and in-hospital prescriptions written by doctors (which specify the type, dosage, and administration of a drug) still apply uniform factors (mainly the type of disease the patient suffers from, the severity of the disease, and the patient's age, weight, and sex, etc.). Such prescriptions fail to specify the type, dosage, and administration of a drug that is appropriate for each individual patient. In fact, multiple patients who use a drug as prescribed have widely different reactions. It has been pointed out that such reactions may include cases where the drug only has adverse effects on the patient (exhibiting only side effects and no efficacy).

[0005] In addition to prescription medications, there are other drugs and other substances (such as anesthetics) whose administration or use to patients requires the supervision of a healthcare professional. It is well known that the administration or use of such drugs or substances can cause an adverse reaction in some individuals and is often accompanied by side effects.

[0006] Individual differences in drug efficacy and side effects are due more to genetic variation in the human population than to the influence of disease type, environmental factors (such as lifestyle) and / or the combination of medications being taken.

[0007] Clinical genome sequencing is the ultimate method for scanning for pathogenic variants, but it often reveals many variants of unknown clinical significance in each individual. An ethical concern is how to handle the incidental discovery of pathogenic variants unrelated to the original sequencing target. Clinical genome sequencing is expected to soon be integrated into existing healthcare systems in many developed countries. However, significant bioinformatics and electronic networking challenges remain. Furthermore, there are ethical concerns about releasing data when knowledge is currently incomplete, particularly when the clinical significance of many variants is unclear.

[0008] Meanwhile, DNA diagnostics are moving from analyzing a limited number of genes to analyzing the entire genome, becoming relevant in almost every medical specialty. As the scope and utility of genetic testing increases, the old system in which clinical geneticists arranged most genetic tests is no longer appropriate. It is expected that members of the clinical team, including the clinicians who analyze and manage patients, will increasingly be required to obtain and use test results directly.

[0009] In the future, clinicians will likely receive complex DNA and chromosome test results, but currently, there is little information available to assist in their interpretation. "Mainstreaming genetics" aims to integrate genetic testing into mainstream routine medical care, and diagnostic testing will likely become the responsibility of the clinician to whom the patient is initially referred. Therefore, clinicians across various specialties who have limited experience with genetic testing will need to be able to interpret and communicate genetic test results and develop the necessary knowledge. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-218684 Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, an object of the present invention is to provide a dosage regimen determination support system, a dosage regimen determination support method, and a dosage regimen determination support program that support users such as clinicians, pharmacists, and nurses in determining a drug dosage regimen appropriate for a patient based on the patient's unique genotype, without requiring the user to have experience in genetic testing that is required of clinical geneticists. [Means for solving the problem]

[0012] In order to solve the above problems, the present invention includes the following embodiments. Item 1. A decision support system for determining an appropriate medication regimen for a patient, a pharmaceutical information acquisition unit that acquires pharmaceutical information representing pharmaceuticals and dosages to be administered to the patient; at least one of a prohibited factor information acquisition unit that acquires prohibited factor information, which is information on the genotype at a locus on the genome where administration of the drug is prohibited, and an essential factor information acquisition unit that acquires essential factor information, which is information on the genotype at a locus on the genome where administration of the drug is required; a patient genotype information acquisition unit that acquires information on the patient's genotype, the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a dosage plan determination unit that determines whether the pharmaceutical information is appropriate for the patient based on at least one of a comparison result between the prohibited factor information and the first genotype information and a comparison result between the essential factor information and the second genotype information; A decision support system with. Item 2. The device includes both the prohibited factor information acquisition unit and the essential factor information acquisition unit, Item 10. The support system according to Item 1, wherein the administration plan determination unit determines an administration plan for the patient based on a comparison result between the prohibited factor information and the first genotype information, and a comparison result between the essential factor information and the second genotype information. Item 3. Further comprising an administration plan output unit that outputs an administration plan for the patient, the administration plan determination unit determines the pharmaceutical information scheduled to be administered to the patient as suitable pharmaceutical information when the first genotype information does not match the prohibited factor information and the second genotype information matches the essential factor information; Item 3. The support system according to Item 1 or 2, wherein when the administration plan determination unit determines that the pharmaceutical information scheduled to be administered to the patient is suitable pharmaceutical information, the administration plan output unit outputs the pharmaceutical information scheduled to be administered to the patient as suitable pharmaceutical information. Item 4. A dosage plan output unit that outputs a dosage plan for the patient; and a medical information modification unit that modifies the medical information if the medical information is inappropriate; Furthermore, the administration plan determination unit determines that the drug information scheduled to be administered to the patient is inappropriate when the first genotype information matches the prohibited factor information or when the second genotype information does not match the essential factor information; Item 4. The support system according to any one of Items 1 to 3, wherein, when the administration plan determination unit determines that the pharmaceutical information scheduled to be administered to the patient is inappropriate, the administration plan output unit outputs a warning indicating that the pharmaceutical information is inappropriate and modified pharmaceutical information modified by the pharmaceutical information modification unit. Item 5. The support system according to any one of Items 1 to 4, wherein the prohibition factor information is a genotype having a mutation associated with the function of a gene encoding a protein involved in the pharmacokinetics or pharmacodynamics of the drug, a genotype relating to a combination of alleles associated with a predisposition to a disease that develops or becomes severe when administered with the drug, a genotype having a mutation associated with a causative gene of a monogenic disease that has been proven to be involved in the onset of side effects when administered with the drug, or a genotype having a rare variant, an individual-specific variant, or a Mendelian-like subset mutation that has been proven to have a strong influence or effect on a multifactorial disease or polygenic disease that has been proven to be involved in the onset of side effects when administered with the drug. Item 6. The support system according to any one of Items 1 to 5, wherein the essential factor information is a genotype having an allele type or a combination of allele types at a specific locus on the genome that is essential for the efficacy of the drug that functions as a molecular target for a specific disease. Item 7. When the first genotype information and / or the second genotype information is not recorded as the patient genotype information, the system obtains information representing the entire nucleotide sequence constituting the patient's genome, detects DNA variants present at the loci of the first genotype and / or the second genotype from the information representing the entire nucleotide sequence, and updates the patient genotype information; Item 7. The support system according to any one of Items 1 to 6, wherein the patient genotype information includes information representing variants whose frequency in the human population is less than 1%. Item 8. The system, in order to detect the DNA variant, generating a junction sequence in which a target nucleotide sequence corresponding to the DNA variant is joined to partial nucleotide sequences on both sides of the position corresponding to the DNA variant in a reference human genome, and comparing the junction sequence with the entire nucleotide sequence constituting the genome of the patient; Item 8. The support system according to Item 7, wherein the partial nucleotide sequence is repeated with increasing length. Item 9. The system, in order to detect the DNA variant, generating two nucleotide sequences corresponding to partial nucleotide sequences on either side of the position corresponding to the DNA variant in a reference human genome, and comparing the two nucleotide sequences with the entire nucleotide sequence constituting the patient's genome; Item 8. The support system according to Item 7, wherein the partial nucleotide sequence is repeated with increasing length. Item 10. Information representing single nucleotide polymorphisms among the DNA variants is determined using the patient's genome fragment or based on the information representing the entire nucleotide sequence, and the determined information representing single nucleotide polymorphisms is recorded; Item 10. The support system according to any one of Items 7 to 9, wherein information representing the unrecorded DNA variant is determined based on character information representing the entire nucleotide sequence. Item 11. Further comprising a dosage plan output unit that outputs a dosage plan for the patient, Item 11. The support system according to any one of items 1 to 10, wherein the administration plan output unit transmits the administration plan for the patient to a user terminal equipped with a display device. Item 12. The assistance system according to any one of Items 1 to 11, wherein the prohibited factor information and / or the required factor information is generated by artificial intelligence. Item 13. A method for supporting the determination of an appropriate dosing regimen for a patient, the method being implemented by a computer, a pharmaceutical information acquisition step of acquiring pharmaceutical information indicating the pharmaceutical and dosage to be administered to the patient; at least one of a step of acquiring information on prohibited factors, which is information on the genotype at a locus on the genome where administration of the drug is prohibited, and a step of acquiring information on essential factors, which is information on the genotype at a locus on the genome where administration of the drug is required; a patient genotype information acquisition step of acquiring information on the patient's genotype, the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a step of determining whether the pharmaceutical information is appropriate for the patient based on at least one of the results of comparing the prohibited factor information with the first genotype information and the results of comparing the essential factor information with the second genotype information; A method comprising: Item 14. A decision support program for determining an appropriate medication regimen for a patient, comprising: a pharmaceutical information acquisition unit that acquires pharmaceutical information representing pharmaceuticals and dosages to be administered to the patient; at least one of a prohibited factor information acquisition unit that acquires prohibited factor information, which is information on the genotype at a locus on the genome where administration of the drug is prohibited, and an essential factor information acquisition unit that acquires essential factor information, which is information on the genotype at a locus on the genome where administration of the drug is required; a patient genotype information acquisition unit that acquires information on the patient's genotype, the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a dosage plan determination unit that determines whether the pharmaceutical information is appropriate for the patient based on at least one of the results of comparing the prohibited factor information with the first genotype information and the results of comparing the essential factor information with the second genotype information; A program to function as a [Effects of the Invention]

[0013] According to the present invention, it is possible to determine a drug administration regimen appropriate for a patient based on the patient's unique genotype, without requiring the systematic knowledge and experience in genetic testing that is required of a clinical geneticist. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a schematic diagram for explaining the concept of the present invention. [Figure 2] 1 is an explanatory diagram of a system according to an embodiment of the present invention; [Figure 3] 1A and 1B are explanatory diagrams showing examples of (a) patient information, (b) pharmaceutical information, (c) patient genotype information, (d) prohibited factor information, and (e) essential factor information. [Figure 4] FIG. 3 is an explanatory diagram of an example of processing executed by the administration regimen determination support system of FIG. 2. [Figure 5] FIG. 3 is an explanatory diagram of an example of processing executed by the administration regimen determination support system of FIG. 2. [Figure 6] FIG. 10 is an explanatory diagram of an example of changed pharmaceutical information in which the dosage of a pharmaceutical has been changed. [Figure 7] FIG. 10 is an explanatory diagram of an example of changed pharmaceutical information in which the type of pharmaceutical has been changed. [Figure 8] 1 is an explanatory diagram of examples of drug information, modified drug information, prohibited factor information, and essential factor information regarding a change in drug dosage. (a) Relevance information A, (b) Modified drug information B regarding dosage [Figure 9] FIG. 1 is a schematic diagram showing the structure of a character string for determining the allele type (genotype) of any DNA variant in the human genome. [Figure 10] FIG. 1 shows an example of a method for determining the allele type (genotype) of a DNA variant (including SNP) present on a genome sequence. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, a "dosing regimen" is a guideline (e.g., a prescription) for administering a certain medication to a specific patient at a certain dosage. A "dosing regimen" includes at least information that identifies the specific patient and information that identifies the type and dosage of the medication that is planned to be administered to the specific patient.

[0016] As used herein, the term "drug" refers to a drug that exerts a medicinal effect in a patient to directly improve the symptoms of a disease, or a substance (such as a contrast agent or anesthetic) used to assist in medical procedures (such as examinations and anesthesia). Drugs include ethical drugs and over-the-counter drugs (also known as over-the-counter drugs). Ethical drugs include prescription drugs that require a doctor's prescription.

[0017] As used herein, "genotype" refers to the genetic makeup of an individual as a whole or at a specific locus on the genome of an individual, and refers to the type of combination of alleles at one or more loci in the genome (when two or more loci are the subject of the genotype, the sum of the types). As used herein, "allele" refers to an individual gene and DNA sequence present at one locus on a single chromosome. When referring to "genotype" or "allele type," these terms are used to include the concept of "mating type."

[0018] In this specification, genotype information of a "prohibited factor" refers to information on the allele type or combination of allele types (genotype) at a locus on the genome at which the administration of a specific drug is prohibited, and genotype information of an "essential factor" refers to information on the allele type or combination of allele types (genotype) at a locus on the genome at which the administration of a specific drug is required.

[0019] "Medical information" refers to information that includes at least information identifying a patient (e.g., a patient's ID number), information identifying a medication (e.g., a drug's trade name or substance name), and information specifying the dosage of the medication for the patient. Medication information may be, for example, a medical record or prescription created by a doctor on a computer.

[0020] "Suitability (of drug information)" indicates whether the relationship between the patient and the type of drug and / or its dosage specified in the drug information is appropriate based on the patient's unique genotype.

[0021] As used herein, the term "DNA variant" refers to a specific site on the genome where two or more nucleotide sequence (including alleles and chromosomal structures) changes exist in the human population (regardless of their frequency), as well as the totality of such changes (i.e., all alleles at the specific site). The change in the nucleotide sequence refers to any change, including substitution, deletion, insertion and / or addition, or duplication of one or more nucleotides.

[0022] Among the above-mentioned "DNA variants," when they are changes that occur frequently (1% or more) in a population, they are called "polymorphisms (P: Polymorphisms)," such as single nucleotide polymorphisms (hereinafter referred to as "SNPs"), copy number polymorphisms (hereinafter referred to as "CNPs"), and microsatellite polymorphisms (short tandem repeat polymorphisms (hereinafter referred to as "STRPs"). Furthermore, when they occur infrequently (less than 1%) in a population, they are called "variants (V: Variants)," such as single nucleotide variants (hereinafter referred to as "SNVs") and copy number variants (hereinafter referred to as "CNVs." As mentioned above, in this specification, the term "DNA variant" encompasses both "polymorphisms" and "variants," regardless of their frequency in the human population.

[0023] The total type of allele combinations ("allele types") including the zygote type at a locus (i.e., all allele types at that particular site) is determined by the nucleotide sequence of each allele and / or the number of alleles contained in the combination. Administration of the drug to a patient in which at least one of the nucleotide sequences is not the most common wild-type nucleotide sequence in the human population and / or the number of alleles is not the usual two (i.e., a patient with an unusual type) may cause undesirable effects in the patient. Such undesirable effects include, for example, (a) a decrease, loss, or excessive increase in the efficacy of the drug, (b) the onset or increase of side effects caused by the drug, and / or (c) a high incidence of a specific disease that did not occur before administration of the drug, compared to a patient with a normal type. However, in reality, such undesirable effects often do not appear in a single "allele type" alone, but rather appear when multiple "allele types" at multiple loci are accumulated.

[0024] FIG. 1 is a schematic diagram illustrating the concept of the present invention. A decision-making support system for drug administration regimens to be administered to a patient according to an embodiment of the present invention supports the determination of a customized administration regimen (e.g., drug B' and dosage C') tailored to the genotype information of patient A. Criteria for determining the administration regimen include (1) the pharmacokinetic factors of drug B, (2) the pharmacodynamic factors of drug B, and (3) the risk of secondary diseases caused by drug B. "Pharmacokinetics" refers to the behavior of a drug or its metabolites in the body that changes the probability of contact between a drug and a target molecule. "Pharmacodynamics" refers to the strength of the effect of a substance (drug) on ​​a target substance in the body. (1) and (2) are used to appropriately control the degree to which the chemical structure of drug B administered to a patient interacts with proteins expressed in the patient's body (the pharmacokinetic or pharmacodynamic factors of drug B). (3) is used to prevent the risk of developing a certain disease based on the patient's unique genetic background from becoming apparent (i.e., preventing the disease from developing) by administering a drug (artificial action). Regarding the above (1) to (3), in this application, "prohibitory factors," which are genotypes that prohibit the administration of a drug, and "essential factors," which are genotypes that are essential for the administration of a drug, are used in the judgment process for determining the administration plan (see "(System of the Invention)" in Figure 1).

[0025] An embodiment of the present invention will be described in detail below.

[0026] [Embodiment 1] 2 to 8, an embodiment of a system for supporting decision-making on a drug administration regimen for a patient, a method for supporting decision-making on a drug administration regimen, and a program for supporting decision-making on a drug administration regimen will be described. The present decision-making support system is a system that assists users in making decisions by creating a drug administration regimen (custom-made administration regimen) that is suitable for the patient. Users include medical professionals such as doctors, nurses, and pharmacists, as well as patients themselves.

[0027] As shown in FIG. 2 , a support system 1 for determining a dosage regimen for a drug to be administered to a patient according to one embodiment of the present invention includes a control unit 10, a display device 20 such as a display connected to the control unit 10, and an input device 30 such as a keyboard or a mouse connected to the control unit 10. The control unit 10 also includes an information acquisition unit 110 (a drug information acquisition unit, a prohibited factor information acquisition unit, an essential factor information acquisition unit, and a patient genotype information acquisition unit), a dosage regimen determination unit 120, a drug information modification unit 130, and a dosage regimen output unit 140. The information acquisition unit 110, the dosage regimen determination unit 120, the drug information modification unit 130, and the dosage regimen output unit 140 are included in a central processing unit (CPU) in the control unit 10. The control unit 10 is connected to a drug-related genetic information DB 40 and a genome information DB 50. The drug-related genetic information DB 40 includes at least genotype information associated with the efficacy and side effects (secondary diseases) of the drug, as well as genotype information on “prohibited factors” and “essential factors” based on the genotype information. The administration regimen determination support system 1 outputs information generated by the control unit 10 based on information acquired from the input device 30, the medical-related genetic information DB 40, and the genome information DB 50 to the user via the display device 20.

[0028] The control unit 10 (FIG. 2) includes a control means such as a CPU, memories such as RAM and ROM, and performs various processes described below. By executing a dosing regimen determination support program, the control unit 10 (FIG. 2) functions as an information acquisition unit 110, a dosing regimen determination unit 120, a medical information change unit 130, and a dosing regimen output unit 140.

[0029] The information acquisition unit 110 (FIG. 2) executes a process of acquiring information including patient information 400, pharmaceutical information 500, patient genotype information 600, prohibited factor information 700, and essential factor information 800 (FIGS. 3(a) to (e)), which will be described later.

[0030] The administration plan determination unit 120 (FIG. 2) executes a process of determining an administration plan based on the information acquired by the information acquisition unit 110 (FIG. 2).

[0031] The medical information changing section 130 (FIG. 2) executes processing to change the medical information 500 (FIG. 3(b)) based on the determination result by the administration plan determining section 120 (FIG. 2).

[0032] The administration plan output unit 140 (FIG. 2) executes a process of outputting the medical information 500 (FIG. 3(b)) or the changed medical information 510 (FIG. 6) based on the determination result by the administration plan determination unit 120 (FIG. 2).

[0033] The patient information 400 is shown in Figure 3(a) and is general information about the patient. The patient information 400 (Figure 3(a)) does not include the patient genotype information 600 (Figure 3(c)), which will be described later. The patient information 400 (Figure 3(a)) is also referred to as patient data. The patient information 400 (Figure 3(a)) may include, but is not limited to, one or more of the following: a patient code such as a patient ID, a patient name, a date of birth, a sex, a weight, a disease name, and a disease severity level.

[0034] The pharmaceutical information 500 is information relating to candidate pharmaceuticals to be administered to a patient, as shown in FIG. 3(b), and is acquired by the pharmaceutical information acquisition unit. The pharmaceutical information 500 (FIG. 3(b)) is also referred to as pharmaceutical data. The pharmaceutical information 500 (FIG. 3(b)) may include, but is not limited to, one or more of the following: the name of the candidate pharmaceutical to be administered to the patient, the dosage of the pharmaceutical (e.g., daily dose), etc. It is preferable that the patient information 400 (FIG. 3(a)) and the pharmaceutical information 500 (FIG. 3(b)) are associated with each other, and in this embodiment, the patient ID, which is one of the patient information 400 (FIG. 3(a)), is included in the pharmaceutical information 500 (FIG. 3(b)).

[0035] As shown in FIG. 3(c), the patient genotype information 600 is information about the patient's genotype, and is acquired by the patient genotype information acquisition unit. The patient genotype information 600 (FIG. 3(c)) is also referred to as patient genotype data. The patient genotype information 600 (FIG. 3(c)) includes specific loci (locus, or loci if plural) on the patient's genome that include gene regions (hereinafter referred to as "genomic loci") 610 (e.g., "gene X" or "gene Y") and the type of alleles at that locus, including the patient's zygosity, i.e., the patient's genotype (hereinafter referred to as "genotype") 620 (e.g., symbolized information such as " * 1 / * 2" or the actual nucleotide types are written as "A (adenine) / C (cytosine)".

[0036] (Patient's genotype information) The patient genotype information 600 (FIG. 3(c)) includes the type ("allele type") of a combination of alleles (alleles associated with one gene in this embodiment) unique to a patient at one locus on the patient's genome. There are two main methods for determining the "allele type." The methods are "Method 1," which uses information representing the structure of the entire genome obtained from the patient ("full-length character string"), and "Method 2," which uses an experimental approach based on genome-wide polymorphism analysis using a patient-derived genomic DNA sample and targets only DNA variants (e.g., SNPs) that are frequent in the population and suitable for automated analysis.

[0037] The former "Method 1" can be implemented using massively parallel DNA sequencing (next-generation sequencing). Massively parallel DNA sequencing allows for simultaneous and uniform sequencing of complex DNA samples containing a large number (sometimes millions) of nucleotide sequences. Therefore, compared to conventional dideoxy sequencing (Sanger sequencing), massively parallel DNA sequencing can convert genomic DNA samples extracted by standard methods from patient-derived blood cells or various tissues into character strings ("full-length character strings") corresponding to the patient's entire genome (approximately 3 billion nucleotides) in a short time and at low cost.

[0038] The genotype of a specific locus on the patient's genome can be determined by determining all of the characters or characters (and their positions) contained in the "full-length character string" and comparing it with a character string ("reference character string") representing the reference nucleotide sequence of the human genome. Reference character strings can be obtained from public databases such as Ensembl (URL: http: / / ensembl.org).

[0039] For example, information on character strings ("allele strings") representing the nucleotide sequences of alleles that can exist at a locus and the locations (known DNA variants) where nucleotide sequence changes occur between the alleles in a population are stored in publicly available databases (e.g., dbSNP (https: / / www.ncbi.nlm.nih.gov / snp / )) if they are frequent in the population (e.g., SNPs). Therefore, by determining which types of allele string combinations ("allele types") at a locus are included in the "full-length string," the genotype of a patient at a locus can be determined. As an example, the process of determining a patient's genotype information 600 (Figure 3(c)) is outlined below. Based on the above information representing the location of known DNA variants stored in publicly available databases (e.g., the above-mentioned dbSNP), determine two adjacent strings (e.g., approximately 10 to 100 characters) on either side of the DNA variant in the "allele string" contained in the "full-length string." Determine the positions in the "full-length string" where the two strings (i.e., the two strings flanking the position on either side of the DNA variant) exactly match the "reference string" using a well-known character comparison application. The "allele type" of the DNA variant in the "full-length character string" (i.e., the patient's "genotype") is determined based on whether or not the characters (strings) corresponding to the DNA variant are identical between the "full-length character string" and the "reference character string" and are located at the positions where the two character strings are identical. (Details of the method ("Method 1") for determining the patient's "genotype" using the above-mentioned "full-length character string" are described later in [Embodiment 2].)

[0040] On the other hand, in the latter "Method 2" mentioned above (a method using an experimental technique based on genome-wide polymorphism analysis), when the DNA variants are frequent in the population and suitable for automated analysis (e.g., SNPs, or deletions or insertions (indels) of one to several nucleotides in the genome), microarray technology, which has already been commercialized (commercially available kits and contracted implementation services), can quickly determine the types of polymorphisms in a large number (tens of thousands to hundreds of thousands) of genome fragments. For details on microarray technology, please refer to the kit manual or the contracted company's website.

[0041] As described above, the patient's genotype information 600 (FIG. 3(c)) can be determined by (or during the implementation of) the former "Method 1" using "full-length character string" information and / or the latter "Method 2" using an experimental approach based on genome-wide polymorphism analysis. Therefore, the patient's genotype information 600 (FIG. 3(c)) stored in the genome information DB 50 (FIG. 2) of FIG. 2 can be at least one of (1) the "full-length character string" (patient's genome information), (2) information representing the patient's "genotype" and information representing the patient, which are associated with each other, and (3) information in which the two pieces of information are encoded (see, for example, "genotype 620" described in the patient's genotype information 600 of FIG. 3(c)). The genotype information is preferably (2) or (3). Using (2) or (3) as the genotype information can reduce the performance requirements for the administration plan determination support system 1 (FIG. 2) and the genome information DB 50 (FIG. 2) and can improve the processing speed of the administration plan determination support system 1 (FIG. 2). Furthermore, by using (3) as the genotype information, (1) and (2) can be kept secret from an unspecified number of third parties who cannot decipher the meaning of the symbols.

[0042] The "allele types" of individual DNA variants used to generate (2) and (3) as the patient's genotype information 600 (FIG. 3(c)) can be determined in two stages depending on the type of DNA variant (determination range) based on its frequency in the population (see the bottom of FIG. 1). In the first stage, all known SNPs are comprehensively determined across the genome as DNA variants with a frequency of 1% or more in the population and suitable for automated analysis, and the information is stored in a database, recording medium, or storage device (not shown). Furthermore, the patient's "genotype" information based on the analysis of all the SNPs is stored in the genome information DB 50 (FIG. 2). The "allele types" of all SNPs (the patient's "genotype") can be determined by "Method 2," an experimental technique using the patient's genomic DNA sample, as described above. That is, the genomic DNA sample is first extracted from the patient's peripheral blood, oral cells, buccal mucosa, or the like by a standard method. Subsequently, the "allele type" (patient's "genotype") for all known SNPs can be determined using the above sample by an experimental method involving genome-wide polymorphism analysis using current microarray technology. Alternatively, the patient's "genotype" ("allele type") for all the above SNPs can be determined by "Method 1" using information analysis using the above-mentioned "full-length character string" (patient's genomic information) (see the bottom of Figure 1; details are described later in [Embodiment 2]).

[0043] Next, in the second step, if necessary, the "allele types" (patient's "genotype") of the remaining DNA variants not stored in the database, recording medium, or storage device are determined by "Method 1" using the "full-length character string" information (patient's genomic information). The "remaining DNA variants" may be DNA variants with low frequency in the population (e.g., SNVs, CNVs), or DNA variants that are not suitable for automated analysis (e.g., CNPs, STRPs, or other special DNA variants) (see the bottom of Figure 1). The "allele types" (patient's "genotype") of the remaining DNA variants are determined after patient information 400 (Figure 3(a)) and medical information 500 (Figure 3(b)) are input via input device 30 (Figure 2).

[0044] As described above, the administration regimen determination support system 1 in Fig. 2 acquires the names of genes or genomic loci associated with the efficacy and side effects (secondary diseases) of drugs from the drug-related genetic information DB 40 (Fig. 2) based on the drug names included in the drug information 500 (Fig. 3(b)). For the drug-related genetic information DB 40 (Fig. 2), related information can be obtained from, for example, DGIdb: Drug Gene Interaction database, URL: http: / / dgidb.org / .

[0045] The administration plan determination support system 1 (Fig. 2) searches the latest genome information DB 50 (Fig. 2) based on the name. If the "allele type" (i.e., the patient's genotype information) for the required DNA variant is not stored, the administration plan determination support system 1 (Fig. 2) searches the "reference string" information as described above and specifies the locus on the genome where the remaining DNA variant exists. The administration plan determination support system 1 (Fig. 2) determines the "allele type" of the remaining DNA variant (the patient's "genotype") present only at that locus by "Method 1" using the above string ("full-length string"). The administration plan determination support system 1 (Fig. 2) stores the determined "allele type" of the remaining DNA variant (the patient's genotype information) in the genome information DB 50 (Fig. 2) as well as in the database, recording medium, or storage device (not shown).

[0046] In Figure 2, the genome information DB 50 is shown as a reading device capable of reading an external storage device or recording medium connected to the control unit 10 (Figure 2), but it can also be replaced by a reading unit capable of reading a storage unit or recording medium built into the control unit 2 (Figure 2), or a configuration existing on a network.

[0047] The genotype information (2) or (3) can be updated based on the latest report. The report is a report of new DNA variants associated with a gene and the total "allele types" ("genotypes") associated with the DNA variants (i.e., all allele types at the specific site). As described above, "Method 1" using the "full-length character string" information (patient's genomic information) can generate new (2) or (3) based on existing and latest reports.

[0048] The genome information DB 50 (FIG. 2) can store all nucleotide sequences that make up the entire genome of a patient. Patient genotype information 600 (FIG. 3(c)) is a part of all nucleotide sequences that make up the entire genome of a patient.

[0049] The prohibited factor information 700 is information on prohibited factors, which is information on the genotype at a locus on the genome where administration of a drug is prohibited, as shown in FIG. 3(d), and is acquired by the prohibited factor information acquisition unit. The prohibited factor information 700 (FIG. 3(d)) is a genotype consisting of a type of allele combination that must not match the genotype at the corresponding locus on the genome in a patient in a drug administration plan. The prohibited factor information 700 (FIG. 3(d)) is also referred to as prohibited factor data. The prohibited factor information 700 (FIG. 3(d)) includes a genome locus 710 (for example, written as "Gene X") associated with a gene and its genotype 720 (for example, written as symbolic information as " * 1 / *Examples of genotypes 720 (Figure 3(d)) include genotypes that constitute specific mutations in genes related to pharmacokinetics (e.g., specific sites in drug-metabolizing enzymes) or pharmacodynamics (e.g., enzyme active sites in target molecules for specific drugs); genotypes of causative genes for single-gene diseases that have been proven to be significantly involved in the development of serious side effects (secondary diseases); and genotypes that constitute important nucleotide mutations related to "rare variants," "private variants," and "Mendelian-like subset" mutations that have been proven to have a strong influence or effect on complex diseases (multifactorial diseases, polygenic diseases).

[0050] One embodiment of the prohibitory factor information 700 (FIG. 3(d)) includes a genotype consisting of a specific genetic variant when the numerical odds ratio of the specific genetic variant associated with a specific disease risk in a patient is equal to or higher than a set value (e.g., 5, 10, or 20). Such genetic variants are known, and rare variants are particularly candidates. The odds ratio is the probability of developing a disease when a specific genetic variant is present divided by the probability of developing a disease when that variant is not present. Another embodiment of the prohibitory factor information 700 (FIG. 3(d)) includes a Mendelian-like subset associated with a specific complex disease.

[0051] The essential factor information 800 is information on essential factors, which is information on the genotype at a locus on the genome, which is essential for administering a drug, as shown in FIG. 3(e), and is acquired by the essential factor information acquisition unit. The essential factor information 800 (FIG. 3(e)) is a genotype consisting of a type of allele combination that must match the genotype at the corresponding locus on the genome in a patient in a drug administration plan. The essential factor information 800 (FIG. 3(e)) is also referred to as essential factor data. The essential factor information 800 (FIG. 3(e)) includes a genome locus 810 (e.g., written as "gene Y") and its genotype 820 (e.g., symbolized information " * 2 / * 3", or the actual nucleotide types are written as "G (guanine) / T (thymine)".

[0052] The essential factor information 800 (FIG. 3(e)) is not particularly limited, but one embodiment of the essential factor information 800 may include an allele type at a specific locus on the genome that is essential for the efficacy of a drug as a molecular targeted drug for a specific disease, or a genotype having a combination of allele types, or a genotype of a DNA mutation that has been proven to be a companion diagnostic for an anticancer drug. Another embodiment of the essential factor information 800 (FIG. 3(e)) may include a genotype of a subtype classification (subtype) that has been proven to be applicable to a specific drug in a limited manner within a certain disease group.

[0053] The prohibited factor information and essential factor information can be obtained from public databases of drug-related gene information (e.g., DGIdb: Drug Gene Interaction database, URL: http: / / dgidb.org / ) or commercially available databases. The prohibited factor information and essential factor information described above, as well as the drug gene-related information that serves as the source of these information, will continue to be expanded and become more accurate as new information is added and old information is updated. Therefore, the information is preferably created based on the latest information available at the time of implementing this embodiment, and can be generated by artificial intelligence (hereinafter referred to as "AI"). The AI ​​that receives the new information can output new drug-gene relationships to be used to update the old information, as well as new prohibited factor information and essential factor information based on this information.

[0054] Some specific examples of prohibited and essential factors are given below.

[0055] (Prohibited factor information, required factor information) One specific example of the inhibiting factor information 700 (FIG. 3(d)) is the promoter region of the gene encoding the UGT1A1 enzyme in the administration of the anticancer drug irinotecan. * 28 / * The UGT1A1 gene polymorphism involves a repeat sequence of two nucleotides [TA] in the transcriptional regulatory region of the gene, which is six times longer than the wild type. * 6 variants, whereas the mutant form increased the number to 7. UGT1A1 * Irinotecan is a prodrug that is converted to its active form in the liver, which has antitumor activity and is normally metabolized by the UGT1A1 enzyme. * Homozygous mutation polymorphism in the promoter region of 28 results in decreased production of the enzyme, significantly increasing the risk of serious drug side effects (toxicity) in the bone marrow and gastrointestinal tract.

[0056] In the case of psychotropic antiepileptic drugs, such as carbamazepine, a drug used to treat manic states, the genotype HLA-A * 31:01 or HLA-B * 15:02 is a forbidden factor. If the genotype of the patient receiving this drug matches this, it may cause serious side effects such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome (mucocutaneous ocular syndrome).

[0057] In the case of allopurinol, a drug used to treat hyperuricemia, the genotype HLA-B*58:01 is a prohibiting factor, and if the genotype of the patient receiving this drug matches this, serious side effects such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome (oculomucocutaneous syndrome) may occur.

[0058] The actual base sequence of the allele type (genotype) of each HLA gene variant can be searched at http: / / hla.alles.org / .

[0059] As a specific example of essential factor information 700 (Figure 3(e)), in the case of crizotinib (trade name Xalkori), an ALK tyrosine kinase inhibitor that is an anti-cancer drug for patients with non-small cell lung cancer, the presence of a genotype of the ALK fusion gene (EML4-ALK fusion gene) due to chromosomal translocation in the genome of the patient to whom the drug is administered or a genotype constituting the ROS1 fusion gene is cited as an essential factor.

[0060] Vemurafenib (generic name: Zelboraf), a BRAF inhibitor for melanoma patients, is thought to inhibit the kinase activity of activating mutant BRAF, including V600 mutations (V600E, V600D, V600R, V600K, V600G, V600M) caused by amino acid mutations in the BRAF gene, thereby inhibiting MEK and ERK phosphorylation due to BRAF activation and suppressing the growth of tumors with BRAF V600 mutations. Therefore, a genetic mutation at a specific genomic site in the BRAF gene caused by the above amino acid mutations is an essential factor.

[0061] Imatinib mesylate (generic name Gleevec), a BCR-ABL tyrosine kinase inhibitor, is administered to patients with chronic myeloid leukemia. Essential factors for this treatment are the presence of a genotype comprising the Philadelphia chromosome (bcr-abl gene) resulting from a chromosomal translocation and the presence of FIP1L1-PDGFRα.

[0062] The genomic loci of the genotype of the prohibited factor and the genotype of the essential factor may overlap. For example, at the same locus, the nucleotide of the genotype of the prohibited factor may be "A (adenine)" while the nucleotide of the genotype of the essential factor may be "G (guanine)."

[0063] (Processing of administration plan decision support system) Next, the processing steps executed by the system of FIG. 2 will be described with reference to FIGS.

[0064] When a doctor, who is the user, inputs patient information such as the type of disease the patient is suffering from, the severity of the disease, and the patient's age, weight, and sex, and pharmaceutical information such as the name of the drug intended to be administered to the patient (here, compound B), via input device 30 (FIG. 2), input device 30 sends the input patient information 400 (FIG. 3(a)) and pharmaceutical information 500 (FIG. 3(b)) to information acquisition unit 110 (FIG. 2) (step S1 in FIG. 4). Note that in this embodiment, patient information 400 (FIG. 3(a)) and pharmaceutical information 500 (FIG. 3(b)) are separate data, but the patient information and pharmaceutical information may be associated and handled as a set of data.

[0065] Next, the information acquisition unit 110 (FIG. 2) acquires the prohibited factor information 700 (FIG. 3(d)) corresponding to the drug from the drug-related genetic information DB 40 (FIG. 2) in FIG. 2 based on the name of the drug represented by the drug name included in the drug information 500 (FIG. 3(b)) (step S2 in FIG. 4). If the determination in step S2 in FIG. 4 is "YES", the information acquisition unit 110 (FIG. 2) then acquires the patient's genotype information 500 (FIG. 3(c)) corresponding to the patient ID and the specific genetic locus associated with the gene from the genome information DB 50 (FIG. 2) based on the patient ID information included in the patient information 400 (FIG. 3(a)) and the name of the specific genetic locus associated with the gene included in the prohibited factor information 700 (FIG. 3(d)) (step S3 in FIG. 4). If the determination in step S3 of Fig. 4 is "YES," the information acquisition unit 110 (Fig. 2) then sends the acquired drug information 500 (Fig. 3(b)), patient genotype information 600 (Fig. 3(c)), and prohibited factor genotype information 700 (Fig. 3(d)) to the administration plan determination unit 120 (Fig. 2). Based on the prohibited factor information 700 (Fig. 3(d)) acquired from the drug-related genetic information DB 40 (Fig. 2), the administration plan determination unit 120 (Fig. 2) determines whether the genotype related to the drug matches the corresponding genotype (first genotype information of the patient) in the patient genotype information 600 (Fig. 3(c)) (step S4 of Fig. 4).

[0066] Regarding step S4 of FIG. 4, in the example shown in FIGS. 3(c) and (d), according to the inhibiting factor information 700 (FIG. 3(d)), the genomic locus 710 associated with the gene that is an inhibiting factor for the compound drug B and the corresponding genotype 720 are "gene X" and " * 1 / * 1 (homozygote)" (actual nucleotide type is "A (adenine) / A (adenine)") (Fig. 3(d)). However, according to the patient's genotype information 600 (Fig. 3(c)), the genomic locus 610 associated with the patient's corresponding gene and the corresponding genotype 620 are "Gene X" and " * 1 / * 2 (heterozygote)" (actual nucleotide type is "A (adenine) / C (cytosine)"), so the two do not match. Therefore, step S4 in FIG. 4 is "NO". In this embodiment, the genotype is* 1 / * 1. * 1 / * Although shown as 2, as shown in parentheses, this symbol may also be represented by the actual symbol for each nucleotide type (A / A, T / G, etc.) corresponding to the genotype.

[0067] If the determination is "NO" in step S2 of FIG. 4, the information acquisition unit 110 of FIG. 2 may further include a step in which the control unit 10 (FIG. 2) displays a warning message on the display device 20 (FIG. 2) indicating that the prohibited factor information 700 (FIG. 3(d)) does not exist before proceeding to step S5 of FIG. 4.

[0068] If the determination in step S4 of Fig. 4 is "NO," the information acquisition unit 110 (Fig. 2) then acquires essential factor information 800 (Fig. 3(e)) corresponding to the drug from the drug-related genetic information DB 40 of Fig. 2 based on the name of the drug represented by the drug name included in the drug information 500 (Fig. 3(b)) (step S5 of Fig. 4). If the determination in step S5 of Fig. 4 is "YES," the information acquisition unit 110 (Fig. 2) then acquires patient genotype information 600 (Fig. 3(c)) corresponding to the patient ID and the specific genetic locus associated with the gene from the genome information DB 50 (Fig. 2) based on the patient ID information included in the patient information 400 (Fig. 3(a)) and the name of the specific genetic locus associated with the gene included in the essential factor information 800 (Fig. 3(e)) (step S6 of Fig. 4). If the determination in step S6 of Fig. 4 is "YES," the information acquisition unit 110 (Fig. 2) then sends the acquired drug information 500 (Fig. 3(b)), patient genotype information 600 (Fig. 3(c)), and essential factor information 800 (Fig. 3(e)) to the administration plan determination unit 120 (Fig. 2). The administration plan determination unit 120 of Fig. 2 determines whether the genotype related to the drug matches the corresponding genotype (second genotype information of the patient) in the patient genotype information 600 (Fig. 3(c)) based on the essential factor information 800 (Fig. 3(e)) acquired from the drug-related genetic information DB 40 (Fig. 2) (step S7 of Fig. 4).

[0069] For example, in the example shown in Figures 3(c) and (e), according to the essential factor information 800 (Figure 3(e)), the specific genome locus 810 and genotype 820 associated with the gene that is an essential factor for drug B are "gene Y" and " * 2 / * 3 (heterozygote)" (actual nucleotide type is "G (guanine) / T (thymine)") (Figure 3(e)). According to the patient's genotype information 600 (Figure 3(c)), the specific genomic locus 610 associated with the patient's corresponding gene and the corresponding genotype 620 are "Gene Y" and " * 2 / * 3 (heterozygote)" (actual nucleotide types are "G (guanine) / T (thymine)"), so the two match. Therefore, the determination in step S7 of FIG. 4 is "YES."

[0070] If the judgment in step S7 of Figure 4 is "YES", the administration plan determination unit 120 (Figure 2) sends the pharmaceutical information 500 (Figure 3(b)) to the administration plan output unit 140 (Figure 2), the administration plan output unit 140 (Figure 2) outputs the pharmaceutical information, the display device 20 (Figure 2) displays the pharmaceutical information (step S8 of Figure 4), and the administration plan determination support system terminates processing.

[0071] If the determination is "NO" in step S5 of FIG. 4, the information acquisition unit 110 of FIG. 2 may further include a step in which the control unit 10 (FIG. 2) displays a warning message on the display device 20 (FIG. 2) indicating that the essential factor information 800 (FIG. 3(e)) does not exist, before proceeding to step S8 of FIG. 4.

[0072] If the determination in step S3 of FIG. 4 is "NO" (for example, the inhibiting factor information 700 (FIG. 3(d)) related to the drug (drug B) has not yet been recorded in the patient's genotype information 600 (FIG. 3(c))), or if the determination in step S6 of FIG. 4 is "NO" (for example, the essential factor information 600 (FIG. 3(e)) related to the drug (drug B) has not yet been recorded in the patient's genotype information 600 (FIG. 3(c))), the information acquisition unit 110 (FIG. 2) of FIG. 2 sends the initially input drug information 500 (FIG. 3(b)) to the display device 20 (FIG. 2). In addition to the drug information 500 (FIG. 3(b)), the display device 20 (FIG. 2) displays a message saying "Determined" together with the reason for the determination (step S9 of FIG. 4), and the system 1 (FIG. 2) ends the processing.

[0073] In step S4 of FIG. 4, if the genotype 720 (FIG. 3(d)) of the specific genomic locus 710 associated with the gene that is a prohibitive factor matches the genotype 620 (FIG. 3(c)) of the specific genomic locus 610 associated with the corresponding gene of the patient, and the result of the determination in step S4 of FIG. 4 is "YES," or if the genotype 820 (FIG. 3(e)) of the specific genomic locus 810 associated with the gene that is an essential factor matches the genotype 620 (FIG. 3(c)) of the specific genomic locus 610 associated with the corresponding gene of the patient, If the determination in step S7 of FIG. 4 is "NO" because the genotype 620 (FIG. 3(c)) of the patient does not match, the administration plan determination unit 120 (FIG. 2) sends the drug information 500 (FIG. 3(b)), the prohibited factor information 700 (FIG. 3(d)) or the essential factor information 800 (FIG. 3(e)) and the suitability "inappropriate" to the drug information change unit 130 (FIG. 2) and the administration plan output unit 140 (FIG. 2). If the administration plan output unit 140 (FIG. 2) determines that the drug is "inappropriate" for the patient, " (together with the "genotype" on which the information is based and the reason), and the display device 20 (Fig. 2) displays the above information (step S10 in Fig. 5). If the pharmaceutical information change unit 130 (Fig. 2) determines that a dose change is necessary, for example, because the metabolic rate of the drug is low, based on the prohibited factor information 700 (Fig. 3(d)) and the essential factor information 800 (Fig. 3(e)), the pharmaceutical information change unit 130 reduces the "daily dose" described in the pharmaceutical information 500 (Fig. 3(b)) (step S11 in Fig. 5). In this case ("NO" in step S12 in Fig. 5), the modified pharmaceutical information 510 (Fig. 6) with the modified dosage or administration method is sent to the administration plan output unit 140 (Fig. 2), the administration plan output unit 140 (Fig. 2) outputs the modified pharmaceutical information, the display device 20 (Fig. 2) displays the modified pharmaceutical information (step S14 in Fig. 5), and the administration plan determination support system ends the processing (a specific example of a drug dose change will be described later).

[0074] Generally, in the changed pharmaceutical information regarding "dosage," if the daily dose exceeds the administration limit, or if no efficacy is expected due to pharmacodynamic factors, the pharmaceutical information change unit (Figure 2) shifts from changing the dose in the pharmaceutical information 500 (Figure 3(b)) to changing the type of pharmaceutical ("YES" in step S12 of Figure 5).

[0075] If the answer is "YES" in step S12 of FIG. 5, for example, if the prodrug cannot be converted into an active compound based on the prohibited factor information 700 (FIG. 3(d)) and the essential factor information 800 (FIG. 3(e)), and therefore efficacy is not expected, the pharmaceutical information modification unit 130 (FIG. 2) modifies the "drug name" entered in the pharmaceutical information 500 (FIG. 3(b)) (step S11 of FIG. 5). In this case ("YES" in step S13 of FIG. 5), the pharmaceutical information modification unit 130 (FIG. 2) sends modified pharmaceutical information 520 (FIG. 7) with the modified pharmaceutical name to the information acquisition unit 110 (FIG. 2), and the process returns to step S2 of FIG. 4.

[0076] If the answer is "NO" in step S13 of FIG. 5, that is, if there are no candidate medicines to be changed, the administration regimen determination support system ends the process.

[0077] As described above, the administration plan determination support system 1 (FIG. 2) of this embodiment verifies whether at least one of the genotypes of inhibitory factors and essential factors related to a certain drug is present in the patient's genome, and supports the determination of an administration plan that is more suitable for the patient. Therefore, the administration plan determination support system 1 (FIG. 2) of this embodiment allows even a user with little knowledge of genetics to accurately and easily determine a customized administration plan with excellent pharmacological effects based on the patient's unique genotype.

[0078] Furthermore, the administration plan determination support system 1 (FIG. 2) of this embodiment also supports doctors in selecting a treatment method appropriate for a patient from various treatment methods for a disease, such as drug therapy, radiation therapy, exercise therapy, and diet therapy. For example, when the administration plan determination support system 1 (FIG. 2) of this embodiment identifies an administration plan for a certain drug appropriate for a patient, the administration plan for the drug can be reflected in the patient's future treatment method. When it is determined that administration of such a drug is not appropriate for the patient, administration of the drug can also be excluded from the patient's future treatment method.

[0079] Furthermore, according to the administration plan determination support system 1 (FIG. 2) of this embodiment, if the genotype of a prohibited factor associated with a certain drug is present in the patient's genome, or if the genotype of an essential factor associated with a certain drug is not present in the patient's genome, the administration plan can be changed by changing the type of drug or its dose included in the drug information 500 (FIG. 3(b)). Therefore, by updating the information on prohibited factors and / or essential factors recorded in the drug-related genetic information DB 40 (FIG. 2) of the system 1 (FIG. 2) to the latest information, the system 1 (FIG. 2) is customized to suit the patient, and the accuracy and precision of the administration plan are improved.

[0080] Below we will explain examples of changing the dosage of a drug (Figure 6) and examples of changing the type of drug (Figure 7) when the genotype of a prohibited factor matches the patient's first genotype, or when the genotype of an essential factor does not match the patient's second genotype.

[0081] In the association information A (FIG. 8(a)), when the prescribed dose of phenytoin in the medical information A (both the initial and maintenance doses are 300 mg per day), the administration plan determination unit 120 in FIG. 2 determines that the patient's genotype information regarding the SNP (rs1057910) in CYP2C9 is heterozygous. * 1 / * 3" (the actual nucleotide type is "A (adenine) / C (cytosine)"), it is called heterozygous " * 1 / * Based on the value "-1 (prohibition factor)" of the metabolic rate (drug efficacy) of phenytoin corresponding to "3", the suitability of the metabolic rate (drug efficacy) of the pharmaceutical information 500 (Fig. 3(b)) is determined to be "inappropriate". The administration plan determination unit 120 (Fig. 2) sends the pharmaceutical information 500 (Fig. 3(b)) (specifically, the prescribed dose of "pharmaceutical information A" in the association information A of Fig. 8(a)) and the suitability "inappropriate" to the pharmaceutical information change unit 130 (Fig. 2).

[0082] The medical information change unit 130 in Fig. 2 determines that the negative metabolic rate (drug efficacy) value "-1 (prohibition factor)" is low. In accordance with the metabolic rate (drug efficacy) "-1," the medical information change unit 130 (Fig. 2) reduces the maintenance dose (the dose of the drug to be continuously administered after the initial administration period has elapsed, which is the "daily dose (maintenance dose)" described in the medical information 500 (Fig. 3(b))) of the daily dose in the medical information 500 (Fig. 3(b)) (specifically, the prescribed dose of "medicinal information A" in the association information A in Fig. 8) by 1 unit (1 unit = 25% described in the medical information 500) to set the drug efficacy to "±0" (step S11 in Fig. 5). Since the change in step S11 in FIG. 5 is to the "daily dose (maintenance dose)" (the determination in step S12 in FIG. 5 is "NO"), as described above, the medical information change unit 130 (FIG. 2) sends to the display device 20 (FIG. 2) changed medical information 510 (FIG. 6) in which the "daily dose (maintenance dose)" has been changed to 225 mg, a dosage that is a 25% reduction from 300 mg. Note that there is no change in the initial dosage, and it remains as "daily dose (initial dose) 300 mg" described in the medical information 500 in FIG. 3(b) (specifically, the prescribed dosage in changed medical information B regarding dosage in FIG. 8(b)). The display device 20 (FIG. 2) displays the changed medical information 510 (FIG. 6), and the administration plan determination support system 1 (FIG. 2) ends the processing. In addition, when the daily dose in the changed pharmaceutical information 510 in Figure 6 exceeds the administration limit, the pharmaceutical information change unit 130 (Figure 2) changes the type of pharmaceutical in the changed pharmaceutical information 510 (Figure 6) ("YES" in step S12 in Figure 5).

[0083] Unlike the above example, the administration plan determination unit 120 (FIG. 2) selects the normal type " * 1 / * When the system acquires "1" (the actual nucleotide type is "A (adenine) / A (adenine)"), it determines the value of the metabolic rate (drug efficacy) of phenytoin as "±0 (essential factor)" and sends the pharmaceutical information 500 (Fig. 3(b)) (specifically, the prescribed dose of "pharmaceutical information A" in the association information A in Fig. 8(a)) to the display device 20 (Fig. 2). The display device 20 (Fig. 2) displays the pharmaceutical information, and the administration plan determination support system 1 (Fig. 2) ends the processing.

[0084] Furthermore, in the above example, the change to the pharmaceutical information was not a change in the type of pharmaceutical, so the pharmaceutical information change unit 130 in FIG. 2 made a "NO" determination in step S12 in FIG. 5. However, in the following example, the pharmaceutical information change unit 130 (FIG. 2) changes the type of pharmaceutical (determines "YES" in step S12 in FIG. 5). Condition: Select an appropriate pharmaceutical for patient S with non-small cell lung cancer. (Drug 1) EGFR tyrosine kinase inhibitor: gefitinib, (Drug 2) EGFR tyrosine kinase inhibitor: osimertinib mesylate. It is assumed that patient S has the following genotypes: EGFR: mutated (G / G) at position 2573 (homozygous), EGFR: mutated (T / T) at position 2369 (homozygous), KRAS: normal (G / GG / G) at positions 34-35 (both homozygous), KRAS: normal (G / G) at position 38 (homozygous).

[0085] If the EGFR tyrosine kinase inhibitor gefitinib (trade name: Iressa) is selected for administration to patient S (drug 1), "prohibitory factor" information for the drug gefitinib is obtained (step S2 in FIG. 4), and the first genotype information for the corresponding patient S is obtained (step S3 in FIG. 4). The genotype information for the "prohibitory factor" for the drug gefitinib is a homozygous mutation "T (thymine) / T (thymine)" or heterozygous mutation "T (thymine) / C (cytosine)" variant at position 2369 of the EGFR gene, which is associated with resistance to gefitinib. Next, as a result of comparing the above "prohibitory factor" information with the first genotype information for the corresponding patient S, it is determined that the genotype of patient S possesses a homozygous mutation ("T / T") at position 2369 of EGFR as the "prohibitory factor," which matches the "prohibitory factor," and is therefore unsuitable ("YES" in step S4 in FIG. 4). Therefore, a warning message stating "The drug is inappropriate" is displayed along with the reason (incompatibility of the "prohibitory factor" genotype (EGFR: T / T or T / C at position 2369): due to a match with the genotype T / T of patient S) (step S10 in Figure 5). Preferably, the following specific information is also displayed: "Patient S's genotype contains a protein with an EGFR T790M amino acid mutation (the 790th amino acid sequence of the EGFR protein is mutated from threonine to methionine) associated with the genotype of patients who exhibit resistance to gefitinib due to a genetic mutation in EGFR gene exon 20 (2369C>T)." Note that the "essential factor" information for the drug gefitinib is compared and collated with the corresponding second genotype information of patient S, and therefore is marked "compatible." The genotype information for essential factors for gefitinib is that position 2573 of EGFR is G / G or G / T, and positions 34-35-38 of KRAS are G / GG / GG / G.

[0086] Next, as described above, the above patient S has the homozygous mutation "T / T" at position 2369 of EGFR, which is associated with gefitinib resistance, as the genotype information of the "prohibitory factor" for the drug gefitinib. Therefore, since the drug is not expected to be effective due to pharmacodynamic factors, this time, a change in medication is required, not a change in dosage. Therefore, the determination in step S12 of Figure 5 is "YES," and the process proceeds to step S13. However, this time, (drug 2) EGFR tyrosine kinase inhibitor: osimertinib mesylate (trade name: Tagrisso) is registered as the alternative medication for (drug 1) gefitinib (trade name: Iressa), so the determination in step S13 of Figure 5 is "YES," and the process returns to step S2 of Figure 4.

[0087] Using the same procedure as for gefitinib, the genotypes of the "essential factors" and "prohibited factors" of (drug 2) osimertinib mesylate and the genotype of the corresponding patient are obtained, and then compared and collated. As a result, since both ("essential factors" and "prohibited factors") are compatible, it is determined to be "not unsuitable" ("NO" in step S4 of Figure 4, "YES" in step S7), and finally, the irreversible EGFR tyrosine kinase inhibitor (drug 2) osimertinib mesylate, which exhibits an inhibitory effect on T790M mutant EGFR protein, is presented to the user as revised pharmaceutical information 520 (Figure 7) (step S8 of Figure 4). The essential factor information for osimertinib mesylate is that position 2573 of EGFR is G / G or G / T, and positions 34-35-38 of KRAS are G / GG / GG / G (note that this drug (osimertinib mesylate) does not have a homozygous mutation ("T / T") or heterozygous mutation ("T / C") at position 2369 of EGFR, which was the genotype information of the prohibited factor for (Drug 1) gefitinib mentioned above).

[0088] If the changed medication is not registered ("NO" in step S13 of Fig. 5), the system ends. Also, if the genotype of the "prohibited factor" or "essential factor" was obtained but the genotype information of the corresponding patient could not be obtained ("NO" in step S3 of Fig. 4 or "NO" in step S6), a message is displayed to the user stating that the medication is "undeterminable" along with the reason (step S9 of Fig. 4).

[0089] The present invention is not limited to the above-described embodiment, and various modifications such as those described below are possible.

[0090] In the processing procedure of the administration regimen determination support system of FIG. 4, when information on a genotype ("first genotype") at a locus on the patient genome associated with prohibited factor information 700 (FIG. 3(d)) related to a drug represented in the drug information 500 (FIG. 3(b)) and / or information on a genotype ("second genotype") at a locus on the patient genome associated with essential factor information 800 (FIG. 3(e)) is not recorded in the genome information DB 50 (FIG. 2) as the patient genotype information 600 (FIG. 3(c)), the administration regimen determination support system 1 of FIG. 2 proceeds from step S3 to step S9 and / or from step S6 to step S9 of FIG. 4 by the control unit 10 (particularly the information acquisition unit 110) of FIG. 2 , information representing the entire nucleotide sequence constituting the patient's genome stored in the genome information DB50 (Figure 2) is obtained, and from the information representing the entire nucleotide sequence, for information representing variants of all frequencies, including information representing variants with a frequency of less than 1% in the human population, DNA variants present at loci on the patient's genome associated with the prohibitive factor information 700 (Figure 3(d)) (the patient's "first genotype") and / or DNA variants present at loci on the patient's genome associated with the essential factor information 800 (Figure 3(e)) (the patient's "second genotype") are detected, the patient genotype information 600 (Figure 3(c)) is updated, and the process may return to step S2 of Figure 4.

[0091] For example, in order to detect the above-mentioned DNA variant, detection method (1) may involve generating a binding sequence in which a target nucleotide sequence corresponding to the DNA variant is bound to partial nucleotide sequences on both sides of the position corresponding to the DNA variant in a reference human genome, and comparing the binding sequence with the entire nucleotide sequence constituting the patient's genome, while repeatedly increasing the length of the partial nucleotide sequence.

[0092] Alternatively, in detection method (2), to detect the above-mentioned DNA variant, two nucleotide sequences corresponding to the partial nucleotide sequences on either side of the position corresponding to the DNA variant in the reference human genome may be generated, and the two nucleotide sequences may be compared with the entire nucleotide sequence constituting the patient's genome, and this process may be repeated while increasing the length of the partial nucleotide sequences.

[0093] [Embodiment 2] Below, we describe two methods for detecting DNA variants (1) and (2), i.e., methods for determining the "allele type" (patient's "genotype") of any DNA variant in the entire nucleotide sequence of a genome obtained from an individual ("full-length string"), rather than in the human genome stored in a public database ("reference string"). The DNA variant is any nucleotide change, including SNPs, SNVs, indels, CNPs, CNVs, and microsatellite polymorphisms ("STRPs"). In these methods, two strings representing the two nucleotide sequences flanking the target nucleotide are extracted from a public string ("reference string") representing a reference human genome and used.

[0094] In the above method, depending on the type of target nucleotide, either (1) a single continuous string representing the combined sequence of the target nucleotide and two nucleotide sequences derived from the "reference string" flanking it, or (2) two strings representing each of the two nucleotide sequences derived from the "reference string" flanking the target nucleotide, are used. (1) is used as a simple method for determining the "allele type" (the patient's "genotype") when the target nucleotide is known in the human genome and is a SNP, SNV, or indel. (2) is applicable to determining the "allele type" of any DNA variant (including the above-mentioned SNP, SNV, or indel), but is particularly effective when the length of the target nucleotide changes, there are multiple options, or the details of the target nucleotide are unknown. The above method using the strings (1) and (2) is described below with reference to Figures 9 and 10.

[0095] (A simple method to determine the "allele type" of a SNP, SNV, or indel) The method using the character string (1) described above is particularly a simple method for determining the allele type of a SNP, SNV, or indel. As shown in FIG. 9 , the character string (1) is a single continuous character string including a character string 902 representing a target nucleotide (SNP, SNV, or indel) and two character strings 901 and 903 representing two nucleotide sequences flanking the character string 902. The character strings 901 and 903 are determined as part of a character string representing a reference human genome (a "reference character string") (e.g., obtainable from Ensemble (URL: http: / / ensembl.org)) (step S15 in FIG. 10 ). The character string 902 (character string representing the target nucleotide) is stored in a known database as a known (hereinafter simply referred to as "known") DNA variant at the time the method according to this embodiment is implemented. In other words, the "DNA variant" may also include DNA variants discovered after the filing of this application. For example, information on all known SNPs can be obtained from the dbSNP database (https: / / www.ncbi.nlm.nih.gov / snp / ). Information on the position where character string 902 (characters (string) representing the target nucleotide) exists in a character string representing a reference human genome ("reference character string") is also stored in the DB (for example, the above-mentioned dbSNP database). In the character string (1), it is preferable to set the lengths of character string 901 and character string 903 to be the same and to position the analysis site (character string 902) in the center.

[0096] Therefore, by the above method, the "allele type" of a known SNP, SNV, or indel is determined based on whether or not the character string (1) is contained in a character string ("full-length character string") representing the nucleotide sequence of an individual's entire genome (step S16 in FIG. 10). The position at which the character string (1) may be contained in the character string ("full-length character string") representing the nucleotide sequence of an individual's entire genome can be estimated from the position information of a reference human genome ("reference character string") stored in the DB. Therefore, for example, when a character string that perfectly matches the character string (1) is found (step S17 in FIG. 10), a character string that may contain the character string (1) is extracted from the character string ("full-length character string") representing the nucleotide sequence of the individual's entire genome, and the extracted character string is compared with the character string (1), thereby determining the "allele type" of the known SNP, SNV, or indel in the nucleotide sequence of the individual's entire genome ("full-length character string") (step S18 in FIG. 10).

[0097] Here, the length of the character strings 901 and 903 in FIG. 9 is at least 10 characters (e.g., 10, 20, 30, 40, 50, 100, 150, 200 characters, or more), preferably 10 to 1,000 characters. The fewer the number of characters in the character string (1), the higher the probability of finding two or more character strings that perfectly match the character string (1) in the character string representing the nucleotide sequence of an individual's entire genome ("full-length character string"). When two or more character strings that perfectly match the character string (1) are found ("NO" in step S17 of FIG. 10), the probability can be reduced by equally extending the lengths of the two character strings (character strings 901 and 903 in FIG. 9) by one or more characters (e.g., 1, 3, 5, 10, 20, 25, 50, or 100 characters) (step S20 of FIG. 10). However, the total length of the two character strings is, for example, 10,000 characters or less. This is because when one of two extremely long strings (string 901 and string 903 in Figure 9) contains a string representing a DNA variant other than the target nucleotide (string 902 in Figure 9), the result "string (1) is not included in the string representing the nucleotide sequence of the individual's entire genome" always appears.

[0098] For example, the allele type of a known SNP at a specific position on the genome can be up to four types, just like the types of nucleotides. For example, when the nucleotide of a normal allele is represented by A, an allele containing nucleotides represented by T, G, and C is a mutant allele. Therefore, by specifying A, T, G, and C as the character string 902 in FIG. 9 and performing the above-mentioned process four times, the allele type of a known SNP at the specific position can be determined (step S18 in FIG. 10). However, in reality, since two types of nucleotides (rarely three types) are common in a population, known SNPs can often be easily determined in two attempts.

[0099] In FIG. 9, character strings 901-903 containing normal character strings (normal character strings) and character strings 901-903 containing mutant character strings (mutant character strings) can be used to determine whether an individual's genome is homozygous or heterozygous for a SNP. For example, when both character strings ("full-length character strings") representing the nucleotide sequence of an individual's entire genome (genomes typically exist as a zygosity possessing two sets of sequences derived from the mother and the father) match the normal character strings and the mutant character strings do not, the individual's genome has a normal allele (normal: N / N). For example, when one character string representing the nucleotide sequence of an individual's entire genome matches the normal character string and the other character string matches the mutant character string, the individual's genome has a mutant allele in one genome (heterozygous: N / M). For example, when both character strings representing the nucleotide sequence of an individual's entire genome match the normal character string and the mutant character string does not, the individual's genome has a mutant allele in both genomes (homozygous: M / M).

[0100] The process of determining the genotype of an individual will be specifically described using a known SNP (rs1057910) present in the coding region of CYP2C9 (a drug-metabolizing enzyme gene) based on the association information A ( FIG. 8( a)) related to phenytoin (an antiepileptic drug). For the character string 902, the wild-type (normal) allele of the SNP (rs1057910) has a nucleotide base type of "adenine (A)," while the poor metabolizer allele, known to reduce the metabolic rate of phenytoin, has a nucleotide base type of "cytosine (C)." For a known SNP, the corresponding character strings 901 and 903 can be easily obtained using the above method. Therefore, by extracting character strings 901-903 containing the wild-type character "A" ("wild-type character strings") and character strings 901-903 containing the poor metabolizer character "C" ("poor metabolizer character strings") and repeating the above process twice, the genotype of the individual can be easily determined.

[0101] Specifically, when the "wild-type string" matches a string representing the nucleotide sequence of an individual's entire genome (the "full-length string"), but the "poor metabolizer string" does not match, the individual's genome has wild-type alleles in both genomes (wild-type: "A / A"). For example, when both the "wild-type string" and the "poor metabolizer string" match the "full-length string," the individual's genome has the poor metabolizer allele in one genome (heterozygous: "A / C"). For example, when the "wild-type string" does not match the "full-length string" but the "poor metabolizer string" matches, the individual's genome has the poor metabolizer allele in both genomes (homozygous poor metabolizer: "C / C").

[0102] According to the type of combination of nucleotide changes ("A / A", "A / C", or "C / C") of the CYP2C9 SNP (rs1057910) in the individual determined by the above process, in the case of the prescribed dose (initial and maintenance doses are both 300 mg per day) of phenytoin drug information A in association information A (Figure 8(a)), different symbolized genotypes (" * 1 / *1", " * 1 / * 3" or " * 3 / * 3"), as well as different metabolic rates (efficacies) (±0 (essential factor), -1 (prohibitive factor) or -2 (prohibitive factor) can be determined.

[0103] The determined genotype, together with information representing the DNA variants present in the individual's genome, is saved in a DB, recording medium or storage device (not shown) and stored in the genome information DB 50 (FIG. 2) (step S19 in FIG. 10).

[0104] (A general method that can be applied to determining the "allele type" of any DNA variant) The method using the character string (2) described above is applicable to determining the allele type ("allele type"), including the zygosity type, of any DNA variant (including the above-described SNP, SNV, or indel), but is particularly effective when the length of the target nucleotide varies, there are multiple options, or the details of the target nucleotide are unknown. The length of the target nucleotide varies and there are multiple options, for example, when the target nucleotide is a simple repeat sequence with a different number of repeats, such as in microsatellite polymorphisms ("STRPs"). In other words, the character string (2) is particularly effective when it is necessary to determine the number of target nucleotides and even the full-length nucleotide sequence of the target nucleotide.

[0105] The total length of the target nucleotide can reach tens of thousands of nucleotides, and the length of the target nucleotide can vary greatly between individuals. Therefore, the full-length nucleotide sequence of a specific target nucleotide must be determined individually based on the genome of that individual. However, the genomic locus where the target nucleotide (CNP, CNV, STRP) is located has already been identified in the human reference genome, as have SNPs, SNVs, or indels. The location of the target nucleotide at that locus has also been relatively determined. In other words, the character string (2) is known in the character string ("reference character string") representing the human reference genome (step S15 in Figure 10).

[0106] The character string (2) can perfectly match character strings representing the nucleotide sequences flanking both sides of the target nucleotide representing a known DNA variant present in the individual's genome. Therefore, by determining whether the character string (2) (a pair: character strings 901 and 903 in FIG. 9 ) is present in the character string representing the nucleotide sequence of the individual's entire genome ("full-length character string") (step S17 in FIG. 10), it is possible to determine whether the target nucleotide is present in the individual's genome (step S18 in FIG. 10). The length of the character string (2) (a pair: character strings 901 and 903 in FIG. 9 ) can be set to the same length as the lengths of the character strings 901 and 903 in the character string (1).

[0107] After the presence of the string (2) (a pair of strings: strings 901 and 903 in Figure 9) in the string representing the nucleotide sequence of the entire genome of an individual (the "full-length string") is confirmed, the string present between the pair of strings (string 902 in Figure 9, which represents the full-length nucleotide sequence of the target nucleotide) is extracted.

[0108] For example, when the extracted string represents a simple repeat sequence of a very short sequence (1 to 4 base pairs in length), such as a microsatellite polymorphism (STRP), the number of repeats (and the total number of nucleotides) contained in the string is further determined. Simple repeat sequences can vary in the number of repeats in an individual's genome, with each repeat unit ranging from a few nucleotides to several tens of nucleotides. The "allele type" corresponding to the number of repeats is detected. For example, if two sequences of different lengths are detected, it is determined to be "heterozygous," and if only one sequence of length is detected, it is determined to be "homozygous."

[0109] We use a trinucleotide (CAG) microsatellite polymorphism (STRP) in the coding sequence of the gene responsible for Huntington's disease (HTT), a late-onset, monogenic disease, as an example to explain the genotype determination process in asymptomatic young adults (or patients with the disease). In Huntington's disease patients, the mutant allele produces an abnormal protein that is harmful to cells (especially neurons). Neuronal loss is gradual, but ultimately leads to a devastating neurodegenerative state. Symptoms usually develop between midlife and menopause. Huntington's disease is caused by unstable expansion of CAG repeats in the coding sequence of the causative gene, HTT, resulting in the production of long polyglutamine tracts. While the normal number of glutamine repeats is 6-35, patients with the disease (or asymptomatic young adults at extremely high risk for the disease) have a number of repeats ranging from 36 to 121.

[0110] In the case of known microsatellite polymorphisms ("STRPs") such as those described above, the corresponding character strings 901 and 903 can be easily obtained using the above method. After confirming the presence of character string (2) (a pair of characters: character strings 901 and 903 in Figure 9) in the character string representing the nucleotide sequence of the entire genome of the patient with the disease (the "full-length character string"), the sequence and length of the character string (902 in Figure 9: representing the full-length nucleotide sequence of the target nucleotide) present between the pair of character strings is extracted and determined. For example, if the extracted sequence and length reveals two types of CAG repeat counts: "80 (number of nucleotides: 240)" and "113 (number of nucleotides: 339)," the patient is heterozygous (both alleles have a repeat count equivalent to the disease-type allele, and therefore have an extremely high risk of developing the disease (e.g., they may be candidates for a genotype that is an "essential factor" for the administration regimen of a therapeutic drug for Huntington's disease, or they may be candidates for a genotype that is a "prohibitive factor" for a drug that is contraindicated for Huntington's disease). Furthermore, if there is only one type of CAG repeat, "5 (number of nucleotides: 15)", it is a homozygous type (since both alleles have the same number of repeats as the normal allele, the risk of developing the disease is low (for example, it could be a candidate for a "prohibited factor" in the administration regimen for Huntington's disease treatment drugs. It could also be a candidate for an "essential factor" for drugs that are contraindicated for Huntington's disease).)

[0111] The determined "allele type" (patient's genotype) together with information representing the DNA variants present in the individual's genome is saved in a database, recording medium or storage device (not shown) and stored in the genome information DB 50 (Figure 2) (step S19 in Figure 10).

[0112] 〔others〕 The entire program that executes the system 1 of Fig. 2 is stored on a server accessible from a user terminal used by the user, and can be executed via an intranet or the Internet accessible from the user terminal. The system 1 may be connected to a printing device (e.g., a printer or a multifunction peripheral) for printing information that the user desires to output on paper.

[0113] In this case, although the display device 20 (FIG. 2) and the input device 30 (FIG. 2) are shown as being connected to the control unit 10 (FIG. 2) in the above embodiment, the display device 20 (FIG. 2) and the input device 30 (FIG. 2) are actually present in a user terminal (e.g., a PC, a tablet, a smartphone, etc.). The server device and the user terminal are connected via a network line, and information input through the input device 30 (FIG. 2) of the user terminal is transmitted to the server device (for example, input can also be performed by scanning a barcode with a smartphone, tablet, etc.). The server device then transmits information generated by the control unit 10 (FIG. 2) based on the input information and information acquired from the pharmaceutical-related genetic information DB 40 (FIG. 2) and the genome information DB 50 (FIG. 2) to the user terminal, and the information is output to the user via the display device 20 (FIG. 2) of the user terminal. That is, the server device performs processing similar to that shown in the flowcharts of FIGS. 4 and 5, and the administration plan output unit 140 (FIG. 2) transmits the administration plan for the patient to the user terminal. The user terminal, upon receiving the administration plan, displays the administration plan on its display device. The administration plan here includes the information displayed in steps S8 and S9 in FIG. 4 and steps S10 and S14 in FIG.

[0114] In FIG. 2, the pharmaceutical-related genetic information DB 40 is shown as a single DB including the prohibited factor information 700 (FIG. 3(d)) and the essential factor information 800 (FIG. 3(e)), but the prohibited factor information 700 (FIG. 3(d)) and the essential factor information 800 (FIG. 3(e)) may be included in separate pharmaceutical-related genetic information DBs 40 (FIG. 2).

[0115] The order of steps S2 to S4 and steps S5 to S7 in Fig. 4 may be reversed. That is, after determining whether the essential factor information matches the genotype information of the patient, it may be determined whether the prohibited factor information matches the genotype information of the patient.

[0116] In the above embodiment, the match (or mismatch) between both the essential factor information and the prohibited factor information and the patient's genotype information is determined, but the match (or mismatch) between only either the essential factor information or the prohibited factor information and the patient's genotype information may also be determined. When the match (or mismatch) between only the essential factor information and the patient's genotype information is determined, steps S2 to S4 in Figure 4 are omitted. On the other hand, when the match (or mismatch) between only the prohibited factor information and the patient's genotype information is determined, steps S5 to S7 are omitted.

[0117] [Software implementation example] In the system 1 of Figure 2, the control unit 10 (particularly the information acquisition unit 110, the administration plan determination unit 120, the medical information change unit 130, and the administration plan output unit 140) may be realized by a logic circuit (hardware) formed on an integrated circuit (IC chip) or the like, or by software.

[0118] In the latter case, the administration regimen determination support system 1 (FIG. 2) includes a computer that executes instructions of a program, which is software that realizes each function. This computer includes, for example, one or more processors and a computer-readable recording medium storing the program. The object of the present invention is achieved when the processor in the computer reads and executes the program from the recording medium. The processor can be, for example, a CPU. The recording medium can be a "non-transitory tangible medium," such as a ROM (Read Only Memory), a tape, a disk, a card, a semiconductor memory, or a programmable logic circuit. The system may also include a RAM (Random Access Memory) for expanding the program. The program may be supplied to the computer via any transmission medium capable of transmitting the program (such as a communication network or broadcast waves). Note that one aspect of the present invention can also be realized in the form of a data signal embedded in a carrier wave, in which the program is embodied by electronic transmission. [Explanation of symbols]

[0119] 1. Decision support system for drug administration plans 10 Control Unit 110 Information Acquisition Department 120 Administration Plan Decision Unit 130 Medical Information Change Department 140 Administration plan output section 20 Display device 30 Input Devices 40 Pharmaceutical-related Gene Information DB 50 Genome Information DB 400 Patient Information 500 Medical Information 510 Changed Drug Information 520 Changed Drug Information 600 Patient Genotype Information 700 Prohibited factor information 800 Required factor information 901 Character Examples 902 string (target nucleotide) 903 String

Claims

1. 1. A decision support system for determining a suitable medication regimen for a patient, comprising: a pharmaceutical information acquisition unit that acquires pharmaceutical information indicating pharmaceuticals and dosages to be administered to the patient; at least one of a prohibited factor information acquisition unit that acquires prohibited factor information, which is information on prohibited factors that are genotypes that are prohibited from matching with the genotype of the patient when the drug is administered, and an essential factor information acquisition unit that acquires essential factor information, which is information on essential factors that are genotypes that are essential for matching with the genotype of the patient when the drug is administered; a patient genotype information acquiring unit that acquires information on the patient's genotype (patient genotype information), the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a dosage plan determination unit that compares prohibited factor information with first genotype information, and determines whether the pharmaceutical information is appropriate for the patient based on at least one of the results of the comparison between the prohibited factor information and the first genotype information and the results of the comparison between the essential factor information and the second genotype information; A decision support system comprising: the first genotype information is genotype information corresponding to a prohibition factor at a locus on the genome of the patient, the second genotype information is genotype information corresponding to an essential factor at a locus on the patient's genome, The patient genotype information includes information representing a variant having a frequency of less than 1% in the human population associated with the prohibitive factor information and / or the essential factor information. Support system.

2. a prohibited factor information acquisition unit and an essential factor information acquisition unit; The support system according to claim 1, wherein the administration plan determination unit determines an administration plan for the patient based on a comparison result between the prohibited factor information and the first genotype information and a comparison result between the essential factor information and the second genotype information.

3. further comprising an administration plan output unit that outputs an administration plan for the patient; the administration plan determination unit determines the pharmaceutical information scheduled to be administered to the patient as suitable pharmaceutical information when the first genotype information does not match the prohibited factor information and the second genotype information matches the essential factor information; 3. The support system according to claim 1, wherein when the administration plan determination unit determines that the pharmaceutical information scheduled to be administered to the patient is suitable pharmaceutical information, the administration plan output unit outputs the pharmaceutical information scheduled to be administered to the patient as suitable pharmaceutical information.

4. a dosage regimen output unit that outputs a dosage regimen for the patient; and a medical information modification unit that modifies the medical information when the medical information is inappropriate; Furthermore, the administration plan determination unit determines that the drug information scheduled to be administered to the patient is inappropriate when the first genotype information matches the prohibited factor information or when the second genotype information does not match the essential factor information; The support system according to any one of claims 1 to 3, wherein, when the administration plan determination unit determines that the pharmaceutical information scheduled to be administered to the patient is inappropriate, the administration plan output unit outputs a warning indicating that the pharmaceutical information is inappropriate and modified pharmaceutical information modified by the pharmaceutical information modification unit.

5. The support system according to any one of claims 1 to 4, wherein the prohibition factor information is a genotype having a mutation associated with the function of a gene encoding a protein involved in the pharmacokinetics or pharmacodynamics of the drug, a genotype relating to a combination of alleles associated with a predisposition to a disease that develops or becomes more severe when administered with the drug, a genotype having a mutation associated with a causative gene of a monogenic disease that has been proven to be involved in the onset of side effects when administered with the drug, or a genotype having a rare variant, an individual-specific variant, or a Mendelian-like subset mutation that has been proven to have a strong influence or effect on a multifactorial disease or polygenic disease that has been proven to be involved in the onset of side effects when administered with the drug.

6. The support system according to any one of claims 1 to 5, wherein the essential factor information is a genotype having an allele type or a combination of allele types at a specific locus on the genome that is essential for the efficacy of the drug that functions as a molecular target for a specific disease.

7. The support system according to any one of claims 1 to 6, wherein when the first genotype information and / or the second genotype information is not recorded as the patient genotype information, the system obtains information representing the entire nucleotide sequence constituting the patient's genome, detects DNA variants present at loci of the first genotype and / or the second genotype from the information representing the entire nucleotide sequence, and updates the patient genotype information.

8. To detect the DNA variants, the system generating a junction sequence in which a target nucleotide sequence corresponding to the DNA variant is joined to partial nucleotide sequences on both sides of the position corresponding to the DNA variant in a reference human genome, and comparing the junction sequence with the entire nucleotide sequence constituting the patient's genome; The support system according to claim 7, wherein the partial nucleotide sequence is repeated with increasing length.

9. To detect the DNA variants, the system generating two nucleotide sequences corresponding to partial nucleotide sequences on either side of the position corresponding to the DNA variant in a reference human genome, and comparing the two nucleotide sequences with the entire nucleotide sequence constituting the genome of the patient; The support system according to claim 7, wherein the partial nucleotide sequence is repeated with increasing length.

10. determining information representing single nucleotide polymorphisms among the DNA variants using the patient's genome fragment or based on the information representing the entire nucleotide sequence, and recording the determined information representing single nucleotide polymorphisms; The support system according to any one of claims 7 to 9, wherein information representing the unrecorded DNA variants is determined based on character information representing the entire nucleotide sequence.

11. further comprising an administration plan output unit that outputs an administration plan for the patient; 11. The support system according to claim 1, wherein the administration plan output unit transmits the administration plan for the patient to a user terminal equipped with a display device.

12. The assistance system according to any one of claims 1 to 11, wherein the prohibited factor information and / or the essential factor information is generated by artificial intelligence.

13. 1. A method for assisting in determining an appropriate dosing regimen for a patient, the method being computer-implemented, comprising: a pharmaceutical information acquisition step of acquiring pharmaceutical information indicating pharmaceuticals and dosages to be administered to the patient; at least one of a prohibited factor information acquisition step of acquiring prohibited factor information, which is information on prohibited factors that are genotypes that are prohibited from matching with the genotype of the patient when the drug is administered, and an essential factor information acquisition step of acquiring essential factor information, which is information on essential factors that are genotypes that are essential for matching with the genotype of the patient when the drug is administered; a patient genotype information acquiring step of acquiring information on the patient's genotype (patient genotype information), the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a dosing regimen determination step of comparing prohibited factor information with first genotype information to determine whether the pharmaceutical information is appropriate for the patient based on at least one of the results of the comparison between the prohibited factor information and the first genotype information and the results of the comparison between essential factor information and second genotype information; a method comprising: the first genotype information is genotype information corresponding to a prohibition factor at a locus on the genome of the patient, the second genotype information is genotype information corresponding to an essential factor at a locus on the patient's genome, The patient genotype information includes information representing a variant having a frequency of less than 1% in the human population associated with the prohibitive factor information and / or the essential factor information. method.

14. A decision support program for determining an appropriate medication regimen for a patient, comprising: a pharmaceutical information acquisition unit that acquires pharmaceutical information indicating pharmaceuticals and dosages to be administered to the patient; at least one of a prohibited factor information acquisition unit that acquires prohibited factor information, which is information on prohibited factors that are genotypes that are prohibited from matching with the genotype of the patient when the drug is administered, and an essential factor information acquisition unit that acquires essential factor information, which is information on essential factors that are genotypes that are essential for matching with the genotype of the patient when the drug is administered; a patient genotype information acquiring unit that acquires information on the patient's genotype (patient genotype information), the patient's genotype information including at least one of genotype information on a first genotype of the patient at a locus on the genome corresponding to the inhibiting factor and genotype information on a second genotype of the patient at a locus on the genome corresponding to the essential factor; and a dosage plan determination unit that compares prohibited factor information with first genotype information, and determines whether the pharmaceutical information is appropriate for the patient based on at least one of the results of the comparison between the prohibited factor information and the first genotype information and the results of the comparison between the essential factor information and the second genotype information; It is a program to function as the first genotype information is genotype information corresponding to a prohibition factor at a locus on the genome of the patient, the second genotype information is genotype information corresponding to an essential factor at a locus on the patient's genome, The patient genotype information includes information representing a variant having a frequency of less than 1% in the human population associated with the prohibitive factor information and / or the essential factor information. program.

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