JP2022181078A - Administration plan decision support system, administration plan decision support method, and administration plan decision support program - Google Patents

Abstract

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

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a system for assisting determination of a pharmaceutical administration regimen, and more particularly to a system for assisting determination of an appropriate pharmaceutical administration regimen for a patient based on the patient's specific genotype.

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

However, even a system for determining whether a drug thought to be effective against a disease is actually safe and effective for a specific patient by using a patient's genetic information has not yet been proposed. That is, there are multiple drugs that are known to have efficacy for one disease, there are multiple genes that affect the efficacy or side effects of one drug, and there are multiple genes that affect the expression of the function of one gene. This is because it is well known that other genes of

Therefore, current out-of-hospital prescriptions and in-hospital prescriptions (which specify the type, dose, and method of use) prepared by physicians are based on uniform factors (mainly the type of disease the patient is suffering from, the severity of the disease, degree and age, weight and sex of the patient) still apply. Such prescriptions fail to specify the appropriate type of drug, its dosage and usage for an individual patient. In fact, patients using the drug as prescribed respond very differently. It has been pointed out that the reaction may include the drug giving only adverse effects to the patient (showing only side effects and not showing efficacy).

In addition to medications for use by patients according to prescription, there are medications and other substances (such as anesthetics) that require the supervision of a healthcare professional for administration or use to patients. It is well known that the administration or use of such drugs or substances can cause exaggerated reactions in some people and is often associated with side effects.

Individual differences in drug efficacy and side effects are due more to genetic variation in the human population than to effects such as type of disease, environmental factors (e.g. lifestyle) and/or combinations of drugs taken. do.

Clinical genome sequencing, the ultimate scan for pathogenic variants, finds a large number of variants of unknown clinical significance in each individual. An ethical concern in this case is how to deal with the accidental discovery of a pathogenic variant unrelated to the original purpose of sequencing. Clinical genome sequencing will soon be integrated into existing healthcare systems in many developed countries. However, major bioinformatic and electronic network challenges remain. There are also ethical concerns about releasing data in the current context of incomplete knowledge, including the uncertain clinical significance of many variants.

On the other hand, DNA diagnosis has moved from analyzing limited genes to analyzing the entire genome, and has become relevant in almost all clinical departments. As the scope and availability of genetic testing increases, the old system of having most genetic tests arranged by clinical geneticists is becoming inadequate. It is expected that clinical team members, including clinicians who analyze and manage patients, will increasingly be required to directly obtain and use test results.

In the future, clinicians are expected to receive complex DNA and chromosomal test results, but at present there is little information available to aid their interpretation. “Mainstreaming genetics” aims to integrate genetic testing into mainstream conventional medicine, with diagnostic testing likely to become the responsibility of the clinician to whom the patient was first referred. Therefore, clinicians in various specialties with limited experience with genetic testing need to develop the necessary knowledge to interpret and communicate genetic test results.

JP 2016-218684 A

It is therefore an object of the present invention to enable users, e.g., clinicians, pharmacists, nurses, etc., to perform genetic testing based on patient-specific genotypes without the need for experience with genetic testing such as that required by clinical geneticists. It is an object of the present invention to provide an administration plan decision support system, an administration plan decision support method, and an administration plan decision support program for assisting in deciding a drug administration plan suitable for a patient.

In order to solve the above problems, the present invention includes the embodiments described below.
Section 1. A decision support system for a suitable dosing regimen for a patient, comprising:
a pharmaceutical information acquisition unit that acquires pharmaceutical information representing a pharmaceutical and a dosage that are scheduled to be administered to the patient;
a prohibited factor information acquiring unit that acquires prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition units that acquire essential factor information that is the information of;
A patient genotype information acquisition unit for acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition unit including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and a comparison result between the essential factor information and the second genotype information, a decision support system comprising a dosing regimen decision unit that decides whether the medical information is appropriate for the patient. .
Section 2. comprising both the prohibited factor information acquisition unit and the required factor information acquisition unit,
The administration plan determination unit determines an administration plan for the patient based on a comparison result between the prohibited factor information and the first genotype information and a comparison result between the essential factor information and the second genotype information. 2. The assistance system of clause 1, wherein the determining.
Item 3. further comprising a dosing plan output unit that outputs a dosing plan for the patient;
The administration plan determination unit administers to the patient when the first genotype information does not match the prohibited factor information and the second genotype information matches the essential factor information is scheduled as a suitable drug information,
When the administration plan determining unit determines that the drug information scheduled to be administered to the patient is suitable medical information, the administration plan output unit selects the drug information scheduled to be administered to the patient. 3. The support system according to item 1 or 2, which outputs as suitable medical information.
Section 4. a dosing regimen output unit that outputs a dosing regimen for the patient; and a medicine information changing unit that modifies the medicine information if the medicine information is inappropriate;
further comprising
The dosing regimen determining unit, when the first genotype information matches the prohibited factor information, or when the second genotype information does not match the essential factor information, administers to the patient determines that the scheduled drug information is inappropriate,
When the administration plan determination unit determines that the medical information scheduled to be administered to the patient is inappropriate, the administration plan output unit outputs a warning indicating that the medical information is inappropriate and changes the medical information. Item 4. The support system according to any one of Items 1 to 3, wherein the modified medicine information modified by the department is output.
Item 5. The prohibited factor information includes genotypes having mutations associated with the functions of genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug, and predispositions for diseases that develop or become aggravated by administration of the drug. a genotype associated with a combination of alleles associated with the administration of said drug, a genotype with mutations associated with causative genes of monogenic diseases that have been demonstrated to be involved in the development of side effects due to administration of said drug, or side effects due to administration of said drug A genotype with a rare, individual, or Mendelian-like subset of mutations that has demonstrated a strong impact or effect on a multifactorial or polygenic disorder that has been demonstrated to be involved in the development of , the support system according to any one of items 1 to 4.
Item 6. Items 1 to 5, wherein the essential factor information is an allele type at a specific locus on the genome that is essential for the efficacy of the drug that functions as a molecular target for a specific disease, or a genotype having a combination of allele types. A support system according to any one of the preceding claims.
Item 7. When the first genotype information and/or the second genotype information is not recorded as the patient genotype information, the system acquires information representing the entire nucleotide sequence constituting the genome of the patient. and detecting a DNA variant present at the locus of the first genotype and/or the second genotype from the information representing the entire nucleotide sequence to update the patient genotype information;
Clause 7. The support system of any one of clauses 1-6, wherein the patient genotype information comprises information representing variants whose frequency in the human population is less than 1%.
Item 8. To detect the DNA variant, the system comprises:
A target nucleotide sequence corresponding to the DNA variant is combined with partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome to generate a binding sequence, and the binding sequence and the patient's genome are constructed. Comparing the whole nucleotide sequence,
8. Assistance system according to clause 7, wherein the partial nucleotide sequence is repeated with increasing length.
Item 9. To detect the DNA variant, the system comprises:
generating two nucleotide sequences corresponding to the partial nucleotide sequences on either side of the position corresponding to the DNA variant in the reference human genome, and comparing the two nucleotide sequences with the entire nucleotide sequence making up the patient's genome. of,
8. Assistance system according to clause 7, wherein the partial nucleotide sequence is repeated with increasing length.
Item 10. Information representing a single nucleotide polymorphism among the DNA variants is determined using the genome fragment of the patient or based on the information representing the entire nucleotide sequence, and the information representing the determined single nucleotide polymorphism is recorded. ,
Item 10. The support system according to any one of items 7 to 9, wherein the information representing the unrecorded DNA variant is determined based on textual information representing the entire nucleotide sequence.
Item 11. further comprising a dosing plan output unit that outputs a dosing plan for the patient;
11. The support system according to any one of Items 1 to 10, wherein the administration plan output unit transmits the administration plan for the patient to a user terminal equipped with a display device.
Item 12. 12. Assistance system according to any one of clauses 1 to 11, wherein said prohibited factor information and/or said required factor information is generated by artificial intelligence.
Item 13. A computer-implemented method for assisting in determining an appropriate dosing regimen for a patient, comprising:
a pharmaceutical information acquisition step of acquiring pharmaceutical information representing a drug and dosage to be administered to the patient;
a prohibited factor information acquisition step of acquiring prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition steps for acquiring essential factor information that is the information of;
A patient genotype information acquisition step of acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition step including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and determining the suitability of said medical information for said patient based on at least one of the comparison results of said essential factor information and said second genotype information.
Item 14. A decision support program for a suitable dosing regimen for a patient, comprising:
a pharmaceutical information acquisition unit that acquires pharmaceutical information representing a pharmaceutical and a dose that are scheduled to be administered to the patient;
a prohibited factor information acquiring unit that acquires prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition units that acquire the essential factor information that is the information of;
A patient genotype information acquisition unit for acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition unit including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and a comparison result between the essential factor information and the second genotype information, and a program for functioning as a dosing plan determination unit that determines the suitability of the medical information for the patient. .

According to the present invention, a drug regimen suitable for a patient based on the patient's unique genotype without the need for systematic knowledge and experience in genetic testing, such as that required by a clinical geneticist. can be determined.

It is a schematic diagram for explaining the concept of the present invention. 1 is an explanatory diagram of a system according to one embodiment of the present invention; FIG. It is explanatory drawing of the example of (a) patient information, (b) medical information, (c) patient genotype information, (d) prohibited factor information, and (e) essential factor information. FIG. 3 is an explanatory diagram of an example of processing executed by the administration plan determination support system of FIG. 2; FIG. 3 is an explanatory diagram of an example of processing executed by the administration plan determination support system of FIG. 2; FIG. 10 is an explanatory diagram of an example of changed medicine information in which the dose of medicine is changed; FIG. 10 is an explanatory diagram of an example of changed medicine information in which the kind of medicine is changed; FIG. 4 is an explanatory diagram of examples of drug information, changed drug information, prohibited factor information, and essential factor information regarding dose change of a drug; (a) Relevance information A; (b) Modified drug information on dosage B FIG. 2 is a schematic diagram showing the structure of a character string for determining the allele type (genotype) of any DNA variant in the human genome. FIG. 1 shows an example of a method for determining the allelic type (genotype) of DNA variants (including SNPs) present on a genome sequence.

As used herein, a "dosing regimen" is a guideline (eg, a prescription) indicating the administration of a drug in a certain dosage to a particular patient. A “administration regimen” includes at least information representing a specific patient, and information representing the type and dosage of a drug scheduled to be administered to the specific patient.

As used herein, "pharmaceutical" means a drug that directly improves symptoms in a disease by exerting its efficacy in a patient who receives the drug, or for the purpose of assisting medical practice (examination, anesthesia, etc.) Represents the substances used (such as contrast agents and anesthetics). Pharmaceuticals include prescription drugs and over-the-counter drugs (also called OTC drugs). Prescription drugs include prescription drugs that require a doctor's prescription.

As used herein, a "genotype" (also called a genotype) is the genetic makeup of an individual or a particular locus on the genome of an individual, the combination of alleles (alleles) at one or more loci in the genome. type (sum of each type when two or more loci are genotyped). "Allele" as used herein refers to individual genes and DNA sequences that occur at a single locus on a single chromosome. The term "genotype" or "allelic type" is used as a concept including "mating type".

As used herein, the genotype information of a "prohibited factor" refers to information of an allele type or a combination of allele types (genotype) at a locus on the genome where administration of a specific drug is prohibited. The genotype information of “essential factors” represents information on the allele type or allele type combination (genotype) at the locus on the genome that is essential for the administration of a specific drug.

"Pharmaceutical information" includes at least information identifying a patient (e.g. patient's ID number), information identifying a medicine (e.g. trade name or substance name of medicine), and information designating dosage of medicine for a patient. represents the information The medical information can be, for example, a chart or a prescription that a doctor creates on a computer.

"Adequacy (of medical information)" refers to whether the relationship between the patient and the type and/or dosage of the drug specified in the medical information is appropriate based on the genotype specific to the patient. or

As used herein, "DNA variant" refers to a specific site on the genome where there are two or more alterations in nucleotide sequence (including alleles and chromosomal structures) in the human population (regardless of their frequency), as well as It is described as a concept of the totality of the changes (ie, all allelic forms of the specific site). Alteration of the above nucleotide sequence means any alteration including substitutions, deletions, insertions and/or additions, duplications of one or more nucleotides.

Among the above-mentioned "DNA variants", when there is a change with a high frequency (1% or more) in the population, it is called "polymorphism (P: Polymorphism)", for example, single nucleotide polymorphism (Single Nucleotide Polymorphism, hereinafter " SNP”), copy number polymorphism (hereinafter referred to as “CNP”), microsatellite polymorphism (short tandem repeat sequence: Short Tandem Repeat Polymorphism, hereinafter referred to as “STRP” ). In addition, when it is a change with low frequency (less than 1%) in the population, it is called "variant (V: Variant)", for example, single nucleotide variant (Single Nucleotide Variant, hereinafter referred to as "SNV"), copy There are several variants (Copy Number Variant, hereinafter referred to as "CNV"). In the present specification, the above-mentioned "DNA variant" is a concept that includes "polymorphism" and "variant" regardless of the frequency in human populations, as described above.

The totality of allele combination types (“allele types”) containing mating types at one locus (i.e., all allele types at that particular site) is included in each allele nucleotide sequence and/or the combination. determined by the number of alleles present. Administration of said medicament to a patient in which at least one of said nucleotide sequences is not the most prevalent wild-type nucleotide sequence in the human population and/or said number of said alleles is not the usual two (i.e. patients whose type is not usual) Undesired effects can occur in the patient. The undesired effects are, for example, (a) decreased, lost or excessively increased efficacy of the medicament, (b) occurrence or increased side effects of the medicament, and/or when the type is compared to normal patients. or (c) a high incidence of a specified disease that did not occur prior to administration of the medicament. However, in practice, the undesired effects often appear not only in one of the above "allele types" but when accumulated by multiple "allele types" for multiple loci.

FIG. 1 is a schematic diagram for explaining the concept of the present invention. A system for supporting the determination of a dosage regimen of a drug to be administered to a patient according to an embodiment of the present invention supports determination of a custom-made dosage regimen (for example, medicine B' and dosage C') that matches genotype information of patient A. . Criteria for determining the dosing schedule include (1) pharmacokinetic factors of drug B, (2) pharmacodynamic factors of drug B, and (3) risk of developing secondary diseases due to drug B. . "Pharmacokinetics" refers to the in vivo behavior of a drug or its metabolites that alters the probability of contact between a drug and its target molecule. "Pharmacodynamics" refers to the strength with which a substance (drug) acts on a target substance in vivo. (1) and (2) are the extent to which the chemical structure of drug B administered to the patient interacts with proteins expressed in the patient's body (pharmacokinetic or pharmacodynamic factors of drug B) is used to properly control the (3) is used to prevent the risk of developing a certain disease based on the patient's unique genetic background from manifesting (that is, developing the disease) by administering medicine (artificial act). With regard to (1) to (3) above, in the present application, the administration regimen is based on a genotype that is prohibited from administration of a drug, a "prohibited factor," and a genotype that is required for administration of a drug, an "essential factor." (See "(Invention System)" in Fig. 1).

Embodiments according to the present invention will be described in detail below.

[Embodiment 1]
2 to 8, an embodiment embodying a system for supporting the determination of the administration schedule of a drug to be administered to a patient, a method for supporting the determination of the administration schedule, and a program for supporting the determination of the administration schedule will be described below. This decision support system is a system that assists the user's decision by creating a suitable administration plan (custom-made administration plan) for the patient. Users include medical professionals such as doctors, nurses, and pharmacists, or patients themselves.

As shown in FIG. 2, a system 1 for supporting the determination of a dosage plan of a drug to be administered to a patient according to one embodiment of the present invention includes a control unit 10, a display device 20 such as a display connected to the control unit 10, a control An input device 30 such as a keyboard and a mouse connected to the unit 10 is provided. In addition, the control unit 10 includes an information acquisition unit 110 (drug information acquisition unit, prohibited factor information acquisition unit, essential factor information acquisition unit, patient genotype information acquisition unit), an administration plan determination unit 120, a medical information change unit 130, and A dosage regimen output unit 140 is provided. The information acquisition unit 110 , the administration plan determination unit 120 , the medicine information change unit 130 , and the administration plan output unit 140 are included in the CPU (Central Processing Unit) of the control unit 10 . The control unit 10 is connected to the drug-related gene information DB 40 and the genome information DB 50 . The drug-related genetic information DB 40 includes at least genotype information related to efficacy and side effects (secondary diseases) of the drug, and genotype information of "prohibited factors" and "essential factors" based on the genotype information. there is The administration plan determination support system 1 outputs information generated by the control unit 10 based on information acquired from the input device 30, the drug-related gene information DB 40, and the genome information DB 50 to the user via the display device 20.

The control unit 10 (FIG. 2) includes control means such as a CPU, memories such as RAM and ROM, and performs various processes to be described later. By executing the administration plan determination support program, the control unit 10 ( FIG. 2 ) functions as the information acquisition unit 110 , the administration plan determination unit 120 , the medicine information change unit 130 , and the administration plan output unit 140 .

The information acquisition unit 110 (FIG. 2) acquires information including patient information 400, drug information 500, patient genotype information 600, prohibited factor information 700, and essential factor information 800 (FIGS. 3(a) to (e)), which will be described later. Execute the process to get the .

The administration plan determination unit 120 (FIG. 2) executes processing for determining the administration plan based on the information acquired by the information acquisition unit 110 (FIG. 2).

The medicine information change unit 130 (Fig. 2) executes processing for changing the medicine information 500 (Fig. 3(b)) based on the determination result by the administration plan determination unit 120 (Fig. 2).

The administration plan output unit 140 (Fig. 2) outputs the medicine information 500 (Fig. 3(b)) or the changed medicine information 510 (Fig. 6) based on the determination result by the administration plan determination unit 120 (Fig. 2). to run.

Patient information 400 is general information about the patient, shown in FIG. 3(a). Patient information 400 (FIG. 3(a)) does not include patient genotype information 600 (FIG. 3(c)) described later. The patient information 400 (FIG. 3(a)) is also called patient data. The patient information 400 (FIG. 3(a)) includes one or more of a patient code such as patient ID, patient name, date of birth, sex, weight, disease name, severity of disease, and the like. include but are not limited to:

The medicine information 500 is information about candidate medicines to be administered to the patient, which is shown in FIG. 3(b), and is acquired by the medicine information acquisition unit. The medicine information 500 (FIG. 3(b)) is also called medicine data. The drug information 500 (FIG. 3(b)) includes one or more of the name of the candidate drug to be administered to the patient, the dose of the drug (for example, daily dose), and the like. but not limited to these. It is preferable that the patient information 400 (FIG. 3(a)) and the medical information 500 (FIG. 3(b)) are associated. is included in the medicine information 500 (FIG. 3(b)).

The patient genotype information 600, as shown in FIG. 3(c), is information on the genotype of the patient, and is acquired by the patient genotype information acquisition unit. Patient genotype information 600 (FIG. 3(c)) is also referred to as patient genotype data. As the patient genotype information 600 (FIG. 3(c)), a specific locus (locus, loci if plural) on the genome of the patient including the gene region (hereinafter referred to as "genomic locus") 610 (for example, , "gene X" or "gene Y") and the type of allele containing the patient's mating type at that locus, i.e., the patient's genotype (hereinafter referred to as "genotype"). 620 (for example, " ^* 1/ ^* 2" as encoded information, or "A (adenine)/C (cytosine)" as the actual type of nucleotide).

(Patient genotype information)
The patient genotype information 600 (FIG. 3(c)) is a patient-specific type of combination of alleles present at one locus on the patient genome (alleles associated with one gene in this embodiment) ("allele type"). There are roughly two methods for determining the “allele type”. The method uses "Method 1" using information representing the structure of the full-length genome obtained from a patient ("full-length character string"), and a genomic DNA sample derived from the patient. "Method 2" uses an experimental technique based on genome-wide polymorphism analysis targeting only DNA variants (for example, SNPs) suitable for analysis.

The former "Method 1" can be carried out using a massively parallel DNA sequencing method (next generation sequencing method). Massively parallel DNA sequencing methods can simultaneously and evenly sequence complex DNA samples containing very many (sometimes millions) of nucleotide sequences. For this reason, compared with the conventional dideoxy base sequencing method (Sanger method), the large-scale parallel DNA sequencing method uses genomic DNA samples extracted by standard methods from patient-derived blood cells and various tissues. , in a short time and at a low cost, it is possible to convert to character string (“full-length character string”) information corresponding to the entire genome (approximately 3 billion nucleotides) of the patient.

The patient's A genotype can be determined for a particular locus on the genome. The reference character string can be obtained from public databases such as ensemble (Ensembl, URL: http://ensembl.org).

For example, a character string representing the nucleotide sequence of an allele that can be present at a certain locus (“allele string”) and information representing positions (known DNA variants) at which nucleotide sequence changes occur between the alleles in the population , where there is a high frequency in the population (eg, SNP), stored in publicly available databases (eg, dbSNP (https://www.ncbi.nlm.nih.gov/snp/)). Therefore, one locus possessed by the patient is determined by determining which type of allele string combination ("allele type") for one locus includes the "full length string". genotype can be determined for As an example, the outline of the determination process of the patient's genotype information 600 (Fig. 3(c)) will be described below.
- in the above "allele string" contained in the "full length string" based on the above information representing the positions of known DNA variants stored in a publicly available database (e.g., dbSNP mentioned above) , determine the two character strings (eg, about 10-100 characters) that flank the position on each side of the DNA variant. Using a well-known character comparison application, determine the position where the "reference string" exactly matches the "reference string" ・ Between the "full length string" and the "reference string", the two strings The "allelic type" of the DNA variant in the "full-length string" (i.e., the patient's "hereditary (Details of the determination method (“Method 1”) regarding the patient’s “genotype” using the above-described “full-length character string” are described later in [Embodiment 2]).

On the other hand, as the latter "Method 2" described above (a method using an experimental technique based on comprehensive genome polymorphism analysis), the DNA variant is a DNA variant that has a high frequency in the population and is suitable for automatic analysis. (e.g., SNPs, or deletions or insertions (indels) of one to several nucleotides in the genome), the number of microarray technologies already commercialized (existence of commercial kits and commissioned implementation services) is large (tens of thousands to Hundreds of thousands) of genome fragments can be determined in a short time. For details of the microarray technology, refer to the kit manual or the contractor's website.

As described above, the patient's genotype information 600 (FIG. 3(c)) is obtained by experimental It can be determined by (or during the performance of these methods) "Method 2" using techniques. Therefore, the patient's genotype information 600 (FIG. 3(c)) stored in the genome information DB 50 (FIG. 2) of FIG. Information representing the patient's "genotype" and information representing the patient that are associated with each other, and (3) information in which the two pieces of information are encoded (for example, the patient's genetic type in FIG. 3(c) described above) (see "genotype 620" described in type information 600). The genotype information is preferably (2) or (3). Using (2) or (3) as the genotype information reduces the performance required of the administration plan decision support system 1 (FIG. 2) and the genome information DB 50 (FIG. 2), and the administration plan decision support system 1 ( 2) can be improved. In addition, using (3) as genotype information makes it possible to keep (1) and (2) secret from unspecified third parties who cannot decipher the meaning of the symbols.

The "allelic type" of individual DNA variants for generating (2) and (3) as patient genotype information 600 (FIG. 3(c)) is the frequency-based DNA variant in the population. can be determined in two stages depending on the type (determination range) of (see the lower part of FIG. 1). As a first step, only all known SNPs are comprehensively determined as DNA variants that have a frequency of 1% or more in the population and are suitable for automatic analysis, and the information is stored in databases, recording media, or It is stored in a storage device (not shown). In addition, the patient's "genotype" information based on the above analysis of all SNPs is stored in the genome information DB 50 (Fig. 2). The “allele type” (patient “genotype”) for all SNPs can be determined by “Method 2”, which is an experimental technique using the patient's genomic DNA sample, as described above. That is, first, the genomic DNA sample is extracted from the patient's peripheral blood, intraoral cells, buccal mucosa, or the like by a standard method. Subsequently, using the above sample, the "allele type" (patient's "genotype") for all known SNPs can be determined by an experimental approach based on genome-wide polymorphism analysis using current microarray technology. Alternatively, the patient's "genotype" ("allele type") for all the above SNPs is determined by "Method 1" by information analysis using the above-described "full-length character string" (patient's genomic information). (See lower part of FIG. 1, details are described later in [Embodiment 2]).

Next, as a second step, if necessary, the "allele type" (patient's "genotype") for the remaining DNA variants not stored in the database, recording medium or storage device is converted to "full-length character string". Determined by "Method 1" using information (patient's genomic information). The above-mentioned "remaining DNA variants" include DNA variants with low frequency in the population (eg, SNV, CNV), DNA variants unsuitable for automatic analysis (eg, CNP, STRP, or other special DNA variants), etc. is assumed (see bottom of FIG. 1). The "allele type" (patient's "genotype") of the remaining DNA variants is input from the input device 30 (FIG. 2) to the patient information 400 (FIG. 3(a)) and the drug information 500 (FIG. 3(b)). is determined after is entered.

The administration plan determination support system 1 of FIG. 2, as described above, based on the drug name included in the drug information 500 (FIG. 3B), from the drug-related gene information DB 40 (FIG. 2) and obtain the name of the gene or the name of the genomic locus associated with the side effect (secondary disease). Regarding the drug-related gene information DB 40 (Fig. 2), related information can be obtained from, for example, DGIdb: Drug Gene Interaction database, URL: http://dgidb.org/.

The administration plan decision support system 1 (Fig. 2) searches the latest genome information DB 50 (Fig. 2) based on the name, and obtains the "allele type" (i.e., the genotype information of the patient ) is not stored, the “reference string” information is searched to specify the locus on the genome where the remaining DNA variants are present, as described above. The administration plan decision support system 1 (Fig. 2) uses the character string ("full-length character string") to determine the "allele type" (patient's "genotype") of the remaining DNA variants present only at the locus. Determined by “Method 1”. The administration plan decision support system 1 (Fig. 2) stores the determined "allele type" (patient genotype information) of the remaining DNA variants in the genome information DB 50 (Fig. 2) and the database, recording medium or storage. Store in the device (not shown).

In FIG. 2, the genome information DB 50 is shown as a reading device capable of reading an external storage device or recording medium connected to the control unit 10 (FIG. 2). It can be replaced by a reading unit that can read the stored storage unit or recording medium, or a configuration that exists on a network.

The genotype information (2) or (3) above can be updated based on the latest reports. The report is a report of a new DNA variant associated with a gene, as well as the overall "allelic type" ("genotype") of the DNA variant (ie, all allelic types at the specific site). As described above, new (2) or (3) can be generated based on the existing report and the latest report by "Method 1" using the above "full-length character string" information (patient's genomic information).

The genome information DB 50 (FIG. 2) can store the entire nucleotide sequence that makes up the patient's entire genome. Patient genotype information 600 (FIG. 3(c)) is a portion of the entire nucleotide sequence that makes up the patient's entire genome.

The prohibited factor information 700 is information of a prohibited factor, which is genotype information at a locus on the genome where drug administration is prohibited, as shown in FIG. 3D, and is acquired by the prohibited factor information acquisition unit. be done. The prohibited factor information 700 (FIG. 3(d)) is a genotype consisting of allele combination types for which the genotypes at the corresponding genomic loci in the patient must not match in the drug administration regimen. The prohibited factor information 700 (FIG. 3(d)) is also called prohibited factor data. The prohibited factor information 700 (FIG. 3(d)) includes a gene-related genomic locus 710 (for example, denoted as “gene X”) and its genotype 720 (for example, encoded information as “ ^* 1/ ^* 1”, or “A (adenine)/A (adenine)” as an actual type of nucleotide))). Examples of genotypes 720 (FIG. 3(d)) include genes associated with pharmacokinetics (e.g., specific sites of drug-metabolizing enzymes) and pharmacodynamics (e.g., enzymatic active sites within target molecules for specific drugs). Genotypes that make up specific mutations; genotypes of causative genes in single-gene disorders that have been demonstrated to be significantly involved in the development of serious side effects (secondary diseases); or complex diseases (multifactorial diseases, polygenic diseases) ``Rare variants,'' ``private variants,'' and ``Mendelian-like subsets'' that have been demonstrated to have strong effects and efficacy among sexually transmitted diseases. Constituent genotypes can be mentioned.

In one embodiment of the inhibited factor information 700 (FIG. 3(d)), the numerical odds ratio for a particular genetic variant associated with a particular disease risk in a patient is set to a set value (e.g., 5, 10, or 20) the genotype consisting of that particular genetic variant if greater than or equal to or higher than a set value; Such genetic variants are known, and particularly rare variants are candidates. The odds ratio is a value obtained by dividing the probability of developing the disease when having a specific genetic variant by the probability of developing the disease when not having that variant. Another embodiment of inhibited factor information 700 (FIG. 3(d)) includes Mendelian-like subsets associated with particular complex diseases.

The essential factor information 800 is information of the essential factor, which is genotype information at the locus on the genome, which is essential for the administration of the medicine, shown in FIG. is obtained. The essential factor information 800 (FIG. 3(e)) is a genotype consisting of allele combination types that must match the genotypes at the corresponding genomic loci in the patient in the drug administration regimen. The essential factor information 800 (FIG. 3(e)) is also called essential factor data. The essential factor information 800 (FIG. 3(e)) includes a genomic locus 810 (for example, denoted as "gene Y") that must match the genotype of the genomic locus associated with the patient's corresponding gene and its genotype. 820 (for example, " ^* 2/ ^* 3" as encoded information, or "G (guanine)/T (thymine)" as the actual type of nucleotide).

The essential factor information 800 (FIG. 3(e)) is not particularly limited, but as one embodiment of the essential factor information 800, a genomic identification that is essential for the efficacy of a drug as a molecular target drug for a specific disease Allele types of loci, genotypes having a combination of allele types, genotypes of DNA mutations proven as companion diagnostics for anticancer drugs, and the like are included. As another embodiment of the essential factor information 800 (FIG. 3(e)), genotypes of subtype classifications (subtypes) for which a limited indication has been demonstrated for a specific drug in a certain disease group is mentioned.

Prohibited factor information and essential factor information can be obtained from public databases (for example, DGIdb: Drug Gene Interaction database, URL: http://dgidb.org/) and commercially available databases on drug-related gene information. The above-mentioned prohibited factor information, essential factor information, and medicinal gene-related information as a source of these information will be further expanded and improved in accuracy by adding new information and updating old information. Therefore, the above information is preferably created based on the latest information at the time of implementation of the present embodiment, and can be generated by artificial intelligence (hereinafter referred to as "AI"). The AI that receives the additional input of the new information can output new relationships between drugs and genes used to update the old information, and prohibited factor information and essential factor information based on these information.

Below are some specific examples of prohibited and essential factors.

(prohibited factor information, required factor information)
One specific example of the inhibited factor information 700 (FIG. 3(d)) is the ^* 28/ ^* 28 homozygous type of the promoter region of the gene encoding the UGT1A1 enzyme in the administration of the anticancer drug irinotecan. Mutation. In the UGT1A1 polymorphism, the UGT1A1 ^* 6 variant has 6 repeats of two types of nucleotides [TA] in the transcriptional regulatory region of the gene, whereas the number of repeats increases to 7 in the mutant. UGT1A1 ^* 28 variants have been recognized. Irinotecan is a prodrug that is converted in the liver to its active form with antitumor activity, and is normally metabolized by the ^UGT1A1 enzyme. , and the risk of serious drug side effects (toxicity) in the bone marrow and gastrointestinal tract is greatly increased.

In the case of psychotropic anti-epileptic drugs, carbamazepine for treating manic state, etc., the genotype HLA-A ^* 31:01 or HLA-B ^* 15:02 is the inhibiting factor. When the corresponding genotype of the patient to whom the drug is administered matches this, side effects of serious skin disorders such as toxic epidermal necrolysis (Lyell's syndrome) and ocular mucocutaneous syndrome (Stevens-Johnson syndrome) can occur.

The genotype HLA-B*58:01 is a prohibitive factor in the case of allopurinol, a drug for treating hyperuricemia. When the corresponding genotype of the patient to whom the drug is administered matches these, side effects of serious skin disorders such as toxic epidermal necrolysis (Lyell's syndrome) and ocular mucocutaneous syndrome (Stevens-Johnson syndrome) may occur. can occur.

The actual base sequences of the allelic types (genotypes) of each HLA gene variant can be searched from http://hla.alles.org/.

As a specific example of the essential factor information 700 (FIG. 3(e)), in the case of the ALK tyrosine kinase inhibitor crizotinib (trade name Xakori), which is an antineoplastic drug for patients with non-small cell lung cancer, the drug is administered. An essential factor is the presence of the genotype of the ALK fusion gene (EML4-ALK fusion gene) due to a chromosomal translocation in the patient's genome or the genotype that constitutes the ROS1 fusion gene.

Vemurafenib (generic name: Zelboraf), a BRAF inhibitor for melanoma patients, is an activating mutant BRAF kinase containing V600 mutations (V600E, V600D, V600R, V600K, V600G, V600M) caused by amino acid mutations in the BRAF gene. Inhibition of its activity is thought to inhibit BRAF activation-induced phosphorylation of MEK and ERK, suppressing the growth of tumors with BRAF V600 mutations. Therefore, genotypes with mutations at specific genomic sites within the BRAF gene due to the above amino acid mutations are essential factors.

Imatinib mesylate (generic name: Gleevec), a BCR-ABL tyrosine kinase inhibitor for patients with chronic myelogenous leukemia, has been associated with the presence of a genotype that constitutes the Philadelphia chromosome (bcr-abl gene) caused by a chromosomal translocation. , the presence of FIP1L1-PDGFRα is an essential factor.

In addition, the loci on the genome of the genotype of the prohibited factor and the genotype of the essential factor may overlap. For example, at the same locus, the genotype nucleotide of the prohibited factor may be "A (adenine)", whereas the genotype nucleotide of the essential factor may be "G (guanine)".

(Processing of administration plan decision support system)
4 and 5, the processing steps performed by the system of FIG. 2 will now be described.

A doctor who is a user provides patient information such as the type of disease the patient is suffering from, the severity of the disease, age, weight, and sex of the patient, and the drug name of the drug intended to be administered to the patient (here, compound B ) via the input device 30 (FIG. 2), the input device 30 displays the input patient information 400 (FIG. 3A) and the medical information 500 (FIG. 3B). is sent to the information acquisition unit 110 (FIG. 2) (step S1 in FIG. 4). In this embodiment, the patient information 400 (Fig. 3(a)) and the medicine information 500 (Fig. 3(b)) are separate data, but the patient information and the medicine information are associated with one set of data. may be handled.

Next, based on the drug name represented by the drug name included in the drug information 500 (FIG. 3B), the information acquisition unit 110 (FIG. 2) acquires the prohibited factor information 700 (FIG. 3B) corresponding to the drug. 3(d)) is obtained from the drug-related gene information DB 40 (FIG. 2) in FIG. 2 (step S2 in FIG. 4). If the determination is "YES" in step S2 of FIG. 4, then the information acquisition unit 110 (FIG. 2) acquires the patient ID information and the prohibited factor information included in the patient information 400 (FIG. 3A). Based on the name of the specific genomic locus associated with the gene contained in 700 (FIG. 3(d)), the patient ID and the patient genotype information 500 (FIG. 3(d)) corresponding to the specific genomic locus associated with the gene. (c)) is obtained from the genome information DB 50 (FIG. 2) (step S3 in FIG. 4). If the determination is "YES" in step S3 of FIG. 4, then the information acquisition unit 110 (FIG. 2) acquires the acquired drug information 500 (FIG. 3B), patient genotype information 600 (FIG. 3C )), and the genotype information 700 (FIG. 3(d)) of the prohibited factor is sent to the administration regimen determining unit 120 (FIG. 2). Based on the prohibited factor information 700 (FIG. 3(d)) acquired from the drug-related gene information DB 40 (FIG. 2), the administration plan determination unit 120 (FIG. 2) determines that the drug-related genotype is the patient's genotype. It is determined whether or not there is a match with the corresponding genotype (first genotype information of the patient) in the information 600 (FIG. 3(c)) (step S4 in FIG. 4).

Regarding step S4 in FIG. 4, for example, in the example shown in FIGS. 3(c) and (d), according to the prohibited factor information 700 (FIG. 3(d)), The genomic locus 710 and the corresponding genotype 720 are " ^* 1/ ^* 1 (homozygous)"("A (adenine)/A (adenine)" as the actual nucleotide type) at "gene X". (FIG. 3(d)), according to the patient's genotype information 600 (FIG. 3(c)), the genomic locus 610 associated with the patient's corresponding gene, and the corresponding genotype 620, is "gene X ” and “ ^* 1/ ^* 2 (heterozygote)” (“A (adenine)/C (cytosine)” as the actual nucleotide type), so they do not match. Therefore, step S4 in FIG. 4 becomes "NO". In the present embodiment, the genotypes are indicated by ^* 1/ ^* 1 and ^* 1/ ^* 2, but as shown in parentheses, these symbols represent the actual types of each nucleotide corresponding to the genotype. symbols (A/A, T/G, etc.) may be used.

If the determination is "NO" in step S2 of FIG. 4, the information acquiring unit 110 of FIG. ) to display a warning display indicating that the prohibited factor information 700 (FIG. 3(d)) does not exist.

If the determination in step S4 of FIG. 4 is "NO", then the information acquisition unit 110 (FIG. 2) selects the drug name represented by the drug name included in the drug information 500 (FIG. 3B). Based on this, the essential factor information 800 (FIG. 3(e)) corresponding to the drug is acquired from the drug-related gene information DB 40 of FIG. 2 (step S5 of FIG. 4). If the determination is "YES" in step S5 of FIG. 4, then the information acquisition unit 110 (FIG. 2) acquires patient ID information and essential factor information included in the patient information 400 (FIG. 3A). Based on the name of the specific genomic locus associated with the gene included in 800 (FIG. 3(e)), the patient ID and the patient genotype information 600 (FIG. 3(e)) corresponding to the specific genomic locus associated with the gene. (c)) is obtained from the genome information DB 50 (FIG. 2) (step S6 in FIG. 4). If the determination is "YES" in step S6 of FIG. 4, then the information acquisition unit 110 (FIG. 2) acquires the acquired drug information 500 (FIG. 3B), patient genotype information 600 (FIG. 3C )), and the essential factor information 800 (FIG. 3(e)) to the regimen determination unit 120 (FIG. 2). Based on the essential factor information 800 (FIG. 3(e)) acquired from the drug-related gene information DB 40 (FIG. 2), the administration plan determination unit 120 of FIG. It is determined whether or not it matches the corresponding genotype (second genotype information of the patient) in 600 (FIG. 3(c)) (step S7 in FIG. 4).

For example, in the example shown in FIGS. 3(c) and (e), according to the essential factor information 800 (FIG. 3(e)), the specific genomic locus 810 and genotype 820 associated with the essential factor gene for drug B are , " ^* 2 / ^* 3 (heterozygote)" in "gene Y"("G (guanine) / T (thymine)" as the actual nucleotide type) (Fig. 3 (e)), the patient genotype information 600 (FIG. 3(c)), a specific genomic locus 610 associated with the patient's corresponding gene, and the corresponding genotype 620 are " ^* 2/ ^* 3 (heterozygous conjugate)” (“G (guanine)/T (thymine)” as the type of actual nucleotide), so both match. Therefore, the determination in step S7 of FIG. 4 is "YES".

If the determination is "YES" in step S7 of FIG. 4, the administration plan determination unit 120 (FIG. 2) sends the drug information 500 (FIG. 3(b)) to the administration plan output unit 140 (FIG. 2), The output unit 140 (Fig. 2) outputs the above medicine information, the display device 20 (Fig. 2) displays the above medicine information (step S8 in Fig. 4), and the administration plan determination support system ends the processing.

If the determination is "NO" in step S5 of FIG. 4, the information acquiring unit 110 of FIG. ) to display a warning indicating that the essential factor information 800 (FIG. 3(e)) does not exist.

If the determination is "NO" in step S3 of FIG. 4 (for example, the prohibited factor information 700 (FIG. 3(d)) related to the drug (medicine B) is still available in the patient's genotype information 600 (FIG. 3(c)). )), or if the determination is “NO” in step S6 of FIG. The type information 600 (not recorded in FIG. 3(c)), the information acquisition unit 110 (FIG. 2) of FIG. Figure 2). The display device 20 (Fig. 2) displays the message "undecidable" along with the reason (step S9 in Fig. 4) in addition to the drug information 500 (Fig. 3(b)), and the system 1 (Fig. 2) processes exit.

At step S4 of FIG. 4, the genotype 720 of the particular genomic locus 710 associated with the gene that is the prohibited factor (FIG. 3(d)) and the genotype 620 of the particular genomic locus 610 associated with the corresponding gene of the patient. (FIG. 3(c)) matches and the determination is "YES" in step S4 of FIG. and the genotype 620 (FIG. 3(c)) of the specific genomic locus 610 associated with the corresponding gene of the patient do not match, so if the determination is "NO" in step S7 of FIG. (Fig. 2) shows the medicine information 500 (Fig. 3(b)), prohibited factor information 700 (Fig. 3(d) or essential factor information 800 (Fig. 3(e)), and (FIG. 2) and the administration regimen output unit 140 (FIG. 2), where the administration regimen output unit 140 (FIG. 2) issues a warning message (based on "genetic The display device 20 (Fig. 2) displays the above items (step S10 in Fig. 5). (d)) and the essential factor information 800 (FIG. 3(e)), for example, because the metabolic rate of the drug is low, if it is determined that the dose needs to be changed, the drug information 500 (FIG. 3(b)) Decrease the described "daily dose" (step S11 in Fig. 5) In this case ("NO" in step S12 in Fig. 5), administer the changed medicine information 510 (Fig. 6) in which the dose or usage is changed The information is sent to the plan output unit 140 (FIG. 2), the administration plan output unit 140 (FIG. 2) outputs the changed drug information, and the display device 20 (FIG. 2) displays the changed drug information (step S14 in FIG. 5). ), the dosing regimen decision support system terminates the process (a specific example of changing the dose of the drug is described later).

In general, in the changed drug information related to "dosage", if the daily dose exceeds the administration limit, or if the drug effect cannot be expected at all due to pharmacodynamic factors, the drug information change unit (Fig. 2) The change in dosage in the information 500 (FIG. 3(b)) shifts to the change in the type of medicine ("YES" in step S12 of FIG. 5).

In the case of "YES" in step S12 of FIG. 5, for example, based on the prohibited factor information 700 (FIG. 3(d)) and the essential factor information 800 (FIG. 3(e)), the prodrug cannot be converted into an active compound and the drug efficacy is determined. If the drug information change unit 130 (Fig. 2) cannot expect the drug information 500 (Fig. 3(b)) to change the "drug name" (step S11 in Fig. 5). 5), the drug information changing unit 130 (FIG. 2) sends the changed drug information 520 (FIG. 7) in which the drug name is changed to the information acquisition unit 110 (FIG. 2), and the step of FIG. Return to S2.

If "NO" in step S13 of FIG. 5, that is, if there is no candidate drug to be changed, the administration plan determination support system ends the process.

As described above, the administration plan decision support system 1 (FIG. 2) of the present embodiment is capable of determining whether at least one of the genotype of a prohibited factor and the genotype of an essential factor related to a drug is present in the patient's genome. to help determine a more appropriate dosing regimen for the patient. Therefore, the administration plan determination support system 1 (FIG. 2) of the present embodiment allows even a user with little knowledge of genetics to accurately and easily determine a personalized administration plan excellent in efficacy based on the patient's unique genotype. be able to.

Furthermore, according to the administration plan determination support system 1 (FIG. 2) of the present embodiment, the doctor can select the treatment method suitable for the patient from among various treatment methods for diseases such as drug therapy, radiation therapy, exercise therapy, and diet therapy. It also assists in choosing treatment. For example, when an administration plan suitable for a patient for a certain drug is specified by the administration plan determination support system 1 (FIG. 2) of the present embodiment, the administration plan of the drug can be reflected in the patient's future treatment method. can. If administration of such medicament is determined to be unsuitable for the patient, administration of the medicament can also be excluded from future treatment of the patient.

Further, according to the administration plan decision support system 1 (FIG. 2) of the present embodiment, when genotypes of prohibited factors related to a certain drug are present in the patient's genome, or genotypes of essential factors related to a certain drug If the type is not present in the patient's genome, the dosing regimen can be changed by changing the type of drug or its dose contained in the drug information 500 (FIG. 3(b)). Therefore, by updating the information on the prohibited factor and/or the essential factor recorded in the drug-related gene information DB 40 (FIG. 2) of the system 1 (FIG. 2) to the latest information, the system 1 (FIG. 2) is adapted to the patient. customized to improve dosing regimen accuracy and precision.

An example of changing the dosage of the drug when the genotype of the prohibited factor matches the first genotype of the patient, or when the genotype of the essential factor and the second genotype of the patient do not match (Fig. 6). An example of changing the type (FIG. 7) will be described below.

In the relevance information A (FIG. 8(a)), the administration plan determination unit 120 in FIG. heterozygous type " ^* 1/ ^* 3" (actual nucleotide type is "A (adenine)/C (cytosine)") as the genotype information of the patient for the SNP (rs1057910) of From the phenytoin metabolic rate (drug efficacy) value "-1 (prohibited factor)" corresponding to the type " ^* 1/ ^* 3", the propriety of the metabolic rate (drug efficacy) of the medical information 500 (Fig. 3(b)) is determined as " determined as unsuitable. The administration plan determination unit 120 (Fig. 2) determines the medical information 500 (Fig. 3(b)) (specifically, the prescribed dose of "medical information A" in the relevance information A in Fig. 8(a)) and the suitability " Inappropriate” is sent to the medicine information changing unit 130 (FIG. 2).

The medicine information changing unit 130 in FIG. 2 determines that the negative metabolic rate (drug efficacy) value “−1 (inhibitory factor)” is low. The drug information changing unit 130 (FIG. 2) changes the drug information 500 (FIG. 3B) (specifically, "medicine information Among the daily doses in the prescribed dose of A”), the maintenance dose (the dose of the drug that is continuously administered after the initial administration period has elapsed, and is described in the medical information 500 (Fig. 3(b)) "Daily dose (maintenance dose)") is reduced by 1 unit (1 unit = 25% described in the medical information 500) to make the efficacy "±0" (step S11 in Fig. 5). Since the change in step S11 of FIG. 5 is the "daily dose (maintenance dose)" (determination in step S12 of FIG. 5 is "NO"), as described above, the medicine information changing unit 130 (FIG. 2) Changed medicine information 510 (FIG. 6) in which the "daily dose (maintenance dose)" is reduced by 25% from 300 mg to 225 mg is sent to the display device 20 (FIG. 2). In addition, there is no change in the initial dose, and it remains "300 mg daily dose (initial dose)" described in the medical information 500 in FIG. Prescription Dosage of Modified Drug Information B for Dosage). The display device 20 (Fig. 2) displays the changed medicine information 510 (Fig. 6), and the administration plan determination support system 1 (Fig. 2) ends the processing. When the daily dose in the changed medicine information 510 of FIG. 6 exceeds the dose limit, the medicine information changing unit 130 (FIG. 2) changes the type of medicine in the changed medicine information 510 (FIG. 6) ( "YES" in step S12 of FIG.

Unlike the above exemplified cases, the administration plan determination unit 120 (Fig. 2) selects the normal type " ^* 1/ ^* 1" (the actual nucleotide type is " A (adenine)/A (adenine)") is acquired, the value of the metabolic rate (medicine efficacy) of phenytoin is determined as "±0 (essential factor)", and the medical information 500 (Fig. 3(b)) (Specifically, the prescribed dosage of "medicine information A" in the relationship information A in FIG. 8A) is sent to the display device 20 (FIG. 2). The display device 20 (Fig. 2) displays the above medicine information, and the administration plan determination support system 1 (Fig. 2) ends the processing.

Further, in the above example, the change in the medicine information was not the change in the kind of medicine, so the medicine information changing unit 130 of FIG. 2 made the determination "NO" in step S12 of FIG. However, for example, in the following example, the medicine information changing unit 130 (FIG. 2) changes the type of medicine (determination "YES" in step S12 of FIG. 5). Conditions: A suitable drug is selected for patient S with non-small cell lung cancer. (Drug 1) EGFR tyrosine kinase inhibitor: gefitinib, (Drug 2) EGFR tyrosine kinase inhibitor: osimertinib mesylate. It is assumed that the patient S has the following genotype. EGFR: position 2573 mutant (G/G) (homozygous), EGFR: position 2369 mutant (T/T) (homozygous), KRAS: positions 34-35 normal (G/G-G/G) ( Both are homozygous), KRAS: position 38 normal type (G/G) (homozygous)

For patient S, when (drug 1) EGFR tyrosine kinase inhibitor: gefitinib (trade name: Iressa), which is scheduled to be administered, is selected, the “prohibited factor” information of the drug gefitinib is acquired (the process in FIG. 4 S2), obtaining the first genotype information of the corresponding patient S (step S3 in FIG. 4). As genotype information of the "prohibition factor" for the drug gefitinib, position 2369 of the EGFR gene associated with resistance to gefitinib is homozygous mutation "T (thymine) / T (thymine)" or heterozygous mutation "T ( thymine)/C (cytosine)" variant. Next, as a result of collating the above "prohibited factor" information with the corresponding first genotype information of patient S, the genotype of patient S is identified as a "prohibited factor", homozygous mutation at position 2369 of EGFR ( “T/T”) and matches the “prohibited factor”, so it is unsuitable (“YES” in step S4 of FIG. 4). Therefore, a warning message that "the drug is unsuitable" is displayed, and the reason ("prohibited factor" genotype (EGFR: 2369 position T/T or T/C) incompatibility: patient S genotype T/T according to matching) and displayed (step S10 in FIG. 5). Preferably, specifically, "the genotype of patient S is an amino acid mutation of the EGFR T790M mutation associated with the genotype of the patient showing resistance to gefitinib due to a genetic mutation in EGFR gene exon 20 (2369C>T) ( It is desirable to also present the content that the EGFR protein contains a protein in which the 790th amino acid sequence of the EGFR protein is mutated from threonine to methionine. As for the "essential factor" information of the drug gefitinib, the result of comparison/verification with the corresponding second genotype information of the patient S is completely matched, so that it is "matched". The genotype information for the essential factors of gefitinib is that position 2573 of EGFR is G/G or G/T, and positions 34-35-38 of KRAS are G/G-G/G-G/G.

Subsequently, as described above, the above patient S has a homozygous mutation "T/T" at position 2369 of EGFR associated with gefitinib resistance as genotype information of the "prohibition factor" for the drug gefitinib. This time, it was a change in the drug, not a change in dosage, because pharmacodynamic factors could not be expected to have a medicinal effect. Therefore, the determination in step S12 in FIG. 5 is "YES", and the process proceeds to step S13. Since osimertinib mesylate (trade name: Tagrisso) is registered, the determination in step S13 in FIG. 5 becomes "YES", and the process returns to step S2 in FIG.

By the same procedure as gefitinib, genotypes of "essential factors" and "prohibited factors" of (Drug 2) osimertinib mesylate and genotypes of the corresponding patients are obtained, and then compared and collated. As a result, since both (“essential factor” and “prohibited factor”) are compatible, it is determined that “not inappropriate” (“NO” in step S4 of FIG. 4, “YES” in step S7), and finally As drug information 520 (FIG. 7), the irreversible EGFR tyrosine kinase inhibitor (drug 2) osimertinib mesylate that exhibits an inhibitory effect on the T790M mutant EGFR protein is presented to the user (step S8 in FIG. 4). ). The essential factor information of osimertinib mesylate is that position 2573 of EGFR is G/G or G/T, and positions 34-35-38 of KRAS are G/G-G/G-G/G. (In addition, the drug (osimertinib mesylate) has a homozygous mutation at position 2369 of EGFR ("T/T ”) or heterozygous mutations (“T/C”) are not present.).

If the changed medicine is not registered (“NO” in step S13 of FIG. 5), the system ends. In addition, if the genotype of the "prohibited factor" or "essential factor" could be acquired, but the genotype information of the corresponding patient could not be acquired ("NO" in step S3 of FIG. 4 or "NO" in step S6) ”), the user is presented with a message that the drug is “undecidable” along with the reason (step S9 in FIG. 4).

The present invention is not limited to the above embodiments, and various modifications such as those described below are possible.

In the processing procedure of the administration plan decision support system of FIG. 4, the prohibited factor information 700 ( genotype (“first genotype”) information at the locus on the patient genome associated with FIG. 3(d)) and/or the locus on the patient genome associated with the essential factor information 800 (FIG. 3(e)) genotype (“second genotype”) information is not recorded in the genome information DB 50 (FIG. 2), the administration plan determination support system 1 in FIG. Alternatively, instead of proceeding from step S6 to step S9, the control unit 10 (in particular, the information acquisition unit 110) of FIG. and, from the information representing the entire nucleotide sequence, prohibiting factor information 700 for information representing variants with any frequency, including information representing variants whose frequency in the human population is less than 1% (Fig. 3 (d)) DNA variant present at a locus on the patient genome associated with (the patient's "first genotype") and/or DNA present at a locus on the patient genome associated with the essential factor information 800 (FIG. 3(e)) A variant (the patient's “second genotype”) may be detected to update the patient genotype information 600 (FIG. 3(c)) and return to step S2 of FIG.

For example, in order to detect the above DNA variant, as the detection method (1), a target nucleotide sequence corresponding to the DNA variant and partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome were bound. Generating a binding sequence and comparing the binding sequence to the entire nucleotide sequence making up the patient's genome may be repeated with increasing length of the partial nucleotide sequence.

Alternatively, as the detection method (2), in order to detect the DNA variant, two nucleotide sequences corresponding to partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome are generated, and the two nucleotide sequences are The comparison of the sequence to the entire nucleotide sequence making up the patient's genome may be repeated with increasing lengths of the partial nucleotide sequences.

[Embodiment 2]
In the following, the two types of DNA variant detection methods (1) and (2) described above, i. A method for determining the "allelic type" (a patient's "genotype") of any DNA variant in a nucleotide sequence ("full-length string") is described. The DNA variants are any nucleotide changes, including SNPs, SNVs, indels, CNPs, CNVs, microsatellite polymorphisms (“STRPs”). In the method, two character strings representing two nucleotide sequences flanking the target nucleotide are extracted from a known reference character string representing the human genome (“reference character string”) 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 "reference character string" sandwiching the target nucleotide are bound, or (2) the target Two strings are used that represent each of the two nucleotide sequences from which the "reference string" flanked 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 a SNP, SNV or indel. (2) is applicable to determining the "allelic type" of any DNA variant (including SNPs, SNVs or indels as described above), but in particular changes in target nucleotide length, as well as numerous options. or when the details of the target nucleotide are unknown. The above method using the strings of (1) and (2) is described below with reference to FIGS.

(A convenient way to determine the "allelic type" of a SNP, SNV or indel)
The method by the string of (1) described above is a convenient method for determining the allele type of SNPs, SNVs or indels in particular. As shown in FIG. 9, the character string in (1) is a character string 902 representing the target nucleotide (SNP, SNV or indel), two character strings 901 representing the two nucleotide sequences flanking the character string 902 and 903 is one continuous string. Strings 901 and 903 are determined as part of a string representing the human genome of reference (the "reference string") (available, for example, from Ensemble, URL: http://ensembl.org) ( Step S15 in FIG. 10). The character string 902 (character (string) representing the target nucleotide) is stored in a known DB as a DNA variant known (hereinafter simply referred to as "known") at the time of performing the method according to this embodiment. ing. That is, the above-mentioned "DNA variant" may also include DNA variants found after the filing of the present application. For example, information on all known SNPs can be obtained from the dbSNP database (https://www.ncbi.nlm.nih.gov/snp/). Information on the position where character string 902 (the character (string) representing the target nucleotide) is present in the reference human genome character string (“reference string”) is also stored in the DB (eg, the dbSNP database described above). ing. In the character string of (1), it is preferable that the character strings 901 and 903 have the same length and the analysis site (character string 902) is arranged in the center.

Therefore, by the above method, the "allele type" of a known SNP, SNV or indel is added to a character string representing the nucleotide sequence of the whole genome of an individual ("full length character string"), and the character string of (1) is included. (Step S16 in FIG. 10). The position where the character string of (1) can be included in the character string representing the nucleotide sequence of the entire genome of an individual ("full length character string") is the reference human genome ("reference character string") stored in the above DB. can be estimated from the position information of Therefore, for example, when one character string that completely matches the character string in (1) is found (step S17 in FIG. 10), from the character string representing the nucleotide sequence of the entire genome of the individual (“full length character string”), Known SNPs in the nucleotide sequence of the entire genome of the individual ("full-length string") by extracting a string that may contain the string of (1) and comparing the string with the string of (1) , SNV or indel "allelic type" can be determined (step S18 in FIG. 10).

Here, the length of character strings 901 and 903 in FIG. 9 is at least 10 characters (eg, 10, 20, 30, 40, 50, 100, 150, 200 characters or more), preferably 10-1000 characters. be. The smaller the number of characters in the character string in (1), the probability of finding two or more character strings that exactly match the character string in (1) in the character string representing the nucleotide sequence of the entire genome of the individual ("full-length character string"). becomes higher. When two or more character strings that completely match the character string in (1) are found ("NO" in step S17 in FIG. 10), the length of the two character strings (character string 901 and character string 903 in FIG. 9) is evenly extended by one or more characters (eg, 1, 3, 5, 10, 20, 25, 50 or 100 characters) (step S20 in FIG. 10), the probability is reduced. However, the total of the two character strings is, for example, 10000 characters or less. When one of the two extremely long character strings (character string 901 and character string 903 in FIG. 9) contains a character string representing a DNA variant other than the target nucleotide (character 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, and "is not included" always appears.

For example, the number of known SNP allele types at a specific position on the genome is at most 4 types, similar to the types of nucleotides. For example, when the nucleotide of the normal allele is represented by A, an allele containing nucleotides represented by T, G and C is a mutant allele. Thus, by assigning the string 902 in FIG. 9 to A, T, G, and C, and performing the above process four times, the allele type of the known SNP at that particular position can be determined ( Step S18 in FIG. 10). In practice, however, known SNPs are readily determinable in almost two trials, since two (rarely three) nucleotides are common in the population.

In FIG. 9, character strings 901-903 containing normal character strings (normal character strings) and character strings 901-903 containing mutant character strings (mutant character strings) indicate that the individual's genome is homozygous or It can be used to determine if you are heterozygous. For example, both strings representing the nucleotide sequence of an individual's entire genome ("full-length strings") (genomes typically exist as mating types that carry two sets of maternal and paternal origins) have normal strings. When there is a match and the mutated strings do not match, the individual's genome is a normal allele (normal: N/N). Further, for example, when one character string representing the nucleotide sequence of the entire genome of an individual matches the normal character string and the other matches the mutated character string, the genome of the individual has a mutant allele in one genome. (heterozygous: N/M). Also, for example, when the normal character string does not match both of the character strings representing the nucleotide sequence of the entire genome of the individual and the mutant character string matches, the individual's genome has the mutant allele in both genomes. (homozygous: M/M).

The genotype determination process in the individual is determined based on the information of the relevance information A (Fig. 8 (a)) on phenytoin (antiepileptic drug), which exists in the coding region of CYP2C9 (drug metabolizing enzyme gene) A known SNP (rs1057910) that For the above character string 902, the base type of the wild-type (normal) allele in the SNP (rs1057910) is "adenine (A)", which is known to decrease the metabolic rate of phenytoin. The base type of the nucleotide of the metabotropic allele is "cytosine (C)". Also, in the case of known SNPs, the corresponding character strings 901 and 903 can be easily obtained by the above method. Therefore, character strings 901-903 containing the wild-type character "A" ("wild-type character string") and character strings 901-903 containing the low-metabolizer character "C" ("low-metabolizer character string") are extracted. Then, the individual's genotype can be easily determined by performing the above steps twice.

Specifically, when the "wild type character string" matches the character string representing the nucleotide sequence of the entire genome of the individual ("full length character string") and the "low metabolizer character string" does not match, the relevant The individual's genome has wild-type alleles in both genomes (wild-type: "A/A"). Also, for example, when the "full length character string" matches both the "wild type character string" and the "low metabolizer character string", the genome of the individual has a low metabolizer allele in one genome ( heterozygous: "A/C"). Further, for example, when the "wild-type character string" does not match the "full-length character string" and the "low-metabolizer character string" matches, the genome of the individual has the low-metabolizer allele in both genomes. Yes (homozygous poor metabolizer: "C/C").

Depending on the type of combination of nucleotide changes ("A/A", "A/C" or "C/C") of the CYP2C9 SNP (rs1057910) in the individual determined by the above process, the relevance information A ( In the case of the prescribed dose of phenytoin pharmaceutical information A in FIG. 8(a) (the daily dose is 300 mg for both the initial dose and the maintenance dose), prohibited factor information A and essential factor information A (FIG. 8(a)) are shown. As such, different encoded genotypes (“ ^* 1/ ^* 1”, “ ^* 1/ ^* 3” or “ ^* 3/ ^* 3”), as well as different metabolic rates (drug efficacy) (“±0 (essential factor) , '-1 (prohibited factor)' or '-2' (prohibited factor)).

Along with the determined genotype, information representing the DNA variants present in the individual's genome is stored in a DB, a recording medium, or a storage device (not shown), and is also stored in the genome information DB 50 (FIG. 2) ( Step S19 in FIG. 10).

(A general method applicable to determining the "allelic type" of any DNA variant)
Although the method by the character string of (2) above is applicable to determination of allele type ("allele type") including mating type of any DNA variant (including SNPs, SNVs or indels as described above). In particular, it is an effective method when the length of the target nucleotide varies, as well as when there are many options or the details of the target nucleotide are unknown. Variations in the length of the target nucleotide, as well as numerous options arise when targeting simple repeat sequences with different numbers of repeats, such as, for example, microsatellite polymorphisms (“STRPs”). Thus, the character string of (2) is particularly effective when the number of target nucleotides and even the full-length nucleotide sequence of the target nucleotides need to be determined.

The total length of target nucleotides can reach tens of thousands of nucleotides, and large individual differences can occur in the length of target nucleotides. Therefore, the full-length nucleotide sequence of a particular target nucleotide must be determined individually based on the individual's genome. However, the genomic loci where the target nucleotides (CNP, CNV, STRP) reside have already been identified in the human reference genome, as have the SNPs, SNVs or indels. The relative position of the target nucleotide at the locus has also been determined. That is, the character string in (2) is known in the character string representing the human reference genome (“reference character string”) (step S15 in FIG. 10).

The character string in (2) can be an exact match with a character string representing nucleotide sequences flanking the target nucleotide representing known DNA variants present in the individual's genome. Therefore, whether or not the character string (2) (pair: character strings 901 and 903 in FIG. 9) of (2) exists in the character string representing the nucleotide sequence of the whole genome of the individual (“full-length character string”). By determining (step S17 in FIG. 10), it can be determined whether the target nucleotide is present on the individual's genome (step S18 in FIG. 10). The length of the strings in (2) (pair: strings 901 and 903 in FIG. 9) can be set similarly to the length of strings 901 and 903 in the strings in (1).

After confirming the presence of the character string of (2) (pair: character strings 901 and 903 in FIG. 9) in the character string representing the nucleotide sequence of the whole genome of the individual (“full-length character string”), two The strings that lie between the set of strings (string 902 in FIG. 9 and representing the full-length nucleotide sequence of the target nucleotide) are extracted.

For example, when an extracted string represents a simple repeat of a very short sequence (1-4 base pairs in length) such as a microsatellite polymorphism (“STRP”), the repeats contained in the string The number of times (and the total number of nucleotides) is further determined. A simple repeat sequence can vary in the number of repeats in an individual's genome, 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, "heterozygous" is determined when sequences of two different lengths are detected, and "homozygous" is determined when sequences of only one length are detected.

For example, a three-nucleotide (CAG) microsatellite polymorphism (“STRP”) in the coding sequence of the gene responsible for Huntington’s disease (HTT), a late-onset monogenetic disorder, was tested in asymptomatic young adults. The process of determining the genotype in a person (or patient with the disease) will be specifically described. In patients with Huntington's disease, the mutated allele produces an abnormal protein that is toxic to cells, especially nerve cells. Neuronal loss is slow but ultimately leads to a devastating neurodegenerative state. Onset of symptoms usually occurs during middle age to menopause. Huntington's disease results from the production of long polyglutamine chains by unstable expansion of CAG repeats present on the coding sequence of its causative gene HTT. The normal form of glutamine has 6-35 repeats, compared to 36-121 in diseased patients (or asymptomatic young adults at very high risk of developing the disease).

For known microsatellite polymorphisms (“STRPs”) such as those described above, the corresponding 901 and 903 strings can be readily obtained by the methods described above. After confirming the presence of the character string (2) (pair: character strings 901 and 903 in FIG. 9) in the character string (“full-length character string”) representing the nucleotide sequence of the whole genome of the patient with the disease , the sequence of the character string (902 in FIG. 9: representing the full-length nucleotide sequence of the target nucleotide) present between the pair of character strings and its length are extracted and determined. For example, as a result of extracting the sequence and its length, if the number of CAG repeats is "80 (number of nucleotides: 240)" and "113 (number of nucleotides: 339)", it is heterozygous ( Both alleles have the number of repeats corresponding to disease-type alleles, so the risk of onset is extremely high It may also be a candidate genotype of "prohibited factor" for drugs that are contraindicated in Huntington's disease.)). Also, if the CAG repeat number is one type of "5 (nucleotide number: 15)", it is homozygous (both allele types have the number of repeats corresponding to the normal allele, so , have a low risk of onset (e.g., it can be a candidate “prohibitory factor” for a regimen of drugs to treat Huntington’s disease, and a candidate “essential factor” for drugs that are contraindicated for Huntington’s disease) can be.)).

Along with the determined "allele type" (patient's genotype), information representing DNA variants present in the individual's genome is stored in a DB, a recording medium, or a storage device (not shown), and is stored in the genome information DB 50. (FIG. 2) (Step S19 in FIG. 10).

〔others〕
The entire program for executing the system 1 of FIG. 2 is stored in a server accessible from the user terminal used by the user, and can be executed via an intranet or the Internet accessible from the user terminal. The system 1 may be connected to a printing device (for example, a printer or a multi-function peripheral) for printing on paper the information that the user desires to output.

In this case, although the display device 20 (FIG. 2) and the input device 30 (FIG. 2) are shown as being connected to the control unit 10 (FIG. 2) in the above embodiment, the display device 20 (FIG. 2) ) and the input device 30 (FIG. 2) reside in the user terminal (PC, tablet, smart phone, etc.). The server device and the user terminal are connected by a network line, and information input by the input device 30 (FIG. 2) of the user terminal is transmitted to the server device (for example, input by scanning a barcode with a smartphone, tablet, etc.) The server device is generated by the control unit 10 (FIG. 2) based on the input information, information acquired from the drug-related gene information DB 40 (FIG. 2) and the genome information DB 50 (FIG. 2). The received information is transmitted to the user terminal and output to the user via the display device 20 (FIG. 2) of the user terminal. 4 and 5, the administration plan output unit 140 (FIG. 2) transmits the administration plan for the patient to the user terminal, and the user who received the administration plan The terminal displays the administration regimen on the display device. The dosing regimen herein includes the information displayed in steps S8 and S9 of FIG. 4 and steps S10 and S14 of FIG.

In FIG. 2, the drug-related gene information DB 40 is shown as one DB including prohibited factor information 700 (FIG. 3(d)) and essential factor information 800 (FIG. 3(e)). FIG. 3(d)) and the essential factor information 800 (FIG. 3(e)) may be contained in separate medicine-related gene information DBs 40 (FIG. 2).

The order of steps S2 to S4 and steps S5 to S7 in FIG. 4 may be reversed. That is, after determining whether the essential factor information matches the patient's genotype information, the determination of whether the prohibited factor information matches the patient's genotype information may be performed.

In the above embodiment, match (or mismatch) between both the essential factor information and the prohibited factor information and the patient's genotype information is determined, but only one of the essential factor information and the prohibited factor information and the patient's genetic information A match (or mismatch) with the type information may be determined. Steps S2 to S4 in FIG. 4 are omitted when determining the match (or mismatch) between only the essential factor information and the genotype information of the patient. On the other hand, when judging whether only the prohibited factor information matches (or does not match) the genotype information of the patient, steps S5 to S7 are omitted.

[Example of realization by software]
In the system 1 of FIG. 2, the control unit 10 (in particular, the information acquisition unit 110, the administration plan determination unit 120, the medicine information change unit 130, and the administration plan output unit 140) is integrated with logic formed in an integrated circuit (IC chip) or the like. It may be implemented by a circuit (hardware) or by software.

In the latter case, the administration plan decision support system 1 (Fig. 2) comprises a computer that executes program instructions, which are software that implements each function. This computer includes, for example, one or more processors, and a computer-readable recording medium storing the program. In the computer, the processor reads the program from the recording medium and executes it, thereby achieving the object of the present invention. For example, a CPU can be used as the processor. As the recording medium, a "non-temporary tangible medium" such as a ROM (Read Only Memory), a tape, a disk, a card, a semiconductor memory, a programmable logic circuit, or the like can be used. In addition, a RAM (Random Access Memory) for developing the above program may be further provided. Also, the program may be supplied to the computer via any transmission medium (communication network, broadcast wave, etc.) capable of transmitting the program. Note that one aspect of the present invention can also be implemented in the form of a data signal embedded in a carrier wave in which the program is embodied by electronic transmission.

1 administration plan determination support system 10 control unit 110 information acquisition unit 120 administration plan determination unit 130 drug information change unit 140 administration plan output unit 20 display device 30 input device 40 drug-related gene information DB
50 Genome Information DB
400 patient information 500 drug information 510 change drug information 520 change drug information 600 patient genotype information 700 prohibited factor information 800 essential factor information 901 character example 902 character string (target nucleotide)
903 string

Claims (14)

A decision support system for a suitable dosing regimen for a patient, comprising:
a pharmaceutical information acquisition unit that acquires pharmaceutical information representing a pharmaceutical and a dosage that are scheduled to be administered to the patient;
a prohibited factor information acquiring unit that acquires prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition units that acquire essential factor information that is the information of;
A patient genotype information acquisition unit for acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition unit including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and a comparison result between the essential factor information and the second genotype information, a decision support system comprising a dosing regimen decision unit that decides whether the medical information is appropriate for the patient. . comprising both the prohibited factor information acquisition unit and the required factor information acquisition unit,
The administration plan determination unit determines an administration plan for the patient based on a comparison result between the prohibited factor information and the first genotype information and a comparison result between the essential factor information and the second genotype information. 2. The assistance system of claim 1, determining. further comprising a dosing plan output unit that outputs a dosing plan for the patient;
The administration plan determination unit administers to the patient when the first genotype information does not match the prohibited factor information and the second genotype information matches the essential factor information is scheduled as a suitable drug information,
When the administration plan determining unit determines that the drug information scheduled to be administered to the patient is suitable medical information, the administration plan output unit selects the drug information scheduled to be administered to the patient. , output as suitable medical information. a dosing regimen output unit that outputs a dosing regimen for the patient; and a medicine information changing unit that modifies the medicine information if the medicine information is inappropriate;
further comprising
The dosing regimen determining unit, when the first genotype information matches the prohibited factor information, or when the second genotype information does not match the essential factor information, administers to the patient determines that the scheduled drug information is inappropriate,
When the administration plan determination unit determines that the medical information scheduled to be administered to the patient is inappropriate, the administration plan output unit outputs a warning indicating that the medical information is inappropriate and changes the medical information. 4. The support system according to any one of claims 1 to 3, which outputs the modified medicine information modified by the department. The prohibited factor information includes genotypes having mutations associated with the functions of genes encoding proteins involved in the pharmacokinetics or pharmacodynamics of the drug, and predispositions for diseases that develop or become aggravated by administration of the drug. a genotype associated with a combination of alleles associated with the administration of said drug, a genotype with mutations associated with causative genes of monogenic diseases that have been demonstrated to be involved in the development of side effects due to administration of said drug, or side effects due to administration of said drug A genotype with a rare, individual, or Mendelian-like subset of mutations that has demonstrated a strong impact or effect on a multifactorial or polygenic disorder that has been demonstrated to be involved in the development of The support system according to any one of claims 1 to 4. Claims 1 to 3, wherein the essential factor information is an allele type at a specific locus on the genome that is essential for the efficacy of the drug that functions as a molecular target for a specific disease, or a genotype having a combination of allele types. 6. The support system according to any one of 5. When the first genotype information and/or the second genotype information is not recorded as the patient genotype information, the system acquires information representing the entire nucleotide sequence constituting the genome of the patient. and detecting a DNA variant present at the locus of the first genotype and/or the second genotype from the information representing the entire nucleotide sequence to update the patient genotype information;
7. The support system of any one of claims 1 to 6, wherein said patient genotype information comprises information representing variants whose frequency in the human population is less than 1%. To detect the DNA variant, the system comprises:
A target nucleotide sequence corresponding to the DNA variant is combined with partial nucleotide sequences on both sides of the position corresponding to the DNA variant in the reference human genome to generate a binding sequence, and the binding sequence and the patient's genome are constructed. Comparing the whole nucleotide sequence,
8. The assistance system of claim 7, wherein the partial nucleotide sequence is repeated with increasing length. To detect the DNA variant, the system comprises:
generating two nucleotide sequences corresponding to the partial nucleotide sequences on either side of the position corresponding to the DNA variant in the reference human genome, and comparing the two nucleotide sequences with the entire nucleotide sequence making up the patient's genome. of,
8. The assistance system of claim 7, wherein the partial nucleotide sequence is repeated with increasing length. Information representing a single nucleotide polymorphism among the DNA variants is determined using the genome fragment of the patient or based on the information representing the entire nucleotide sequence, and the information representing the determined single nucleotide polymorphism is recorded. ,
10. The support system according to any one of claims 7 to 9, wherein information representing said unrecorded DNA variants is determined based on textual information representing said entire nucleotide sequence. further comprising a dosing plan output unit that outputs a dosing plan for the patient;
11. The support system according to any one of claims 1 to 10, wherein the administration plan output unit transmits the administration plan for the patient to a user terminal equipped with a display device. Assistance system according to any one of the preceding claims, wherein said prohibited factor information and/or said required factor information is generated by artificial intelligence. A computer-implemented method for assisting in determining an appropriate dosing regimen for a patient, comprising:
a pharmaceutical information acquisition step of acquiring pharmaceutical information representing a drug and dosage to be administered to the patient;
a prohibited factor information acquisition step of acquiring prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition steps for acquiring essential factor information that is information of;
A patient genotype information acquisition step of acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition step including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and determining the suitability of said medical information for said patient based on at least one of the comparison results of said essential factor information and said second genotype information. A decision support program for a suitable dosing regimen for a patient, comprising:
a pharmaceutical information acquisition unit that acquires pharmaceutical information representing a pharmaceutical and a dosage that are scheduled to be administered to the patient;
a prohibited factor information acquiring unit that acquires prohibited factor information, which is genotype information at a locus on the genome where administration of the drug is prohibited; and a genotype at the locus on the genome that is essential for administration of the drug. At least one of the essential factor information acquisition units that acquire essential factor information that is the information of;
A patient genotype information acquisition unit for acquiring genotype information of the patient, wherein the genotype information of the patient includes a first genotype of the patient at a locus on the genome corresponding to the prohibited factor; a patient genotype information acquisition unit including genotype information of at least one of the second genotypes of the patient at the locus on the genome corresponding to the essential factor; and the prohibited factor information and the first genotype information; and a comparison result between the essential factor information and the second genotype information, and a program for functioning as a dosing regimen determination unit that determines the suitability of the medical information for the patient. .

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