WO2022004200A1 - Dosage regime proposing system, method, and program - Google Patents

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

Dosage planning proposal system, method and program

The present invention relates to a system for proposing a drug administration plan to a user, and more particularly to a system for proposing a drug administration plan suitable for a patient based on a genotype peculiar to the patient.

The relationship between gene function and drug efficacy has been pointed out for some time. In addition, there have been proposals to prescribe a drug suitable for the specific patient by utilizing the information of the specific patient (for example, Patent Document 1).

Japanese Unexamined Patent Publication No. 2016-218684 (published on December 22, 2016)

However, even a system that uses the genetic information of a patient to determine whether a drug that is considered to be effective for a certain disease is actually safe and effective for a specific patient has not been proposed. It is because there are multiple drugs known to have medicinal properties for one disease, there are multiple genes that affect the medicinal effects or side effects of one drug, and there are multiple genes for the expression of the function of one gene. It is well known that other genes are involved.

Therefore, the current out-of-hospital and in-hospital prescriptions (specifying the type, dose and usage of the drug) prepared by the doctor have uniform factors (mainly the type of disease the patient is suffering from and the severity of the disease). Degree and patient age, weight and gender, etc.) are still applied. Such a prescription may mean that it is not possible to specify the type, dose and dosage of the drug suitable for the individual patient. In fact, multiple patients who use the drug as prescribed show very different reactions. It has been pointed out that the reaction may include the drug having only adverse effects on the patient (showing only side effects and no efficacy).

In addition to the drugs used by patients according to the prescription, there are drugs that require the control of healthcare professionals and other substances (anesthetics, etc.) for administration or use to patients. It is well known that administration or use of such agents or substances can cause excessive reactions in some people and is often accompanied by side effects. For example, a study in the United Kingdom reported that about 7% of inpatients in medical facilities had some side effects. The overreactions or side effects described above have serious consequences for the patient (disability, irreparable damage, manifestation of congenital abnormalities or death). The death toll from overreaction or side effects is about 100,000 per year in the United States.

As described above, the effectiveness of drugs and substances used in general medical treatment shows large individual differences. Even drugs or substances that have been approved by the state (that meet certain efficacy and safety requirements) are rarely effective for all patients who receive or use them. In other words, at present, there are patients who are receiving drugs that cannot show efficacy, and patients who are receiving drugs in an inappropriate amount to show efficacy.

Among them, drugs used for the treatment of mental illness show relatively low efficacy. Administration of less effective drugs delays recovery and increases treatment costs, thus imposing a physical, mental or financial burden on the patient. In addition to these burdens, as mentioned above, the side effects of the drug can cause distress that is inherently unrelated to the disease.

Individual differences in drug efficacy and side effects are more due to genetic diversity in the human population than to the effects of disease type, environmental factors (such as lifestyle) and / or the combination of drugs being taken. to cause.

Therefore, one aspect of the present invention is to propose to the user a drug administration plan suitable for the patient based on the genotype peculiar to the patient.

In order to solve the above problems, the system according to one aspect of the present invention is a system that proposes a suitable administration plan for a patient.
The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
Genotype information acquisition department that acquires the genotype information of the above patients;
Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
A medical information changing unit that changes the medical information when the goodness of fit is low; and an information presentation unit that presents the changed medical information that the medical information changing department has changed to the user.
The system captures the genome of the patient when the genotype information does not record the genotype present in the locus associated with the drug represented in the drug information in the association represented by the relevance information. Information representing all the constituent nucleotide sequences is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
The genotype information includes information representing variants having a frequency of less than 1% in the human population.

In order to solve the above-mentioned problems, the method according to another aspect of the present invention is a method for proposing a suitable administration plan for a patient.
A drug information acquisition step in which a computer acquires drug information representing the drug to be administered to the patient and the dose thereof;
Relevance information acquisition step in which the computer acquires relevance information representing the relevance between the drug and the genotype;
The genotype information acquisition step in which the computer acquires the genotype information of the patient;
A goodness-of-fit determination step in which the computer determines the goodness of fit of the pharmaceutical information based on the relevance information and the genotype information;
When the computer has a low goodness of fit, a drug information change step of changing the drug information; and an information presentation process in which the computer presents the changed drug information changed in the drug information change step to the user. Including,
In the above method, when the genotype information does not record the genotype present in the locus associated with the drug represented by the drug information in the relevance represented by the relevance information, the computer described above. Information representing all the nucleotide sequences constituting the genome of the patient is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
The genotype information includes information representing variants having a frequency of less than 1% in the human population.

In order to solve the above-mentioned problems, the administration plan proposal program according to another aspect of the present invention is a dose plan proposal program for operating a computer as a system for proposing a suitable administration plan for a patient.
The above system is equipped with a control unit.
The control unit
Obtain drug information indicating the drug to be administered to the above patients and its dose;
Obtained relevance information indicating the relevance of the above drugs and genotypes;
Obtain genotype information for the above patients;
Based on the relevance information and genotype information, the goodness of fit of the above drug information is determined;
When the goodness of fit is low, the above medical information is changed;
The modified drug information with the modification is presented to the user; and the genotype information contains a genotype existing in a locus associated with the drug represented by the drug information in the relevance represented by the relevance information. When not recorded, information representing all the nucleotide sequences constituting the genome of the patient is acquired, and the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence to update the genotype information. death,
The genotype information includes information representing variants having a frequency of less than 1% in the human population.
The computer functions as the control unit.

In order to solve the above problems, the system according to one aspect of the present invention is a system that proposes a suitable administration plan for a patient.
The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
Genotype information acquisition department that acquires the genotype information of the above patients;
Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
Based on the goodness of fit of the drug information determined by the goodness-of-fit determination unit, the administration plan determination unit that determines suitable drug information for the patient; and the drug information determined by the administration plan determination unit are used by the user. Equipped with an information presentation unit to present to
The system captures the genome of the patient when the genotype information does not record the genotype present in the locus associated with the drug represented in the drug information in the association represented by the relevance information. Information representing all the constituent nucleotide sequences is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
The genotype information includes information representing variants having a frequency of less than 1% in the human population.

According to one aspect of the present invention, it is possible to propose a drug administration plan suitable for a patient based on the genotype peculiar to the patient.

It is a figure which shows the concept of this invention schematically. It is a figure which shows the structure of the system which concerns on Embodiment 1 of this invention. It is a figure which shows an example of the process which the said system executes. It is a figure which shows the example of the medicine information, the modified medicine information and the relevance information. It is a figure which shows the structure of the system which concerns on Embodiment 2 of this invention. It is a figure which shows the other example of the process performed by the said system. It is a figure which shows other examples of pharmaceutical information and relevance information. It is a figure which shows the structure of the system which concerns on Embodiment 3 of this invention. It is a schematic diagram which shows the structure of the character string for determining the allele type (genotype) of an arbitrary DNA variant in the human genome. It is a figure which shows an example of the method of determining the allele type (genotype) of the DNA variant (including SNP) present on a genomic sequence. It is a figure which shows the other example of a drug information, a modified drug information and a relevance information. It is a figure which shows the structure of the modification of the system which concerns on Embodiment 1 of this invention. It is a figure which shows the structure of the system which concerns on other embodiment of this invention.

One aspect of the present invention is a system that proposes a suitable administration plan for a patient based on a genotype peculiar to the patient, and obtains pharmaceutical information indicating a drug to be administered to the patient and a dose thereof. Acquisition unit; Relevance information acquisition unit that acquires relevance information indicating the relationship between the drug and the genotype; Genotype information acquisition unit that acquires the genotype information of the patient; Based on the relevance information and genotype information The conformity determination unit that determines the conformity of the drug information; the drug information change unit that changes the drug information when the conformity is low; and the modified drug information that the drug information change department has changed. It has an information presentation unit to present to the user.

The "administration plan" includes at least information indicating a specific patient and information indicating the type and dose of the drug to be administered to the specific patient. The administration plan is a guideline (for example, a prescription) indicating that a certain drug is administered to the specific patient at a certain dose. The above system is a system that assists the judgment of healthcare professionals (particularly doctors) by creating an administration plan (custom-made administration plan) suitable for the patient.

The term "pharmaceutical" is used herein for the purpose of a drug that directly causes improvement of symptoms in a disease by exerting a medicinal effect in a patient receiving administration, or for the purpose of assisting medical practice (examination and anesthesia, etc.). Represents the substance used (contrast, anesthetic, etc.).

A "genotype" (also referred to as a genotype) is the genetic composition of an individual or a particular locus of an individual, herein a type of combination of alleles (alleles) in one or more loci in the genome. When targeting two or more loci for genotypes, it refers to the sum of each type). "Allele" as used herein refers to an individual gene and DNA sequence present at one locus of a chromosome. The term "genotype" or "allelic type" is used herein as a concept that includes "zygotes."

"Pharmaceutical information" includes at least information that identifies the patient (eg, the patient's ID number), information that identifies the drug (eg, the brand name or substance name of the drug), and information that specifies the dose of the drug to the patient. Represents the information you have. The pharmaceutical information can be, for example, a medical record or prescription created by a doctor on a computer.

"Relevance information" refers to information indicating the type of drug and the relevance of genes (groups) that affect the action of the drug in vivo.

"Goodness of fit (of pharmaceutical information)" refers to the patient and the type and / or dose of the drug specified in the drug information, based on the patient's specific genetic type specified in the drug information. The relationship is appropriate and represents a certain degree.

A "DNA variant" as used herein is a specific site on the genome in which two or more changes in a nucleotide sequence (including alleles and chromosomal structures) are present in a human population (regardless of its frequency) and the like thereof. Described as a general concept of change. Nucleotide sequence changes in the above "DNA variant" mean the sum of all changes, including substitutions, deletions, insertions and / or additions, duplications of one or more nucleotides (see bottom of FIG. 1).

Among the above "DNA variants", when the change is frequent (1% or more) in the population, it is called "polymorphism (P: Polymorphism)". ”), Copy number polymorphism (hereinafter referred to as“ CNP ”), Microsatellite polymorphism (short chain column repeat sequence: Short Tandem Repeat Polymorphism, hereinafter referred to as“ STRP ”) There is. In addition, when the change is infrequent (less than 1%) in the population, it is called a "variant (V: Variant)", for example, a single nucleotide variant (Single Nucleotide Variant, hereinafter referred to as "SNV"), copy number. There is a variant (Copy Number Variant, hereinafter referred to as "CNV"). In the present 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).

The total type of allele combination (“allele type”), including the mating type in one locus, is determined by the nucleotide sequence of each allele and / or the number of alleles contained in the combination. Administration of the drug to a patient (ie, a patient with an unusual type) in which at least one of the nucleotide sequences is not the most abundant wild-type nucleotide sequence in the human population and / or the number of alleles is not the usual two is It can have undesired effects on the patient. The undesired effects are, for example, (a) a decrease, loss or excessive increase in the efficacy of the drug, (b) the onset or increase of side effects of the drug, and / / when the type is compared to a normal patient. Or (c) a high incidence of a specific disease that did not occur prior to administration of the above-mentioned drug. However, in practice, as illustrated in [Embodiment 2] below, the undesired effect does not appear in just one "allele type", but in many "allele types" for many sitting positions. It often appears when it is accumulated.

Therefore, as shown in FIG. 1, the system has a doctor-designated dosing regimen for drug B (including dose C designation) for patient A according to the uniform factors described above, with the adverse effects described above being patient. We propose to change to a tailor-made administration plan (eg, drug B'and dose C') that is suppressed according to the genotype information of A. Criteria for changing the dosing regimen include (1) pharmacokinetic factors of drug B, (2) pharmacodynamic factors of drug B, and (3) risk of developing secondary diseases due to drug B. .. In [Embodiment 1] described later, an example in which (1) and (2) are used as the above-mentioned determination criteria will be described. In [Embodiment 2] described later, an example in which (3) is used as the above-mentioned determination criterion will be described. In [Embodiment 3] described later, an example in which the combination of (1) to (3) is used as the above-mentioned determination criterion will be described. In addition, "pharmacokinetics" represents the behavior of a drug or its metabolite in vivo, which changes the probability of contact between a drug and a target molecule, and "pharmacodynamics" is a substance. Represents the intensity with which (drug) acts on a target substance in the living body. The above-mentioned "pharmacokinetics" and "pharmacodynamics" are described later in [Embodiment 1] together with the characteristics of related proteins.

In (1) and (2), the degree to which the chemical structure of drug B administered to the patient interacts with the protein expressed in the patient's body (pharmacokinetic factor or pharmacodynamic factor of drug B). Is used to properly control. (3) is used to prevent the risk of developing a certain disease based on the genetic background peculiar to the patient from being manifested (that is, developing the disease) by administration of a drug (artificial act).

The graph in (the system of invention) of FIG. 1 visually shows the risk of developing a specific disease. In the graph, when the frequency of the genetic background in the human population is on the vertical axis and the susceptibility (susceptibility) to a certain disease that correlates with each genetic background is on the horizontal axis, the human population for one disease The risk of developing the disease has been shown to be approximately normally distributed. As shown in the graph, in the human population, the population to the right of the threshold (horizontal axis, dashed line of threshold and part surrounded by curve / horizontal axis and part surrounded by curve) is inherited to develop a certain disease. (See also Falconer DS (1965) The inheritance of liability to protect diseases estimated from the inclusion relatives. Ann Hum Genet 29: 51-76; doi 10.111 / j.1469-1809.) .. However, the human individuals A1 and A2 existing on the right side of the threshold have only a high risk of developing the disease, and do not necessarily actually develop the disease. A1 and A2 have a very close risk of developing. However, for example, A1 may have not developed, but A2 may have. Various factors are involved in the onset of the disease, but the purpose is to prevent the administration of drugs (artificial environmental factors that link the genetic predisposition of a certain disease to the onset of the disease) to cause the onset of the unaffected A1 disease. So, the above (3) is used.

The genotype information of patient A can be determined, for example, by two different methods shown below (see the bottom of FIG. 1). For example, at least one locus of 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 "full-length string"). A character string (hereinafter referred to as "allergen character string") representing a partial nucleotide sequence containing a known DNA variant present in is extracted. The string is then compared to a 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 "reference string"). It can be determined by identifying the type of allele combination of the DNA variant (the patient's "hereditary type"). The reference character string can be obtained from a public database such as an ensemble (Ensembl, URL: http://ensembl.org). Alternatively, as another method, the genotype information of patient A is obtained by, for example, using a part of the genomic DNA sample obtained from the patient using the current microarray technology (genome-exhaustive polymorphism analysis technology). By hybridizing each fragment consisting of a nucleotide sequence containing all known SNPs corresponding to the "reference string" under stringent conditions (conditions that allow only perfectly matched sequences (temperature, salt concentration)). It can be determined by experimental methods. The details of the method for determining the "genotype" information of the patient are also described later in each embodiment (in particular, in [Embodiment 4], the information analysis using the above-mentioned "full-length character string" is performed. The determination method is described in detail, including specific examples).

Some embodiments of the present invention will be described in detail below.

[Embodiment 1]
In the present embodiment, the goodness of fit will be determined based on the efficacy of the drug expected to occur in the patient, as an example. The system of this embodiment is a combination of allele types ("" Allelic type ") is at least referred to as the above genotype. That is, the system of the present embodiment refers to the information indicating the degree to which the genotype related to the gene (“allele type”) affects the drug efficacy of the drug (pharmaceutical efficacy-related gene information), and refers to the above-mentioned goodness of fit. To determine.

(Pharmacokinetics and proteins involved in pharmacodynamics)
The efficacy of a drug is partially determined 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. That is, pharmacokinetics refers to the in vivo behavior of a drug or its metabolites that alters the probability of contact between the drug and the target molecule. Proteins involved in pharmacodynamics can be drug target molecules. Target molecules include, for example, receptors, signal molecules, and proteins that constitute biological pathways associated with pharmacological and genetic actions of drugs.

As shown in FIG. 2, the administration plan proposal system (system that presents an administration plan suitable for a patient) 1 includes a control unit 2 built in a computer and a display device (information display unit) 3. The control unit 2 (FIG. 2) includes an information acquisition unit (medicine information acquisition unit, relevance information acquisition unit, and genotype information acquisition unit) 21, a goodness-of-fit determination unit 22, and a drug information change unit 23 of FIG. .. The information acquisition unit 21, the goodness-of-fit determination unit 22, and the medical information change unit 23 of FIG. 2 are included in the CPU (Central Processing Unit) of the control unit 2 (FIG. 2). The control unit 2 (FIG. 2) is connected to the input device 4 (for example, keyboard and / or mouse) of FIG. 2, the pharmaceutical efficacy-related gene information DB 5 and the genomic information DB 6. The administration plan proposal system 1 of FIG. 2 is controlled by the control unit 2 (FIG. 2) based on the information acquired from the input device 4 and the above two DBs (database: that is, the drug efficacy-related gene information DB 5 and the genomic information DB 6). This is a system that outputs the generated information to the user via the display device 3 (FIG. 2).

(Processing of administration plan proposal system 1)
An example of the processing performed by the administration plan proposal system 1 of FIG. 2 in order to improve the effectiveness of the medicine will be described below with reference to FIG. The input device 4 (FIG. 2) is provided by the user's physician according to conventional uniform factors (mainly the type of disease the patient is suffering from, the severity of the disease and the patient's age, weight and gender, etc.). The input medical information 301 (FIG. 4) is sent to the information acquisition unit 21 (FIG. 2) (S1 step in FIG. 3). The information acquisition unit 21 of FIG. 2 has the name of the drug represented by the drug name contained in the drug information 301 (FIG. 4), the name of the gene related to the efficacy of the drug, and the known DNA related to the gene. The relevance information 311 (FIG. 4) describing the entire “genotype” in the variant (for example, SNP) and the drug efficacy of the drug according to the genotype is provided in the pharmaceutical efficacy-related gene information DB 5 of FIG. (For example, it can be constructed based on the information of DGIdb: Drug Gene Interaction database, URL: http://dgidb.org/) (“YES” in the S2 step of FIG. 3). The information acquisition unit 21 of FIG. 2 has a patient ID and a gene based on the "patient ID" information described in the drug information 301 (FIG. 4) and the gene name contained in the relevance information 311 (FIG. 4). The genetic type information of the patient corresponding to the above is acquired from the genomic information DB 6 (FIG. 2) as a symbol according to the notation of "genetic type" described in the relevance information 311 of FIG. 4 (in the step S3 of FIG. 3). "YES"). The information acquisition unit 21 (FIG. 2) determines the goodness of fit of the patient's genotype information acquired from the acquired drug information 301 (FIG. 4), the relevance information 311 (FIG. 4), and the genomic information DB 6 (FIG. 2). Send to 22 (Fig. 2).

When the result is "NO" in the step S2 of FIG. 3 (for example, since the drug has just been developed, there is no relevance information), the information acquisition unit 21 of FIG. 4) is sent to the display device 3 (FIG. 2) (step S9 in FIG. 3). The display device 3 of FIG. 2 displays the above-mentioned drug information, and the administration plan proposal system 1 (FIG. 2) ends the process. Further, when "NO" (for example, the genotype information corresponding to a specific gene in the patient has not been determined yet) in the S3 step of FIG. 3, the information acquisition unit 21 (FIG. 2) receives the drug information 301 (for example, FIG. 4) is sent to the display device 3 (FIG. 2) (step S9 in FIG. 3). The display device 3 (FIG. 2) displays the above-mentioned drug information, and the administration plan proposal system 1 of FIG. 2 ends the process.

The goodness-of-fit determination unit 22 in FIG. 2 has medical information based on the genotype information of the patient acquired from the relevance information 311 (FIG. 4) and the genomic information DB 6 (FIG. 2) via the information acquisition unit 21 (FIG. 2). The goodness of fit of 301 (FIG. 4) is determined (step S4 of FIG. 3). The details of the S4 process of FIG. 3 will be described with reference to FIG.

The relevance information 311 shown in FIG. 4 refers to an active ingredient corresponding to a drug name (pharmaceutical name: phenytoin (antiepileptic drug)) and a gene encoding a protein involved in the pharmacokinetics of the active ingredient (related gene). : CYP2C9 (drug metabolizing enzyme gene)), known SNP (SNP site: rs1057910) existing on the gene, total of symbolized "hereditary type" in SNP (rs1057910) (hereditary type: "* 1 / *" 1 ”,“ * 1 / * 3 ”and“ * 3 / * 3 ”), and the metabolic rate of the active ingredient corresponding to each genetic type (corresponding to the medicinal effect) (metalytic rate (medicinal effect):“ ± 0 ”,“ Relevance information including -1 "and" -2 ") is shown. Phenytoin is a drug that has the effect of relieving symptoms such as seizures of epilepsy such as tonic seizures (generalized seizures, major seizures), focal epilepsy (including Jackson-type seizures), autonomic seizures, and psychomotor seizures. be.

In the relevance information 311 (Fig. 4), SNP (rs1057910) is present at position 1075 in the coding region of CYP2C9, and its genotype type "* 1" represents a wild-type allele, and the actual nucleotide type of the nucleotide. Is "Adenine (A)". In addition, the genotype type "* 3" represents a low-metabolic allele that is known to reduce the metabolic rate of phenytoin, and the actual base type of nucleotide is "cytosine (C)". Relevance information 311 (Fig. 4) shows the most frequent CYP2C9 genetic type (normal type) "* 1 / * 1" (actual nucleotide combination type: "A / A") in the population. Based on the corresponding phenitoin metabolic rate (medicinal effect) "± 0", the number of genetic types of a specific patient containing a low metabolic rate allele "* 3" (actual nucleotide base: "C") ( The metabolic rate (medicinal effect) subtracted by the number of anonymous numbers) is shown. In other words, the relevance information 311 (Fig. 4) shows that the administration of phenytoin according to the conventional uniform factor is the combination type of nucleotide change of SNP at the 1075 position of the gene CYP2C9 (“A / A”, “A / C”). Or "C / C") in patients with different symbolized genotypes ("* 1 / * 1", "* 1 / * 3" or "* 1 / * 1") On the other hand, it indicates that they show different metabolic rates (drug effects) (“± 0”, “-1” or “-2”).

According to the step S4 of FIG. 3 described above, the goodness-of-fit determination unit 22 (FIG. 2) uses the pharmaceutical information 301 (FIG. 4), the relevance information 311 (FIG. 4), and the patient's genotype information as “* 1”. When "/ * 3" is acquired from the information acquisition unit 21 (FIG. 2), the value of the metabolic rate (medicinal efficacy) of phenytoin in the drug information 301 (FIG. 4) is determined 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 obtained based on the "patient ID: 123456789" described in the drug information 301 (FIG. 4) and the "related gene: CYP2C9" described in the relevance information 311 (FIG. 4). Obtained from genomic information DB 6 (FIG. 2) by unit 21 (FIG. 2).

In addition, there are two genes related to the drug name M (medicine) included in the drug information 301 of FIG. 4 (two gene names G (gene) 1 and G2 are described in the relationship information 311 of FIG. 4). When the information acquisition unit 21 (FIG. 2) is displayed, the information acquisition unit 21 (FIG. 2) has two relational information R (relationship) 1 and R2 corresponding to the gene names G1 and G2, and the genotype information Gt (genotype) 1 and Gt2 of the patient. Is sent to the fitness determination unit 22 (FIG. 2). The goodness-of-fit determination unit 22 (FIG. 2), which received the two relevance information R1 and R2 and the genotype information Gt1 and Gt2 of the two patients, determines the value of the goodness-of-fit element F (factor) corresponding to the drug name. Is determined for each gene name G1 and G2, and the value "-2", which is the sum of the two values (for example, G1: ± 0, G2: -2), is determined as the goodness of fit of the drug M.

In the above explanation, the metabolic rate (medicinal effect) of phenytoin is exemplified as an element of the above goodness of fit. Depending on the drug and the type of gene involved in the drug, the goodness-of-fit factor varies. For example, in the relevant information 312 of FIG. 4, due to pharmacokinetic factors, the antiplatelet drug clopidogrel sulfate (prodrug, hereinafter simply referred to as "clopidogrel") is CYP2C19 (drug metabolizing enzyme gene). ) Is used to convert the active compound of clopidogrel into a metabolic rate (corresponding to the medicinal effect). Clopidogrel is a drug that inhibits the action of ADP (adenosine diphosphate), suppresses platelet aggregation based on platelet activation, suppresses the formation of thrombi and prevents blood vessels from becoming clogged, and is usually an ischemic cerebrovascular disease. It is used to suppress the recurrence of disorders and to suppress thrombus / embolism formation in peripheral arterial diseases. Further, for example, in the relevant information 313 of FIG. 4, angiotensin converting enzyme (hereinafter, "ACE"), which is a target molecule of perindopril erbumin (active ingredient), which is a therapeutic agent for hypertension, is described as "ACE" due to pharmacodynamic factors. ) Direct action (that is, medicinal effect) is used. Perindopril erbumin is a prodrug that is hydrolyzed to a diacid form (perindoprilate) after oral absorption, and this diacid form specifically inhibits ACE in blood and tissues, and angiotensin II, which is a pressor substance, It suppresses production and reduces peripheral vascular resistance. When polymorphisms and variants are known for multiple alleles involved in the metabolism rate and fitness (goodness of fit) of one drug, the same association information as the number of goodness-of-fit factors F (factor) (Fig. 2). The information acquisition unit 21 (FIG. 2) acquires the medicinal drug efficacy-related gene information DB5) and the patient's genotype information (stored in the genome information DB6 of FIG. 2), and F1, F2, for each goodness-of-fit element. The final goodness of fit is calculated by determining the value of Fn and summing it up.

As described above, the conformity determination unit 22 in FIG. 2 acquires the heterozygous type “* 1 / * 3” as the genotype information regarding the SNP (rs1057910) in CYP2C9 in the relevance information 311 (FIG. 4). When present, the metabolic rate (medicinal effect) value "± 0" corresponding to the normal genotype (normal type) "* 1 / * 1" and the metabolic rate of phenitoin corresponding to the heterozygous type "* 1 / * 3" The value "-1", which is the sum of the values "-1" of the rate (drug efficacy), is determined as the degree of suitability (only 1 lower) with respect to the metabolic rate (drug efficacy) of the drug information 301 (FIG. 4). The goodness-of-fit determination unit 22 (FIG. 2) sends the pharmaceutical information 301 (FIG. 4) and the goodness of fit “-1” to the pharmaceutical information change unit 23 (FIG. 2).

The pharmaceutical information changing unit 23 in FIG. 2 determines that the goodness of fit “-1”, which is a negative value, is low (step S5 in FIG. 3). The drug information change unit 23 (FIG. 2) continuously adjusts the maintenance dose (after the lapse of the initial administration period) among the daily doses in the drug information 301 (FIG. 4) according to the metabolic rate (drug efficacy) “-1”. The dose of the drug administered to the drug is reduced by 1 unit (1 unit = 25% described in the drug information 301) in the “daily dose (maintenance amount)” described in the drug information 301 (FIG. 4). The medicinal effect is set to "± 0" (step S6 in FIG. 3). Since the change in the step S6 of FIG. 3 is the “daily dose (maintenance amount)” (the judgment in the step S7 of FIG. 3 is “NO”), as described above, the drug information change unit 23 (FIG. 2) The modified drug information 302 (FIG. 4) changed to 225 mg is sent to the display device 3 (FIG. 2) as the dose obtained by reducing the “daily dose (maintenance dose)” from 300 mg by 25%. The initial dose is unchanged, and remains the same as the "daily dose (initial dose) 300 mg" described in Pharmaceutical Information 301 in FIG. The display device 3 (FIG. 2) displays the changed drug information 302 (FIG. 4), and the administration plan proposal system 1 (FIG. 2) ends the process. When the daily dose in the modified drug information 302 of FIG. 4 exceeds the administration limit, the drug information changing unit 23 (FIG. 2) executes the drug change in the modified drug information 302 (FIG. 4) (shown). figure).

Unlike the S4 step of FIG. 3 illustrated above, the suitability determination unit 22 (FIG. 2) acquires the normal type “* 1 / * 1” as the genotype information of the patient from the genomic information DB 6 (FIG. 2). At that time, the value of the metabolic rate (medicinal effect) of phenytoin is determined to be "± 0" and sent to the drug information change unit 23 (FIG. 2). The drug information changing unit 23 (FIG. 2) determines that the value “± 0” of the metabolic rate (medicinal effect) is not low, and sends the drug information 301 (FIG. 4) to the display device 3 (FIG. 2). The display device 3 (FIG. 2) displays the above-mentioned drug information, and the administration plan proposal system 1 (FIG. 2) ends the process.

Further, in the above example, the change to the drug information was not a change in the type of drug, so the drug information change unit 23 in FIG. 2 made a judgment "NO" in the step S7 in FIG. However, for example, when the following conditions are met, the drug information changing unit 23 (FIG. 2) changes the type of drug. Condition: The drug name described in the drug information is "clopidogrel", the information acquisition unit 21 (FIG. 2) is the relevance information 312 (FIG. 4), and the information is acquired from the genomic information DB 6 (FIG. 2). Since the patient's genotype information is either "* 2 / * 2", "* 3 / * 3" or "* 2 / * 3", the metabolic rate (drug efficacy) is very low "-2". As mentioned above, clopidogrel is a prodrug and has no medicinal properties unless it is converted to its active compound. That is, when the above conditions are met, the active compound of clopidogrel, which is an active ingredient, is hardly produced in the patient's body regardless of the dose. Therefore, since an increase in the dose cannot be expected to have a drug effect, the drug information changing unit 23 (FIG. 2) in FIG. 2 changes the type of drug. The drug information changing unit 23 (FIG. 2) sends the drug information whose drug name has been changed (corresponding to the determination “YES” in the step S7 in FIG. 3) to the information acquisition unit 21 (FIG. 2), and processes S2 in FIG. Return to the process. The details of the relevance information 311 to 313 in FIG. 4 and other related matters are described later in the items (relevance information 311 to 313) in the present embodiment.

As described above, the administration plan proposal system 1 (FIG. 2) of the present embodiment sets the type or dose of the drug described in the drug information 301 (FIG. 4) specified by the doctor as the "genotype" of the patient (the relevant). Change when determined to be incompatible with the patient's "genotype") as a combination of alleles associated with genes that affect the efficacy of the drug. Therefore, the administration plan proposal system 1 (FIG. 2) can propose a tailor-made administration plan having excellent drug efficacy according to the genotype of the patient, without being bound by the conventional uniform factors.

The details of the genotype information and the relevance information for the administration plan proposal system 1 (Fig. 2) to present an appropriate administration plan for the patient will be described below.

(Patient genotype information)
The genotype information represents a combination type (“allele type”) of an allele (in this embodiment, an allele associated with one gene) that is unique to the patient and is present in one lotus coition. There are roughly two methods for determining the "allele type". The method uses "Method 1", which uses information representing the structure of the full length of the genome obtained from the patient ("full length character string"), and a genomic DNA sample derived from the patient, which is frequently and automatically performed in the population. This is "Method 2", which uses an experimental method based on genome-wide polymorphism analysis targeting only DNA variants suitable for analysis (for example, SNP).

The former "method 1" can be carried out by using a large-scale massively parallel DNA sequence determination method (next-generation nucleotide sequence determination method). Large-scale parallel DNA sequencing methods can simultaneously and evenly sequence complex DNA samples containing a large number (sometimes millions) of nucleotide sequences. For this reason, the large-scale parallel DNA sequencing method uses genomic DNA samples extracted by a conventional method from patient-derived blood cells and various tissues, as compared with the conventional dideoxy sequencing method (Sanger method). It is possible to convert the information into a character string (“full-length character string”) corresponding to the entire genome (about 3 billion nucleotides) of the patient in a short time and at low cost. By determining all the characters or strings (and their positions) contained in the above "full length string" and comparing them with the string representing the reference nucleotide sequence of the human genome ("reference string"), the patient's The genetic type for a particular locus on the genome can be determined.

For example, a string representing the nucleotide sequence of an allele that may be in a locus (“allele string”) and information representing a position within the population that causes a nucleotide sequence change between the alleles (known DNA variant) , If the frequency is high in a group (eg, SNP), it is stored in a generally available DB (eg, dbSNP (https://www.ncbi.nlm.nih.gov/snp/)). Therefore, one lotus coition possessed by the patient is determined by determining which type the "full-length character string" includes among the types of allele character strings combined for one lotus coition ("allele type"). Can determine the hereditary type of. As an example, the outline of the process of determining the genotype information of a patient will be described below.
-In the above-mentioned "all-character string" included in the "full-length character string" based on the above information indicating the position of a known DNA variant stored in a generally available DB (eg, the above-mentioned dbSNP). , Determine two character strings (for example, about 10 to 100 characters) adjacent to the positions on both sides of the DNA variant.-The above two character strings in the "full-length character string" (that is, adjacent to the positions on both sides of the DNA variant). Use a well-known character comparison application to determine the position where the two character strings) exactly match the "reference character string".-Between the "full-length character string" and the "reference character string", the above two character strings According to the match or mismatch of the character (string) corresponding to the DNA variant sandwiched at the position where is exactly matched, the "allergen type" (that is, the patient's "inheritance" of the DNA variant in the "full-length character string" Type ") is determined.

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

On the other hand, as the latter "method 2" (method using an experimental method by genome-wide polymorphism analysis) described above, the above DNA variant is a DNA variant that is frequently used in the population and suitable for automatic analysis. A large number (tens of thousands to tens of thousands) of microarray technologies already commercialized (existence of commercial kits and commissioned services) when (eg, SNPs, or deletions or insertions of one to several nucleotides in the genome (Indel)). The types of polymorphisms in hundreds of thousands) genomic fragments can be determined in a short time. For more information on microarray technology, see the kit manual or the contractor's HP.

As described above, the genotype information of the patient is obtained by the above-mentioned "method 1" using the former "full-length character string" information and / or the latter "method 2" using an experimental method by genome-wide polymorphism analysis. It can be determined (or during the implementation of these methods). Therefore, the patient's genetic type information stored in the genomic information DB 6 of FIG. 2 includes (1) "full-length character string" (patient's genomic information) and (2) the patient's "hereditary type" associated with each other. At least one of the information representing and the information representing the patient, and (3) the information in which the two relevant information are symbolized (see, for example, the "genome type" described in the relevance information 311 of FIG. 4 above). Can be one. The genotype information is preferably (2) or (3). Using (2) or (3) as the genotype information reduces the performance required for the administration plan proposal system 1 (FIG. 2) and the genomic information DB 6 (FIG. 2), and reduces the performance required for the administration plan proposal system 1 (FIG. 2). ) Can be improved. Further, by using (3) as the genotype information, (1) and (2) can be concealed from an unspecified number of third parties who cannot decipher the meaning of the symbol. For example, as shown in the relevance information 312 of FIG. 4, the "genotype" determined for the SNP (rs4244285) present in the drug metabolizing enzyme gene CYP2C19 is symbolized ("* 1 / * 1", "*". 1 / * 2 "," * 1 / * 3 "," * 2 / * 2 "," * 2 / * 3 "or" * 3 / * 3 ").

The "allele type" of the individual DNA variants to generate (2) and (3) as patient genotype information depends on the type (determination range) of the DNA variant based on the frequency within the population. Can be determined in two stages (see bottom of FIG. 1). As a first step, only all known SNPs are genomically determined as DNA variants with a frequency of 1% or higher in the population and suitable for automated analysis, and the information is stored in DB, recording media, or It is stored in a storage device (not shown). In addition, the patient's "genotype" information based on the analysis of all SNPs described above is stored in the genomic information DB 6 (FIG. 2). In addition, as described above, the determination of the "allele type" (genotype of the patient) for all SNPs can be determined by "method 2" by an experimental method using the genomic DNA sample of the patient. That is, first, the genomic DNA sample is extracted from the patient's peripheral blood, oral cells, buccal mucosa, or the like by a conventional method. Subsequently, using the above sample, the "allelic type" (patient's "genotype") for all known SNPs can be determined by an experimental method by genome-wide polymorphism analysis by the current microarray technology. Alternatively, the patient's "genotype" ("allele type") for all SNPs described above is determined by "method 1" by information analysis using the above-mentioned "full-length character string" (genome information of the patient). May be (see bottom of Figure 1).

Then, as a second step, if necessary, the "allelic type" (patient's "genotype") for the remaining DNA variants not stored in the DB, recording medium or storage device is the "full length string". It is determined by "Method 1" using information (patient's genomic information). The "remaining DNA variants" include DNA variants that are infrequent in the population (eg, SNV, CNV), or DNA variants that are not suitable for automated analysis (eg, CNP, STRP, or other special DNA variants). Is assumed (see the bottom of FIG. 1). The "allelic type" (patient "genotype") of the remaining DNA variants is determined after input of pharmaceutical information 301 (FIG. 4) to input device 4 (FIG. 2). As described above, the administration plan proposal system 1 of FIG. 2 is related to the drug efficacy from the drug efficacy-related gene information DB 5 (FIG. 2) based on the drug name included in the drug information 301 (FIG. 4). Get the name of the gene. The dosing regimen proposal system 1 (FIG. 2) searches for the latest genomic information DB 6 (FIG. 2) based on the name and "allelic type" (ie, patient genotype information) for the required DNA variant. If is not stored, as described above, the "reference string" information is searched to specify the loci on the genome where the remaining DNA variants are located. The administration plan proposal system 1 (FIG. 2) used the above-mentioned character string (“full-length character string”) for the “allelic type” (patient's “genotype”) of the remaining DNA variants existing only in the locus. Determined by "method 1". The dosing regimen proposal system 1 (FIG. 2) displays the "allelic type" (patient genotype information) of the remaining DNA variants determined in the genomic information DB 6 (FIG. 2), as well as the DB, recording medium or storage device. Store in (not shown). The method (“method 1”) for determining the “allele type” (patient genotype information) of the DNA variant using the above character string (“full-length character string”) information will be described later, including specific examples. It is also described in detail in [Embodiment 4].

Although the genome information DB 6 is shown in FIG. 2 as a configuration existing on a network, a storage unit or a storage unit built in the control unit 2 (FIG. 2), a reading unit that can read a recording medium, or a control unit. The external storage device or recording medium connected to 2 (FIG. 2) can be replaced as a readable reader.

The above genotype information according to (2) or (3) can be updated based on the latest report. The report is a comprehensive report of new DNA variants associated with a gene, as well as "allelic types" ("genotypes") for the DNA variants. As described above, the "method 1" using the above-mentioned "full-length character string" information (patient's genomic information) can generate a new (2) or (3) based on the existing report and the latest report.

As described above, as the process executed by the administration plan proposal system 1 (FIG. 2) described with reference to FIGS. 3 and 4, the genotype of the patient is divided into two stages from the genomic information DB 6 (FIG. 2). An example of acquiring (2) and (3) as information is shown. That is, as the first step, it was determined by "Method 2" using an experimental method using known DNA microarray technology (or "Method 1" using "full-length character string" information (patient's genomic information)). All SNP analysis information of the patient is stored in the genome information DB 6 (FIG. 2). Subsequently, as a second step, the remaining DNA variant information is analyzed by "Method 1" using the "full-length character string" information (patient's genomic information), if necessary.

However, the control unit 2 in FIG. 2 does not store all the SNP analysis information of the patient in the genomic information DB 6 (FIG. 2) as the first step described above, and from the beginning, as the second step, if necessary. In order to determine the "allelic type" (patient's "genotype") of a particular DNA variant, "method 1" using "full length string" information (patient's genomic information) may be performed. That is, the control unit 2 (FIG. 2) acquires (1) the "full-length character string" (patient's genome information) from the genome information DB 6 (FIG. 2), and extracts the allele character string contained in (1). However, the above procedure may be performed to determine the genotype for a particular locus or loci on a patient's genome. For example, from the beginning, the patient's "genotype" ("allele type") related to a specific SNP or new SNV is individually referred to as "full-length character string" information (patient's genomic information) described above. It may be determined by the method 1 ”. That is, regardless of conditions such as frequency in the population and suitability for automatic analysis, "method 1" using "full-length character string" information may be applied to all DNA variants from the beginning (FIG. 1). See bottom).

Alternatively, depending on the situation, for example, if the "full length string" information (patient's genomic information) is not yet stored in the genomic information DB 6 (FIG. 2), the patient's "genotype" for a particular SNP or new SNV. However, you may dare to use a method by an individual experimental technique that requires time and effort. For example, the current amplification-resistant mutation system (a technique for detecting specific point mutations) by PCR using allele-specific primers for the "genotype" of patients with the above-mentioned specific SNPs or novel SNVs. , A method capable of distinguishing a mutant allele that is one base different from a normal allele) may be used to individually identify the genotype.

From the viewpoint of protecting personal information, the information in the genome information DB 6 in FIG. 2 may be encrypted, or the information in the genome information DB 6 (FIG. 2) may be provided with access restrictions. The above encryption and access restriction can be realized by a method known in the field of information technology. From a similar point of view of protecting personal information, the system may acquire genotype information recorded on a recording medium instead of the genomic information DB6 (FIG. 2).

(Relevance information 311 to 313)
In this embodiment, the genotype is a genotype relating to a gene encoding a protein involved in pharmacokinetics, as shown in relevance information 311 in FIG. Relevance information 311 in FIG. 4 represents drug-gene association (particularly the effect of the metabolic rate of the active ingredient on the genotype of the allele associated with the gene function of the gene).

Relevance information 311 (Fig. 4) shows the CYP2C9 gene as a gene encoding a protein involved in pharmacokinetics for phenytoin. The presence of SNPs associated with enzyme activity (rs1057910: see relevance information 311 in FIG. 4) has been demonstrated in the CYP2C9 gene. Proteins expressed by the CYP2C9 gene, including mutant alleles, have low activity to oxidize (metabolize) phenytoin, the active ingredient of antiepileptic drugs. As shown in the relevance information 311 (Fig. 4), the less active CYP2C9 slows down the metabolic rate of phenytoin (metabolic rate (metabolic rate): "-1" or "-2"), so that the circulation time of phenytoin Can be extended more than necessary. Prolonged circulation time results in increased side effects and excessive efficacy (both are adverse events), especially for long-term drug administration.

The relevance 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 there may be several mutant allele types in the known SNPs (rs4244285) present within the CYP2C19 gene (see relevance information 312 in FIG. 4). The protein expressed by the CYP2C19 gene containing the mutant allele does not metabolize in the body of a drug that is oxidized and exerts a medicinal effect like clopidogrel, or weakens the metabolism. That is, the CYP2C19 gene containing the mutant allele lowers the metabolic rate of clopidogrel to the active compound depending on the genetic type of the patient, as shown in the association information 312 (Fig. 4) (metabolic rate (medicinal effect): "-". 1 "), or make the metabolic rate substantially 0 (metabolic rate (medicinal effect):" -2 "). In addition, according to "Recommended treatment policy (dose adjustment)" (see CLIMINICAL PHARMACOLOGY & THERAPEUTICS 89 (5): 662-673, 2011 and Organ Biology 21 (2): 247-253, 2014, etc.) When the daily dose described in is close to the dose limit, the drug information changing unit 23 in FIG. 2 has a negative metabolic rate (metabolic rate (medicinal effect): "-1" and "-2"). However, the type of medicine may be changed uniformly.

In the relevance information 313 of FIG. 4, which is another example, as one of the special DNA variants, the ACE gene as a gene encoding a protein (direct target protein) involved in the pharmacokinetics of perindopril erbumin. Is known to contain a polymorph of deletion / insertion of the Alu sequence, which is a short interspersed repeat sequence, within the intron 15. A gene into which an Alu sequence has been inserted causes splicing abnormalities or exon deletions, so the expression of abnormal proteins or abnormal protein expression patterns is higher than that of the gene lacking the Alu sequence. show. That is, perindopril erbumin has low or little efficacy in individuals carrying the ACE gene with the Alu sequence inserted. For example, in the case of a heterozygote (“Alu + / Alu-”) that retains one allele with an Alu sequence inserted in the ACE gene, the drug efficacy is determined to be “-1”. Alternatively, in the case of a homozygote (“Alu + / Alu +”) that retains both alleles into which the Alu sequence has been inserted, the drug efficacy is determined to be “-2” (see relevance information 313 in FIG. 4).

The relevance information 311 to 313 in FIG. 4 shows the gene encoding the pharmacokinetics of the drug or the protein involved in pharmacodynamics, the genotype of the gene, and the fitness element that changes depending on the genotype. Information representing each is included. The relevance information (pharmaceuticals, related genes, genotypes, and pharmacological efficacy information) described in the above information (relevance information 311 to 313 in FIG. 4) and other relevance information relating to the drug are known documents (eg, for example). CLINICAL PHARMACOLOGY & THERAPEUTICS 89 (5): 662-673, 2011 Tabel 1 and Organ Biology 21 (2): 247-253, 2014 Table 1 and Table 2) are summarized and easily available. It is possible. Table 1 of Organ Biology 21 (2): 247-253, 2014 is an excerpt from the old version of the prescription drug collection. For the contents of the latest ethical drug collection, refer to the book title "JAPIC ethical drug collection 2020 (issue date: August 30, 2019, publisher: Maruzen Publishing Co., Ltd.). CLINICAL PHARMACOLOGY & THERAPEUTICS 89 ( 5): As is clear from the partial "An Update of Guideline" title of 662-673, 2011 and the update of the contents in the ethical drug collection, the relevance of the above information (relevance information 311 to 313 in Fig. 4). Information, as well as other drug-related relevant information, will continue to be expanded and more accurate with the addition of new information and updates to old information. Therefore, it is preferable that the relevance information 311 to 313 (FIG. 4) and the relevance information regarding other medicines are prepared based on the latest information at the time of the embodiment of the present embodiment. For example, relevance information 311-313 (FIG. 4), as well as relevance information about other medicines, can be generated by artificial intelligence (hereinafter referred to as "AI") (see FIG. 1). Upon receiving the additional input of the new information, the AI may output new drug and gene relevance used to update the old information.

Among the above information (relevance information 311 to 313 in FIG. 4), the information representing the goodness-of-fit element (for example, metabolic rate and drug efficacy) that changes depending on the genotype is related to the above-mentioned known documents and materials. It can be described arbitrarily according to the sexual information. In the relevance information 312 (Fig. 4), the metabolic rate (drug efficacy) values corresponding to each genotype in the SNP (rs4244285) in the drug metabolizing enzyme gene CYP2C19 are "± 0", "-1" and "-". 2 "is described. For example, in Organ Biology 21 (2): 247-253, 2014, "CYP2C19 * 2 and * 3 types are important for CYP2C19 gene polymorphisms. Since both are types with loss of activity, this is the type. A combination of the two types of correspondence is diagnosed as an enzyme deficient person. " According to this description, the value "-2" of the metabolic rate (medicinal effect) in the relevance information 312 (FIG. 4) may be rewritten as "disappearance". The metabolic rate (drug effect) "disappearance" in the relevance information 312 (FIG. 4) can indicate, for example, that the prodrug clopidogrel is not metabolized (converted to a medicinal component) by CYP2C19 into its active compound. Therefore, the metabolic rate (medicinal effect) "disappearance" is determined by the goodness-of-fit determination unit 22 in FIG. Change the drug name in 4) to an alternative drug. At this time, if there is no alternative drug, the changed drug information in which the dose is changed to "0" may be output to the user. Further, regardless of the presence or absence of an alternative drug, a warning indicating that the drug name (or drug information including the dose) in the drug information 301 in FIG. 4 has a low goodness of fit may be issued to the user. .. The configuration of the system 1a at this time (which further includes the warning unit 24) is illustrated in FIG. 12 as an example.

Of course, the drug and genotype to be the subject of the present invention are not limited to those shown above, and various drugs and genotypes can be targeted. For example, examples of genotypes related to pharmacokinetic factors include the following are examples of transporter gene polymorphisms.

HMG-CoA reductase inhibitors (bravastatin, atorvastatin, etc.), which are therapeutic agents for dyslipidemia, are selectively taken up by the liver and show efficacy, but the transporter protein OATP1B1 (Organic Anion Transporting Polypeptide 1B1) is used for the uptake. It plays an important role. Among the SNPs in the gene encoding OATP1B1, the mutant type with amino acid substitution (base change: "521T> C") was orally administered due to decreased uptake into the liver compared to the normal type. Drugs such as statins and atorvastatin escape metabolism and excretion in bile and flow through the central vein, resulting in increased blood levels. As a result, the drug concentration in the blood becomes higher than the therapeutic concentration range, and there is a high risk of causing side effects such as drug addiction. Therefore, the heterozygous type is "-1" (genotype: "T / C") and homozygous type (hereditary) compared to the medicinal effect value "± 0" of the normal type (genotype: "T / T"). Genotype: "C / C") can be determined to be "-2" lower.

In addition, examples of gene polymorphisms of drug receptors as examples of genotypes related to pharmacodynamic factors are as follows.

Among the SNPs in the gene encoding the drug receptor protein β ₂ -adrenaline receptor (ADRB2), in the mutant type with amino acid substitution (base change: "46A>G"), β such as the bronchodilator clenbuterol hydrochloride ₂ Administration of the agonist causes down-regulation that reduces the expression level of the gene encoding ADRB2. As a result, bronchial asthma _{becomes more severe and responsiveness to β 2} agonists decreases. Therefore, the heterozygous type (genotype: "A / G") is "-1" and homozygous type compared to the medicinal effect value "± 0" of the normal receptor (genotype: "A / A"). (Genotype: "G / G") can be determined to be "-2" lower.

In addition, in another mutation of the ADRB2 gene (base change: "491C>T"), the _{ability to bind to agonists such as β 2} receptor agonists is 4 minutes of the normal type (hereditary type: "C / C"). It decreases to 1 and the reactivity to _{β 2 agonist decreases.} Therefore, the heterozygous type (genotype: "C / T") is "-1" and the homozygous type (genotype: "T / T") is "-1" compared to the normal drug efficacy value "± 0". -2 "Can be determined to be low.

As described above, the relevance information 311-313 (including the above-mentioned additional example contents) of FIG. 4 regarding pharmacokinetics and pharmacodynamics has a low goodness of fit for the specific patient in the administration plan specified by the doctor. When, at least a dose change (increase or decrease) change or drug change is described as a suggestion to improve the low goodness of fit. The administration plan proposal system 1 (FIG. 2), which uses the relevance information 311 to 313 (FIG. 4) as a criterion for determining the goodness of fit of the pharmaceutical information 301 (FIG. 4), makes a proposal to the doctor for improvement of the low goodness of fit. It can be presented.

(Examples of drug names and relevance information in drug information and processing using them)
The information acquisition unit 21 of FIG. 2 can acquire a plurality of relevance information at the same time (see “(administration plan)” of FIG. 1), and systemizes the drug information 304 (FIG. 11) for patients with non-small cell lung cancer. The case of inputting in 1 (FIG. 2) will be described as an example. Upon receiving the drug information 304 (FIG. 11) describing the drug name (ALK tyrosine kinase inhibitor) including the target molecule or the mechanism of action in the name, the information acquisition unit 21 of FIG. 2 receives the drug information 304 (FIG. 11) in the S1 step of FIG. , As will be described later, a plurality of relevance information 315 and 316 are acquired at the same time. Such drug names can generally refer to a plurality of specific drugs. For example, the relevance information 315 (including lyxothinib as a specific drug name) and 316 (including ceritinib as a specific drug name) in FIG. 11 are both based on the ALK tyrosine kinase inhibitor and its genotype. Information that describes the medicinal effect.

The information acquisition unit 21 and the goodness-of-fit determination unit 22 of FIG. 2 that acquired the relevance information 315 and 316 of FIG. 11 are the treatment when the drug name in the drug information 304 of FIG. 11 is lyxotinib and the drug name in the drug information 304. The treatment when is ceritinib (S3 to S5 in FIG. 3) is carried out in parallel. When the non-small cell lung cancer patient described in Pharmaceutical Information 304 of FIG. 11 does not have the EML-ALK fusion gene (genotype :-), the suitability determination unit 22 of FIG. 2 is of lyxotinib and ceritinib. Both are determined to be invalid "-∞" for the patient in S4 of FIG. 3 and sent to the drug information changing unit 23 of FIG.

The drug information changing unit 23 in FIG. 2 changes the drug name in the drug information 304 (including the ALK tyrosine kinase inhibitor) in FIG. 11 according to the negative symbol “−” and the infinity “∞”. The drug name includes the mechanism of action as described above. Therefore, it is a therapeutic agent for non-small cell lung cancer different from the ALK tyrosine kinase inhibitor (therapeutic agent for non-small cell lung cancer) in the pharmaceutical information 304 of FIG. EGFR tyrosine kinase inhibitor) is selected.

When the drug name is changed to EGFR tyrosine kinase inhibitor (“YES” in S7 of FIG. 3), the information acquisition unit 21 (FIG. 2) provides relevant information 317 and 318 of FIG. 11 in S2 of FIG. get. The information acquisition unit 21 and the goodness-of-fit determination unit 22 in FIG. 2 are processed when the drug name in the drug information 304 of FIG. 11 is gefitinib and when the drug name in the drug information 304 is ossimertinib mesylate. (S3 to S5 in FIG. 3) are carried out in parallel.

Here, the non-small cell lung cancer patient described in Pharmaceutical Information 304 of FIG. 11 has, for example, a homozygous mutation at position 2573 of the EGFR gene (genotype: G / G), and the EGFR gene. It has a heterozygous mutation (genotype: T / C) at position 2369 of. At this time, the goodness-of-fit determination unit 22 in FIG. 2 determines the goodness of fit of gefitinib as "1" from the total numerical value of each element (medicinal effect) (that is, the total value of 2 and -1) (that is, the total value of 2 and -1). (Refer to the relevance information 317 in FIG. 11), the goodness of fit of osimertinib mesylate was determined to be "3" from the total numerical value of each element (medicinal effect) (that is, the total value of 2 and 1). (See relevance information 318 in FIG. 11). The goodness-of-fit determination unit 22 of FIG. 2 sends the two determined goodness of fits to the pharmaceutical information changing unit 23 of FIG.

The drug information changing unit 23 in FIG. 2 is an absolute value among the two goodness of fit (the reference value for changing the drug is a value lower than 0 and both are positive values, so “YES” in S5 in FIG. 3). Select the "osyltinib mesylate" corresponding to the large "3" and send the modified drug information 306 of FIG. 11 to the display device 3 of FIG. The display device 3 presents the modified drug information 306 of FIG. 11 to the user.

The above-mentioned treatment proposes one of the optimal administration plans for the treatment of non-small cell lung cancer of a patient identified by the patient ID in the drug information 304 of FIG. 11 for the following reasons. Administration of ALK tyrosine kinase inhibitors (lyxotinib and ceritinib) is not effective for non-small cell lung cancer in the patient (who does not have the EML-ALK fusion gene (ie, does not develop a chromosomal translocation)). Relevance information of FIG. 11 Medicinal efficacy “−∞” in 315 and 316). EGFR tyrosine kinase inhibitors are only effective against non-small cell lung cancer in patients who have at least a homozygous or heterozygous mutation (G / G or G / T) at position 2573 of the EGFR gene (" The efficacy “2” and “1” of the relevant information 317 and 318 in FIG. 11). On the other hand, among the EGFR tyrosine kinase inhibitors, the patient may show resistance to the administration of gefitinib (drug efficacy "-1" in the relevant information 317 of FIG. 11). Among the above-mentioned EGFR tyrosine kinase inhibitors, ossimertinib mesylate is a drug expected to have a therapeutic effect in patients who are resistant to gefitinib. The ossimeltinib mesylate irreversibly inhibits the kinase activity of the EGFR protein having the T790M mutation (replacement of threonine with methionine at position 790) associated with the above resistance to gefitinib.

In the above, as the drug name included in the drug information 304 of FIG. 11, a name including a mechanism of action (which may include a plurality of drugs) is exemplified. Further exemplifying that a plurality of relevance information can be acquired at the same time even when the drug information 305 representing a single drug as a drug name is input to the system 1 (FIG. 2). When the information acquisition unit 21 of FIG. 2 acquires the drug information 305 of FIG. 11 as the drug information, the drug information change unit 23 of FIG. 2 determines “NO” in S5 of FIG. Since the same patient ID and (a type of) ALK tyrosine kinase inhibitor as in the drug information 304 of FIG. 11 are described in the drug information 305 of FIG. 11, the same process as the above-mentioned process (YES in S7 of FIG. 3). ") Is carried out.

The drug name in the drug information 305 of FIG. 11 is changed to a drug name that is not an ALK tyrosine kinase inhibitor that always has insufficient goodness of fit. Since the condition for selecting the drug name is "not an ALK tyrosine kinase inhibitor", the drug name can be "EGFR tyrosine kinase inhibitor".

System 1 of FIG. 2 acquires the relevance information 317 and 318 of FIG. 11 as described above based on the pharmaceutical information 305 of FIG. 11 whose drug name has been changed to "EGFR tyrosine kinase inhibitor". The information acquisition unit 21 and the goodness-of-fit determination unit 22 in FIG. 2 are processed when the drug name in the drug information 304 of FIG. 11 is gefitinib and when the drug name in the drug information 304 is ossimertinib mesylate. (S3 to S5 in FIG. 3) are carried out in parallel. Finally, by the steps described above, the modified pharmaceutical information 306 (including osimertinib mesylate) of FIG. 11 is displayed on the display device 3 of FIG.

In addition, the administration plan proposal system 1 includes the above-mentioned four drug names (lyxotinib, seritinib, gefitinib and osimertinib mesylate) as the drug name and "123456789" as the patient ID (that is, the above-mentioned drug information). Even when the input of the non-small cell lung cancer patient having the same hereditary type is received, the modified drug information 306 of FIG. The determination is "YES", and there is no change in the drug information 305 (FIG. 11). Finally, the ossimertinib mesylate is displayed by the above-mentioned step. That is, the administration plan proposal system 1 can select and propose one drug having the highest goodness of fit from a plurality of input drug names.

The above-exemplified ALK tyrosine kinase inhibitor and EGFR tyrosine kinase inhibitor are called molecular-targeted drugs used for the treatment of non-small cell lung cancer. Molecular-targeted drug is a term that refers to a drug that targets a gene product with a specific mutation. For example, as mentioned above, the ALK tyrosine kinase inhibitor is only effective in patients who carry the EML-ALK fusion gene (ie, have a chromosomal translocation) (relevance information 315 and FIG. 11). See 316). The EGFR tyrosine kinase inhibitor is only effective in patients who have at least a homozygous or heterozygous mutation at position 2573 of the EGFR gene (see relevance information 317 and 318 in FIG. 11). Currently, most of the above molecular-targeted drugs are anticancer agents. However, in the future, it is expected that molecular-targeted drugs will be developed as therapeutic agents for other diseases.

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

[Embodiment 1-1]
Another aspect of the present invention exemplifying the configuration in FIG. 13 is a system (administration plan proposal system 10) that proposes an administration plan suitable for a patient, and is a medicine that represents the medicine to be administered to the patient and the dose thereof. Pharmaceutical information acquisition unit (information acquisition unit 21) for acquiring information; relevance information acquisition unit (information acquisition unit 21) for acquiring relevance information indicating the relationship between the drug and the genotype; genotype information of the patient The genotype information acquisition unit (information acquisition unit 21) to be acquired; the conformity determination unit 22 that determines the degree of conformity of the pharmaceutical information based on the relevance information and the genotype information; and the conformity determination unit. Administration plan determination unit 25 that determines suitable drug information for the patient based on the suitability of the drug information; an information presentation unit (display) that presents the drug information determined by the administration plan determination unit to the user. It is equipped with a device 3).

That is, the administration plan proposal system 10 of FIG. 13 is different from the administration plan proposal system 1 of FIG. 2 in that the administration plan determination unit 25 is provided instead of the drug information change unit 23 (FIG. 2). Therefore, the administration plan proposal system 10 of FIG. 13 executes the process shown in FIG. 3, except for the process of the administration plan determination unit 25 (FIG. 13) described below.

The administration plan determination unit 25 in FIG. 13 determines suitable pharmaceutical information for the patient based on the goodness of fit of the pharmaceutical information determined by the goodness-of-fit determination unit 22 (FIG. 13).

In one embodiment, the administration plan determination unit 25 (FIG. 13) may have the same function as the drug information change unit 23 (FIG. 2). That is, the drug information whose goodness of fit determined by the goodness-of-fit determination unit 22 (FIG. 13) is less than the reference value (for example, “0”) is determined as the drug information unsuitable for the patient (“NO” in S5 of FIG. 3). ), The drug information obtained by modifying the drug information may be determined as the drug information suitable for the patient (see S6 in FIG. 3).

Further, in one embodiment, the administration planning unit 25 (FIG. 13) suitable for the patient the medical information whose goodness of fit determined by the goodness of fit determination unit 22 (FIG. 13) is equal to or higher than the reference value (for example, “0”). The drug information may be determined as the appropriate drug information (“YES” in S5 of FIG. 3), or the drug information having the highest goodness of fit may be determined as the drug information suitable for the patient (for example, [Embodiment 1] above]. (Refer to the series of examples of anti-cancer drug administration plans for patients with non-small cell lung cancer described in the item (Examples of drug names and relevance information in drug information and treatments using them)). ..

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

[Embodiment 2]
In the present embodiment, the goodness of fit will be described as an example in which the goodness of fit is determined based on the predisposition (risk of onset) to develop a disease that is not the target of treatment by administration of a drug. The system according to this embodiment refers to a set of allele combinations for multiple loci on the human genome as the genotype, but the present embodiment is not limited to this, and alleles for one or a few loci are loci. A set of combinations of types can be referred to as the above genotypes (eg, examples of "monogenic disease" described below). The presence or absence of the above predisposition is determined by the genotype. That is, the system of the present embodiment determines the goodness of fit with reference to information indicating a predisposition to develop a disease in connection with administration of a drug (pharmaceutical-related disease information). That is, in this embodiment, a contraindicated drug for a disease that the patient is genetically prone to develop but has not yet developed (a serious side effect that aggravates the condition when the drug is administered appears. Suppress the onset of continuous and high-dose administration of (drugs known to increase the possibility of diminishing the effect of the drug).

As shown in FIG. 5, the administration plan proposal system 1'provides a drug-related disease information DB 7 (FIG. 5) in place of the drug efficacy-related gene information DB 5 (FIG. 2) in the administration plan proposal system 1 of FIG. It is the same as the administration plan proposal system 1 (FIG. 2) except that. The administration plan proposal system 1'(FIG. 5) is a system that proposes a highly safe administration plan that avoids the onset of a disease that is not a treatment target by administration of a drug. The above-mentioned diseases may include symptoms of serious side effects due to idiosyncratic drug and related diseases (details of "serious side effects due to idiosyncratic drug" will be described later).

(Processing of administration plan proposal system 1')
An example of the process performed by the dosing regimen proposal system 1'in FIG. 5 in order to enhance the safety of the dosing regimen will be described below with reference to FIG. The input device 4 (FIG. 5) is provided by the user's physician according to conventional uniform factors (mainly the type of disease the patient is suffering from, the severity of the disease and the patient's age, weight and gender, etc.). The input medical information 303 (FIG. 7) is sent to the information acquisition unit 21 (FIG. 5) (step S1'in FIG. 6). The information acquisition unit 21 (FIG. 5) determines the name of the drug represented by the drug name included in the drug information 303 of FIG. 7, the name of the disease that may develop due to the administration of the drug, and the presence or absence of a predisposition to the disease. Relevance information 314 (FIG. 7) describing the range of the represented hereditary type is acquired from the drug-related disease information DB 7 (FIG. 5) (step S2'in FIG. 6). The information acquisition unit 21 (FIG. 5) provides the patient ID (see Pharmaceutical Information 303 in FIG. 7) and DNA variant group information regarding the genotype indicating the presence or absence of a predisposition to the disease (see relevance information 314 in FIG. 7). Based on this, genotype information corresponding to the patient ID and the name of the disease is acquired from the genomic information DB 6 (FIG. 5) (step S3'in FIG. 6). The information acquisition unit 21 (FIG. 5) determines the goodness of fit of the patient's genotype information acquired from the acquired pharmaceutical information 303 (FIG. 7), relevance information 314 (FIG. 7), and genomic information DB 6 (FIG. 5). Send to section 22 (FIG. 5).

When "NO" (for example, there is no relevant information because the drug has just been developed or there is no corresponding disease) in the S2'step of FIG. 6, the information acquisition unit 21 (for example, FIG. 5) sends the medical information 303 of FIG. 7 to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the above-mentioned drug information, and the administration plan proposal system 1'(FIG. 5) ends the process. Further, when “NO” (for example, the genotype information corresponding to a specific gene in the patient has not been determined yet) in the step S3 ′ of FIG. 6, the information acquisition unit 21 (FIG. 5) is shown in FIG. The medical information 303 is sent to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the above-mentioned drug information, and the administration plan proposal system 1'in FIG. 5 ends the process.

The goodness-of-fit determination unit 22 of FIG. 5 determines the goodness of fit of pharmaceutical information 303 (FIG. 7) based on the genotype information acquired from the relevance information 314 (FIG. 7) and the genomic information DB 6 (FIG. 5). (Step S4'in FIG. 6). The details of the S4'process of FIG. 6 will be described with reference to FIG. 7.

The relevance information 314 of FIG. 7 shows an active ingredient corresponding to a drug name (medicine name: olanzapine, a multi-receptor action antipsychotic drug MARTA), and a disease name known to be caused by administration of the active ingredient (medicine name: olanzapine, antipsychotic drug MARTA). Disease name: type 2 diabetes), the numerical range of the PRS percentile associated with the hereditary type that determines the predisposition to the disease (hereditary type (PRS percentile): 0-69, 70-84 and 85-100), of type 2 diabetes Includes effects on onset (risk of onset: ± 0, +1 and +2), and "alternative dosing regimen" (none, glycemic control, and drug change to X). Details of the above "PRS percentile" are described later in the following items (patient genotype information). Olanzapine is an atypical antipsychotic drug that is effective in treating schizophrenia, improving manic and depressive symptoms in bipolar disorder, and improving gastrointestinal symptoms (nausea and vomiting) associated with administration of antineoplastic agents. Is. The genomic information DB 6 of FIG. 5 stores a numerical value (PRS percentile) from 0 to 100, which represents a predisposition for a patient to develop a certain disease, as hereditary information for each disease name. The closer the value is to 100, the greater the predisposition to develop a certain disease. Therefore, when the goodness-of-fit determination unit 22 in FIG. 5 acquires the relevance information 314 (FIG. 7) and the genetic type information of the patient representing the predisposition to develop type 2 diabetes, the pharmaceutical information 303 (FIG. 7). The risk of developing type 2 diabetes due to administration of olanzapine in FIG. 7) is determined to be "+2". The goodness-of-fit determination unit 22 (FIG. 5) determines the goodness of fit as “-2”, which is obtained by multiplying the onset risk “+2”, which is a negative factor, by the value “-1”, which represents a negative factor. Next, the goodness-of-fit determination unit 22 (FIG. 5) of the pharmaceutical information 303 (FIG. 7), the goodness of fit “-2”, and the relevance information 314 (FIG. 7) corresponding to the goodness of fit (“-2”). "Drug change to X" as an alternative administration plan is sent to the drug information change department 23 (FIG. 5).

The pharmaceutical information changing unit 23 in FIG. 5 determines that the goodness of fit "-2", which is a negative value, is very low (S5'step in FIG. 6). The drug information changing unit 23 (FIG. 5) changes the drug name in the drug information 303 (FIG. 7) to “X” according to the alternative administration plan “drug change to X” (S6'step in FIG. 6). Since the change in the step S6'(FIG. 6) is a change in the drug (the judgment in the step S7' in FIG. 6 is "YES"), the drug information change unit 23 (FIG. 5) changed the drug name to X. The drug information is sent to the information acquisition unit 21 (FIG. 5), and the process returns to the S2'step of FIG. The administration plan proposal system 1'(FIG. 5) repeats the steps S2'to S7' in FIG. 6 until the judgment in the S7'step (FIG. 6) becomes "NO" (changes when it becomes "NO". The drug information is sent to the display device 3 (FIG. 5) (step S8'in FIG. 6). When the daily dose is changed in the step S6'(FIG. 6), the changed drug information is displayed in the display device 3 (FIG. 6). Finally, the display device 3 (FIG. 5) displays the changed drug information, and the administration plan proposal system 1'in FIG. 5 ends the process.

Unlike S4'in FIG. 6 illustrated above, the goodness-of-fit determination unit 22 (FIG. 5) sets the value of the risk of developing type 2 diabetes by administration of olanzapine to "60" when the genotype information is "60". ± 0 "is determined. The goodness-of-fit determination unit 22 (FIG. 5) determines the goodness of fit as “± 0”, which is obtained by multiplying the negative factor “onset risk” “± 0” by the value “-1” representing the negative factor, and changes the goodness of fit. Send to section 23 (FIG. 5). The pharmaceutical information changing unit 23 (FIG. 5) determines that the goodness of fit “± 0” is not low, and sends the pharmaceutical information 303 (FIG. 7) to the display device 3 (FIG. 5). The display device 3 (FIG. 5) displays the drug information 303 (FIG. 7), and the administration plan proposal system 1'of FIG. 5 ends the process.

As described above, the administration plan proposal system 1'in FIG. 5 uses the drug information (type of drug or its dose) specified in the prescription as the genotype of the patient specified in the prescription (secondary to the drug). Change when determined to be incompatible with a genotype that represents a combination of alleles associated with a predisposition to the risk of developing the disease. Secondary diseases caused by the drug include serious side effects due to idiosyncratic constitution (details will be described later). Therefore, the dosing regimen proposal system 1'(FIG. 5) enables the presentation of low-risk, high-safety prescriptions according to the genotype of the patient.

The details of the genotype information and the relevance information according to the present embodiment for the administration plan proposal system 1'in FIG. 5 to present an appropriate administration plan for the patient will be described below.

(Patient genotype information)
In the present embodiment, the genotype information for the patient is expressed as a value corresponding to each disease (PRS (Polygenes Risk Score) percentile). The PRS percentile for type 2 diabetes indicates what percentage of the patient's PRS corresponds to the lowest percentage of the normal distribution of PRS for the risk of developing type 2 diabetes (see Figure 1) in the human population. Represents. That is, the PRS percentile is 0 to 100, and the larger the PRS percentile, the higher the risk of onset. The PRS for type 2 diabetes is the sum of the combinations of "aller types" of all DNA variants that affect the onset of type 2 diabetes. The "allergen types" of all DNA variants that affect the development of a disease are identified, for example, by a genome-wide association study (GWAS), which is a standard method for identifying factors that govern susceptibility to complex diseases. Has been done. For an overview of the PRS percentile and PRS for any disease, see ReFlections Vol 45, September 2018 (https://rgare.com/docs/default-source/newsletters-articles/reflections-vol-45-sept-2018.pdf?sfvrsn) = 66979288_0), etc.

It is known that in most diseases, the presence of a large number (tens to millions) of DNA variants (for example, SNPs) on the genome is involved in the onset of each disease. Although individual DNA variants have little effect on the incidence of disease, the combination of these DNA variants significantly increases the incidence of disease. Therefore, among the DNA variants included in the above combinations, some DNA variants present in the patient's genome are, for example, predisposed (and to some extent) to develop type 2 diabetes in patients receiving olanzapine. ) Can be a material for judging. In this embodiment, the genotype information represents, by the PRS percentile, how many DNA variants a patient has as part of a combination of DNA variants that contributes to the predisposition to develop a particular disease.

Most preferably, the genotype information contains the same number of PRS percentiles corresponding to each disease as the number of all known diseases. The "combination of these DNA variants" described above varies from disease to disease. Therefore, including the above-mentioned genotype information necessary for creating the PRS percentile corresponding to all diseases as the genotype information for a certain patient maximizes the convenience of the administration plan proposal system 1'. It is preferable that the number of PRS percentiles contained in the genotype information is close to the number of all known diseases, because the convenience of the administration plan proposal system 1'is improved.

The two methods described in the item (Patient genotype information) of [Embodiment 1] for the allele type (“allele type”) including the junction type of a known DNA variant for the patient's genome (the patient's genotype information). It can be determined according to "Method 1" and "Method 2"). This method is an experimental method for performing genome-wide polymorphic analysis using "Method 1" using "full-length character string" information determined using the large-scale parallel DNA sequence determination method and DNA microarray technology. It is "method 2" using the method. DNA variants (eg, SNV, CNV) that are infrequent in the population to generate genotypic information containing the PRS percentile corresponding to the disease, as well as or close to the number of all diseases, or Information on DNA variants that are not suitable for automatic analysis (eg, CNP, STRP, or other special DNA variants) is likely to be needed, so the former "method 1" using "full-length string" information is preferred. .. The details of the "method 1" using the "full-length character string" information are also described later in [Embodiment 4].

For the above reason, it is preferable that the genome information DB 6 of FIG. 5 further stores "full-length character string" information in addition to the patient's "genotype" information. That is, when a DNA variant involved in a disease is newly identified and it is necessary to determine the patient's "allergenotype" for the DNA variant and score it as part of the PRS, also in [Embodiment 1]. As explained, "Method 1" by information analysis using the above-mentioned "full-length character string" is time-consuming and labor-intensive due to experimental techniques such as "Method 2" using DNA microarray technology and individual methods by PCR. There is no burden and some genotypic information about the disease can be easily updated.

(Relevance information 314)
In this embodiment, the genotype is a genotype relating to a combination of DNA variants that contributes to a predisposition to develop a particular disease. Relevance information 314 (FIG. 7) represents the relevance of a drug to a disease not treated (particularly the effect of administration of the drug on the onset of the disease).

Relevance information 314 of FIG. 7 shows type 2 diabetes as a disease whose incidence can be increased by administration of olanzapine. As mentioned above, it is known that the presence of a large number of DNA variants (genetic predisposition) is involved in the increase in the incidence of type 2 diabetes. Relevance information 314 (FIG. 7) shows a numerical range representing the genotype as a criterion for determining the degree of genetic predisposition. Each numerical range is associated with the degree of risk of onset (“± 0” to “+2”).

Each numerical range can be set arbitrarily, but the lower limit of the numerical range corresponding to "+1" (dose reduction or necessary response) is 70 or more (eg 70, 75, 80, 85, 90 and). 95), and the lower limit of the numerical range corresponding to "+2" (drug change) can be 85 or greater (eg, 85, 90, 95 and 99). The goodness-of-fit determination unit 22 of FIG. 5 determines that the goodness of fit of the pharmaceutical information 303 (FIG. 7) is low (in the genomic information, a part of the combination of DNA variants contributing to the predisposition to type 2 diabetes is present above the threshold value). As a reference, at least one of the above lower limit values is used. The PRS percentile with a median of 50 represents the average risk of onset in the population, and the numerical range corresponding to "± 0" includes 50.

The relevance information 314 of FIG. 7 shows three numerical ranges, but may show only two numerical ranges (eg 0-84 and 85-100). At this time, for example, 0 to 84 correspond to "± 0", and 85 to 100 correspond to "+2" or "+1". That is, the relevance information 314 (FIG. 7) may allow the dosing regimen proposal system 1'of FIG. 5 to select only drug changes or dose changes. Further, for example, the relevance information 314 (FIG. 7) may correspond the numerical range 70 to 84 with the alternative drug X rather than without the alternative drug. In other words, the relevance information 314 (Fig. 7) assigns "very low goodness of fit" to drugs (contraindicated drugs for certain diseases) that increase the risk of developing the disease as much as possible according to the genotype, and "the drug of the drug". Only "change" may be selected by the dosing regimen proposal system 1'in FIG.

The dosing regimen proposal system 1'of FIG. 5 using relevance information 314 (FIG. 7) is of olanzapine (multireceptor-acting antipsychotic: MARTA) regardless of whether the patient has type 2 diabetes. It may be suggested to reduce the dose, take the necessary response, or change the type of the drug. In addition to olanzapine, timiperone, a treatment for schizophrenia, can promote the onset or aggravation of Parkinson's disease, and carvedilol, a treatment for chronic heart failure and arrhythmic, can promote the onset or aggravation of bronchial asthma. Are known. It is well known that one therapeutic agent (particularly a small molecule drug) acts on more than one molecular target or affects the bioactivity of multiple molecules that are not molecular targets. In particular, the dosing regimen proposal system 1'(FIG. 5) using relevance information 314 (FIG. 7) is a contraindicated drug (here, olanzapine) for the above patients with a genotype showing a high risk of developing type 2 diabetes. ) It is preferable to make a proposal to change the administration.

According to the Pharmaceuticals and Medical Devices Agency, the definition of "contraindicated drug" is as follows. That is, the "contraindication" in the "package insert" information of the ethical drug describes the patient who should not use the drug. Considering the following points, it is decided not to use a certain drug because it is highly likely that the condition will worsen, side effects will be more likely to occur, and the effect of the drug will be weakened. :
・ Current illness (current illness)
・ Another illness (complication) caused by one illness
・ Illnesses (history)
・ Illness of family members (family history)
・ Other medicines currently used (concomitant medicines)
・ The constitution of those who use medicines (from the website of "Pharmaceuticals and Medical Devices Agency").

That is, "contraindication" is one of the items described in the "package insert" of a drug, and indicates a patient who should not take a certain drug, its condition, and a drug that should not be used in combination. If the drug is not followed, there is a high possibility that the condition will be aggravated, serious side effects will occur, and the effect of the drug will be weakened. The condition in which it is determined that medication should not be taken may indicate the patient's current disease name, complications, medical history, family history, constitution, and the like.

Further, the above-mentioned "constitution" includes a genetic constitution and corresponds to a secondary disease having an extremely high risk of onset due to administration of a drug in this embodiment and other embodiments. The genetic constitution may also include symptoms and related diseases as "serious side effects due to the idiosyncratic constitution" described later. Therefore, in the present embodiment, various disease names specified as "contraindicated" in the "package insert" of the current various drugs, as well as symptoms and related diseases of "serious side effects due to idiosyncratic drug" are used. It can be registered as disease information for the drug in the related disease information DB 7 (FIG. 5).

In addition, therapeutic drugs and other drugs (anesthetics, etc.) used in medical treatment may show an excessive reaction in some people. There are various causes for side effects of drugs. Type A side effects are relatively common and dose-dependent. This is pharmacologically predictable and usually mild. Type B side effects, on the other hand, are idiosyncratic reactions and are not merely drug-related. This side effect is rare but often severe. Genetic diversity is important for both type A and type B side effects.

As described above, the symptoms of so-called "serious side effects due to idiosyncratic constitution" such as type B side effects and related diseases can be dealt with by the criteria for determining the risk of developing a secondary disease in the present embodiment.

For example, treatment with carbamazepine, an antiepileptic drug, or allopurinol, a therapeutic drug for hyperuric acid disease / gout, rarely induces side effects of serious skin disorders such as toxic epidermal necrolysis (Riel syndrome). As one of the important genetic factors for the side effect, a specific genetic type (for example, "HLA-B * 1502") among the genes encoding human leukocyte antigen (hereinafter referred to as "HLA") , "HLA-A * 3101", "HLA-B * 5801")) are at high risk of developing the above diseases. Therefore, information related to the risk of developing toxic epidermal necrolysis (Riel syndrome) to drugs such as carbamazepine and allopurinol can be registered in the drug-related disease information DB7 (FIG. 5) and dealt with.

In addition, as symptoms of "serious side effects due to idiosyncratic constitution" caused by drugs and related diseases, rhizome myolysis (destruction of muscle tissue) due to statin drugs such as atrubastatin (drug for treating lipid disorders), suxamethonium chloride Respiratory palsy due to hydrate (quick-acting muscle relaxant), myelotoxicity due to mercaptopurine hydrate (anti-malignant tumor drug) and azathiopurine (immunosuppressive drug), induction of liver damage due to isoniazide (anti-tuberculosis drug), and Polymorphic ventricular tachycardia caused by various drugs such as clarislomycin (antibacterial drug) may be mentioned and may be life-threatening. In addition to the above-mentioned examples, the symptoms and related diseases of "serious side effects due to idiosyncratic drug" corresponding to the above-mentioned type B due to various drugs are also affected by the genetic type of the patient due to genetic diversity, and therefore develop. Risk-related information can be registered in the drug-related disease information DB 7 (FIG. 5) and dealt with.

In addition, the scope of indication of "onset risk" includes monogenic diseases to multigene diseases (multifactorial diseases, complex diseases). Human genetic traits, including various diseases, often depend on the expression of many genes and environmental factors. However, for certain diseases and some traits, a particular genotype in a single locus acts as the primary determinant, and this genotype expresses the trait, or develops the disease, in normal environmental conditions. Necessary and sufficient for.

"Monogenic diseases", in which the involvement of genes in the disease is basically determined by one locus, are rare, and common hereditary diseases are dependent on multiple loci and are multigene. It is called a sexual disorder (complex disorder, multifactorial disorder). The scope of application of this embodiment mainly assumes "multigene disease", but can also deal with "monogenic disease".

For example, young adults with a high risk of developing a variant of the causative gene of Huntington's disease, which is a late-onset monogenic disease, and mutants of the causative genes BRCA1 and BRCA2 of breast cancer are retained in the future. Even for asymptomatic individuals who have a high risk of developing symptoms, the onset risk-related information in the present embodiment can be registered in the drug-related disease information DB 7 (FIG. 5) and dealt with.

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

[Embodiment 3]
In this embodiment, a system for executing the processes described in [Embodiment 1] and [Embodiment 2] in a complex manner will be described (see FIG. 1). That is, in the present embodiment, as shown in FIG. 1, the pharmacodynamic factors of (1) Pharmacodynamic B ([Embodiment 1]) and (2) Pharmacodynamic B are used as criteria for changing the administration plan. A system based on the combination of pharmacodynamic factors ([Embodiment 1]), (3) risk of developing a secondary disease due to drug B ([Embodiment 2]), and the above (1) to (3) as the above-mentioned criteria. To explain. 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 (medicine information acquisition unit, relevance information acquisition unit, and genotype information acquisition unit) 21, a goodness-of-fit determination unit 22, and a drug information change unit 23 (FIG. 8). reference). Further, the control unit 2 (FIG. 8) is connected to the input device 4, the drug efficacy-related gene information DB 5, the genome information DB 6, and the drug-related disease information DB 7 (see FIG. 8). That is, the system 1 ″ of the present embodiment of FIG. 8 is: (i) information indicating the degree to which the genotype of the gene affects the efficacy of the drug ([Embodiment 1]) and (ii) inheritance of the predisposition. The degree of suitability is determined with reference to both onset risk information ([Embodiment 2]) indicating the extent to which the type affects the onset risk of the disease (secondary disease) by administration of the drug.

The dosing regimen proposal system 1'' (FIG. 8) performs the S1 to S7 (including S9) steps (see FIG. 3) and does not perform the S8 step (see FIG. 3), but the modified drug information or The steps S2'to S8'(including S9') (see FIG. 6) for the unchanged drug information are performed. Therefore, the process of shifting from S7 of FIG. 3 to the S2'process of FIG. 6 and the details of executing the S2'process (FIG. 6) will be described.

For example, in the case of phenytoin (pharmaceutical information 301 in FIG. 4) shown in [Embodiment 1], heterozygotes as genotype information regarding SNP (rs1057910) in CYP2C9 in the relevance information 311 (FIG. 4) as described above. When the type "* 1 / * 3" is acquired, in the S7 step (FIG. 3), the drug information changing unit 23 of the administration plan proposal system 1'' (FIG. 8) makes a judgment "NO". , The changed drug information 302 (FIG. 4) in which the "daily dose (maintenance dose)" is changed to 225 mg is sent to the information acquisition unit 21 (FIG. 8) (shift to the S2'step of FIG. 6). In the step S2'(FIG. 6), when the change included in the changed drug information is the daily dose, the information acquisition unit 21 (FIG. 8) receives the drug-related disease from the drug-related disease information DB 7 (FIG. 8). Get information. In the subsequent steps S3'to S9'(FIG. 6), "medicine information" was replaced with "changed drug information", and the drug information changing unit 23 (FIG. 8) changed the drug name (S7' in FIG. 6). As described above, the present embodiment is described in the above-described embodiment, except for two points in which the drug information (corresponding to the determination “YES” in the process) is sent to the information acquisition unit 21 (FIG. 8) and the process returns to the process S2 step of FIG. It conforms to the system that executes the processes described in 1] and [Embodiment 2].

As described above, the administration plan proposal system 1'' in FIG. 8 uses the drug information (type of drug or its dose) specified in the prescription as the genotype of the patient specified in the prescription (effectiveness of the drug). If it is determined that the genotype of a specific gene that affects sex and the genotype of a specific gene that indicates the existence of a risk of developing a secondary disease due to the drug are not compatible, the change is made. Therefore, the dosing regimen proposal system 1 ″ (FIG. 8) enables the presentation of a comprehensive prescription (excellent in efficacy, low risk and safe) according to the patient's genotype.

[Embodiment 4]
In this embodiment, the "allergen" of any DNA variant in the entire nucleotide sequence of the genome obtained from an individual ("full length string") rather than the human genome ("reference string") stored in a known DB. A method for determining a type (genotype of a patient) (“method 1” described in each item (genotype information of a patient) of [Embodiment 1] and [Embodiment 2]) will be described. The DNA variants are variations of any nucleodo, including SNPs, SNVs, indels, CNPs, CNVs, microsatellite polymorphisms (“STRP”). In this method, two character strings representing the two nucleotide sequences sandwiching the target nucleotide are extracted from a known character string (“reference character string”) representing the reference human genome and used.

In the above method, depending on the type of target nucleotide, (1) one continuous character string representing a sequence in which two nucleotide sequences derived from the target nucleotide and the "reference character string" sandwiching the target nucleotide are combined, or (2) the target. Two strings are used that indicate each of the two nucleotide sequences derived from the "reference string" that sandwiches the nucleotides. (1) is used as a convenient method for determining the "allelic type" (patient's "genotype") when the target nucleotide is known in the human genome and is SNP, SNV or indel. (2) is applicable for determining the "allele type" of any DNA variant (including the SNPs, SNVs or indels described above), but in particular there are variations in the length of the target nucleotide and numerous options. This is an effective method when the details of the target nucleotide are unknown. The above method using the character strings of (1) and (2) will be described below with reference to FIGS. 9 and 10.

(A simple way to determine the "allele type" of an SNP, SNV or indel)
The above-mentioned method using the character string (1) is, in particular, a simple method for determining the type of SNP, SNV, or indel allele. As shown in FIG. 9, the character string (1) is a character string 902 representing a target nucleotide (SNP, SNV or indel), a two character string 901 representing two nucleotide sequences sandwiching the character string 902, and a character string 901. One contiguous string containing 903. The strings 901 and 903 are determined as part of a string representing the reference human genome (“reference string”) (eg, available from an ensemble (URL: http://ensembl.org)) (ensemble, URL: http://ensembl.org). Step S11 in FIG. 10). The character string 902 (character (string) representing the target nucleotide) is stored in a known DB as a DNA variant known at the time of carrying out the method according to the present embodiment (hereinafter, simply referred to as "known"). ing. That is, the above-mentioned "DNA variant" may also include a DNA variant found after the filing of the present application. For example, information about all known SNPs can be obtained from the dbSNP database (https://www.ncbi.nlm.nih.gov/snp/). Information on the position where the character string 902 (character (string) representing the target nucleotide) exists in the character string representing the reference human genome (“reference character string”) is also stored in the DB (for example, the above dbSNP database). ing. In the character string of (1), it is preferable that the lengths of the character string 901 and the character string 903 are set to be the same, and the analysis part (character string 902) is arranged in the center.

Therefore, by the above method, 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 with the known “allele type” of SNP, SNV or indel. It is determined depending on whether or not it is present (step S12 in FIG. 10). The position where the character string of (1) can be included in the character string (“full-length character string”) representing the nucleotide sequence of the entire genome of an individual is the reference human genome (“reference character string”) stored in the above DB. It can be estimated from the information of the position of. Therefore, for example, when one character string that completely matches the character string of (1) is found (step S13 in FIG. 10), from the character string representing the nucleotide sequence of the entire genome of an individual (“full-length character string”), By extracting a character string that can contain the character string of (1) and comparing the character string with the character string of (1), a known SNP in the nucleotide sequence (“full-length character string”) of the entire genome of an individual. , SNV or Indel "type of allele" can be determined (step S14 in FIG. 10).

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. be. The smaller the number of characters in the character string of (1), the higher the probability of finding two or more character strings that exactly match the character string of (1) in the character string representing the nucleotide sequence of the entire genome of an individual (“full-length character string”). Will be higher. When two or more character strings that exactly match the character string of (1) are found (“NO” in step S13 in FIG. 10), the lengths of the two character strings (character string 901 and character string 903 in FIG. 9). Is evenly extended by one or more characters (for example, 1, 3, 5, 10, 20, 25, 50 or 100 characters) (step S16 in FIG. 10) to reduce the above probability. However, the total of the two character strings is, for example, 10,000 characters or less. When one of the two extremely long strings (string 901 and string 903 in FIG. 9) contains a string representing a DNA variant other than the target nucleotide (string 902 in FIG. 9), the result "( This is because "the character string of 1) is not included in the character string representing the nucleotide sequence of the entire genome of an individual" always appears.

For example, there are up to four types of known SNP alleles at specific positions on the genome, similar to nucleotide types. For example, when the nucleotides of a normal allele are represented by A, the allele containing the nucleotides represented by T, G and C is a mutant allele. Therefore, by designating the character string 902 of FIG. 9 as A, T, G, and C and trying the above process four times, it is possible to determine the type of allele of a known SNP at the specific position (). Step S14 in FIG. 10). However, in practice, known SNPs can be easily determined in almost two trials, as two (rarely three) nucleotides are common in the population.

In FIG. 9, the character strings 901 to 903 (normal character strings) including the normal character strings and the character strings 901 to 903 (variable character strings) including the mutant character strings are homozygous or homozygous with respect to the SNP of the individual's genome. It can be used to determine if it is heterojunction. For example, both strings (“full-length strings”) that represent the nucleotide sequences of an individual's entire genome (usually the genome exists as a conjugation that holds two sets from the mother and father) have normal strings. When they match and the mutant strings do not match, the individual's genome is a normal allele (normal: N / N). Also, for example, when a normal character string matches one of the character strings representing the nucleotide sequence of the entire genome of an individual and a mutant character string matches the other, the individual's genome has a mutant allele in one genome. (Heterojunction type: N / M). Also, for example, when the normal string does not match both the strings representing the nucleotide sequences of the entire genome of the individual and the mutant strings match, the individual's genome has the mutant allele in both genomes. (Homozygous type: M / M).

The process of determining the genetic type in the individual is CYP2C9 based on the information of the pharmaceutical information 301 (FIG. 4) regarding the phenytoin (antiepileptic drug) described in [Embodiment 1] and the relevance information 311 (FIG. 4). A known SNP (rs1057910) existing in the coding region of (drug metabolizing enzyme gene) will be specifically described as an example. With respect to the above character string 902, the base type of the nucleotide of the wild type (normal type) allele in SNP (rs1057910) is "adenine (A)", and it is known that the metabolism rate of phenitoin is lowered. The base type of nucleotides in metabolic alleles is "cytosine (C)". Further, in the case of a known SNP, the corresponding character strings 901 and 903 can be easily obtained by the above method. Therefore, the character strings 901 to 903 containing the wild type character "A" ("wild type character string") and the character strings 901 to 903 containing the low metabolism type character "C" ("low metabolism type character string") are extracted. Then, by trying the above steps twice, the genetic type of the individual can be easily determined.

Specifically, when the "wild-type character string" matches the character string representing the nucleotide sequence of the entire genome of an individual ("full-length character string") and the "low-metaphoric character string" does not match, the relevant character string is concerned. The individual's genome has wild-type alleles in both genomes (wild-type: "A / A"). Also, for example, when both the "wild-type character string" and the "low-metabolizing character string" are matched with respect to the "full-length character string", the genome of the individual has the low-metabolizing allele in one of the genomes ( Heterozygous type: "A / C"). Also, for example, when the "wild-type string" does not match the "full-length string" and the "low-metabolizing string" matches, the individual's genome has the low-metabolizing allele in both genomes. Has (homogeneous low metabolism: "C / C").

Relevance information 311 (“A / A”, “A / C” or “C / C”) depending on the type of combination of nucleotide changes in SNP (rs1057910) of CYP2C9 in the individual determined by the above process. As shown in Figure 4), different symbolized genotypes (“* 1 / * 1”, “* 1 / * 3” or “* 3 / * 3”), and different metabolic rates (drug effects) (“±”). 0 ”,“ -1 ”or“ -2 ”) can be determined.

Information representing DNA variants present in an individual's genome, along with the determined genotype, is stored in a DB, recording medium or storage device (not shown), as well as genomic information DB 6 (FIGS. 2, 5 and 8). ) (Step S15).

(General method applicable to determine "allergen type" of any DNA variant)
Although the method according to the string of (2) above is applicable for determining the type of allele (“allele type”) including the mating type of any DNA variant (including the SNP, SNV or indel described above). In particular, it is an effective method when the length of the target nucleotide is changed, and there are many options, or the details of the target nucleotide are unknown. Changes in the length of the target nucleotide, as well as a large number of options, occur when simple repeat sequences with different repeat counts are used as the target nucleotide, for example, microsatellite polymorphisms (“STRP”). When the details are unknown, for example, in addition to the polymorphism analysis of the deletion / insertion of the Alu sequence present in the ACE gene shown in [Embodiment 1], a known chromosomal translocation can be assumed. .. That is, the character string (2) is particularly effective when it is necessary to determine the number of target nucleotides and also the full-length nucleotide sequence of the target nucleotides.

The total length of the target nucleotide can reach tens of thousands of nucleotides, and the length of the target nucleotide can vary greatly from individual to individual. Therefore, the full-length nucleotide sequence of a particular target nucleotide needs to be determined individually based on the genome of the individual. However, the loci on the genome where the target nucleotides (CNP, CNV, STRP) are present have already been identified in the human reference genome, as are SNPs, SNVs or indels. The location of the target nucleotide in the locus is also relatively determined. That is, the character string (2) is known in the character string representing the human reference genome (“reference character string”) (step S11 in FIG. 10).

The character string of (2) can completely match the character string representing the nucleotide sequences adjacent to both sides of the target nucleotide representing the known DNA valinant existing in the genome of an individual. Therefore, whether or not the character string (two pairs: character strings 901 and 903 in FIG. 9) of (2) exists in the character string (“full-length character string”) representing the nucleotide sequence of the entire genome of an individual. By determining (step S13 in FIG. 10), it is possible to determine whether or not the target nucleotide is present on the genome of an individual (step S14 in FIG. 10). The length of the character string (two sets: character strings 901 and 903 in FIG. 9) of (2) can be set in the same manner as the lengths of the character strings 901 and 903 in the character string of (1).

After confirming the existence of the character string (2 pairs: 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 an individual, two A string existing between a set of strings (string 902 in FIG. 9, representing the full-length nucleotide sequence of the target nucleotide) is extracted.

For example, when the extracted string represents a simple repetitive sequence (length of 1 to 4 base pairs) of a very short sequence (length of 1 to 4 base pairs) such as a microsatellite polymorph (“STRP”), the repetition contained in the string. The number of times (and the total number of nucleotides) is further determined. The simple repetitive sequence may have different number of repetitions in the genome of an individual, for example, with a unit of several nucleotides to several tens of nucleotides. Detect the "allele type" corresponding to the number of times. For example, when two types of sequences having different lengths are detected, it is determined to be "heterozygous type", and when only one type of sequence is detected, it is determined to be "homozygous type".

A 3-nucleotide (CAG) microsatellite polymorphism (“STRP”) in which the causative gene (HTT) of Huntington's disease, which is a late-onset monogenic disease described in [Embodiment 2], is present in the coding sequence. As an example, the process of determining the genotype in the asymptomatic young adult will be specifically described. In patients with Huntington's disease, mutant alleles produce abnormal proteins that are detrimental to cells, especially nerve cells. The disappearance of neurons is slow, but eventually leads to a destructive neurodegenerative state. The onset of symptoms usually occurs from middle age to menopause. Huntington's disease results from the production of long polyglutamine chains by the unstable elongation of CAG repeats present on the coding sequence of its causative gene HTT. Normal glutamine repeats are 6-35, whereas diseased patients (or young adult asymptomatic individuals at extremely high risk of developing the disease) are 36-121.

In the case of the known microsatellite polymorphism (“STRP”) as described above, the corresponding character strings 901 and 903 can be easily obtained by the above method. The presence of the character string (2 pairs: the 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 person of the young adult After confirmation, the sequence of the character string (902 in FIG. 9: representing the full-length nucleotide sequence of the target nucleotide) existing between the two character strings and the length thereof are extracted and determined. For example, when the number of CAG repeats 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. (Since both alleles have the number of repeats corresponding to disease-type alleles, the risk of developing the disease is extremely high "+2".) In addition, the number of CAG repeats is one type of "5 (number of nucleotides: 15)". If it is, it is a homozygous type. (Since both allele types have the same number of repeats as normal alleles, the risk of developing the disease is low "± 0".)

The above method using the character string (2) described above can also be applied to the presence or absence of known chromosomal translocations (generation of DNA variants). However, the target nucleotide at this time is the character string (2) ( character strings 901 and 903 in FIG. 9). The genomic location of the translocation point in a known chromosomal translocation is all known as the linking site between fragment A1 present on chromosome A and fragment B2 present on chromosome B, and the linking site between fragment A2 and fragment B1. Has been done. When no translocation has occurred, the fragments A1 and A2 are arranged in the order of 1 → 2 on the chromosome A, and the fragments B1 and B2 are arranged in the order of 1 → 2 on the chromosome B. Therefore, the sequences of the fragments A1, A2, B1 and B2 are also known.

From the above, if, for example, the fragment A1 is represented by the character string 901 and the fragment B2 is represented by the character string 903 around the translocation point, the character strings 901 and 903 are continuous or discontinuous on the genome of the individual. The presence may indicate the presence or absence of translocation. Discontinuity represents the absence of translocation, and continuity represents the possibility of translocation. To reliably distinguish the possibility of existence as existence or non-existence, for example, the fragment A1 is represented by the character string 901 and the fragment A2 is represented by the character string 903, centering on the connecting portion of the fragment A1 and the fragment A2. Just do it. When the fragments A1 and A2 are present consecutively, the above possibility (existence of translocation) is completely denied, and when they are present discontinuously, the existence of translocation is confirmed.

Information representing a DNA variant present in an individual's genome, along with the determined "allelic type" (genotype of the patient), is stored in a DB, recording medium or storage device (not shown), as well as genomic information DB6. It is stored in (FIG. 2, FIG. 5 and FIG. 8) (step S15).

[Example of implementation by software]
The administration plan proposal system 1-1'' (FIG. 2, FIG. 5 and FIG. 8) has a control block (particularly, an information acquisition unit (medicine information acquisition unit, relevance information acquisition unit, and genetic information acquisition unit) 21), and a degree of conformity. The determination unit 22 and the medical information change unit 23) may be realized by a logic circuit (hardware) formed in an integrated circuit (IC chip) or the like, or may be realized by software.

In the latter case, the administration plan proposal systems 1 to 1 ″ (FIGS. 2, 5 and 8) include a computer that executes the instructions of the program which is the software that realizes each function. The computer includes, for example, one or more processors and a computer-readable recording medium that stores the program. Then, in the computer, the processor reads the program from the recording medium and executes the program, thereby achieving the object of the present invention. As the processor, for example, a CPU can be used. As the recording medium, a “non-temporary tangible medium”, for example, a ROM (Read Only Memory) or the like, a tape, a disk, a card, a semiconductor memory, a programmable logic circuit, or the like can be used. Further, a RAM (RandomAccessMemory) for expanding the above program may be further provided. Further, the program may be supplied to the computer via an arbitrary transmission medium (communication network, broadcast wave, etc.) capable of transmitting the program. It should be noted that one aspect of the present invention can also be realized in the form of a data signal embedded in a carrier wave, in which the above program is embodied by electronic transmission.

〔summary〕
The inventions described so far can be summarized as follows.

[1] A system that proposes a suitable administration plan for patients.
The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
Genotype information acquisition department that acquires the genotype information of the above patients;
Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
A system including a drug information changing unit that changes the drug information when the goodness of fit is low; and an information presentation unit that presents the changed drug information that the drug information changing unit has changed to the user.

[2] The goodness-of-fit determination unit determines the goodness of fit by referring to the pharmacokinetics of the drug or the drug efficacy-related gene information regarding the gene encoding the protein involved in pharmacodynamics.
The genotype is a genotype related to the gene, and the relevance information includes the drug efficacy-related gene information.
The system according to [1], wherein the change is an increase or decrease in the dose or a change in the drug.

[3] The goodness-of-fit determination unit determines the goodness of fit with reference to drug-related disease information indicating a disease that develops or becomes serious due to administration of the drug.
The genotype is a genotype relating to a combination of alleles associated with the predisposition to the disease, and the relevance information includes the drug-related disease information.
The system according to [1] or [2], wherein the modification is a modification of the pharmaceutical or a reduction of the dosage.

[4] When the drug is a contraindicated drug for the disease, the fitness determination unit determines that the fitness for the genotype including the combination of alleles associated with the predisposition to the disease is very low.
When the fitness determination unit determines that the fitness for the genotype, including combinations of alleles associated with the predisposition to the disease, is very low, the fitness information change unit is a contraindicated drug for the disease. The system according to [3], which adds a drug change to the above drug information.

[5] The system according to [3], wherein the above-mentioned disease includes a disease related to a serious side effect due to an idiosyncratic drug, or a symptom of a serious side effect due to an idiosyncratic drug.

[6] The goodness-of-fit determination unit includes information on pharmaceutical efficacy-related genes representing genes encoding the pharmacokinetics of the drug or proteins involved in pharmacodynamics, and diseases that develop or become serious due to administration of the drug. The above-mentioned goodness of fit is determined by referring to the drug-related disease information indicating
The genotype is a genotype relating to a gene encoding a pharmacokinetics or a protein involved in the pharmacokinetics of the drug and a genotype relating to a combination of alleles associated with the predisposition to the disease, and the relevance information is provided. It contains the above-mentioned drug-related genetic 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 dose or a change in the drug.

[7] The genetic type information is determined based on the information representing the DNA variant contained in the information representing all the nucleotide sequences constituting the genome of the patient acquired from the genome information DB using the patient ID. The system according to any one of [1] to [6].

[8] When the genetic type information does not record the genetic type existing in the locus associated with the drug represented by the pharmaceutical information in the relevance represented by the relevant information, the genetic type information is recorded. The system according to [7], which is updated based on the information representing the DNA variant present in the locus contained in the information representing all the nucleotide sequences constituting the genome of the patient.

[9] Information representing a single nucleotide polymorphism among the above DNA variants is determined using the genomic fragment of the patient or based on the information representing the entire nucleotide sequence, and the information representing the single nucleotide polymorphism determined. Record,
The system according to [7] or [8], wherein the information representing the unrecorded DNA variant is determined based on the textual information representing the entire nucleotide sequence.

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

[11] The system according to any one of [1] to [10], wherein the above-mentioned relevance information is generated by artificial intelligence.

[12] When the above-mentioned change includes the change of the above-mentioned medicine and there are a plurality of candidate medicines as candidates for the change, the information presenting unit selects the medicine having the highest goodness of fit among the plurality of candidate medicines. The system according to any one of [1] to [11] shown to the user.

[13] When there are a plurality of candidate drug information that the information presenting unit is suitable for presenting to the user, the information presenting unit is the drug having the highest goodness of fit among the plurality of suitable candidate drug information. The system according to any one of [1] to [12], which presents information to the user.

[14] When the drug represented in the drug information is a molecular target drug that targets a gene product having a specific mutation, the fitness determination unit corresponds to the mutation in the genome of the patient. The system according to any one of [1] to [13], wherein the fitness is determined based on the presence or absence of a DNA variant.

[15] Any of [1] to [14] further comprising a warning unit for warning that the medical information is inappropriate when the goodness of fit determined by the goodness-of-fit determination unit is below the standard. The system according to item 1.

[16] A method for proposing a suitable administration plan for a patient.
A drug information acquisition step in which a computer acquires drug information representing the drug to be administered to the patient and the dose thereof;
Relevance information acquisition step in which the computer acquires relevance information representing the relevance between the drug and the genotype;
The genotype information acquisition step in which the computer acquires the genotype information of the patient;
A goodness-of-fit determination step in which the computer determines the goodness of fit of the pharmaceutical information based on the relevance information and the genotype information;
When the computer has a low goodness of fit, a drug information change step of changing the drug information; and an information presentation process in which the computer presents the changed drug information changed in the drug information change step to the user. Including,
In the above method, when the genotype information does not record the genotype present in the locus associated with the drug represented by the drug information in the relevance represented by the relevance information, the computer described above. Information representing all the nucleotide sequences constituting the genome of the patient is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
The genotype information comprises information representing variants having a frequency of less than 1% in the human population.

[17] A dosing plan proposal program for operating a computer as a system for proposing a dosing plan suitable for a patient.
The above system is equipped with a control unit.
The control unit
Obtain drug information indicating the drug to be administered to the above patients and its dose;
Obtained relevance information indicating the relevance of the above drugs and genotypes;
Obtain genotype information for the above patients;
Based on the relevance information and genotype information, the goodness of fit of the above drug information is determined;
When the goodness of fit is low, the above medical information is changed;
The modified drug information with the modification is presented to the user; and the genotype information contains a genotype existing in a locus associated with the drug represented by the drug information in the relevance represented by the relevance information. When not recorded, information representing all the nucleotide sequences constituting the genome of the patient is acquired, and the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence to update the genotype information. death,
The genotype information includes information representing variants having a frequency of less than 1% in the human population.
A dosing plan proposal program for operating a computer as the control unit.

[18] A system that proposes a suitable administration plan for patients.
The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
Genotype information acquisition department that acquires the genotype information of the above patients;
Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
Based on the goodness of fit of the drug information determined by the goodness-of-fit determination unit, the administration plan determination unit that determines suitable drug information for the patient; and the drug information determined by the administration plan determination unit are used by the user. Equipped with an information presentation unit to present to
The system captures the genome of the patient when the genotype information does not record the genotype present in the locus associated with the drug represented in the drug information in the association represented by the relevance information. Information representing all the constituent nucleotide sequences is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
The genotype information is a system comprising information representing variants having a frequency of less than 1% in the human population.

1 Administration plan proposal system (system that proposes a suitable administration plan for patients)
1a Administration plan proposal system (system that proposes a suitable administration plan for patients)
1'Administration plan proposal system (system that proposes a suitable administration plan for patients)
1'' Dosing plan proposal system (system that proposes a suitable dosing plan for patients)
2 Control unit 2a Control unit 2b Control unit 3 Display device (information presentation unit)
4 Input device 5 Pharmaceutical efficacy-related gene information DB
6 Genome information DB
7 Pharmaceutical-related disease information DB
10 Administration plan proposal system (system that proposes a suitable administration plan for patients)
21 Information acquisition department (medicine information acquisition department, relevance information acquisition department and genotype information acquisition department)
22 Goodness of fit determination unit 23 Pharmaceutical information change department 24 Warning unit 25 Administration plan determination unit 301 Pharmaceutical information (phenytoin)
302 Changed Pharmaceutical Information 303 Pharmaceutical Information (Olanzapine)
304 Pharmaceutical information (candidate drug group)
305 Pharmaceutical Information (Lixotinib)
306 Modified Pharmaceutical Information 311 Relevance Information (Phenytoin)
312 Relevance information (clopidogrel)
313 Relevance Information (Perindopril Elbumin)
314 Relevance Information (Olanzapine)
315 Relevance Information (Lixotinib)
316 Relevance Information (Ceritinib)
317 Relevance Information (Gefitinib)
318 Relevance Information (Osimertinib Mesylate)
901 string 902 string (target nucleotide)
903 string

Claims (18)

1. It is a system that proposes a suitable administration plan for patients.
   The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
   Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
   Genotype information acquisition department that acquires the genotype information of the above patients;
   Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
   A medical information changing unit that changes the medical information when the goodness of fit is low; and an information presentation unit that presents the changed medical information that the medical information changing department has changed to the user.
   The system captures the genome of the patient when the genotype information does not record the genotype present in the locus associated with the drug represented in the drug information in the association represented by the relevance information. Information representing all the constituent nucleotide sequences is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
   The genotype information is a system comprising information representing variants having a frequency of less than 1% in the human population.
2. The system is used to detect the DNA variant.
   A binding sequence is generated in which the target nucleotide sequence corresponding to the DNA variant and the partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome are bound to form the binding sequence and the genome of the patient. Comparing with the entire nucleotide sequence,
   The system according to claim 1, wherein the system is repeated while increasing the length of the partial nucleotide sequence.
3. The system is used to detect the DNA variant.
   Generate two nucleotide sequences corresponding to the partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome, and compare the two nucleotide sequences with all the nucleotide sequences constituting the patient's genome. of,
   The system according to claim 1, wherein the system is repeated while increasing the length of the partial nucleotide sequence.
4. The goodness-of-fit determination unit determines the goodness of fit by referring to the pharmacokinetics of the drug or the drug efficacy-related gene information regarding the gene encoding the protein involved in the pharmacodynamics.
   The genotype is a genotype related to the gene, and the relevance information includes the drug efficacy-related gene information.
   The system according to any one of claims 1 to 3, wherein the change is an increase or decrease in the dose or a change in the drug.
5. The goodness-of-fit determination unit determines the goodness of fit with reference to drug-related disease information indicating a disease that develops or becomes serious due to administration of the drug.
   The genotype is a genotype relating to a combination of alleles associated with the predisposition to the disease, and the relevance information includes the drug-related disease information.
   The system according to any one of claims 1 to 4, wherein the modification is a modification of the drug or a reduction of the dosage.
6. When the drug is a contraindicated drug for the disease, the fitness determination unit determines that the fitness for the genotype, including combinations of alleles associated with the predisposition to the disease, is very low.
   When the fitness determination unit determines that the fitness for the genotype, including combinations of alleles associated with the predisposition to the disease, is very low, the fitness information change unit is a contraindicated drug for the disease. The system of claim 5, wherein changes in the drug are added to the above drug information.
7. The system according to claim 5, wherein the disease includes a disease associated with a serious side effect due to an idiosyncratic drug, or a symptom of a serious side effect due to an idiosyncratic drug.
8. The goodness-of-fit determination unit includes information on pharmacokinetics-related gene information representing a gene encoding a protein involved in pharmacokinetics or pharmacodynamics of the drug, and a drug representing a disease that develops or becomes serious due to administration of the drug. With reference to related disease information, determine the above goodness of fit,
   The genotype is a genotype relating to a gene encoding a pharmacokinetics or a protein involved in the pharmacokinetics of the drug and a genotype relating to a combination of alleles associated with the predisposition to the disease, and the relevance information is provided. It contains the above-mentioned drug-related genetic information and drug-related disease information.
   The system according to any one of claims 1 to 7, wherein the change is an increase or decrease in the dose or a change in the drug.
9. Information representing a single nucleotide polymorphism among the above DNA variants was determined using the genomic fragment of the patient or based on the information representing the entire nucleotide sequence, and the information representing the determined single nucleotide polymorphism was recorded. ,
   The system according to any one of claims 1 to 8, wherein the information representing the unrecorded DNA variant is determined based on the textual information representing the entire nucleotide sequence.
10. The system according to any one of claims 1 to 9, wherein the drug information acquisition department acquires the drug information from a prescription or a medicine notebook.
11. The system according to any one of claims 1 to 10, wherein the relevant information is generated by artificial intelligence.
12. When the change includes the change of the medicine and there are a plurality of candidate medicines as candidates for the change, the information presenting unit indicates to the user the medicine having the highest goodness of fit among the plurality of candidate medicines. , The system according to any one of claims 1 to 11.
13. When there are a plurality of candidate drug information that the information presenting unit is suitable for presenting to the user, the information presenting unit selects the drug information having the highest goodness of fit among the plurality of suitable candidate drug information. The system according to any one of claims 1 to 12, which is presented in 1.
14. When the fitness represented by the drug information is a molecular target drug that targets a gene product having a specific mutation, the fitness determination unit has a DNA variant corresponding to the mutation in the genome of the patient. The system according to any one of claims 1 to 13, wherein the fitness is determined based on the presence or absence.
15. The invention according to any one of claims 1 to 14, further comprising a warning unit for warning that the pharmaceutical information is inappropriate when the goodness of fit determined by the goodness-of-fit determination unit is less than the standard. system.
16. A method of proposing a suitable dosing regimen for a patient,
    A drug information acquisition step in which a computer acquires drug information representing the drug to be administered to the patient and the dose thereof;
    Relevance information acquisition step in which the computer acquires relevance information representing the relevance between the drug and the genotype;
    The genotype information acquisition step in which the computer acquires the genotype information of the patient;
    A goodness-of-fit determination step in which the computer determines the goodness of fit of the pharmaceutical information based on the relevance information and the genotype information;
    When the computer has a low goodness of fit, a drug information change step of changing the drug information; and an information presentation process in which the computer presents the changed drug information changed in the drug information change step to the user. Including,
    In the above method, when the genotype information does not record the genotype present in the locus associated with the drug represented by the drug information in the relevance represented by the relevance information, the computer described above. Information representing all the nucleotide sequences constituting the genome of the patient is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
    The genotype information comprises information representing variants having a frequency of less than 1% in the human population.
17. A dosing plan proposal program for operating a computer as a system for proposing a dosing plan suitable for a patient.
    The above system is equipped with a control unit.
    The control unit
    Obtain drug information indicating the drug to be administered to the above patients and its dose;
    Obtained relevance information indicating the relevance of the above drugs and genotypes;
    Obtain genotype information for the above patients;
    Based on the relevance information and genotype information, the goodness of fit of the above drug information is determined;
    When the goodness of fit is low, the above medical information is changed;
    The modified drug information with the modification is presented to the user; and the genotype information contains a genotype existing in a locus associated with the drug represented by the drug information in the relevance represented by the relevance information. When not recorded, information representing all the nucleotide sequences constituting the genome of the patient is acquired, and the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence to update the genotype information. death,
    The genotype information includes information representing variants having a frequency of less than 1% in the human population.
    A dosing plan proposal program for operating a computer as the control unit.
18. It is a system that proposes a suitable administration plan for patients.
    The drug information acquisition department that acquires drug information indicating the drugs to be administered to the above patients and their doses;
    Relevance information acquisition department that acquires relevance information indicating the relevance of the above drugs and genotypes;
    Genotype information acquisition department that acquires the genotype information of the above patients;
    Goodness-of-fit determination unit that determines the goodness of fit of the above-mentioned pharmaceutical information based on the above-mentioned relevance information and genotype information;
    Based on the goodness of fit of the drug information determined by the goodness-of-fit determination unit, the administration plan determination unit that determines suitable drug information for the patient; and the drug information determined by the administration plan determination unit are used by the user. Equipped with an information presentation unit to present to
    The system captures the genome of the patient when the genotype information does not record the genotype present in the locus associated with the drug represented in the drug information in the association represented by the relevance information. Information representing all the constituent nucleotide sequences is acquired, the DNA variant existing in the locus is detected from the information representing the whole nucleotide sequence, and the genotype information is updated.
    The genotype information is a system comprising information representing variants having a frequency of less than 1% in the human population.

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