Administration plan suggestion system, method and program

Abstract

A dosage regime proposing system 1 of the present disclosure is provided with: a medicine information acquiring unit (21) for acquiring medicine information representing a medicine and a dosage for administration to a patient; a relevance information acquiring unit (21) for acquiring relevance information representing relevance between the medicine and a genotype; a genotype information acquiring unit (21) for acquiring genotype information representing a genotype of the patient; a matching degree determination unit (22) for determining a matching degree of the medicine information on the basis of the relevance information and the genotype information; a medicine information modifying unit (23) for modifying the medicine information when the matching degree is low; and an information presenting unit (3) for presenting to the user modified medicine information obtained by the modifying performed by the medicine information modifying unit.

Description

[Technical field]

[0001] The present invention relates to a system for proposing a drug administration regimen to a user, and more particularly to a system for proposing to a user a drug administration regimen suitable for a patient based on a genotype specific to the patient. [Background technology]

[0002] The relationship between gene function and the efficacy 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). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2016-218684 A (Published December 22, 2016) Summary of the Invention [Problem to be solved by the invention]

[0004] However, no system has yet been proposed that uses the genetic information of a patient to determine whether a drug that is thought to be effective against a certain disease is actually safe and effective for a specific 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.

[0005] Therefore, the current outpatient and in-hospital prescriptions (which specify the type, dose and administration of the drug) written by doctors 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 may mean that the type of drug, its dose and administration method suitable for each patient cannot be specified. In fact, multiple patients who use the drug as prescribed have widely different reactions. It has been pointed out that such reactions may include the drug only having an adverse effect on the patient (only showing side effects and no efficacy).

[0006] In addition to the drugs used by patients according to prescription, there are drugs and other substances (such as anesthetics) whose administration or use to patients requires the supervision of medical professionals. It is well known that the administration or use of such drugs or substances can cause an overreaction in some people and is often accompanied by side effects. For example, a British study reported that about 7% of patients admitted to a medical facility experience some kind of side effect. The above-mentioned overreactions or side effects can have serious consequences for the patient (such as physical disability, irreparable damage, manifestation of congenital abnormalities, or death). Overreactions or side effects cause about 100,000 deaths per year in the United States.

[0007] As mentioned above, the effectiveness of drugs and substances used in medical care generally varies greatly from person to person. Even drugs or substances approved by the government (meeting certain standards for efficacy and safety) are rarely effective for all patients who receive them. In other words, at present, there are patients who receive drugs that do not show any efficacy, and patients who receive drugs in amounts that are inappropriate for the drug to show efficacy.

[0008] Among them, drugs used to treat mental disorders show relatively low efficacy. The administration of drugs with low efficacy delays recovery and increases treatment costs, imposing physical, mental, or economic burdens on patients. In addition to these burdens, as mentioned above, side effects of drugs can cause suffering that is essentially unrelated to the disease.

[0009] Individual differences in drug efficacy and side effects are due more to genetic variation within the human population than to the influence of the type of disease, environmental factors (such as lifestyle) and / or the combination of medications being taken.

[0010] Therefore, one aspect of the present invention aims to suggest to a user a drug administration regimen suitable for a patient based on the patient's unique genotype. [Means for solving the problem]

[0011] In order to solve the above problems, a system according to one aspect of the present invention is a system for proposing a suitable administration regimen for a patient, comprising: a medical information acquisition unit for acquiring medical information indicating a medicine to be administered to the patient and its dosage; an association information acquiring unit for acquiring association information indicating an association between the medicine and the genotype; a genotype information acquisition unit for acquiring genotype information of the patient; a suitability determining unit that determines the suitability of the medical information based on the association information and the genotype information; a medical information modification unit for modifying the medical information when the degree of conformity is low; and an information presenting unit that presents to a user the changed pharmaceutical information that has been changed by the pharmaceutical information changing unit Equipped with When the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the system obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The genotype information includes information representing variants that have a frequency of less than 1% in the human population.

[0012] In order to solve the above problems, a method according to another aspect of the present invention is a method for proposing a suitable dosing regimen for a patient, comprising: a medical information acquisition step in which a computer acquires medical information indicating a medicine to be administered to the patient and the dosage thereof; an association information acquisition step in which the computer acquires association information indicating an association between the medicine and the genotype; a genotype information acquiring step in which the computer acquires genotype information of the patient; a suitability determination step in which the computer determines the suitability of the medical information based on the association information and the genotype information; a medical information changing step in which the computer changes the medical information when the degree of conformity is low; and an information presenting step in which the computer presents to the user the changed medical information that has been changed in the medical information changing step; Including, In the above method, when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the computer obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The genotype information includes information representing variants that have a frequency of less than 1% in the human population.

[0013] In order to solve the above problems, a dosage plan proposal program according to another aspect of the present invention is a dosage plan proposal program for causing a computer to function as a system for proposing a dosage plan suitable for a patient, the dosage plan proposal program comprising: The system includes a controller, The control unit is obtaining medical information indicating a medication and its dosage to be administered to said patient; obtaining association information representing an association between the drug and the genotype; Obtaining genotype information of said patients; determining the relevance of the medical information based on the association information and the genotype information; When the compatibility is low, modify the medical information; presenting the modified medical information to the user with the changes; and when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, obtain information representing the entire nucleotide sequence constituting the genome of the patient, detect a DNA variant present at the locus from the information representing the entire nucleotide sequence, and update the genotype information; The genotype information includes information representing variants having a frequency of less than 1% in the human population. A computer functions as the control unit.

[0014] In order to solve the above problems, a system according to one aspect of the present invention is a system for proposing a suitable administration regimen for a patient, comprising: a medical information acquisition unit for acquiring medical information indicating a medicine to be administered to the patient and its dosage; an association information acquiring unit for acquiring association information indicating an association between the medicine and the genotype; a genotype information acquisition unit for acquiring genotype information of the patient; a suitability determining unit that determines the suitability of the medical information based on the association information and the genotype information; an administration plan determination unit that determines the appropriate medical information for the patient based on the suitability of the medical information determined by the suitability determination unit; and an information presentation unit that presents the medical information determined by the administration plan determination unit to a user; Equipped with When the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the system obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The genotype information includes information representing variants that have a frequency of less than 1% in the human population. Effect of the Invention

[0015] According to one aspect of the present invention, a drug administration regimen suitable for a patient can be proposed based on the patient's unique genotype. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a diagram illustrating the concept of the present invention. [Diagram 2] FIG. 1 is a diagram illustrating a configuration of a system according to a first embodiment of the present invention. [Diagram 3] FIG. 2 is a diagram illustrating an example of a process executed by the system. [Figure 4] FIG. 13 is a diagram showing examples of pharmaceutical information, modified pharmaceutical information, and related information. [Diagram 5] FIG. 11 is a diagram illustrating a configuration of a system according to a second embodiment of the present invention. [Figure 6] FIG. 11 is a diagram illustrating another example of the process executed by the system. [Figure 7] FIG. 13 is a diagram showing another example of medical information and related information. [Figure 8] FIG. 11 is a diagram illustrating a configuration of a system according to a third embodiment of the present invention. [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 in a genome sequence. [Figure 11] 13 is a diagram showing other examples of pharmaceutical information, changed pharmaceutical information, and relevance information. FIG. [Figure 12] FIG. 13 is a diagram illustrating a configuration of a modified example of the system according to the first embodiment of the present invention. [Figure 13] FIG. 13 is a diagram illustrating a configuration of a system according to another embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] One aspect of the present invention is a system for proposing a suitable administration regimen for a patient based on a genotype specific to the patient, and includes a pharmaceutical information acquisition unit for acquiring pharmaceutical information indicating the medicine to be administered to the patient and the dosage thereof; an association information acquisition unit for acquiring association information indicating the association between the medicine and the genotype; a genotype information acquisition unit for acquiring genotype information of the patient; a suitability determination unit for determining the suitability of the pharmaceutical information based on the association information and the genotype information; a pharmaceutical information modification unit for modifying the pharmaceutical information when the suitability is low; and an information presentation unit for presenting to a user the modified pharmaceutical information modified by the pharmaceutical information modification unit.

[0018] An "administration plan" includes at least information describing a specific patient, and information describing the type and dosage of a medicine to be administered to the specific patient. The administration plan is a guideline (e.g., a prescription) indicating that a certain medicine should be administered to the specific patient at a certain dosage. The system is a system that assists the judgment of medical professionals (particularly physicians) by creating an administration plan (custom-made administration plan) suitable for the patient.

[0019] As used herein, the term "medicine" refers to a medicine that exerts a medicinal effect in a patient administered thereto, thereby directly bringing about an improvement in symptoms of a disease, or a substance (such as a contrast agent or anesthetic) used for the purpose of assisting medical procedures (such as examinations and anesthesia).

[0020] "Genotype" (also called genotype) refers to the genetic constitution of an entire individual or of a specific locus of an individual, and as used herein 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 genotype, the sum of each type). As used herein, "allele" refers to an individual gene and DNA sequence present at one locus on a chromosome. When referring to "genotype" or "allele type," these terms are used herein to include the concept of "mating type."

[0021] "Medical information" refers to information that includes at least information identifying a patient (e.g., a patient ID number), information identifying a drug (e.g., a trade name or substance name of the drug), and information specifying the dosage of the drug for the patient. Medical information may be, for example, a medical record or a prescription created by a doctor on a computer.

[0022] "Relationship information" refers to information that indicates the relationship between a type of drug and a gene (group of genes) that influences the action of the drug in the living body.

[0023] "Goodness of fit (of pharmaceutical information)" refers to the degree to which the relationship between a patient and the type of medicine and / or its dosage specified in the pharmaceutical information is appropriate, based on the genotype specific to the patient specified in the pharmaceutical information.

[0024] In this specification, the term "DNA variant" is described as a concept of a specific site on the genome where two or more changes in nucleotide sequence (including alleles and chromosomal structures) exist in the human population (regardless of their frequency), and the totality of such changes. The change in nucleotide sequence in the above-mentioned "DNA variant" refers to the totality of all changes, including substitution, deletion, insertion and / or addition, and duplication of one or more nucleotides (see the lower part of Figure 1).

[0025] Among the above-mentioned "DNA variants", when the change is frequent (1% or more) in a population, it is called "polymorphism (P: Polymorphism)", for example, single nucleotide polymorphism (hereinafter referred to as "SNP"), copy number polymorphism (hereinafter referred to as "CNP"), and microsatellite polymorphism (short tandem repeat polymorphism, hereinafter referred to as "STRP"). When the change is frequent (less than 1%) in a population, it is called "variant (V: Variant)", for example, single nucleotide variant (hereinafter referred to as "SNV") and copy number variant (hereinafter referred to as "CNV"). In this specification, the above-mentioned "DNA variant" is described as a concept including "polymorphism" and "variant" regardless of the frequency in the human population as described above (see the lower part of FIG. 1).

[0026] The total type of allele combinations ("allele types") including the zygote type at one locus is determined by the nucleotide sequence of each allele and / or the number of alleles contained in the combination. Administration of the medicine 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 the alleles is not the usual two (i.e., a patient with an unusual type) may cause undesirable effects in the patient. The undesirable effects are, for example, (a) a decrease, loss or excessive increase in efficacy of the medicine, (b) the appearance or increase of side effects caused by the medicine, and / or (c) a high incidence of a specific disease that did not occur before administration of the medicine, compared to a patient with a normal type. However, in reality, as exemplified in [Embodiment 2] described later, the undesirable effects do not appear only in one of the "allele types" but often appear when accumulated by a large number of "allele types" at a large number of loci.

[0027] Therefore, as shown in FIG. 1, the system proposes changing the administration plan of drug B (including the designation of dosage C) for patient A specified by the doctor according to the uniform factors described above to a custom-made administration plan (e.g., drug B' and dosage C') in which the above-mentioned adverse effects are suppressed in accordance with the genotype information of patient A. Criteria for changing the administration plan include (1) pharmacokinetic factors of drug B, (2) pharmacodynamic factors of drug B, and (3) the risk of developing secondary diseases due to drug B. In the embodiment 1 described later, an example in which (1) and (2) are used as the above-mentioned criteria will be explained. In the embodiment 2 described later, an example in which (3) is used as the above-mentioned criteria will be explained. In the embodiment 3 described later, an example in which a combination of (1) to (3) is used as the above-mentioned criteria will be explained. "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, and "pharmacodynamics" refers to the strength of the action of a substance (drug) on ​​a target substance in the body. The above "pharmacokinetics" and "pharmacodynamics" are described later in [Embodiment 1] along with the characteristics of related proteins.

[0028] (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) through the administration of the drug (artificial action).

[0029] The graph in FIG. 1 (System of the Invention) visually shows the risk of developing a certain disease. In this graph, when the frequency of genetic backgrounds in the human population is plotted on the vertical axis and the susceptibility (ease of developing) to a certain disease correlated with each genetic background is plotted on the horizontal axis, it is shown that the risk of developing a certain disease in the human population is approximately normally distributed. As shown in the graph, the population on the right side of the threshold (the part surrounded by the horizontal axis, the dashed line of the threshold, and the curved line / the part surrounded by the horizontal axis and the curved line) has a genetic background that is prone to developing a certain disease (see, for example, Falconer DS (1965) The inheritance of liability to certain diseases estimated from the incidence among relatives. Ann Hum Genet 29:51-76; doi 10.1111 / j.1469-1809.). However, human individuals A1 and A2 on the right side of the threshold merely have a high risk of developing the disease, and do not necessarily actually develop the disease. A1 and A2 have very similar risks of developing the disease. However, for example, A1 may not have developed the disease, while A2 may have developed the disease. Various factors are involved in the development of a disease, but the above (3) is used for the purpose of preventing the administration of medicine (an artificial environmental factor that connects a genetic predisposition to a disease to the development of the disease) from causing the development of a disease in the undeveloped A1.

[0030] The genotype information of patient A can be determined by, for example, the following two different methods (see the lower part of FIG. 1). For example, from a string representing the entire nucleotide sequence of the genome obtained from the patient (approximately 3 billion characters represented by the four alphabets ATGC, hereinafter referred to as the "full-length string"), a string representing a partial nucleotide sequence including a known DNA variant present at at least one locus (hereinafter referred to as the "allele string") is extracted. Then, the string is compared with a full string representing the entire nucleotide sequence of a standard human genome (approximately 3 billion characters represented by the four alphabets ATGC, hereinafter referred to as the "reference string") to identify the type of allele combination of the DNA variant (the "genotype" of the patient). The reference string can be obtained from public databases such as Ensembl (URL: http: / / ensembl.org). Alternatively, as another method, the genotype information of patient A can be determined by an experimental method, for example, by hybridizing a portion of a genomic DNA sample obtained from the patient with each fragment consisting of a nucleotide sequence containing all known SNPs corresponding to the "reference string" under stringent conditions (conditions (temperature, salt concentration) that allow only perfectly matching sequences) using current microarray technology (genome-wide polymorphism analysis technology). Details of the method for determining the "genotype" information of a patient are described later in each embodiment (particularly, in [Embodiment 4], a method for determining the "genotype" information by information analysis using the above-mentioned "full-length string" is described in detail, including specific examples).

[0031] Several embodiments of the present invention are described in detail below.

[0032] [Embodiment 1] In this embodiment, the compatibility is determined based on the expected efficacy of the drug in the patient. The system of this embodiment at least refers to the type of allele combination ("allele type") including the zygosity at the locus where the gene encoding the protein involved in the pharmacokinetics or pharmacodynamics of the drug is located and the zygosity at the locus related to the gene as the genotype. In other words, the system of this embodiment determines the compatibility by referring to information (drug efficacy-related gene information) that indicates the degree to which the genotype ("allele type") related to the gene affects the efficacy of the drug.

[0033] (Proteins involved in pharmacokinetics and pharmacodynamics) The efficacy of a drug is determined in part by the genetic diversity of proteins involved in pharmacokinetics and / or proteins involved in pharmacodynamics. Proteins involved in pharmacokinetics include, for example, proteins involved in drug absorption, circulation, delivery, metabolism, and excretion. In other words, pharmacokinetics refers to the behavior of a drug or its metabolites in vivo that changes the probability of contact between the drug and the target molecule. Proteins involved in pharmacodynamics can be the target molecules of the drug. Such target molecules include, for example, receptors, signal molecules, and proteins that constitute biological pathways related to the pharmacogenetic action of a drug.

[0034] As shown in FIG. 2, a dosage plan suggestion system (a system for presenting a dosage plan suitable for a patient) 1 includes a control unit 2 built into a computer, and a display device (information display unit) 3. The control unit 2 (FIG. 2) includes an information acquisition unit (medicinal information acquisition unit, relevance information acquisition unit, and genotype information acquisition unit) 21, a compatibility determination unit 22, and a medical information change unit 23 of FIG. 2. The information acquisition unit 21, the compatibility determination unit 22, and the medical information change unit 23 of FIG. 2 are included in a CPU (Central Processing Unit) in the control unit 2 (FIG. 2). The control unit 2 (FIG. 2) is connected to an input device 4 (e.g., a keyboard and / or a mouse), a drug efficacy-related gene information DB5, and a genome information DB6 of FIG. 2. The administration plan suggestion system 1 of FIG. 2 is a system that outputs information generated by the control unit 2 (FIG. 2) based on information acquired from the input device 4 and the above two DBs (databases: i.e., drug efficacy-related gene information DB5 and genome information DB6) to a user via the display device 3 (FIG. 2).

[0035] (Processing of administration plan proposal system 1) An example of a process executed by the administration plan proposal system 1 in Fig. 2 to improve the effectiveness of medicine will be described below with reference to Fig. 3. The input device 4 (Fig. 2) sends medical information 301 (Fig. 4) input by a doctor who is a user to the information acquisition unit 21 (Fig. 2) according to conventional 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.) (step S1 in Fig. 3). The information acquisition unit 21 of FIG. 2 acquires the name of the drug represented by the drug name included in the medical information 301 (FIG. 4), the name of the gene related to the efficacy of the drug, all the "genotypes" of known DNA variants (e.g., SNPs) related to the gene, and the efficacy of the drug according to the genotype from the medical efficacy related gene information DB5 of FIG. 2 (for example, DGIdb: Drug Gene Interaction database, which can be constructed based on information from URL: http: / / dgidb.org / ) ("YES" in step S2 of FIG. 3). The information acquisition unit 21 of FIG. 2 acquires the genotype information of the patient corresponding to the patient ID and the gene from the genome information DB6 (FIG. 2) as a symbol according to the notation method of "genotype" described in the association information 311 of FIG. 4 based on the "patient ID" information described in the medical information 301 (FIG. 4) and the gene name included in the association information 311 (FIG. 4) ("YES" in step S3 of FIG. 3). The information acquisition unit 21 (FIG. 2) sends the acquired medical information 301 (FIG. 4), relevance information 311 (FIG. 4), and patient genotype information acquired from the genome information DB6 (FIG. 2) to the compatibility determination unit 22 (FIG. 2).

[0036] If the result of step S2 in FIG. 3 is "NO" (e.g., the drug has only recently been developed, and therefore there is no association information), the information acquisition unit 21 in FIG. 2 sends the medical information 301 (FIG. 4) to the display device 3 (FIG. 2) (step S9 in FIG. 3). The display device 3 in FIG. 2 displays the medical information, and the administration plan proposal system 1 (FIG. 2) ends the processing. If the result of step S3 in FIG. 3 is "NO" (e.g., the genotype information corresponding to a specific gene in a patient has not yet been determined), the information acquisition unit 21 (FIG. 2) sends the medical information 301 (FIG. 4) to the display device 3 (FIG. 2) (step S9 in FIG. 3). The display device 3 (FIG. 2) displays the medical information, and the administration plan proposal system 1 in FIG. 2 ends the processing.

[0037] The compatibility determination unit 22 in Fig. 2 determines the compatibility of the medical information 301 (Fig. 4) based on the relevance information 311 (Fig. 4) and the genotype information of the patient acquired from the genome information DB6 (Fig. 2) via the information acquisition unit 21 (Fig. 2) (step S4 in Fig. 3). Details of step S4 in Fig. 3 will be described with reference to Fig. 4.

[0038] The association information 311 shown in FIG. 4 shows association information including an active ingredient corresponding to a drug name (drug name: phenytoin (antiepileptic drug)), a gene encoding a protein involved in the pharmacokinetics of the active ingredient (related gene: CYP2C9 (drug metabolizing enzyme gene)), a known SNP (SNP site: rs1057910) present on the gene, the sum of the symbolized "genotypes" in the SNP (rs1057910) (genotypes: "*1 / *1", "*1 / *3", and "*3 / *3"), and the metabolic rate (corresponding to the drug efficacy) of the active ingredient corresponding to each genotype (metabolic rate (drug efficacy): "±0", "-1", and "-2"). Phenytoin is a drug that has the effect of relieving symptoms of epilepsy convulsive seizures such as tonic-clonic seizures (generalized convulsive seizures, grand mal seizures), focal seizures (including Jacksonian seizures), autonomic seizures, and psychomotor seizures.

[0039] In the relationship information 311 (Figure 4), an SNP (rs1057910) exists at position 1075 in the coding region of CYP2C9, and its genotype type "*1" represents a wild-type allele, and the actual type of nucleotide base is "adenine (A)". In addition, the genotype type "*3" represents a poor metabolizer allele known to reduce the metabolic rate of phenytoin, and the actual type of nucleotide base is "cytosine (C)". The relationship information 311 (Figure 4) shows the metabolic rate (drug efficacy) of phenytoin, which is calculated by subtracting the number (absolute number) of the genotype of a specific patient that includes the poor metabolizer allele "*3" (actual nucleotide base: "C") from the metabolic rate (drug efficacy) "±0" of phenytoin corresponding to the genotype (normal type) "*1 / *1" (actual nucleotide combination type: "A / A") that is most frequent in the population. In other words, the association information 311 (FIG. 4) shows that administration of phenytoin according to the conventional uniform factors shows different metabolic rates (drug effects) ("±0", "-1" or "-2") for patients having different coded genotypes ("*1 / *1", "*1 / *3" or "*1 / *1") depending on the type of nucleotide change combination ("A / A", "A / C" or "C / C") of the SNP at position 1075 of the CYP2C9 gene.

[0040] According to the above-described S4 step in FIG. 3, when the compatibility determination unit 22 (FIG. 2) acquires the medical information 301 (FIG. 4), the relevance information 311 (FIG. 4), and "*1 / *3" as the genotype information of the patient from the information acquisition unit 21 (FIG. 2), the compatibility determination unit 22 (FIG. 2) determines the value of the metabolic rate (efficacy) of phenytoin in the medical information 301 (FIG. 4) to be "-1". The above "*1 / *3" is genotype information indicating that the "allele type" of CYP2C9 in the patient is a heterozygous type. The genotype information is acquired from the genome information DB6 (FIG. 2) by the information acquisition unit 21 (FIG. 2) based on the "patient ID: 123456789" described in the medical information 301 (FIG. 4) and the "related gene: CYP2C9" described in the relevance information 311 (FIG. 4).

[0041] When there are two genes related to the medicine name M (medicine) included in the medicine information 301 in Fig. 4 (two gene names G (gene) 1 and G2 are described in the relationship information 311 in Fig. 4), the information acquisition unit 21 (Fig. 2) sends two pieces of relationship information R (relationship) 1 and R2 corresponding to the gene names G1 and G2, and the patient genotype information Gt (genotype) 1 and Gt2 to the compatibility determination unit 22 (Fig. 2). The compatibility determination unit 22 (Fig. 2), which has received the two pieces of relationship information R1 and R2, and the two pieces of patient genotype information Gt1 and Gt2, determines the value of the compatibility factor F (factor) corresponding to the medicine name for each of the gene names G1 and G2, and determines the value "-2" obtained by adding up the two values ​​(for example, G1: ±0, G2: -2) as the compatibility of the medicine M.

[0042] In the above description, the metabolic rate (drug efficacy) of phenytoin is exemplified as an element of the degree of compatibility. The elements of the degree of compatibility change depending on the type of drug and the gene related to the drug. For example, the relevance information 312 in FIG. 4 uses the metabolic rate (corresponding to the drug efficacy) at which clopidogrel sulfate (a prodrug, hereinafter simply referred to as "clopidogrel"), an antiplatelet drug, is converted into the active compound of clopidogrel by CYP2C19 (a drug metabolizing enzyme gene) due to pharmacokinetic factors. Clopidogrel is a drug that inhibits the action of ADP (adenosine diphosphate), suppresses platelet aggregation based on platelet activation, and suppresses the formation of thrombus to prevent blood vessels from clogging, and is usually used to suppress the recurrence of ischemic cerebrovascular disease and the formation of thrombus and embolism in peripheral arterial disease. Also, for example, the association information 313 in Fig. 4 uses a direct action (i.e., drug effect) on angiotensin converting enzyme (hereinafter, abbreviated as "ACE"), which is the target molecule of perindopril erbumine (active ingredient), a drug for treating hypertension, due to pharmacodynamic factors. Perindopril erbumine is a prodrug, which is hydrolyzed into a diacid form (perindoprilat) after oral absorption, and this diacid form specifically inhibits ACE in the blood and tissues, suppresses the production of angiotensin II, a blood pressure booster, and reduces peripheral vascular resistance. When polymorphisms or variants are known for multiple alleles that are respectively involved in the metabolic rate and efficacy (degree of fitness) of a single drug, the information acquisition unit 21 (FIG. 2) acquires the same amount of association information (stored in the drug efficacy related gene information DB5 in FIG. 2) as the number of fitness factors F (factor) and the patient's genotype information (stored in the genome information DB6 in FIG. 2), determines the values ​​of F1, F2...Fn for each fitness factor, and calculates the final degree of fitness by summing them up.

[0043] When the heterozygous type "*1 / *3" is acquired as genotype information related to SNP (rs1057910) in CYP2C9 in the association information 311 (FIG. 4) as described above, the compatibility determination unit 22 in FIG. 2 determines the total value "-1" of the metabolic rate (efficacy) value "±0" corresponding to the normal genotype (normal type) "*1 / *1" and the metabolic rate (efficacy) value "-1" of phenytoin corresponding to the heterozygous type "*1 / *3" as the compatibility (lower by 1) related to the metabolic rate (efficacy) of the medical information 301 (FIG. 4). The compatibility determination unit 22 (FIG. 2) sends the medical information 301 (FIG. 4) and the compatibility "-1" to the medical information change unit 23 (FIG. 2).

[0044] The medical information change unit 23 in Fig. 2 judges the negative value of the degree of suitability "-1" to be low (step S5 in Fig. 3). The medical information change unit 23 (Fig. 2) reduces the maintenance dose (the dose of a drug that is continuously administered after the initial administration period has elapsed, and the "daily dose (maintenance dose)" described in the medical information 301 (Fig. 4)) of the daily dose in the medical information 301 (Fig. 4) by 1 unit (1 unit = 25% described in the medical information 301) according to the metabolic rate (drug efficacy) "-1", and sets the drug efficacy to "±0" (step S6 in Fig. 3). Since the change in step S6 in FIG. 3 is the "daily dose (maintenance dose)" (the determination in step S7 in FIG. 3 is "NO"), as described above, the medical information change unit 23 (FIG. 2) sends the changed medical information 302 (FIG. 4) in which the "daily dose (maintenance dose)" is changed to 225 mg, which is a dosage that is 25% less than 300 mg, to the display device 3 (FIG. 2). There is no change in the initial dosage, and it remains as "daily dose (initial dose) 300 mg" written in the medical information 301 in FIG. 4. The display device 3 (FIG. 2) displays the changed medical information 302 (FIG. 4), and the administration plan proposal system 1 (FIG. 2) ends the process. When the daily dosage in the changed medical information 302 in FIG. 4 exceeds the administration limit, the medical information change unit 23 (FIG. 2) executes the change of the medicine in the changed medical information 302 (FIG. 4) (not shown).

[0045] Unlike the above-described example S4 step in FIG. 3, when the compatibility determination unit 22 (FIG. 2) acquires normal type "*1 / *1" as the genotype information of the patient from the genome information DB6 (FIG. 2), it determines the value of the metabolic rate (drug efficacy) of phenytoin to be "±0" and sends it to the medical information change unit 23 (FIG. 2). The medical information change unit 23 (FIG. 2) determines that the metabolic rate (drug efficacy) value "±0" is not low, and sends the medical information 301 (FIG. 4) to the display device 3 (FIG. 2). The display device 3 (FIG. 2) displays the above medical information, and the administration plan proposal system 1 (FIG. 2) ends the process.

[0046] In the above example, the change to the medical information was not a change in the type of medicine, so the medical information change unit 23 in FIG. 2 made the determination "NO" in step S7 in FIG. 3. However, for example, when the following conditions are met, the medical information change unit 23 (FIG. 2) changes the type of medicine. Condition: The name of the medicine described in the medical information is "clopidogrel", and the information acquisition unit 21 (FIG. 2) is the association information 312 (FIG. 4), and the patient's genotype information acquired from the genome information DB6 (FIG. 2) is either "*2 / *2", "*3 / *3", or "*2 / *3", so the metabolic rate (drug efficacy) is very low "-2". As described above, clopidogrel is a prodrug, and does not produce a drug efficacy unless it is converted into its active compound. In other words, when the above conditions are met, the active compound of clopidogrel, which is the active ingredient, is hardly produced in the patient's body regardless of the dosage. Therefore, since an increase in the dosage is not expected to have any medicinal effect, the medical information change unit 23 (FIG. 2) in FIG. 2 changes the type of medicine. The medical information change unit 23 (FIG. 2) sends the medical information with the changed name (determined as "YES" in step S7 in FIG. 3) to the information acquisition unit 21 (FIG. 2), and returns to processing step S2 in FIG. 3. Details of the relationship information 311-313 in FIG. 4 and other related matters will be described later in the section of this embodiment (relationship information 311-313).

[0047] As described above, the administration plan proposal system 1 (FIG. 2) of this embodiment changes the type of medicine or its dose described in the medical information 301 (FIG. 4) designated by the doctor when it is determined that the type or dose does not match the patient's "genotype" (the patient's "genotype" as a combination of alleles related to genes that affect the efficacy of the medicine). Therefore, the administration plan proposal system 1 (FIG. 2) can propose a custom-made administration plan with excellent efficacy according to the patient's genotype, without being bound by conventional uniform factors.

[0048] The genotype information and association information used by the administration regimen suggestion system 1 (FIG. 2) to suggest an appropriate administration regimen for a patient will be described in detail below.

[0049] (Patient's genotype information) Genotype information represents the type of combination ("allele type") of alleles (alleles associated with one gene in this embodiment) present at one locus that is specific to the patient. There are roughly two 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 technique based on genome-wide polymorphism analysis using a genomic DNA sample derived from the patient, targeting only DNA variants (e.g., SNPs) that are frequent in the population and suitable for automated analysis.

[0050] The former "method 1" can be carried out by using a massively parallel DNA sequencing method (next-generation sequencing method). Massively parallel DNA sequencing method can simultaneously and uniformly sequence complex DNA samples containing a large number (sometimes millions) of nucleotide sequences. For this reason, compared with the conventional dideoxy sequencing method (Sanger method), massively parallel DNA sequencing method can convert genomic DNA samples extracted by a standard method from blood cells and various tissues derived from a patient into character string ("full-length character string") information corresponding to the entire genome (approximately 3 billion nucleotides) of the patient in a short time and at low cost. By determining all the characters or character strings (and their positions) contained in the above "full-length character string" and comparing it with a character string ("reference character string") representing a reference nucleotide sequence of the human genome, the genotype of a specific locus on the patient's genome can be determined.

[0051] For example, information on a character string ("allele character string") representing the nucleotide sequence of an allele that may be present at a locus and the location (known DNA variant) at which the nucleotide sequence change occurs between the alleles in a population is stored in a publicly available database (e.g., dbSNP (https: / / www.ncbi.nlm.nih.gov / snp / )) if it is frequent in the population (e.g., SNP). Therefore, by determining which type of combination of allele character strings ("allele types") for a locus contains in the "full-length character string," the genotype for a locus held by the patient can be determined. As an example, the process of determining the genotype information of a patient is outlined below. Based on the above information representing the position of a known DNA variant stored in a publicly available database (e.g., the above-mentioned dbSNP), determine two adjacent strings (e.g., about 10 to 100 characters) on either side of the position of the DNA variant in the above-mentioned "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 string" (i.e., the patient's "genotype") is determined according to whether or not there is a match between the "full-length string" and the "reference string" and the characters (strings) corresponding to the DNA variant that are sandwiched between the positions where the two strings match perfectly.

[0052] Details of the method for determining the "patient's genotype information" by information analysis using the above-mentioned "full-length character string" ("Method 1"), including specific examples, will be described later in [Embodiment 4].

[0053] On the other hand, in the latter "Method 2" mentioned above (a method using an experimental technique based on comprehensive genome polymorphism analysis), when the above DNA variant is a DNA variant that occurs frequently in a population and is suitable for automated analysis (e.g., SNP, or a deletion or insertion (indel) of one to several nucleotides in the genome), microarray technology that has already been commercialized (available commercially as kits and contracted implementation services) can determine the types of polymorphisms in a large number (tens of thousands to hundreds of thousands) of genome fragments in a short period of time. For details on microarray technology, please refer to the kit manual or the contracted company's website.

[0054] As described above, the genotype information of a patient can be determined by the above-mentioned "Method 1" using the "full-length character string" information and / or the latter "Method 2" using an experimental method based on comprehensive genome polymorphism analysis (or during the implementation of these methods). Therefore, the genotype information of a patient stored in the genome information DB6 of FIG. 2 can be at least one of (1) the "full-length character string" (patient's genome information), (2) information representing the "genotype" of a patient and information representing the patient, which are associated with each other, and (3) information in which the two pieces of information are symbolized (for example, see the "genotype" described in the relationship information 311 of FIG. 4 described above). The genotype information is preferably (2) or (3). Using (2) or (3) as the genotype information can reduce the performance required for the administration plan proposal system 1 (FIG. 2) and the genome information DB6 (FIG. 2), and can improve the processing speed of the administration plan proposal system 1 (FIG. 2). Using (3) as the genotype information can conceal (1) and (2) from an unspecified number of third parties who cannot decipher the meaning of the symbols. For example, as shown in relationship information 312 in Figure 4, the "genotype" determined for a SNP (rs4244285) present in the drug metabolizing enzyme gene CYP2C19 can be symbolized ("*1 / *1", "*1 / *2", "*1 / *3", "*2 / *2", "*2 / *3" or "*3 / *3").

[0055] The "allele type" of each DNA variant for generating (2) and (3) as the genotype information of the patient can be determined in two stages according to the type (determination range) of the DNA variant based on the frequency in the population (see the lower part of FIG. 1). In the first stage, only all known SNPs are comprehensively determined in the genome as DNA variants that have a frequency of 1% or more in the population and are also suitable for automatic analysis, and the information is stored in a DB, a recording medium, or a storage device (not shown). In addition, the "genotype" information of the patient based on the analysis of all the SNPs is stored in the genome information DB6 (FIG. 2). The "allele type" of all SNPs (the "genotype" of the patient) can be determined by the "Method 2" using an experimental method using a genomic DNA sample of the patient, as described above. That is, the genomic DNA sample is first extracted from the peripheral blood, oral cells, buccal mucosa, or the like of the patient by a standard method. Next, the "allele type" (patient's "genotype") of all known SNPs can be determined by an experimental method using the above sample and comprehensive genome polymorphism analysis by current microarray technology. Alternatively, the patient's "genotype" ("allele type") of all the above SNPs may be determined by "Method 1" using information analysis using the above-mentioned "full-length character string" (patient's genomic information) (see the lower part of Figure 1).

[0056] Next, in the second step, the "allele type" (patient's "genotype") of the remaining DNA variants not stored in the DB, recording medium or storage device is determined by "Method 1" using the "full-length character string" information (patient's genome information) as necessary. The "remaining DNA variants" are assumed to be DNA variants with low frequency in the population (e.g., SNV, CNV), or DNA variants not suitable for automatic analysis (e.g., CNP, STRP, or other special DNA variants) (see the lower part of FIG. 1). The "allele type" of the remaining DNA variants (patient's "genotype") is determined after inputting the pharmaceutical information 301 (FIG. 4) to the input device 4 (FIG. 2). As described above, the administration plan proposal system 1 in FIG. 2 acquires the name of the gene related to the pharmaceutical efficacy of the drug from the pharmaceutical efficacy-related gene information DB 5 (FIG. 2) based on the pharmaceutical name included in the pharmaceutical information 301 (FIG. 4). The administration plan proposal system 1 (FIG. 2) searches the latest genome information DB6 (FIG. 2) based on the name, and if the "allele type" (i.e., the patient's genotype information) for the required DNA variant is not stored, it searches the "reference string" information as described above to specify the locus on the genome where the remaining DNA variant exists. The administration plan proposal system 1 (FIG. 2) determines the "allele type" (the patient's "genotype") of the remaining DNA variant present only at the locus by "Method 1" using the above string ("full length string"). The administration plan proposal system 1 (FIG. 2) stores the determined "allele type" (the patient's genotype information) of the remaining DNA variant in the above genome information DB6 (FIG. 2), as well as the above DB, recording medium, or storage device (not shown). The method ("Method 1") of determining the "allele type" (the patient's genotype information) of the DNA variant using the above string ("full length string") information is also described in detail in the following section [Embodiment 4], including specific examples.

[0057] In Figure 2, the genome information DB6 is shown as being configured to exist on a network, but it can be replaced by a reading unit capable of reading a memory unit or recording medium built into the control unit 2 (Figure 2), or a reading device capable of reading an external memory unit or recording medium connected to the control unit 2 (Figure 2).

[0058] The genotype information (2) or (3) above can be updated based on the latest report, which is a report of new DNA variants associated with a gene and the overall "allele type" ("genotype") of the DNA variants. As described above, the "Method 1" using the "full-length character string" information (patient genome information) can generate new (2) or (3) based on the existing report and the latest report.

[0059] As described above, the process executed by the administration plan proposal system 1 (FIG. 2) with reference to FIG. 3 and FIG. 4 is an example of obtaining (2) and (3) as the patient's genotype information from the genome information DB6 (FIG. 2) in two steps. That is, in the first step, all SNP analysis information of the patient determined by "Method 2" using an experimental method utilizing a known DNA microarray technology (or "Method 1" using "Full-length character string" information (patient's genome information)) is stored in the genome information DB6 (FIG. 2). Then, in the second step, the remaining DNA variant information is analyzed by "Method 1" using "Full-length character string" information (patient's genome information) as necessary.

[0060] However, the control unit 2 in FIG. 2 may execute "Method 1" using "full-length character string" information (patient's genome information) to determine the "allele type" of a specific DNA variant (patient's "genotype") as needed from the beginning as a second step, without storing the entire SNP analysis information of the patient in the genome information DB6 (FIG. 2) as the first step described above. That is, the control unit 2 (FIG. 2) may execute the above-mentioned procedure of acquiring (1) the "full-length character string" (patient's genome information) from the genome information DB6 (FIG. 2), extracting the allele character string contained in (1), and determining the genotype for a specific locus or multiple loci on the patient's genome. For example, from the beginning, the patient's "genotype" ("allele type") for a specific SNP or novel SNV may be determined individually by "Method 1" using the above-mentioned "full-length character string" information (patient's genome information). That is, "Method 1" using "full-length character string" information may be applied from the beginning to all DNA variants, regardless of conditions such as frequency in a population and suitability for automatic analysis (see the lower part of FIG. 1).

[0061] Alternatively, depending on the situation, for example, when the "full-length character string" information (patient genome information) has not yet been stored in the genome information DB6 (Figure 2), a method using an individual experimental technique that requires time and effort may be used for the patient's "genotype" regarding the specific SNP or new SNV. For example, the genotype may be individually identified for the patient's "genotype" regarding the above-mentioned specific SNP or new SNV using an analysis technique such as the current amplification-resistant mutation system by PCR using allele-specific primers (a technique that detects specific point mutations and can distinguish between normal alleles and mutant alleles that differ by one base).

[0062] From the viewpoint of protecting personal information, the information in the genome information DB6 in FIG. 2 may be encrypted, or access restrictions may be set for the information in the genome information DB6 (FIG. 2). The encryption and access restrictions may be realized by techniques known in the information technology field. From the viewpoint of protecting personal information, the system may obtain genotype information recorded on a recording medium, instead of the genome information DB6 (FIG. 2).

[0063] (Related information 311~313) In this embodiment, the genotype is a genotype related to a gene encoding a protein involved in pharmacokinetics, as shown in the association information 311 in Fig. 4. The association information 311 in Fig. 4 represents the association between a drug and a gene (in particular, the effect of the metabolic rate of an active ingredient on the genotype of an allele associated with the gene function of a gene).

[0064] The relationship information 311 (FIG. 4) shows the CYP2C9 gene as a gene encoding a protein involved in the pharmacokinetics of phenytoin. The presence of an SNP (rs1057910: see the relationship information 311 in FIG. 4) associated with enzyme activity has been proven in the CYP2C9 gene. The protein expressed by the CYP2C9 gene containing the mutant allele has low activity in oxidizing (metabolizing) phenytoin, which is an active ingredient of antiepileptic drugs. As shown in the relationship information 311 (FIG. 4), low-activity CYP2C9 reduces the metabolic rate of phenytoin (metabolic rate (drug efficacy): "-1" or "-2"), and therefore may prolong the circulation time of phenytoin more than necessary. Prolonged circulation time leads to increased side effects and excessive drug efficacy (both of which are adverse events), especially for long-term drug administration.

[0065] The relationship information 312 in FIG. 4 shows the CYP2C19 gene as a gene encoding a protein involved in the pharmacokinetics of clopidogrel. It is known that a known SNP (rs4244285) present in the CYP2C19 gene may have several variant allele types (see the relationship information 312 in FIG. 4). The protein expressed by the CYP2C19 gene containing the variant allele does not metabolize in the body a drug that exerts its pharmacological effect upon oxidation, such as clopidogrel, or weakens the metabolism. In other words, as shown in the relationship information 312 (FIG. 4), the CYP2C19 gene containing the variant allele reduces the metabolic rate of clopidogrel to an active compound (metabolic rate (drug efficacy): "-1") or makes the metabolic rate substantially zero (metabolic rate (drug efficacy): "-2") depending on the genotype of the patient. In addition, according to the "Recommended Treatment Policy (Dosage Adjustment)" (see, for example, CLINICAL PHARMACOLOGY & THERAPEUTICS 89(5): 662-673, 2011 and Organ Biology 21(2): 247-253, 2014), when the daily dosage described in the medical information is close to the maximum dosage, the medical information change unit 23 in FIG. 2 may uniformly change the type of medicine for negative metabolic rates (metabolic rate (drug effect): "-1" and "-2").

[0066] Another example, the relationship information 313 in FIG. 4, shows that the ACE gene, which is a gene encoding a protein (direct target protein) involved in the pharmacodynamics of perindopril erbumine, may contain a polymorphism of deletion / insertion of an Alu sequence, which is a short interspersed repeat sequence, in intron 15 of the ACE gene, as one of the special DNA variants. A gene with an Alu sequence inserted therein exhibits splicing abnormality or exon deletion, etc., and therefore exhibits abnormal protein expression or abnormal protein expression patterns at a higher frequency than the corresponding gene lacking the Alu sequence. In other words, an individual having an ACE gene with an Alu sequence inserted therein has low or almost no efficacy of perindopril erbumine. For example, in the case of a heterozygote ("Alu+ / Alu-") having one allele with an Alu sequence inserted in the ACE gene, the efficacy is determined to be "-1". Alternatively, in the case of a homozygote ("Alu+ / Alu+") that retains both alleles with the Alu sequence inserted, the efficacy is determined to be "-2" (see relationship information 313 in FIG. 4).

[0067] The relationship information 311-313 in FIG. 4 includes information representing genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of drugs, the genotypes of the genes, and fitness factors that change depending on the genotypes. The relationship information (drugs, related genes, genotypes, and efficacy information) described in the above information (relationship information 311-313 in FIG. 4) and other drug-related relationship information are summarized in publicly known documents (see, for example, Table 1 in CLINICAL PHARMACOLOGY & THERAPEUTICS 89(5): 662-673, 2011, and Tables 1 and 2 in Organ Biology 21(2): 247-253, 2014, etc.) and are easily available. Table 1 in Organ Biology 21(2): 247-253, 2014 is excerpted from an old edition of the medical drug collection. The contents of the latest medical drug collection may be referred to in the book "JAPIC Medical Drug Collection 2020 (published on August 30, 2019, published by Maruzen Publishing Co., Ltd.)". As is clear from the part of the title "An Update of Guideline" in CLINICAL PHARMACOLOGY & THERAPEUTICS 89(5): 662-673, 2011 and the update of the contents in the medical drug collection, the above information (relevant information 311-313 in FIG. 4) and other related information on medicines will be further expanded and more accurate by adding new information and updating old information. Therefore, it is preferable that the related information 311-313 (FIG. 4) and other related information on medicines are created based on the latest information at the time of implementing this embodiment. For example, the related information 311-313 (FIG. 4) and other related information on medicines may be generated by artificial intelligence (hereinafter referred to as "AI") (see FIG. 1). With the addition of this new information, the AI ​​can output new drug and gene associations that can be used to update the old information.

[0068] Among the above information (relevance information 311 to 313 in FIG. 4), information expressing the elements of the degree of compatibility (e.g., metabolic rate and efficacy) that change depending on the genotype may be arbitrarily described according to the relevance information described in the above known literature and materials. In the relevance information 312 (FIG. 4), the metabolic rate (efficacy) values ​​corresponding to each genotype in the SNP (rs4244285) in the drug metabolizing enzyme gene CYP2C19 are described as "±0", "-1", and "-2". For example, Organ Biology 21(2): 247-253, 2014 describes that "In the genetic polymorphism of CYP2C19, CYP2C19*2 and *3 types are important. Both types are accompanied by loss of activity, so a combination of these two types is used to diagnose an enzyme deficiency." According to this description, the metabolic rate (efficacy) value "-2" in the relevance information 312 (FIG. 4) may be rewritten to "loss". The metabolic rate (drug effect) "disappeared" in the relevance information 312 (FIG. 4) may indicate, for example, that the prodrug clopidogrel is not metabolized to its active compound by CYP2C19 (not converted to a medicinal component). Therefore, the compatibility determination unit 22 in FIG. 2 judges the metabolic rate (drug effect) "disappeared" to be "-∞ (the drug is not compatible)", and the drug information change unit 23 (FIG. 2) changes the drug name in the drug information 301 (FIG. 4) to an alternative drug. In this case, if there is no alternative drug, the changed drug information in which the dosage is changed to "0" may be output to the user. In addition, regardless of the presence or absence of an alternative drug, a warning may be issued to the user indicating that the drug name (or the drug information including the dosage) in the drug information 301 in FIG. 4 has a low compatibility. The configuration of the system 1a in this case (further including the warning unit 24) is exemplarily illustrated in FIG. 12.

[0069] The drugs and genotypes that are the subject of the present invention are not limited to those described above, and various drugs and genotypes can be targeted. For example, examples of genotypes related to pharmacokinetic factors include gene polymorphisms of transporters as follows:

[0070] HMG-CoA reductase inhibitors (bravastatin, atorvastatin, etc.), which are used to treat dyslipidemia, are selectively taken up by the liver to exert their therapeutic effects, and the transporter protein OATP1B1 (Organic Anion Transporting Polypeptide 1B1) plays an important role in this uptake. In the SNPs in the gene encoding OATP1B1, a mutant type with an amino acid substitution (base change: "521T>C") reduces uptake into the liver compared to the normal type, and orally administered drugs such as bravastatin and atorvastatin flow through the central vein without being metabolized or excreted in the bile, resulting in an increase in blood concentration. As a result, the drug concentration in the blood becomes higher than the therapeutic concentration range, and there is a high risk of side effects such as drug poisoning. Therefore, it can be determined that the efficacy value of the heterozygous type is "-1" (genotype: "T / C") and that of the homozygous type (genotype: "C / C") is "-2" lower than that of the normal type (genotype: "T / T"), which is "±0".

[0071] Furthermore, examples of genetic polymorphisms of drug receptors related to pharmacodynamic factors are as follows:

[0072] Among the SNPs in the gene encoding the drug receptor protein β2-adrenergic receptor (ADRB2), in the mutant type with amino acid substitution (base change: "46A>G"), administration of β2 agonists such as the bronchodilator clenbuterol hydrochloride causes downregulation, which reduces the expression level of the gene encoding ADRB2. As a result, the severity of bronchial asthma increases and responsiveness to β2 agonists decreases. Therefore, compared to the efficacy value of the normal receptor (genotype: "A / A"), which is "±0," it can be determined that the heterozygous type (genotype: "A / G") is "-1" lower, and the homozygous type (genotype: "G / G") is "-2" lower.

[0073] In addition, another mutation in the ADRB2 gene (base change: "491C>T") reduces the binding ability to agonists such as β2 receptor agonists to one-quarter of that of the normal type (genotype: "C / C"), resulting in reduced responsiveness to β2 agonists. Therefore, compared to the efficacy value of the normal type (±0), the heterozygous type (genotype: "C / T") can be determined to be "-1" lower, and the homozygous type (genotype: "T / T") can be determined to be "-2" lower.

[0074] As described above, the association information 311-313 (including the above-mentioned additional example contents) in Fig. 4 on pharmacokinetics and pharmacodynamics at least describes a change in dosage (increase or decrease) or a change in medication as a proposal to improve the low suitability when the administration plan designated by the doctor has a low suitability for a specific patient. The administration plan proposal system 1 (Fig. 2), which uses the association information 311-313 (Fig. 4) as a criterion for judging the suitability of the medical information 301 (Fig. 4), can present the doctor with a proposal to improve the low suitability.

[0075] (Examples of drug names and related information in medical information and processing using them) The information acquisition unit 21 in FIG. 2 can simultaneously acquire multiple pieces of association information (see "(administration plan)" in FIG. 1), which will be described by taking as an example a case where medical information 304 (FIG. 11) for a non-small cell lung cancer patient is input to the system 1 (FIG. 2). When the information acquisition unit 21 in FIG. 2 receives medical information 304 (FIG. 11) describing a medical name (ALK tyrosine kinase inhibitor) including a target molecule or mechanism of action in the name in step S1 in FIG. 3, it simultaneously acquires multiple pieces of association information 315 and 316 as described below. Such a medical name may generally refer to multiple specific drugs. For example, the association information 315 (including rixotiniib as a specific medical name) and 316 (including ceritinib as a specific medical name) in FIG. 11 are both information describing an ALK tyrosine kinase inhibitor and its efficacy based on genotype.

[0076] The information acquiring unit 21 and the compatibility determining unit 22 of FIG. 2 that have acquired the association information 315 and 316 of FIG. 11 perform in parallel the processing when the drug name in the drug information 304 of FIG. 11 is rixotinib and the processing when the drug name in the drug information 304 of FIG. 11 is ceritinib (S3 to S5 of FIG. 3). When a non-small cell lung cancer patient described in the drug information 304 of FIG. 11 does not have the EML-ALK fusion gene (genotype: -), the compatibility determining unit 22 of FIG. 2 determines in S4 of FIG. 3 that both rixotinib and ceritinib are ineffective for the patient, "-∞", and sends this to the drug information changing unit 23 of FIG. 2.

[0077] The medical information change unit 23 in Fig. 2 changes the drug name in the medical information 304 in Fig. 11 (including the ALK tyrosine kinase inhibitor) according to the negative symbol "-" and infinity "∞". The drug name includes a mechanism of action as described above. Therefore, a drug name (e.g., an EGFR tyrosine kinase inhibitor) that is a therapeutic drug for non-small cell lung cancer different from the ALK tyrosine kinase inhibitor (therapeutic drug for non-small cell lung cancer) in the medical information 304 in Fig. 11 and includes another mechanism of action is selected.

[0078] When the drug name is changed to EGFR tyrosine kinase inhibitor ("YES" in S7 of Fig. 3), the information acquisition unit 21 (Fig. 2) acquires the relevance information 317 and 318 of Fig. 11 in S2 of Fig. 3. The information acquisition unit 21 and the compatibility determination unit 22 of Fig. 2 perform, in parallel, processing when the drug name in the drug information 304 of Fig. 11 is gefitinib and processing when the drug name in the drug information 304 is osimertinib mesylate (S3 to S5 of Fig. 3).

[0079] Here, the non-small cell lung cancer patient described in the medical information 304 of FIG. 11 has, for example, a homozygous mutation at position 2573 of the EGFR gene (genotype: G / G) and a heterozygous mutation at position 2369 of the EGFR gene (genotype: T / C). At this time, the compatibility determination unit 22 of FIG. 2 determines the compatibility of gefitinib to be "1" from the sum of the numerical values ​​of each element (drug efficacy) (i.e., the sum of 2 and -1) (see the relationship information 317 of FIG. 11), and determines the compatibility of osimertinib mesylate to be "3" from the sum of the numerical values ​​of each element (drug efficacy) (i.e., the sum of 2 and 1) (see the relationship information 318 of FIG. 11). The compatibility determination unit 22 of FIG. 2 sends the two determined compatibility degrees to the medical information change unit 23 of FIG. 2.

[0080] The medical information change unit 23 in Fig. 2 selects "osimertinib mesylate" corresponding to the larger absolute value of "3" from the two suitability scores (the reference values ​​for the above-mentioned medical change are lower than 0, and both are positive values, so "YES" is selected in S5 in Fig. 3), and sends the changed medical information 306 in Fig. 11 to the display device 3 in Fig. 2. The display device 3 presents the changed medical information 306 in Fig. 11 to the user.

[0081] The above-mentioned process proposes one of the optimal dosing regimens for the treatment of non-small cell lung cancer of a patient identified by the patient ID in the medical information 304 in FIG. 11 for the following reasons: Administration of ALK tyrosine kinase inhibitors (rixotinib and ceritinib) is not effective for non-small cell lung cancer of the patient (who does not have the EML-ALK fusion gene (i.e., does not have chromosomal translocation)) (drug efficacy "-∞" in the relationship information 315 and 316 in FIG. 11). EGFR tyrosine kinase inhibitors are only effective for non-small cell lung cancer of patients who have homozygous or heterozygous mutations (G / G or G / T) at least at position 2573 of the EGFR gene (drug efficacy "2" and "1" in the relationship information 317 and 318 in FIG. 11). On the other hand, among the above EGFR tyrosine kinase inhibitors, the above patient may show resistance to administration of gefitinib (efficacy "-1" in the related information 317 in FIG. 11). Among the above EGFR tyrosine kinase inhibitors, osimertinib mesylate is a drug that is expected to have a therapeutic effect on patients who show resistance to gefitinib. The osimertinib mesylate irreversibly inhibits the kinase activity of EGFR protein having the T790M mutation (substitution of threonine with methionine at position 790) associated with the above resistance to gefitinib.

[0082] In the above, a name including a mechanism of action (which may include multiple drugs) has been exemplified as a drug name included in the medical information 304 in FIG. 11. This will be further illustrated as a case where multiple pieces of association information can be simultaneously acquired even when the medical information 305 representing a single drug as a drug name is input to the system 1 (FIG. 2). When the information acquisition unit 21 in FIG. 2 acquires the medical information 305 in FIG. 11 as the medical information, the medical information change unit 23 in FIG. 2 judges "NO" in S5 in FIG. 3. Since the same patient ID and (a type of) ALK tyrosine kinase inhibitor as the medical information 304 in FIG. 11 are described in the medical information 305 in FIG. 11, the same process as the above-mentioned process ("YES" in S7 in FIG. 3) is executed.

[0083] The drug name in the drug information 305 in Figure 11 is changed to a drug name that is not an ALK tyrosine kinase inhibitor, which necessarily has an insufficient degree of suitability. Since the condition for selecting the drug name is "not an ALK tyrosine kinase inhibitor", the drug name may be "EGFR tyrosine kinase inhibitor".

[0084] The system 1 in FIG. 2 acquires the relevance information 317 and 318 in FIG. 11 as described above based on the medical information 305 in FIG. 11 in which the medical name has been changed to "EGFR tyrosine kinase inhibitor". The information acquisition unit 21 and the compatibility determination unit 22 in FIG. 2 perform in parallel the process when the medical name in the medical information 304 in FIG. 11 is gefitinib and the process when the medical name in the medical information 304 is osimertinib mesylate (S3 to S5 in FIG. 3). Finally, by the above-mentioned steps, the changed medical information 306 in FIG. 11 (including osimertinib mesylate) is displayed on the display device 3 in FIG. 2.

[0085] In addition, even when the administration plan proposal system 1 receives input of medical information including the above-mentioned four drug names (rixotinib, ceritinib, gefitinib, and osimertinib mesylate) as medical names and "123456789" as a patient ID (i.e., medical information of a non-small cell lung cancer patient who has the above-mentioned genotype), it displays osimertinib mesylate as the changed medical information 306 in FIG. 11 (or as the unchanged medical information 305 (FIG. 11) because the suitability is above the reference value and is suitable, and the judgment in S5 in FIG. 3 is "YES"). In other words, the administration plan proposal system 1 can select and propose one drug with the highest suitability from the multiple drug names input.

[0086] The ALK tyrosine kinase inhibitors and EGFR tyrosine kinase inhibitors exemplified above are called molecular targeted drugs used to treat non-small cell lung cancer. Molecular targeted drugs is a term that refers to drugs that target gene products with specific mutations. For example, as described above, the ALK tyrosine kinase inhibitors are only effective for patients with EML-ALK fusion genes (i.e., chromosomal translocations) (see related information 315 and 316 in Figure 11). The EGFR tyrosine kinase inhibitors are only effective for patients with homozygous or heterozygous mutations at least at position 2573 of the EGFR gene (see related information 317 and 318 in Figure 11). Currently, most of the molecular targeted drugs are anticancer drugs. However, in the future, molecular targeted drugs are expected to be developed as therapeutic drugs for other diseases.

[0087] (others) The entire program that executes the above system can be executed via an intranet or the Internet that can be accessed from the outside (the computer used by the user). The above system may be connected to a printing device (e.g., a printer or a multifunction device) for printing information output to the user on paper.

[0088] [Embodiment 1-1] Another aspect of the present invention, the configuration of which is exemplified in Figure 13, is a system (administration plan proposal system 10) that proposes a suitable administration plan for a patient, and includes a pharmaceutical information acquisition unit (information acquisition unit 21) that acquires pharmaceutical information indicating the pharmaceutical to be administered to the patient and the dosage thereof; an association information acquisition unit (information acquisition unit 21) that acquires association information indicating the association between the pharmaceutical and a genotype; a genotype information acquisition unit (information acquisition unit 21) that acquires genotype information of the patient; a suitability determination unit 22 that determines the suitability of the pharmaceutical information based on the association information and the genotype information; and a dosage plan determination unit 25 that determines the pharmaceutical information suitable for the patient based on the suitability of the pharmaceutical information determined by the suitability determination unit; and an information presentation unit (display device 3) that presents the pharmaceutical information determined by the administration plan determination unit to a user.

[0089] That is, the administration plan proposal system 10 in Fig. 13 is different from the administration plan proposal system 1 in Fig. 2 in that it includes an administration plan determination unit 25 instead of the medical information change unit 23 (Fig. 2). Therefore, the administration plan proposal system 10 in Fig. 13 executes the processing shown in Fig. 3 except for the processing of the administration plan determination unit 25 (Fig. 13) described below.

[0090] The administration plan determination unit 25 in FIG. 13 determines suitable medical information for a patient based on the suitability of the medical information determined by the suitability determination unit 22 (FIG. 13).

[0091] In one embodiment, the administration plan determination unit 25 (FIG. 13) may have the same function as the medical information modification unit 23 (FIG. 2). That is, the medical information having a degree of suitability determined by the suitability determination unit 22 (FIG. 13) less than a reference value (e.g., "0") may be determined as medical information that is not suitable for the patient ("NO" in S5 of FIG. 3), and the medical information that has been modified may be determined as medical information suitable for the patient (see S6 of FIG. 3).

[0092] In one aspect, the administration plan determination unit 25 (Figure 13) may determine pharmaceutical information whose compatibility determined by the compatibility determination unit 22 (Figure 13) is a reference value (e.g., "0") or higher as the pharmaceutical information suitable for the patient ("YES" in S5 of Figure 3), or may determine pharmaceutical information whose compatibility is the highest as the pharmaceutical information suitable for the patient (see, for example, a series of example contents regarding the administration plan of an anticancer drug for a non-small cell lung cancer patient described in the item (examples of drug names and related information in pharmaceutical information, and processing using them) in the above [Embodiment 1]).

[0093] As described above, according to the administration plan proposal system 10 of FIG. 13, it is possible to propose an administration plan suitable for a patient.

[0094] [Embodiment 2] In this embodiment, the above-mentioned compatibility is determined based on a predisposition (risk of onset) to develop a disease that is not the target of treatment by administration of a medicine. The system according to this embodiment refers to a set of allele combination types related to a large number of loci on the human genome as the above-mentioned genotype, but this embodiment is not limited thereto, and a set of allele combination types related to one or a small number of loci may be referred to as the above-mentioned genotype (for example, an example of a "single gene disease" will be described later). The presence or absence of the above-mentioned predisposition is determined based on the genotype. That is, the system according to this embodiment determines the above-mentioned compatibility by referring to information (medicine-related disease information) that represents a predisposition to develop a disease in association with administration of a medicine. That is, this embodiment suppresses the onset of a disease that a patient is genetically prone to develop but has not yet developed, by continuous and large administration of a contraindicated drug for the disease (a drug known to increase the possibility of worsening the condition, causing serious side effects, weakening the effect of the drug, etc., when administered).

[0095] As shown in Fig. 5, the administration plan proposal system 1' is the same as the administration plan proposal system 1 (Fig. 2) except that it has a drug-related disease information DB7 (Fig. 5) instead of the drug efficacy related gene information DB5 (Fig. 2) in the administration plan proposal system 1 of Fig. 2. The administration plan proposal system 1' (Fig. 5) is a system that proposes a highly safe administration plan that avoids the onset of diseases that are not the target of treatment by administering medicine. The above diseases may also include symptoms of serious side effects due to idiosyncratic constitutions and related diseases (details of "serious side effects due to idiosyncratic constitutions" will be described later).

[0096] (Processing of administration plan proposal system 1') An example of the process executed by the administration plan proposal system 1' in Fig. 5 to improve the safety of the administration plan will be described below with reference to Fig. 6. The input device 4 (Fig. 5) sends the medical information 303 (Fig. 7) input by the doctor, who is the user, to the information acquisition unit 21 (Fig. 5) according to the conventional uniform factors (mainly the type of disease the patient suffers from, the severity of the disease, and the age, weight, and sex of the patient, etc.) (step S1' in Fig. 6). The information acquisition unit 21 (Fig. 5) acquires the association information 314 (Fig. 7) describing the name of the drug represented by the medical name included in the medical information 303 in Fig. 7, the name of the disease that may develop by administration of the drug, and the range of genotypes indicating the presence or absence of a predisposition to the disease, from the medical-related disease information DB7 (Fig. 5) (step S2' in Fig. 6). The information acquisition unit 21 (Fig. 5) acquires genotype information corresponding to the patient ID and the name of the disease from the genome information DB6 (Fig. 5) based on the patient ID (see medical information 303 in Fig. 7) and DNA variant group information on genotypes indicating the presence or absence of a predisposition to the disease (see relevance information 314 in Fig. 7) (step S3' in Fig. 6). The information acquisition unit 21 (Fig. 5) sends the acquired medical information 303 (Fig. 7), relevance information 314 (Fig. 7), and genotype information of the patient acquired from the genome information DB6 (Fig. 5) to the compatibility determination unit 22 (Fig. 5).

[0097] If the answer is "NO" in step S2' in FIG. 6 (for example, there is no association information because the drug is recently developed or there is no corresponding disease), the information acquisition unit 21 (FIG. 5) sends the medical information 303 in FIG. 7 to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the medical information, and the administration plan proposal system 1' (FIG. 5) ends the processing. If the answer is "NO" in step S3' in FIG. 6 (for example, genotype information corresponding to a specific gene in a patient has not yet been determined), the information acquisition unit 21 (FIG. 5) sends the medical information 303 in FIG. 7 to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the medical information, and the administration plan proposal system 1' in FIG. 5 ends the processing.

[0098] The compatibility determination unit 22 in Fig. 5 determines the compatibility of the medical information 303 (Fig. 7) based on the relevance information 314 (Fig. 7) and the genotype information acquired from the genome information DB6 (Fig. 5) (step S4' in Fig. 6). Details of step S4' in Fig. 6 will be described with reference to Fig. 7.

[0099] The association information 314 in FIG. 7 includes the active ingredient corresponding to the drug name (drug name: olanzapine, multi-receptor antipsychotic MARTA), the name of a disease known to be developed by administration of the active ingredient (disease name: type 2 diabetes), the numerical range of the PRS percentile associated with the genotype that determines the predisposition to the disease (genotype (PRS percentile): 0-69, 70-84, and 85-100), the effect on the development of type 2 diabetes (risk of development: ±0, +1, and +2), and the "alternative dosing plan" (none, blood sugar control required, and change of drug to X). Details of the above "PRS percentile" are described later in the following section (patient's genotype information). Olanzapine is an atypical antipsychotic that is effective in treating schizophrenia, improving manic and depressive symptoms in bipolar disorder, and improving gastrointestinal symptoms (nausea, vomiting) associated with the administration of anticancer drugs. The genome information DB6 in FIG. 5 stores, as genotype information for each disease name, a numerical value (PRS percentile) ranging from 0 to 100 that indicates a patient's predisposition to develop a certain disease. The closer the numerical value is to 100, the greater the predisposition to develop a certain disease. Therefore, when the compatibility determination unit 22 in FIG. 5 acquires "90" as the association information 314 (FIG. 7) and the patient's genotype information that indicates a predisposition to develop type 2 diabetes, it determines the risk of developing type 2 diabetes due to administration of olanzapine in the medical information 303 (FIG. 7) to be "+2". The compatibility determination unit 22 (FIG. 5) determines "-2", which is the negative element of the risk of development "+2", multiplied by the value "-1" that indicates a negative element, as the compatibility. Next, the compatibility determination unit 22 (Figure 5) sends the medical information 303 (Figure 7), the compatibility "-2", and "drug change to X" as an alternative administration plan in the association information 314 (Figure 7) corresponding to that compatibility ("-2") to the medical information change unit 23 (Figure 5).

[0100] The medical information change unit 23 in Fig. 5 judges the negative value of the degree of suitability "-2" to be very low (step S5' in Fig. 6). The medical information change unit 23 (Fig. 5) changes the drug name in the medical information 303 (Fig. 7) to "X" in accordance with the alternative administration plan "drug change to X" (step S6' in Fig. 6). Since the change in step S6' (Fig. 6) is a change in drug (the determination in step S7' in Fig. 6 is "YES"), the medical information change unit 23 (Fig. 5) sends the changed medical information in which the drug name has been changed to X to the information acquisition unit 21 (Fig. 5), and returns to step S2' in Fig. 6. The administration plan proposal system 1' (Fig. 5) repeats steps S2' to S7' in Fig. 6 until the judgment in step S7' (Fig. 6) becomes "NO". If the judgment becomes "NO", the modified pharmaceutical information is sent to the display device 3 (Fig. 5) (step S8' in Fig. 6). Furthermore, if the daily dose is changed in step S6' (Fig. 6), the modified pharmaceutical information is sent to the display device 3 (Fig. 5). Finally, the display device 3 (Fig. 5) displays the modified pharmaceutical information, and the administration plan proposal system 1' in Fig. 5 ends the processing.

[0101] Unlike S4' in FIG. 6 exemplified above, when "60" is acquired as genotype information, the compatibility determination unit 22 (FIG. 5) determines the value of the risk of developing type 2 diabetes due to olanzapine administration to be "±0". The compatibility determination unit 22 (FIG. 5) determines the compatibility to be "±0" obtained by multiplying the negative element of the risk of development "±0" by the value "-1" representing a negative element, and sends it to the medical information change unit 23 (FIG. 5). The medical information change unit 23 (FIG. 5) determines that the compatibility "±0" is not low, and sends the medical information 303 (FIG. 7) to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the medical information 303 (FIG. 7), and the administration plan proposal system 1' in FIG. 5 ends the process.

[0102] As described above, the administration plan proposal system 1' in FIG. 5 changes the medical information (type of medicine or its dosage) specified in the prescription when it is determined that it does not match the genotype (genotype representing the combination of alleles related to the predisposition to the risk of developing a secondary disease caused by the medicine) of the patient specified in the prescription. The secondary disease caused by the medicine includes serious side effects due to idiosyncrasies (details will be described later). Therefore, the administration plan proposal system 1' (FIG. 5) makes it possible to present a prescription with low risk and high safety according to the patient's genotype.

[0103] The genotype information and association information according to this embodiment, which is used by the administration regimen proposal system 1' in FIG. 5 to propose an appropriate administration regimen for a patient, will be described in detail below.

[0104] (Patient's genotype information) In this embodiment, the genotype information for a patient is expressed as a value (PRS (Polygenes Risk Score) percentile) corresponding to each disease. The PRS percentile corresponding to type 2 diabetes indicates what percentage the patient's PRS corresponds to, counting from the lowest, in the normal distribution of PRS related to the risk of developing type 2 diabetes in the human population (see FIG. 1). In other words, the PRS percentile is 0 to 100, and the higher the PRS percentile, the higher the risk of developing type 2 diabetes. The PRS related to type 2 diabetes is a value obtained by scoring and summing up the combinations of "allele types" of all DNA variants that affect the development of type 2 diabetes. The "allele types" of all DNA variants that affect the development of a certain disease are identified, for example, by Genomewide Association Study (GWAS), a standard method for identifying factors that govern susceptibility to complex diseases. An overview of PRS percentiles and PRS for any disease is given in, for example, ReFlections Vol 45, September 2018 (https: / / rgare.com / docs / default-source / newsletters-articles / reflections-vol-45-sept-2018.pdf?sfvrsn=66979288_0).

[0105] It is known that the presence of a large number (tens to millions) of DNA variants (e.g., SNPs) on the genome is involved in the onset of most diseases. Although each DNA variant only has a small effect on the onset of a disease, the combination of these DNA variants significantly increases the onset of the disease. Therefore, among the DNA variants contained in the above combinations, some DNA variants present in the patient's genome can be used to determine, for example, whether or not a patient who has been administered olanzapine has a predisposition to developing type 2 diabetes (and the extent of the predisposition). In this embodiment, the genotype information is expressed by the PRS percentile, which indicates how many DNA variants the patient has as part of the combination of DNA variants that contribute to the predisposition to developing a certain disease.

[0106] It is most preferable that the genotype information includes PRS percentiles corresponding to each disease, the number of which is the same as the number of all known diseases. The above-mentioned "combination of these DNA variants" differs for each disease. Therefore, including the above genotype information required to create PRS percentiles corresponding to all diseases as genotype information for a certain patient maximizes the convenience of the administration plan proposal system 1'. The closer the number of PRS percentiles included in the genotype information is to the number of all known diseases, the more convenient the administration plan proposal system 1' is, which is preferable.

[0107] The type of alleles ("allele types") including known DNA variant zygosity types can be determined for the patient's genome according to two methods ("Method 1" and "Method 2") described in the section (Patient's genotype information) of [Embodiment 1]. The methods are "Method 1" using "full-length character string" information determined using a massively parallel DNA sequencing method, and "Method 2" using an experimental method of genome-wide polymorphism analysis using DNA microarray technology. Since it is highly likely that information on DNA variants with low frequency in the population (e.g., SNV, CNV) or DNA variants not suitable for automated analysis (e.g., CNP, STRP, or other special DNA variants) will also be required to generate genotype information containing the same or close to the number of all diseases, the former "Method 1" using "full-length character string" information is preferred. Details of "Method 1" using "full-length character string" information are also described later in [Embodiment 4].

[0108] For the above reasons, it is preferable that the genome information DB6 in Fig. 5 further stores "full-length character string" information in addition to the "genotype" information of the patient. That is, when a DNA variant involved in a certain disease is newly identified and it is necessary to determine the "allele type" of the patient related to the DNA variant and score it as part of the PRS, as described in [Embodiment 1], the above-mentioned "method 1" using information analysis using the "full-length character string" can easily update part of the genotype information related to the disease without the burden of time and labor due to experimental procedures such as "method 2" using DNA microarray technology or individual methods using PCR.

[0109] (Related information 314) In this embodiment, the genotype is a genotype related to a combination of DNA variants that contribute to a predisposition to developing a certain disease. The association information 314 (FIG. 7) represents an association between a drug and a disease that is not the subject of treatment (particularly, the effect of administration of the drug on the development of the disease).

[0110] The association information 314 in FIG. 7 shows type 2 diabetes as a disease whose incidence may increase with the administration of olanzapine. As described above, it is known that the presence of multiple DNA variants (genetic predisposition) is involved in the increase in the incidence of type 2 diabetes. The association information 314 (FIG. 7) shows numerical ranges representing the above genotypes as a criterion for determining the degree of genetic predisposition. Each numerical range is associated with the degree of impact on the risk of onset ("±0" to "+2").

[0111] Each numerical range may be set arbitrarily, but the lower limit of the numerical range corresponding to "+1" (reduction in dosage or necessary corresponding measures) may be 70 or more (e.g., 70, 75, 80, 85, 90, and 95), and the lower limit of the numerical range corresponding to "+2" (change in medication) may be 85 or more (e.g., 85, 90, 95, and 99). The compatibility determination unit 22 in FIG. 5 uses at least one of the above lower limits as a criterion for determining that the compatibility of the medical information 303 (FIG. 7) is low (genomic information contains a part of the combination of DNA variants that contribute to a predisposition to type 2 diabetes above a threshold). Note that the PRS percentile with a median value of 50 represents the average risk of onset in the population, and the numerical range corresponding to "±0" includes 50.

[0112] The association information 314 in FIG. 7 shows three numerical ranges, but may show only two numerical ranges (for example, 0 to 84 and 85 to 100). In this case, for example, 0 to 84 corresponds to "±0", and 85 to 100 corresponds to "+2" or "+1". That is, the association information 314 (FIG. 7) may cause the administration plan proposal system 1' in FIG. 5 to select only a change in medicine or a change in dosage. Also, for example, the association information 314 (FIG. 7) may cause the numerical range 70 to 84 to correspond to an alternative medicine X, not to no alternative medicine. That is, the association information 314 (FIG. 7) may assign a "very low suitability" to medicines that increase the risk of onset even slightly depending on the genotype (medicines that are contraindicated for a certain disease), and cause the administration plan proposal system 1' in FIG. 5 to select only a "change in medicine".

[0113] The administration plan suggestion system 1' in FIG. 5 using the association information 314 (FIG. 7) can suggest reducing the dose of olanzapine (multi-receptor acting antipsychotic: MARTA), taking necessary countermeasures, or changing the type of drug, regardless of whether the patient has developed type 2 diabetes. In addition to olanzapine, it is known that timiperone, a drug for treating schizophrenia, can promote the onset or aggravation of Parkinson's disease, and carvedilol, a drug for treating chronic heart failure and arrhythmia, can promote the onset or aggravation of bronchial asthma. It is well known that one therapeutic drug (especially a small molecule drug) acts on two or more molecular targets, or affects the physiological activity of multiple molecules that are not molecular targets. In particular, the administration plan suggestion system 1' (FIG. 5) using the association information 314 (FIG. 7) preferably suggests changing the administration of a contraindicated drug (here, olanzapine) to the above patient who has a genotype that indicates a high risk of developing type 2 diabetes.

[0114] According to the Pharmaceuticals and Medical Devices Agency, the definition of a "contraindicated drug" is as follows: In other words, "contraindications" in the package insert information of a medical drug indicate patients who should not use the drug. Considering the following points, a certain drug should not be used because there is a high possibility that the use of the drug will worsen the patient's condition, increase the likelihood of side effects, or weaken the drug's effectiveness: Current illness (current disease) Complications caused by one disease -Illnesses you have had in the past (medical history) -Illnesses of family members (family history) Other medications currently being used (concomitant medications) The constitution of the person using the medicine (Above from the website of the Pharmaceuticals and Medical Devices Agency.)

[0115] In other words, a "contraindication" is one of the items listed in a drug's "package insert," and indicates patients and conditions to whom a certain drug should not be administered, as well as drugs that should not be used in combination. If a drug is administered without following these rules, there is a high possibility that the condition will worsen, serious side effects will occur, or the drug's effectiveness will be weakened. Conditions that are deemed to be contraindicated for a drug may include the patient's current disease, complications, medical history, family history, or constitution.

[0116] The above-mentioned "constitution" includes a genetic constitution, and corresponds to a secondary disease with an extremely high risk of developing due to administration of a medicine in this embodiment and other embodiments. A genetic constitution may also include symptoms and related diseases as "serious side effects due to specific constitutions" described below. For this reason, the names of various diseases specified as "contraindications" in the "package inserts" of various current medicines, as well as symptoms and related diseases of "serious side effects due to specific constitutions", can be registered as disease information for the medicine in the medicine-related disease information DB7 (FIG. 5) in this embodiment.

[0117] Additionally, therapeutic drugs and other drugs used in clinical practice (e.g. anesthetics) can cause exaggerated reactions in some people. Drug side effects have many causes. Type A side effects are relatively common and dose-dependent. They are pharmacologically predictable and usually mild. Type B side effects, on the other hand, are idiosyncratic reactions and are not simply related to the drug dose. They are rare but can often be severe. Genetic variation is important for both type A and B side effects.

[0118] As described above, symptoms of so-called "serious side effects due to idiosyncratic constitutions" such as type B side effects and related diseases can be dealt with using the criteria for determining the risk of developing secondary diseases in this embodiment.

[0119] For example, treatment with carbamazepine, an antiepileptic drug, or allopurinol, a drug used to treat hyperuricemia and gout, rarely induces side effects such as severe skin disorders, such as toxic epidermal necrolysis (Lyell's syndrome). As one of the important genetic factors for such side effects, individuals who possess certain genotypes (e.g., HLA-B*1502, HLA-A*3101, and HLA-B*5801) among the genes encoding human leukocyte antigens (hereinafter referred to as "HLA") have a high risk of developing the above-mentioned diseases. For this reason, information related to the risk of developing toxic epidermal necrolysis (Lyell's syndrome) for drugs such as carbamazepine and allopurinol can be registered in the Drug-Related Disease Information DB7 (Figure 5) and addressed.

[0120] Other examples of symptoms and related diseases of "serious side effects due to idiosyncratic constitution" caused by drugs include rhabdomyolysis (destruction of muscle tissue) caused by statin drugs (drugs for treating dyslipidemia) such as atorvastatin, respiratory paralysis caused by suxamethonium chloride hydrate (fast-acting muscle relaxant), bone marrow toxicity caused by mercaptopurine hydrate (antineoplastic drug) and azathioprine (immunosuppressant), liver damage caused by isoniazid (antituberculosis drug), and polymorphic ventricular tachycardia caused by various drugs including clarithromycin (antibiotic), which may be life-threatening. As for symptoms and related diseases of "serious side effects due to idiosyncratic constitution" caused by various drugs, including the above-mentioned examples, which fall under the above-mentioned type B, they are influenced by the genotype of the patient due to genetic diversity, so that the risk-related information on onset can be registered in the pharmaceutical-related disease information DB7 (Figure 5).

[0121] The scope of application of "risk of onset" includes single-gene diseases to polygenic diseases (multifactorial diseases, complex diseases). Human genetic traits, including various diseases, often depend on the expression of multiple genes and environmental factors. However, for certain diseases and some traits, a specific genotype at a single locus acts as the primary determinant, and this genotype is necessary and sufficient to express the trait, i.e., to develop the disease, under normal environmental conditions.

[0122] "Monogenic diseases," in which the contribution of genes to a disease is basically determined by one locus, are rare, and common genetic diseases depend on multiple loci and are called polygenic diseases (complex diseases, multifactorial diseases). The scope of application of this embodiment is mainly assumed to be "polygenic diseases," but it can also deal with "monogenic diseases."

[0123] For example, for young adults who carry a mutated form of the causative gene for Huntington's disease, a late-onset single-gene disease, and are therefore at high risk of developing the disease, or for asymptomatic individuals who carry mutated forms of the causative genes BRCA1 and BRCA2 for breast cancer, and are at high risk of developing symptoms in the future, the risk-related information in this embodiment can be registered in the pharmaceutical-related disease information DB7 (Figure 5) and used accordingly.

[0124] Specifically, as a method of registering a single gene disease in the pharmaceutical-related disease information DB7 (FIG. 5), in the case of a recessive genetic disease, if the allele associated with the causative gene is a homozygous mutant type (having two mutant alleles), the risk of onset is extremely high, the onset risk value is determined to be "+2", and the setting may be "change of drug". In addition, in the case of a dominant genetic disease, if the allele associated with the causative gene is a heterozygous type (having a normal allele and a mutant allele) or a homozygous type, the risk of onset is extremely high, the onset risk value is determined to be "+2", and the setting may be "change of drug". Taking the above Huntington's disease as an example, a method of determining the genotype associated with the causative gene will be described later in [Embodiment 4].

[0125] [Embodiment 3] In this embodiment, a system that performs the processes described in [Embodiment 1] and [Embodiment 2] in a composite manner will be described (see FIG. 1). That is, in this embodiment, as shown in FIG. 1, a system will be described in which the judgment criteria for changing the administration plan are a combination of (1) pharmacokinetic factors of medicine B ([Embodiment 1]), (2) pharmacodynamic factors of medicine B ([Embodiment 1]), and (3) the risk of developing a secondary disease due to medicine B ([Embodiment 2]), as described above (1) to (3). As shown in FIG. 8, the administration plan proposal system 1'' includes a control unit 2 and a display device (information display unit) 3. The control unit 2 (FIG. 8) includes an information acquisition unit (medicinal information acquisition unit, association information acquisition unit, and genotype information acquisition unit) 21, a compatibility determination unit 22, and a medical information change unit 23 (see FIG. 8). In addition, the control unit 2 (FIG. 8) is connected to an input device 4, a medical efficacy-related gene information DB 5, a genome information DB 6, and a medical-related disease information DB 7 (see FIG. 8). In other words, the system 1'' of this embodiment in Figure 8 determines the degree of compatibility by referring to both (i) information representing the extent to which the genotype of the gene affects the efficacy of the drug ([embodiment 1]) and (ii) onset risk information representing the extent to which the genotype of the predisposition affects the risk of onset of the disease (secondary disease) by administration of the drug ([embodiment 2]).

[0126] The administration regimen proposal system 1'' (Fig. 8) executes steps S1 to S7 (including S9) (see Fig. 3), does not execute step S8 (see Fig. 3), and executes steps S2' to S8' (including S9') (see Fig. 6) for changed or unchanged pharmaceutical information. Therefore, the process of transitioning from S7 in Fig. 3 to step S2' in Fig. 6, and the details of executing step S2' (Fig. 6) will be described.

[0127] For example, in the case of phenytoin (medical information 301 in FIG. 4) shown in [Embodiment 1], when the heterozygous type "*1 / *3" is acquired as the genotype information on the SNP (rs1057910) in CYP2C9 in the association information 311 (FIG. 4) as described above, in step S7 (FIG. 3), the medical information change unit 23 of the administration plan proposal system 1'' (FIG. 8) judges "NO" and then sends the changed medical information 302 (FIG. 4) in which the "daily dose (maintenance dose)" has been changed to 225 mg to the information acquisition unit 21 (FIG. 8) (transition to step S2' in FIG. 6). In step S2' (FIG. 6), when the change included in the changed medical information is the daily dose, the information acquisition unit 21 (FIG. 8) acquires medical-related disease information from the medical-related disease information DB7 (FIG. 8). In the subsequent steps S3' to S9' (Figure 6), the "pharmaceutical information" is replaced with "changed pharmaceutical information", and the pharmaceutical information change unit 23 (Figure 8) sends the pharmaceutical information with the changed pharmaceutical name (corresponding to the "YES" judgment in step S7' of Figure 6) to the information acquisition unit 21 (Figure 8), and the process returns to step S2 of Figure 3. Except for these two points, this embodiment is equivalent to the system that executes the processing described in [Embodiment 1] and [Embodiment 2] as described above.

[0128] As described above, the administration plan proposal system 1'' in FIG. 8 changes the medical information (type of medicine or its dosage) specified in a prescription when it is determined that the information does not match the patient's genotype specified in the prescription (the genotype of a specific gene that affects the effectiveness of the medicine, and the genotype of a specific gene that indicates the presence of a risk of developing a secondary disease due to the medicine). Therefore, the administration plan proposal system 1'' (FIG. 8) makes it possible to present a comprehensive prescription (one that is highly effective, has low risks, and is safe) according to the patient's genotype.

[0129] [Embodiment 4] In this embodiment, a method for determining the "allele type" (patient's "genotype") of any DNA variant in the entire nucleotide sequence ("full-length string") of a genome obtained from an individual, rather than in the human genome ("reference string") stored in a publicly known database, is described ("Method 1" described in each section (patient's genotype information) of [Embodiment 1] and [Embodiment 2]). The DNA variant is any nucleoside change, including SNPs, SNVs, indels, CNPs, CNVs, and microsatellite polymorphisms ("STRPs"). In this method, two strings representing two nucleotide sequences flanking the target nucleotide are extracted from a publicly known string ("reference string") representing a reference human genome, and used.

[0130] In the above method, depending on the type of the target nucleotide, (1) one continuous string representing the sequence of the target nucleotide and two nucleotide sequences from the "reference string" flanking it, or (2) two strings representing each of the two nucleotide sequences from the "reference string" flanking the target nucleotide are used. (1) is used as a simple method for determining the "allele type" (the "genotype" of the patient) 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 and there are multiple options or the details of the target nucleotide are unknown. The above method using the strings of (1) and (2) is described below with reference to Figures 9 and 10.

[0131] (A simple way to determine the "allele type" of a SNP, SNV or indel) The method using the character string (1) described above is a simple method for determining the type of allele, particularly 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 sandwiching the character string 902. The character strings 901 and 903 are determined as part of a character string ("reference character string") representing a reference human genome (for example, obtainable from Ensemble (URL: http: / / ensembl.org)) (step S11 in FIG. 10). The character string 902 (character string (string) representing the target nucleotide) is stored in a known DB as a DNA variant known (hereinafter simply referred to as "known") at the time of carrying out the method according to this embodiment. In other words, the above "DNA variant" may also include a DNA variant found after the filing of the present 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 of character string 902 (characters (string) representing target nucleotides) in a character string representing a reference human genome ("reference character string") is also stored in the DB (e.g., the above-mentioned dbSNP database). In the character string of (1), it is preferable to set the lengths of character string 901 and character string 903 to be the same, and to place the analysis site (character string 902) in the center.

[0132] 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 included in the character string ("full-length character string") representing the nucleotide sequence of the entire genome of an individual (step S12 in FIG. 10). The position where the character string (1) may be included in the character string ("full-length character string") representing the nucleotide sequence of the entire genome of an individual can be estimated from the position information of the reference human genome ("reference character string") stored in the above DB. Therefore, for example, when a character string that completely matches the character string (1) is found (step S13 in FIG. 10), a character string that may include the character string (1) is extracted from the character string ("full-length character string") representing the nucleotide sequence of the entire genome of an individual, and the character string is compared with the character string (1), thereby determining the "allele type" of a known SNP, SNV, or indel in the nucleotide sequence of the entire genome of an individual ("full-length character string") (step S14 in FIG. 10).

[0133] Here, the length of the character strings 901 and 903 in FIG. 9 is at least 10 characters (for example, 10, 20, 30, 40, 50, 100, 150, 200 characters or more), preferably 10 to 1000 characters. The fewer the characters in the character string (1), the higher the probability of finding two or more character strings that completely match the character string (1) in the character string representing the nucleotide sequence of the entire genome of an individual ("full-length character string"). When two or more character strings that completely match the character string (1) are found ("NO" in step S13 in FIG. 10), the above probability is reduced by equally extending the lengths of the two character strings (character strings 901 and 903 in FIG. 9) by one or more characters (for example, 1, 3, 5, 10, 20, 25, 50 or 100 characters) (step S16 in 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 the 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 “The string (1) is not included in the string representing the nucleotide sequence of the individual's entire genome” always appears.

[0134] For example, the allele type of a known SNP at a specific position on the genome is a maximum of four types, similar to the type of nucleotide. 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 designating the character string 902 in FIG. 9 as A, T, G, and C and performing the above-mentioned process four times, the allele type of a known SNP at the specific position can be determined (step S14 in FIG. 10). However, in reality, since two types (rarely three types) of nucleotides are common in a population, a known SNP can be easily determined in almost two attempts.

[0135] In FIG. 9, character strings 901-903 including normal character strings (normal character strings) and character strings 901-903 including mutant character strings (mutant character strings) can be used to determine whether an individual's genome is homozygous or heterozygous with respect to SNPs. For example, when the normal character string matches both character strings ("full-length character strings") representing the nucleotide sequence of an individual's entire genome (genomes usually exist as zygotic types that retain two sets derived from the mother and the father) and the mutant character string does not match, the individual's genome is a normal allele (normal type: N / N). For example, when the normal character string matches one of the character strings representing the nucleotide sequence of the individual's entire genome and the mutant character string matches the other, the individual's genome has a mutant allele in one genome (heterozygous type: N / M). For example, when the normal character string does not match both character strings representing the nucleotide sequence of the individual's entire genome and the mutant character string matches, the individual's genome has a mutant allele in both genomes (homozygous type: M / M).

[0136] The process of determining the genotype of the individual will be specifically described using a known SNP (rs1057910) present in the coding region of CYP2C9 (drug metabolizing enzyme gene) based on the medical information 301 (FIG. 4) on phenytoin (antiepileptic drug) described in [Embodiment 1] and the information on the association information 311 (FIG. 4). For the above character string 902, the type of nucleotide base of the wild type (normal type) allele in the SNP (rs1057910) is "adenine (A)", and the type of nucleotide base of the poor metabolizer allele, which is known to have a reduced metabolic rate of phenytoin, is "cytosine (C)". In addition, in the case of a known SNP, the corresponding character strings 901 and 903 can be easily obtained by the above method. Therefore, by extracting strings 901-903 containing the wild-type character "A" ("wild-type strings") and strings 901-903 containing the poor metabolizer character "C" ("poor metabolizer strings") and performing the above steps twice, the genotype of the individual can be easily determined.

[0137] 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 a 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 a poor metabolizer allele in both genomes (homozygous poor metabolizer: "C / C").

[0138] Depending on 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, different symbolized genotypes ("*1 / *1", "*1 / *3" or "*3 / *3") as well as different metabolic rates (drug efficacy) ("±0", "-1" or "-2") can be determined, as shown in association information 311 (Figure 4).

[0139] Together with the determined genotype, 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 DB6 (Figures 2, 5 and 8) (step S15).

[0140] (A general method that can be applied to determine the "allele type" of any DNA variant) The method using the character string (2) described above is applicable to determining the type of alleles ("allele types") including the junction type of any DNA variant (including the above-mentioned SNPs, SNVs, or indels), but is particularly effective when there is a change in the length of the target nucleotide, as well as a large number of options, or when the details of the target nucleotide are unknown. The change in the length of the target nucleotide and a large number of options occur when a simple repeat sequence with a different number of repeats is used as the target nucleotide, such as microsatellite polymorphism ("STRP"). When the details are unknown, for example, in addition to polymorphism analysis of deletion / insertion of the Alu sequence present in the ACE gene shown in [Embodiment 1], a known chromosomal translocation may be assumed. 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.

[0141] The total length of the target nucleotide may reach tens of thousands of nucleotides, and the length of the target nucleotide may vary greatly from person to person. Therefore, the total nucleotide sequence of a particular target nucleotide must be determined individually based on the genome of the individual. However, the locus on the genome where the target nucleotide (CNP, CNV, STRP) exists has already been identified in the human reference genome, as well as SNP, SNV, or indel. The location of the target nucleotide at the locus has also been relatively determined. In other words, the character string in (2) is known in the character string ("reference character string") representing the human reference genome (step S11 in FIG. 10).

[0142] The character string (2) may perfectly match character strings representing nucleotide sequences adjacent to both sides of a target nucleotide representing a known DNA variant present in an individual's genome. Therefore, by determining whether the character string (2) (a pair: character strings 901 and 903 in FIG. 9) exists in a character string ("full length character string") representing the nucleotide sequence of an individual's entire genome (step S13 in FIG. 10), it is possible to determine whether the target nucleotide exists on an individual's genome (step S14 in FIG. 10). The length of the character string (2) (a pair: character strings 901 and 903 in FIG. 9) may be set to be the same as the length of character strings 901 and 903 in the character string (1).

[0143] After the presence of string (2) (a pair of strings: strings 901 and 903 in FIG. 9 ) in a string representing the nucleotide sequence of an individual's entire genome (the "full-length string") is confirmed, the string present between the pair of strings (string 902 in FIG. 9 , which represents the full-length nucleotide sequence of the target nucleotide) is extracted.

[0144] For example, when the extracted character string represents a simple repeat sequence of a very short sequence (1-4 base pairs in length) such as a microsatellite polymorphism (STRP), the number of repeats (and the total number of nucleotides) contained in the character string is further determined. A simple repeat sequence may have different repeat counts in an individual's genome, with a unit of, for example, several nucleotides to several tens of nucleotides. The "allele type" corresponding to the number of repeats is detected. For example, when two sequences of different lengths are detected, it is determined to be a "heterozygous type," and when a sequence of only one length is detected, it is determined to be a "homozygous type."

[0145] The process of determining the genotype in asymptomatic young adults will be specifically described using a microsatellite polymorphism ("STRP") of three nucleotides (CAG) present in the coding sequence of the causative gene (HTT) of Huntington's disease, a late-onset single gene disease described in [Embodiment 2]. In patients with Huntington's disease, the mutant allele produces abnormal proteins that are harmful to cells (especially nerve cells). The loss of neurons is slow, but eventually leads to a destructive neurodegenerative state. The onset of symptoms usually occurs in middle age to menopause. Huntington's disease occurs because a long polyglutamine chain is produced by unstable expansion of the CAG repeat present in the coding sequence of its causative gene HTT. The number of glutamine repeats in normal type is 6 to 35, while in patients with the disease (or asymptomatic young adults with a very high risk of developing the disease), it is 36 to 121.

[0146] In the case of known microsatellite polymorphisms ("STRP") as described above, the corresponding character strings 901 and 903 can be easily obtained by the above method. After the presence of the character string (2) (a pair of characters: character strings 901 and 903 in FIG. 9) in the character string ("full-length character string") representing the nucleotide sequence of the entire genome of the asymptomatic young adult is confirmed, the sequence and length of the character string (902 in FIG. 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 number of repeats of CAG is two types, "80 (number of nucleotides: 240)" and "113 (number of nucleotides: 339)" as a result of extracting the sequence and its length, it is a heterozygous type. (Both alleles have a repeat number equivalent to the disease-type allele, so the risk of developing the disease is extremely high, "+2.") Also, if the number of repeats of CAG is one type, "5 (number of nucleotides: 15)," it is a homozygous type. (Because both alleles have the same number of repeats as the normal allele, the risk of developing the disease is low (±0).)

[0147] The above method using the character string (2) can also be applied to the presence or absence of a known chromosomal translocation (generation of DNA variants). However, the target nucleotide in this case is the character string (2) (character strings 901 and 903 in FIG. 9). The genomic positions of the translocation points in the known chromosomal translocations are all known as the junctions between fragment A1 present on chromosome A and fragment B2 present on chromosome B, and the junctions between fragment A2 and fragment B1. When no translocation has occurred, fragments A1 and A2 are arranged in the order 1→2 on chromosome A, and fragments B1 and B2 are arranged in the order 1→2 on chromosome B. Therefore, the sequences of the above fragments A1, A2, B1, and B2 are also known.

[0148] From the above, for example, if fragment A1 is represented by character string 901 and fragment B2 is represented by character string 903 with the translocation point at the center, the presence of character strings 901 and 903 contiguously or non-contiguously on the genome of an individual can indicate the presence or absence of a translocation. Non-contiguity indicates the absence of a translocation, and contiguity indicates the possibility of the presence of a translocation. To reliably distinguish the possibility of the presence as presence or absence, for example, fragment A1 can be represented by character string 901 and fragment A2 can be represented by character string 903 with the junction of fragment A1 and fragment A2 at the center. When fragments A1 and A2 exist contiguously, the above possibility (the presence of a translocation) is completely denied, and when they exist discontinuously, the presence of a translocation is confirmed.

[0149] Information representing the DNA variants present in the individual's genome together with the determined "allele type" (the patient's genotype) is saved in a DB, recording medium or storage device (not shown) and is stored in the genome information DB6 (Figures 2, 5 and 8) (step S15).

[0150] [Software implementation example] The administration plan proposal system 1-1'' (Figures 2, 5 and 8) may be realized by a logic circuit (hardware) formed in an integrated circuit (IC chip) or the like, or by software, in the control block (particularly the information acquisition unit (medical information acquisition unit, relevance information acquisition unit and genotype information acquisition unit) 21, the compatibility determination unit 22 and the medical information modification unit 23).

[0151] In the latter case, the administration schedule proposal system 1-1'' (FIGS. 2, 5, and 8) includes a computer that executes instructions of a program, which is software that realizes each function. The computer includes, for example, one or more processors, and a computer-readable recording medium that stores the program. In the computer, the processor reads the program from the recording medium and executes it, thereby achieving the object of the present invention. The processor may be, for example, a CPU. The recording medium may be a "non-transient tangible medium", such as a ROM (Read Only Memory), tape, disk, card, semiconductor memory, programmable logic circuit, or the like. The system may further include a RAM (Random Access Memory) in which the program is expanded. The program may be supplied to the computer via any transmission medium (such as a communication network or broadcast waves) that can transmit the program. Note that one aspect of the present invention may also be realized in the form of a data signal embedded in a carrier wave, in which the program is embodied by electronic transmission.

[0152] 〔summary〕 The invention described so far can be summarized as follows.

[0153] [1] A system for proposing a suitable dosing regimen for a patient, comprising: a medical information acquisition unit for acquiring medical information indicating a medicine to be administered to the patient and its dosage; an association information acquiring unit for acquiring association information indicating an association between the medicine and the genotype; a genotype information acquisition unit for acquiring genotype information of the patient; a suitability determining unit that determines the suitability of the medical information based on the association information and the genotype information; a medical information modification unit for modifying the medical information when the degree of conformity is low; and an information presenting unit that presents to a user the changed pharmaceutical information that has been changed by the pharmaceutical information changing unit The system comprises:

[0154] [2] The compatibility determination unit determines the compatibility by referring to drug efficacy-related gene information on genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug; The genotype is a genotype related to the gene, and the association information includes the pharmaceutical efficacy-related gene information, The system described in [1], wherein the change is an increase or decrease in the dosage or a change in the medication.

[0155] [3] The compatibility determination unit determines the compatibility by referring to drug-related disease information indicating a disease that develops or becomes severe by administration of the drug; the genotype is a genotype relating to a combination of alleles associated with a predisposition to the disease, and the association information includes the drug-related disease information; The system described in [1] or [2], wherein the change is a change in the medication or a reduction in the dosage.

[0156] [4] When the medicine is contraindicated for the disease, the compatibility determination unit determines that the compatibility for the genotype including a combination of alleles associated with a predisposition to the disease is very low; The system described in [3], wherein when the compatibility determination unit determines that the compatibility for the genotype including a combination of alleles related to a predisposition to the disease is very low, the pharmaceutical information change unit adds a change to the pharmaceutical information for the medication that is contraindicated for the disease.

[0157] [5] The system described in [3], wherein the disease includes a disease associated with serious side effects due to an idiosyncratic trait, or a symptom of serious side effects due to an idiosyncratic trait.

[0158] [6] The compatibility determination unit determines the compatibility by referring to drug efficacy-related gene information representing genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug and drug-related disease information representing diseases that develop or become severe by administration of the drug; the genotype is a genotype related to a gene encoding a protein involved in the pharmacokinetics or pharmacodynamics of the drug and a genotype related to a combination of alleles related to a predisposition to the disease, and the association information includes the drug efficacy-related gene information and drug-related disease information, The system according to any one of [1] to [5], wherein the change is an increase or decrease in the dosage or a change in the medication.

[0159] [7] A system described in any of [1] to [6], wherein the genotype information is determined based on information representing a DNA variant contained in information representing the entire nucleotide sequence constituting the patient's genome obtained from a genome information DB using a patient ID.

[0160] [8] The system described in [7], wherein when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the genotype information is updated based on information representing a DNA variant present at the locus contained in information representing the entire nucleotide sequence constituting the patient's genome.

[0161] [9] determining information representing a single nucleotide polymorphism 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 the single nucleotide polymorphism; The system according to claim 7 or 8, wherein information representing the unrecorded DNA variant is determined based on character information representing the entire nucleotide sequence.

[0162]

[10] The system described in any of [1] to [9], wherein the medical information acquisition unit acquires the medical information from a prescription or a medicine notebook.

[0163]

[11] The system described in any one of [1] to

[10] , wherein the relevance information is generated by artificial intelligence.

[0164]

[12] A system described in any of [1] to

[11] , wherein when the change includes a change in the medication and there are multiple candidate medications for the change, the information presentation unit shows the user the most suitable medication among the multiple candidate medications.

[0165]

[13] A system described in any of [1] to

[12] , wherein, when there are multiple candidate pharmaceutical information items that are suitable for the information presentation unit to present to the user, the information presentation unit presents to the user the most suitable pharmaceutical information item among the multiple suitable candidate pharmaceutical information items.

[0166]

[14] The system described in any of [1] to

[13] , wherein when the drug represented in the drug information is a molecular targeted drug that targets a gene product having a specific mutation, the compatibility determination unit determines the compatibility based on whether or not a DNA variant corresponding to the mutation is present in the patient's genome.

[0167]

[15] The system described in any one of [1] to

[14] , further comprising a warning unit that warns that the medical information is inappropriate if the suitability determined by the suitability determination unit is below a standard.

[0168]

[16] A method for proposing a suitable dosing regimen for a patient, comprising: a medical information acquisition step in which a computer acquires medical information indicating a medicine to be administered to the patient and the dosage thereof; an association information acquisition step in which the computer acquires association information indicating an association between the medicine and the genotype; a genotype information acquiring step in which the computer acquires genotype information of the patient; a suitability determination step in which the computer determines the suitability of the medical information based on the association information and the genotype information; a medical information changing step in which the computer changes the medical information when the degree of conformity is low; and an information presenting step in which the computer presents to the user the changed medical information that has been changed in the medical information changing step; Including, In the above method, when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the computer obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The method, wherein the genotype information includes information representing variants having a frequency of less than 1% in the human population.

[0169]

[17] A dosage plan suggestion program for causing a computer to function as a system for suggesting a dosage plan suitable for a patient, comprising: The system includes a controller, The control unit is obtaining medical information indicating a medication and its dosage to be administered to said patient; obtaining association information representing an association between the drug and the genotype; Obtaining genotype information of said patients; determining the relevance of the medical information based on the association information and the genotype information; When the compatibility is low, modify the medical information; presenting the modified medical information to the user with the changes; and when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, obtain information representing the entire nucleotide sequence constituting the genome of the patient, detect a DNA variant present at the locus from the information representing the entire nucleotide sequence, and update the genotype information; The genotype information includes information representing variants having a frequency of less than 1% in the human population. A dosage plan suggestion program for causing a computer to function as the control unit.

[0170]

[18] A system for proposing a suitable dosing regimen for a patient, comprising: a medical information acquisition unit for acquiring medical information indicating a medicine to be administered to the patient and its dosage; an association information acquiring unit for acquiring association information indicating an association between the medicine and the genotype; a genotype information acquisition unit for acquiring genotype information of the patient; a suitability determining unit that determines the suitability of the medical information based on the association information and the genotype information; an administration plan determination unit that determines the appropriate medical information for the patient based on the suitability of the medical information determined by the suitability determination unit; and an information presentation unit that presents the medical information determined by the administration plan determination unit to a user; Equipped with When the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the system obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The genotype information includes information representing variants having a frequency of less than 1% in the human population. [Explanation of symbols]

[0171] 1. Dosage plan suggestion system (a system that suggests optimal dosage plans for patients) 1a Dosage plan suggestion system (a system that suggests an optimal dosage plan for patients) 1' Dosage plan suggestion system (a system that suggests an optimal dosing plan for patients) 1'' Dosage plan suggestion system (a system that suggests an optimal dosing plan for patients) 2. Control section 2a Control section 2b Control section 3 Display device (information presentation section) 4 Input Devices 5. Pharmaceutical efficacy-related gene information database 6 Genome Information Database 7. Drug-related disease information database 10. Dosage plan suggestion system (a system that suggests an optimal dosage plan for a patient) 21 Information acquisition unit (medicinal information acquisition unit, association information acquisition unit, and genotype information acquisition unit) 22 Compatibility determination unit 23 Medical Information Change Department 24 Warning section 25 Administration Plan Decision Department 301 Drug Information (Phenytoin) 302 Changes in medical information 303 Medical Information (Olanzapine) 304 Drug Information (Candidate Drug Group) 305 Drug Information (Rixotinib) 306 Changes to medical information 311 Related Information (Phenytoin) 312 Related Information (Clopidogrel) 313 Related Information (Perindopril Erbumine) 314 Related Information (Olanzapine) 315 Related Information (Rixotinib) 316 Related Information (Ceritinib) 317 Related Information (Gefitinib) 318 Related Information (Osimertinib Mesylate) 901 String 902 String (target nucleotide) 903 String

Claims

1. A system for proposing a suitable dosing regimen for a patient, comprising: a medical information acquisition unit for acquiring medical information indicating a medicine to be administered to the patient and the dosage thereof; an association information acquisition unit that acquires association information indicating an association between the medicine and the genotype; a genotype information acquiring unit for acquiring genotype information of the patient; a suitability determining unit that determines the suitability of the medical information based on the association information and the genotype information; an administration plan determination unit that determines the appropriate medical information for the patient based on the suitability of the medical information determined by the suitability determination unit; and an information presentation unit that presents the medical information determined by the administration plan determination unit to a user; Equipped with When the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the system obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The genotype information includes information representing variants having a frequency of less than 1% in the human population.

2. In order to detect the DNA variant, the system The system of claim 1 , which generates a junction sequence in which a target nucleotide sequence corresponding to the DNA variant is combined with partial nucleotide sequences on both sides of the position corresponding to the DNA variant in a reference human genome, and compares the junction sequence with the entire nucleotide sequence constituting the patient's genome.

3. In order to detect the DNA variant, the system The system of claim 1, further comprising: 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.

4. the compatibility determining unit determines the compatibility by referring to drug efficacy-related gene information on genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug; The genotype is a genotype related to the gene, and the association information includes the pharmaceutical efficacy-related gene information, The system according to any one of claims 1 to 3, wherein the determination of the medical information by the administration plan determination unit includes an increase or decrease in the dosage or a change in the medicine.

5. the compatibility determination unit determines the compatibility by referring to medicine-related disease information indicating a disease that develops or becomes severe by administration of the medicine; the genotype is a genotype relating to a combination of alleles associated with a predisposition to the disease, and the association information includes the drug-related disease information; The system according to any one of claims 1 to 4, wherein the determination of the medical information by the administration plan determination unit includes changing the medicine or reducing the dosage.

6. When the medicine is contraindicated for the disease, the compatibility determination unit determines that the compatibility for the genotype including a combination of alleles associated with a predisposition to the disease is very low; The system described in claim 5, wherein when the compatibility determination unit determines that the compatibility for the genotype including a combination of alleles associated with a predisposition to the disease is very low, the determination of the pharmaceutical information by the administration plan determination unit includes a change in the medication that is contraindicated for the disease.

7. 6. The system of claim 5, wherein the disease comprises a disease associated with a severe idiosyncratic side effect or a symptom of a severe idiosyncratic side effect.

8. the compatibility determination unit determines the compatibility by referring to drug efficacy-related gene information representing genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug and drug-related disease information representing diseases that develop or become severe by administration of the drug; the genotype is a genotype related to a gene encoding a protein involved in the pharmacokinetics or pharmacodynamics of the drug and a genotype related to a combination of alleles related to a predisposition to the disease, and the association information includes the drug efficacy-related gene information and drug-related disease information, The system according to any one of claims 1 to 7, wherein the determination of the medical information by the administration plan determination unit includes an increase or decrease in the dosage or a change in the medication.

9. determining information representing single nucleotide polymorphisms among the DNA variants using the patient's genomic fragment or based on the information representing the entire nucleotide sequence, and recording the determined information representing single nucleotide polymorphisms; The system according to any one of claims 1 to 8, wherein information representing the unrecorded DNA variants is determined based on character information representing the entire nucleotide sequence.

10. The system according to any one of claims 1 to 9, wherein the medical information acquisition unit acquires the medical information from a prescription or a medicine notebook.

11. The system according to any one of claims 1 to 10, wherein said relevance information is generated by artificial intelligence.

12. A system as described in any one of claims 1 to 11, wherein when the determination of the pharmaceutical information by the administration plan determination unit includes a change in the pharmaceutical and there are multiple candidate pharmaceuticals for the change, the information presentation unit shows the user the pharmaceutical that is most suitable among the multiple candidate pharmaceuticals.

13. A system as described in any one of claims 1 to 12, wherein, when there are multiple candidate pharmaceutical information items that are suitable for the information presentation unit to present to the user, the information presentation unit presents to the user the most suitable pharmaceutical information among the multiple suitable candidate pharmaceutical information items.

14. The system according to any one of claims 1 to 13, wherein, when the drug represented in the drug information is a molecular targeted drug that targets a gene product having a specific mutation, the compatibility determination unit determines the compatibility based on whether or not a DNA variant corresponding to the mutation is present in the patient's genome.

15. The system according to any one of claims 1 to 14, further comprising a warning unit that warns that the medical information is inappropriate when the degree of suitability determined by the degree of suitability determination unit falls below a standard.

16. A method for suggesting a suitable dosing regimen for a patient, comprising: a pharmaceutical information acquisition step in which a computer acquires pharmaceutical information indicating a pharmaceutical to be administered to the patient and the dosage thereof; an association information acquiring step in which the computer acquires association information indicating an association between the medicine and a genotype; a genotype information acquiring step in which the computer acquires genotype information of the patient; a suitability determining step in which the computer determines the suitability of the pharmaceutical information based on the association information and the genotype information; a dosing regimen determination step in which the computer determines suitable medical information for the patient based on the suitability of the medical information determined in the suitability determination step; and An information presentation step in which the computer presents the medical information determined in the administration plan determination step to a user. Including, In the above method, when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the association represented by the association information, the computer obtains information representing the entire nucleotide sequence constituting the genome of the patient, detects a DNA variant present at the locus from the information representing the entire nucleotide sequence, and updates the genotype information; The method, wherein the genotype information includes information representing variants having a frequency of less than 1% in the human population.

17. A dosage plan suggestion program for causing a computer to function as a system for suggesting a dosage plan suitable for a patient, The system includes a controller, The control unit is obtaining medical information indicative of a medication and its dosage to be administered to said patient; obtaining association information representing an association between the drug and the genotype; Obtaining genotype information of the patient; determining the relevance of the medical information based on the association information and the genotype information; determining the appropriate medical information for the patient based on the degree of suitability; presenting the determined medical information to a user; and when the genotype information does not record a genotype present at a locus associated with the drug represented in the drug information in the relationship represented by the relationship information, obtain information representing the entire nucleotide sequence constituting the genome of the patient, detect a DNA variant present at the locus from the information representing the entire nucleotide sequence, and update the genotype information; The genotype information includes information representing variants having a frequency of less than 1% in the human population. A dosage plan suggestion program for causing a computer to function as the control unit.

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