JP2004517394A - System, method and computer program for guiding the selection of a therapy based on DNA methylation status - Google Patents

Abstract

The present invention relates to systems, methods and computer programs for guiding the selection of a therapeutic or prophylactic treatment based on the methylation status of DNA.
A system, method, and computer program for guiding the selection of a therapy based on the methylation status of DNA are disclosed. The method comprises: (A) a plurality of different methylation states of a selected site of DNA of a known diseased or medical condition and / or healthy cells with respect to the methylation status of a selected site of a patient's DNA. And a second knowledge base consisting of a plurality of specialized rules for assessing and selecting the type of disease or treatment related to the methylation status of selected sites in the patient's DNA. Input to a computer device; (B) generating a ranking list of diseases or medical conditions based on information regarding the methylation status of selected sites in the patient's DNA, a first knowledge base and a second knowledge base with the computer device; To do.

Description

(Background of the Invention)
[0001]
(Field of the Invention)
The present invention is based on information on the methylation status of selected sites in a patient's DNA and clinically useful information for the treatment of a patient, and ranks the appropriate treatment to produce cancer viruses, bacterial infections, etc. Systems, methods and computer programs for guiding the selection of treatments for such complex diseases.
[0002]
(Related technology)
Recently, methodological developments in molecular biology, including the gene itself, the genetic decoding of RNA and the resulting protein, have made remarkable progress. Among individual developments, genes are switched, and the activation and inhibition of specific genes in specific cells and the manner of controlling tissues correlate with the high potential for development and the nature of gene or genomic methylation. In this regard, it is reasonable to assume that the pathogenic conditions are manifested in the limited methylation patterns of individual genes or genomes. The state of the art has made it possible to study the methylation patterns of individual genes. A further development of this method in recent years allows the analysis of very small amounts of starting material, leaving only two digits of all measured points, at least in the theoretical range of 107 measured points.
[0003]
1. State of molecular analysis of phenomenon type cells
Studies of gene expression are possible at the RNA or protein level. Both levels affect important phenotypic parameters. Protein assays using two-dimensional gels (Mc Farrel method) have been used for about 15 years. Using these assays, detailed analysis of the chromatographic position of thousands of proteins is possible. Already, such electropherograms have been processed and evaluated by data processing means. Although the effectiveness of this method is high in principle, it is inferior to recent gene expression methods based on RNA analysis at two points.
[0004]
In particular, detection of regulatoryly important proteins from small amounts of cells fails because the method used is too insensitive. In fact, proteins cannot be amplified compared to nucleic acids. In addition, the method is complex, cannot be automated and is very expensive. In contrast, the analysis of RNA has considerable advantages and is quite sensitive because of the use of PCR. In particular, each RNA species is considered important because it can be immediately identified by its sequence.
Overexpression or underexpression of individual RNAs of known sequence is usually easily detected. However, in the context of applications, those discussed here are exceptionally valid.
Differential displays are suitable for semi-quantitative analytical studies of expression. The expression material amplified by PCR is separated by gel electrophoresis. The effectiveness of gel electrophoresis is limited by the results. In addition, this method has poor sensitivity and is rough for use in routine determinations (Liang, P. and Pardee, AB, Science 257, 967-971).
Over- or under-expressed genes are often identified by reduction techniques. Here, a complementary DNA (cDNA) clone of the cell or tissue fragment to be examined is plated. The cDNA is hybridized to the clone as a control. Using this technique does not make the expression pattern reliable.
One of the jobs of the US Human Genome Project is the organization of gene expression. The data obtained from this can be used for the creation of expression chips, in which the study of sequences in which the cell or tissue type is practically all expressed can be done in a single experiment.
[0005]
2. Status of cancer analysis technology
Gene mutations lead to cancer, a degeneration of cells. The cause of these mutations can be external factors or intracellular events. In a few exceptional cases, individual mutations are large regions of the genome (translocations, deletions) that often occur as a result of cell degeneration. However, most cases involve different cell mutation chains. And this is the binding effect due to the malignant disease. These factors at the DNA level also reflect at the RNA and protein levels. In this discussion, the likelihood of increase is high, as in many cases it is certain that the quantity and type of one RNA will affect the synthesis range of several other RNA fragments. This leads to changes in the rate of protein synthesis, resulting in metabolism of deregulation, which initiates the corresponding regulation of mechanisms and counterregulation. The result is a pattern of cell expression that has been altered in a very specific (but uncertain) manner, such as the specificity of a tumor, the extent of tumor progression, the grade of the tumor, and the like. Such a phenomenon was the outside world of natural science research. In fact, it was not possible to examine gene expression or cellular metabolism as a whole. Early chip technology offered that potential (Schena, M. et al., Science 270, 467-470).
[0006]
If one seeks to solve the diagnostic problem of early diagnosis (finding) of a tumor at the molecular level, today it is confronted with insurmountable difficulties and few exceptions. Because, for most tumors, the molecular mutations that differ from one another are fragmentary and researchers do not know what to look for in a medical research sample. This means that it is absolutely impossible to apply the remarkable sensitivity and specificity of the polymerase chain reaction. Examples of this are certain intestinal tumors, Ewing's sarcoma and some forms of leukemia, each of which is, in fact, simply a correctly described mutation. In such cases, it is possible to identify degenerated cells among millions of cells. However, even within these distinct, unambiguous and defined tumor groups, the conclusion is that the conclusions are additional, unknown, genetic parameters (eg, individual genetic background). Points play an important role. Immunological tumor markers are auxiliary parameters that continue to make a modest contribution in addition to other usual diagnostic parameters. However, they can be used for preliminary selection of suspect cells. Histology plays an important and essential role in the identification of degenerative tissues. However, it is not accurate for early diagnosis. Thus, most tumors are not well characterized by molecular diagnosis and cannot be classified as stage sub-category or even as risk sub-category, but such sub-categories are There is an absolute need in advance for the choice of treatment methods used, especially for the development of effective new drugs and gene therapy.
[0007]
3. Status of research on the number, type and nature of possible stable states of higher animal cells
Recently, when one complex regulatory system (a good example of cell regulation) remains, it has a limited number of stable states, ie, the lower limit is the critical minimum complexity and the upper limit is the maximum connectivity (for any given component). There is an increasing number of indications that can be the mean of the components to which they bind (Kauffman, SA, Origins of Order, Oxford University Press, 1993). In this connection, state was understood to be the concept of general phenomenon selection. Binding to cells as a biological regulatory system can be described as a compartmental state or cell type. Although such a connection has not been presented, and merely a limitation of the possible states for a biological system has been presented, the real relationships are of great importance. If, with respect to the constant information of the contents of living cells (in fact, the existence of such a constant is essential in one species), only a limited number of stable states exist, and degenerative cells are in these states May be present in only one of them, or move between possible states. At this time, it is unlikely that these molecular-based states can be defined. Very little can be associated between the individual states and the range of cells in the artificial state. However, such analysis has made an important contribution to the diagnosis and prognosis of disease. It is also possible to establish a correlation between the possible state of the diseased cells and the optimal treatment. Furthermore, such methods can have a significant effect on the choice of treatment time. For example, discover that tumor cells move between possible states. It can be assumed that the number of cells results in a successful treatment for the selection pressure. The cell number in such a scenario, in the mobile state, is considerably more flexible, the possible stable selection pressure is reduced, and the treatment is easily rendered ineffective. The way in which cells or groups of cells can be classified according to their status helps to recognize, understand and solve such problems. However, the state of the art cannot determine whether there is a limited number of cellular states. In addition, it is not possible to differentiate groups of cells according to a standard abstract on their state and to predict these states with certain behaviors of the cells.
[0008]
4. Hereditary diseases
Today, the genetic map of the human genome consists of 2,500, so-called microsatellites. They are used by linkage analysis to identify and identify a number of genes whose defects cause genetic disease. Common genetic diseases resulting from a single genetic defect are thus elucidated. From a geneticist's point of view, polygenic diseases can also be understood in this way. Polygenic diseases are very common diseases and are included among so-called prevalent diseases. Asthma and diabetes are examples of this. Many cancer types are included. The above linkage analysis tactics also had considerable initial success. In many instances, many causative genes of important polygenic diseases such as diabetes, schizophrenia, atherosclerosis, and obesity have been discovered. In addition to the usefulness of molecular biology research, the availability of a relatively large number of patients and disease-affected analogs is an important and prerequisite for genetic elucidation. Over the past two years, hundreds of patients have been used in the analysis of polygenic diseases and, preferably, have had an order of magnitude reduction in patient numbers. This is used in the case of all causal genes that we want to elucidate. The level of human work that requires such linkage analysis is so high that progress has been very modest in the analysis of polygenic diseases. It is accurate, and these diseases are so socially and economically important that they require novel strategies.
[0009]
5. Current status of methylation analysis technology
Conversion of the genomic base cytosine to 5'-methylcytosine, which represents an epigenetic parameter, is today the most important and most studied topic. Today, there are methods for genotyping a wide range of cells and individual cells, but nonetheless, today, on a large scale, a comparable method of generating and evaluating epigenetic types of information Does not exist.
In principle, there are three methods that differ in the principle of determining the 5-methylation status of cytosine in the context of the sequence.
The first method is based on the principle of the use of a methylation sensitive restriction endonuclease (RE). REs are characterized by producing cleavage of certain DNA sequences with DNA, usually 4-8 bases in length. The location of such cleavages can be detected by gel electrophoresis, migrate to the membrane and hybridize. A means of methylation sensitivity is that certain bases in the recognition sequence are not methylated at the stage of occurrence. After restriction cleavage and gel electrophoresis, the band pattern changes to be dependent on the methylated form of the DNA. However, most methylable CpGs are outside the recognition of the RE sequence and cannot be examined here.
The sensitivity of this method is very low (Bird, AP, Southern, EMJ Mol. Biol. 118, 27-47). A variant uses PCR with this method. Amplification by two primers located on both sides of the recognition sequence occurs after cleavage, if the recognition sequence is in a methylated form. In this case, the sensitivity is theoretically increased to a single molecule of the target sequence, but only individual positions can be examined, but the costs are enormous (Shemer, R. et al., PNAS 93). , 6371-6376).
[0010]
The second variant is based on partial chemical degradation of the entire DNA, using the Maxam Gilbert sequence reaction model, with adapters at the ends. It is thus produced, amplified with common primers and separated by gel electrophoresis. Using this method, defined regions of thousands or fewer base pairs in size are examined. However, this method is no longer practical because of its complexity and poor reliability.
[0011]
Methods of examining DNA to determine the presence of 5-methylcytosine in DNA are based on the specific reaction of bisulfite with cytosine. The latter converts to uracil under appropriate conditions. Uracil is equivalent to thymidine as long as base pairing is involved, and corresponds to other bases. 5-methylcytosine does not change. As a result, the original DNA is converted by hybridization in a manner in which methylcytosine cannot be distinguished from cytosine and detected by conventional molecular biological techniques. All of these techniques are based on fully exploitable base pairs today. As far as sensitivity is concerned, the state of the art is limited in the way that the DNA to be examined is contained in an agarose matrix, preventing DNA diffusion and reconstitution (bisulfite reacts only with a single standard DNA), and by rapid dialysis, (Olek, A., et a., Nucl. Acids. Res. 24, 5064-5066).
Using this method, individual cells were examined, demonstrating the potential of this method.
However, individual regions up to about 3,000 base pairs in length were investigated. And to identify thousands of methylation states, it is not possible to examine the cells all over. However, this method does not reliably analyze small fragments from small samples. Despite measures to prevent diffusion, the sample is lost by the matrix.
[0012]
6. Technology for using bisulfite
Today, with a few exceptions (eg Zeschnigk, M. et al., Eur. J. Hum. Gen. 5, 94-98; Kubota, T. et al. Nat. Genet. 16, 16-17). Bisulfite technology is the only technology used in research. However, particularly small samples of known bisulfite-treated DNA are routinely amplified and fully sequenced (Olek, A. and Walter, J., NG 17, 275-276) or The presence of individual cytosine positions can be determined by a primer extension reaction (Gonzalgo, ML and Jones, PA, Nucl. Acids. Res. 25, 2529-2531), or by enzymatic cleavage (Xiong, Z. and Laid, P.W., Nucl.Acids.Res.25, 2532-2534). All these materials have been published since 1997. The concept of using complex methylation patterns associated with phenotypic data on complex genetic diseases has not previously been described in the literature, depending on evaluation techniques such as, for example, nervous system networks. Furthermore, it is not done by state of the art methodology.
[0013]
7. Current status on methylation and diagnosis of human diseases
In the past, modified methylation patterns have been analyzed to study and understand the genetic mechanisms involved in the sudden development or progression of disease. All of these studies were performed on a case-by-case basis only in the field of genes / chromosomes, and no diagnostic / therapeutic treatment was performed based on a modified methylation pattern. In fact, the association between disease type and methylation pattern was known before methylation analysis was performed. Thus, the following publications show only a well-known relationship between variants of methylation patterns and human diseases. The publication contains both hyper- or hypo-methylation of selected sites in the DNA.
[0014]
Examples of diseases associated with a variant of the methylation pattern are:
Leukemia [Aoki E et al. Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes Leakes 2000 (14) 4: 586-93; Nosaka K et al. "Increasing methylation of the CDKN2A gene is associated with the progress of adult T-cell leukemia" Cancer Res 2000 Feb 15; 60 (4); "ABL1 methylation is a distinct molecular event associated with with chronic evolution of chronic myloid leukemia" Blood 1999 Oct 1; 94 (2); et al. "Detailed Mapping Methylcytosine Positions at the CpG Island Surrounding the Pa Promoter at the bcr-abl Locus in CML Patients and in Two Cell Lines, K562and BV173" Blood Cells Mol Dis 2000 June; 26 (3): 193~204; Lite CE et al. "Methylation status of the major breakpoint cluster region in Philadelphia chromasome negative negative leukemias" Leukemia 1992 Jan. 6 (1): 35-41].
[0015]
Head and neck cancer
[Sanchez-Cespedes M et al. "Gene promoter hypermethylation in tumor and serum of head and neck cancer patients" Cancer Res 2000 Feb 15; 60 (4) 892-5].
Hodgkin's disease
[Garcia JF et al. "Loss of p16 protein expression associated with with methylation of the p16 INK4A gene is a frequency finding in Hodgkin's disease", Rab.
stomach cancer
[Yanagisawa Y et al. "Methylation of the hMLH1" promoter in family gastric cancer with microsatellite instability "Int J Cancer 2000 Jan 1; 85 (1): 50-3].
[0016]
Prostate cancer
[Rennie PSet al. "Epigenetic mechanisms for progress of prostate cancer," Cancer Metastasis Rev 1998-99; 17 (4): 401-9].
Kidney cancer
[Clifford SC et al "Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene and allelic losses at chromosomes arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis" Genes Chromosomes Cancer 1998Jul; 22 (3) 200-9].
Bladder cancer
[Sardi et al. “Molecular genetic alterations of c-myconcogene in superficial and locally advanced blader cancer”, Eur Urol 1998; 33 (4) 424-30].
Breast cancer
[Mancini DN et al. "CpG methylation within 5'regulation of the BRCA1 gene is tumor specific and includees a putative CREBbinding site; Oncogene.RTM. "DNA methylation status of the MUC1 gene coding for a breast-cancer associated protein" Int J cancer 1995 Jul 28; 62 (3): 245-51; Kass DH et al. "Examination of DNA methylation of chromosomal hot spots associated with breast cancer" Anticancer Res 1993 Sep-Oct; 13 (5A): 1245-51]
Burkidd lymphoma
[Tao Q et al "Epstein-Barr virus (EBV) enduric Burkitt's lymphoma: molecular analysis of primary tumor tissue" Blood 1998, Feb. 15: 914;
Wilms tumor
[Kleymenova EV et al. "Identification of a tumor-specific methylation site in the Wilms tumor suppressor gene" Oncogene 1998 Feb 12; 16 (6) 713-20].
[0017]
Prader-Willie / Angelman Syndrome
[Zechnight et al. Im printed segments in the human genome: different DNA methylation patterns in the Prader-Willi / Angelman syndrome region as determined by the genomic sequencing method ". Human Mol Genetics (1997) (6) 3pp 387~395; Fang P et al." The spectrum of mutations in UBE3A causing Angelman syndrome "Hum Mol Genet 1999 Jan; 8 (1): 129-35].
ICF syndrome
[Tuck-Muller et al. "CMDNA hypomethylation and unusual chromasome instability in cell lines from ICF syndrome patents", Cytogenet Cell Genet 2000; 89 (1-2): 121-8].
Cutaneous fibroma
[ChemTC et al. "Dermatofibroma is a clonal proliferative disease" J Cutan Pathol 2000 Jan; 27 (1): 36-9].
Hypertonia
[Lee SD et al. "Monoclonal endothelial cell promotion is present in primary but not secondary pulmonary hyperpertension" J Clin Invest 1998 Mar1; 101 (5): 927.
Pediatric neurobiology
[Campos Castello J et al. "The phenomenon of genomic imprinting" and its implications in clinical neuropediatics "Rev Neurol 1999 Jan 1-15; 28 (1): 69-73].
autism
[Klauck SM et al. "Molecular genetic analysis of the FMR-1 gene in a large collection of authentic patients" Hum Genet 1997 August; 100 (2): 224-9].
Ulcerative colitis
[Gloria L et al. "DNA hypomethylation and proliferative activity are included in the rectal mucosa of the patents with longstanding ulcerative colitis 78"11;
Fragile X syndrome
[Hornstra IK et al. "High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome" Hum Mol Genet 1993 Oct. 5910;
Huntington's disease
[Ferluga J et al. "Possible organ and age-related epigenetic factors in Huntington's disease and colloidal carcinoma" Med Hypotheses 1989 May; 29 (1): 51-51.
All references cited are incorporated herein by reference.
[0018]
8 individual treatment
Successful treatment for patients in need of treatment depends on several factors.
First, there is a high degree of diagnostic or medical care of the disease. In the case of infectious diseases, cancer or acute life-threatening diseases, diagnosis can be made quickly and effectively, since time plays an important role in the survival of patients with these diseases. I have to. Thus, the ideal diagnosis must be based on patient data that is easy to evaluate and does not include time-consuming diagnostics. In addition, a less invasive method must be selected when collecting samples from target patients. One aspect of the patented method is that it offers special diagnostic possibilities, for example, for cancer.
Second, if the diagnosis is accurate, the treatment of the individual patient will be more effective. Currently, for example, for cancer patients, a standard mixture of a plurality of anti-cancer agents that exhibit strict side effects is often administered. Nevertheless, at least some cancers have low survival rates. Thus, cancer or other illness was precisely determined because individual therapies for one illness were exponentially more effective than the other. The effectiveness in this case was directly dependent on the application of the individual treatment to the patient.
If the treatment is cross-checked with a successful treatment already applied to other patients, more effective treatment is possible.
[0019]
Furthermore, accurate diagnosis reduces the cost of individual therapies because unnecessary and ineffective medical care can be avoided. In addition, the treatment of human diseases such as AIDS and cancer is becoming increasingly complex. New data and new treatments are continually modified to make them easier to use. For non-experts, it is difficult to stay up-to-date with the latest information.
Furthermore, even for those who remain in the latest information being disseminated, they digest the information into their own to provide the patient with the best treatment, Need time to understand what is relevant. Combination therapies further exacerbate this problem by becoming more complex with potential drug interactions.
Eventually, the increasing number of patients and the increasing consumption of information on disease treatments have created a mere description of treatments that are unexplained and difficult to accept by patients.
Another desirable form of treatment consists of prophylactic treatments that can be applied in the early stages of the upcoming illness. To know when to apply such therapies, a form of diagnostic method is needed that can diagnose changes in the patient's health, even before the occurrence of an acute illness is diagnosed. This occurrence can be prevented or reduced by the rigorous application of preventive measures to patients with non-acute illness.
In summary, the ideal treatment is to combine the elements in order to apply the most effective medical treatment to the individual patient. This individual diagnostic / medical method is summarized in individualized medical terms.
[0020]
U.S. Pat. No. 5,672,154 (Sillen) describes a method of providing individualized, contextual medical advice to a patient. Recommended medical types include at least two different medical types. There is no description of the means of ranking the multiple treatment options, nor does it explain why the treatment selection is rejected. Rather, the system first concerns the creation of new rules for patient information that optimize the special treatment of diseases such as Parkinson's disease, epilepsy, and blood pressure abnormalities. Sillen does not disclose the need for more accurate diagnostics or the use of DNA methylation for individual medical advice.
U.S. Pat. No. 5,918,568 (Gjerlov) describes medical methods and shampoo treatment of pet skin disorders. Gjerlov further describes a special preparation system for personalized therapeutic shampoos for the treatment of special and individual skin disorders of individual pets. The disclosed method involves adding a premixed, medically effective, concentrate correlating to a specific skin disorder to a skin disorder diagnosis and premix shampoo base, wherein the composition is owned by a pet. Provided to the person. Furthermore, kits for performing the method and shipping packaging and display of the kits are disclosed.
U.S. Pat. No. 5,694,950 (McMichael) describes a method and system for use in treating a patient with an immunosuppressant such as cyclosporine. A sophisticated system is used to provide advice (recommendations) as to whether the dose of the immunosuppressant should be changed, and if so, to what extent. No ranking or selection between multiple different combination therapies has been proposed.
[0021]
U.S. Pat. No. 5,594,638 (Iliff) describes a system for providing medical advice over a common telephone network. This system is not involved in providing recommendations for combination treatments for known diseases (see also US Pat. No. 5,660,176, Iliff).
U.S. Pat. No. 6,081,786 (Barry et al.) Discloses systems, methods and computer programs for guiding the selection of treatments for known diseases such as HIV infection. The method comprises the following (a), (b) and (c).
(A) providing patient information to a computer (computer comprising a first information base comprising a plurality of different disease treatments; a second information base comprising a plurality of precise rules for the selection of disease treatments; A third information base consisting of useful advisory information on treatments comprising different components of different therapies for the patient, and (b) listing of therapies for the patient in the computer (preferably a ranking list); (C) Computer generation of advisory information on one or more treatment lists based on patient information and precise rules.
[0022]
(Summary of the Invention)
As mentioned above, it is an object of the present invention to provide a system for patient treatment, wherein suitable treatments are listed, ranked and based on information on the methylation status of the selected DNA site of the patient. Methods and computer programs.
It is a further object of the present invention to provide systems, methods and computers for avoiding or delaying disease outbreaks based on information on the methylation status of selected DNA sites in patients for prophylactic treatment of patients. It is a program.
Additionally, for the purposes of the present invention, ineffective or unnecessary treatments (eg, ineffective or dangerous treatments) are not displayed or ranked low and are not user-friendly. Or other factors that are specific to the patient, such as drug interactions that occur concomitantly with medical practice.
It is a further object of the present invention to provide a system, method for selecting a treatment or prophylactic treatment based on information on the methylation status of a selected DNA site in a patient, in which the selection of an effective treatment is easily understood. And the provision of computer programs.
It is a further object of the present invention to provide systems, methods and computer programs based on information on the methylation status of selected DNA sites in a patient, in which the complexity of selecting a particular treatment can be easily understood.
It is a further object of the present invention to provide systems, methods and computer programs based on information on the methylation status of selected DNA sites in a patient, in which the reasons for the elimination of special treatments can be easily understood.
It is a further object of the present invention to provide a system, a method and a computer program for obtaining information regarding the effect of a treatment previously performed on a patient.
[0023]
The method of the invention comprises providing information on the methylation status of a selected DNA site in a patient to a computer containing various information bases. For example, a first knowledge base that contains information about a plurality of different methylation statuses of selected sites in DNA of cells of known disease or medical condition and / or healthy cells. A second knowledge base that includes multiple specialized rules for evaluating and selecting the type of disease or treatment based on the methylation status of selected sites in the patient's DNA.
The computer generates a listing (preferably a rank list) or a rank list based on information about the methylation status of the selected site in the patient's DNA, the first knowledge base, the second knowledge base. Based on this list, the treatment is applied to the patient.
According to a specific embodiment of the invention, the treatment is a prophylactic treatment that prevents the acute outbreak of the disease.
In addition, in a preferred embodiment of the invention, the method further comprises a third knowledge base consisting of a plurality of different therapies for diseased or medical condition cells, treatment for diseased or medical condition cells. Preferred treatment for said patient based on a fourth knowledge base consisting of a plurality of expert rules for the evaluation and selection of the method, and on the information generated in the step and on the third and fourth knowledge bases Computerized generation of a ranked list of laws.
In a preferred embodiment of the invention, the method further comprises a fifth knowledge base comprising advisory information having different components of said different therapies, said method and the fifth knowledge base useful for treating a patient. Generating advisory information for one or more therapies in the ranked list based on the information generated in the computer.
[0024]
In another embodiment of the present invention, the method further comprises the step of inputting a user-defined therapy for the disease or medical condition, which is not included in the third knowledge base, and one or more Generating advisory information on said computer for further user-defined treatment combinations. Preferably, the patient information is gender, age, weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, in addition to information on the methylation status of the selected site of DNA. Includes patient information consisting of drug allergy and hypersensitivity information. Patient information includes treatment information preferentially. The patient information preferentially includes the patient information stored in the computer.
In another preferred embodiment of the method of the invention, the advisory information is clinically effective to carry out a warning to isolate the patient from contraindicated drugs and the corresponding treatment prior to the performance of the corresponding treatment. Contains information that there is.
The method of the present invention includes, in a computer, a sixth knowledge base including a history of treatment of the patient, and wherein the advisory information includes previously performed treatment information retrieved from the sixth knowledge base. .
The disease or medical condition to be treated by the method of the present invention is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis or HIV infection.
Further, in another embodiment of the method of the invention, the dosage information is recommended and adjusted, if necessary, according to the patient's information. Yet another method of the invention further comprises accessing, via a computer, information about one or more treatments from a drug reference.
[0025]
The present invention further provides a method for treating a patient in a disease or medical condition, comprising the steps of:
(A) collecting a DNA-containing sample from a patient; (B) analyzing cytosine methylation at a selected site of DNA contained in the sample; (C) methylation status of a selected site of patient DNA And thereby a first knowledge base consisting of said data, information on a plurality of different methylation states of selected sites of DNA of cells in known disease or medical condition and / or healthy cells A second knowledge base consisting of a plurality of expert rules for the evaluation and selection of a type of disease or medical condition based on the methylation status of a selected site in the patient's DNA, and ( D) Generating a rank list of a disease or medical condition based on the data of the first knowledge base, the second knowledge base, and the third knowledge base. In a preferred embodiment of the method of the invention, the data is input to a computer.
The method of the present invention preferably comprises a method for treating a diseased cell or medical condition wherein the fourth knowledge base is a plurality of different diseases and a method for treating a diseased cell or medical condition. It consists of several specialized rules for the evaluation and selection of the law.
In this case, the method of the present invention includes the step (E) of generating a rank list for a preferred treatment for a patient based on the information generated in the step (D) and the fourth and fifth knowledge bases. .
The method of the present invention further comprises a sixth knowledge base consisting of advisory information useful for treating the patient, having different components of said different therapies, and the step (E) and the sixth knowledge base. Generating (F) advisory information for one or more special treatments in the ranked list based on the generated information; and illness or medical condition based on the advisory information generated in step (F). Providing (G) providing the one or more special treatments to the patient.
[0026]
Further, in another specific embodiment of the method of the present invention, the method further includes the following steps (H) and (I). Entering a user-defined therapy for the disease or medical condition (H) and advisory information for one or more user-defined combination therapies not included in the fourth knowledge base (I).
The patient information includes, in addition to information on the methylation status of the selected site of DNA, gender, age, weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy And hypersensitivity information. The patient data preferentially includes treatment information and preferentially includes patient information input to the computer.
In a preferred method of the present invention, it is clinically effective that the advisory information warns the patient not to take a drug contraindicated to the patient prior to the corresponding treatment and to perform the corresponding treatment. Contains information that there is.
Other preferred embodiments of the method of the present invention include a seventh knowledge base consisting of a history of patient treatment, and advisory information obtained from the seventh knowledge base, including information on previously performed treatments. The disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis or HIV infection.
In another embodiment of the method of the invention, the dosage information is recommended and adjusted, if necessary, according to the patient's information.
The invention further includes accessing, via a computer, information about one or more therapies from the drug reference material.
The present invention further provides a treatment or prophylactic treatment selection guide system for a patient in a disease or medical condition. The system is based on a first knowledge base consisting of information on a plurality of different methylation states of cells in a known diseased or medical condition and / or on selected sites of DNA in healthy cells, the patient's DNA. A second knowledge base consisting of a plurality of expert rules for assessing and selecting the type of disease or medical condition with respect to the methylation status of the selected site, multiple different treatments for diseased or medical condition cells A third knowledge base consisting of methods and / or prophylactic therapies, a fourth knowledge base consisting of several specialized rules for the evaluation and selection of treatments for diseased or medical condition cells. .
The system comprises means for providing to the computer information on the methylation status of the selected site in the patient's DNA, wherein the computer relates to the methylation status of the selected site in the patient's DNA, the first knowledge base and the second knowledge base. Means for generating a rank list of diseases or medical conditions from the information.
[0027]
A preferred embodiment of the system of the present invention further relates to a fifth knowledge base of advisory information having different components of said different treatments, one or more treatments in the rank list, useful for treating the patient. And means for generating advisory information for one or more user-defined therapies in the computer.
Another preferred embodiment of the system of the present invention further comprises a user-defined therapy input means and one or more user-defined combination treatments for a disease or medical condition, which are not included in the third knowledge base. Includes means for computer-generated advisory information for the law.
In another system of the invention, the patient information includes gender, age, weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver, in addition to information about the methylation status of the selected site in the DNA. Includes function, renal function, drug allergy and hypersensitivity information. The patient information preferentially includes treatment information. The patient information preferentially includes the patient information stored in the computer.
In other systems of the present invention, the advisory information may be used to warn the patient not to take medications that are contraindicated to the patient before starting the corresponding treatment and to clinically perform the corresponding treatment. Contains information that it is valid.
The system of the present invention preferably contains a sixth knowledge base containing the patient's history of treatment, a computer containing previously performed treatment information, where advisory information was derived from the sixth knowledge base. .
In another system of the invention, the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis or HIV infection.
In another preferred embodiment of the invention, the dosage information is recommended and adjusted, if necessary, by said patient information.
Other systems of the present invention further include a means for accessing, via a computer, information about one or more therapies from standard drug references.
[0028]
The invention further provides a computer program for guiding the selection of a treatment or prophylaxis for a patient in a disease or medical condition. The computer program includes a computer readable storage medium having computer readable program code means formed on the medium, wherein the computer readable program code means comprises a known disease or medical condition. A first knowledge base consisting of information about a plurality of different methylation statuses of selected sites in DNA of cells in a state and / or healthy cells, a disease or medical condition related to the methylation status of selected sites in DNA of a patient Second knowledge base containing multiple expert rules for assessment or selection of types of disease, third knowledge base containing multiple different and / or prophylactic treatments for diseased cells or medical conditions The evaluation or selection of treatments for diseased cells or medical conditions A fourth knowledge base comprising a plurality of specialized rules of the invention, a fifth knowledge base comprising the different components of said different therapies and comprising advisory information useful for treating the patient. Possible computer program code means and readable computer program code means for providing information about the methylation status of the selected site in the patient's DNA, based on information about the methylation status of the selected site in the patient's DNA Readable computer program code means for generating a rank list of a disease or medical condition and readable computer program code means for generating, in a computer, a rank list of preferred treatments for the patient.
[0029]
A preferred embodiment of the computer program of the present invention further comprises readable computer program code means for computer-generating advisory information for one or more treatments in a ranked list. The computer program of the present invention may further comprise a readable computer program code means for inputting a user-defined therapy for a disease or medical condition, one or more users not included in the third knowledge base. A computer program comprising readable program code means for generating, by computer, advisory information for a defined combination therapy.
[0030]
The computer program of the present invention preferably comprises, in addition to information about the methylation status of the selected site of DNA, gender, age, weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, Includes patient information, including renal function, drug allergy and hypersensitivity information. The patient information preferentially includes the treatment information, and the patient information preferentially includes the patient information.
Another preferred embodiment of the computer program of the invention is that the advisory information warns against taking a drug that is contraindicated for the patient before starting the corresponding therapy and the corresponding therapy. Is to include information that it is clinically effective.
[0031]
In another, specific embodiment of the computer program of the present invention, the readable computer program code means comprises a readable computer program code means and a sixth knowledge generating a sixth knowledge base comprising a patient's medical history. And readable computer program code means for generating said advisory information containing previously performed treatment information obtained from the base.
In another preferred embodiment of the computer program according to the invention, the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis or HIV infection.
Furthermore, in another preferred embodiment of the computer program according to the invention, the dosage information is recommended and adjusted, if necessary, by said patient information.
Further, the computer program of the present invention comprises readable computer program code means for accessing information about one or more therapies from standard drug references.
Further objects and interpretations of the present invention are described in detail in the drawings and the following specification.
[0032]
(Brief description of drawings)
The accompanying drawings are incorporated and are a part of the specification, which illustrate specific embodiments of the present invention and are annotated to help explain the principles of the invention.
FIG. 1 illustrates the process of the present invention, including the mechanical work of data entry for specific sites of methylation status of a patient's DNA, treatment and prophylactic treatment.
FIG. 2 is a schematic diagram of the system or apparatus of the present invention.
FIG. 3 is an illustration of a client / server working environment in which the system of FIG. 2 is operated according to an embodiment of the present invention, wherein a central server has at least one local server connected via a computer network such as the Internet. , Indicating that at least one client can access each local server.
[0033]
(Detailed description of the invention)
The preferred embodiments of the present invention have been described with reference to the accompanying drawings. The invention has many different embodiments and cannot be construed as limited to the above embodiments. Rather, these embodiments are provided so that this disclosure will be thorough, and will fully convey the scope of the invention as compared to the prior art. Compare numbers to components.
Compared with the prior art, the present invention comprises a method, a data processing system and a computer program. Accordingly, the present invention represents a purely hardware embodiment, a purely software embodiment, or a combined software and hardware embodiment. Furthermore, the invention takes the form of a computer program on a computer-usable storage medium having computer readable program code means, wherein the computer program is in a medium. Suitable readable media include, but are not limited to, hard disks, CD-ROMs, optical storage devices, and magnetic storage devices.
The present invention will be described below with reference to flowchart diagrams of methods, apparatus (systems), and computer programs in accordance with specific embodiments of the invention. That is, each block in the flowchart diagram and a combination of each block in the flowchart diagram are executed in accordance with the instructions of the computer program. The instructions of the computer program are issued to a general purpose computer, special purpose computer or other programmable data processing device for machine manufacture, and the instructions are via a computer processor or other programmable data processing device. To create means for implementing the flowchart blocks or the special functions of the blocks.
[0034]
These computer program instructions are stored in computer readable memory. This memory allows the computer or programmable data processing device to function in a special way, and the instructions stored in the readable computer memory create a flowchart block or a manufacturing item that includes instruction means to perform the special function in the block. I do.
The instructions of the computer program are also put into a computer or other programmable data processing device, and a series of operating steps are performed on a computer or other programmable device creating a computer-implemented process, the process being performed on a computer. Or other programmable devices allow performing steps in a flowchart block or a special function in a block.
[0035]
The method of the present invention is illustrated by FIG. In a first step 10, a sample to be analyzed is taken from a patient and the patient's DNA is analyzed to obtain patient data regarding the methylation status of selected sites of the patient's DNA. This information is then entered into the computer device 11. Patients may also have sex, age, weight, CD4. Sup. + Cell information, virus infection information, HIV genotype and phenotype information, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy and hypersensitivity information and drug treatment under other conditions Is consulted to obtain one or more patient information comprising The information initially includes a history of the treatment of the disease or medical condition. On the other hand, at the first interview to determine patient information, it can be routinely examined. The patient information is stored on a computer device or, if the information has been obtained in advance, transferred from another computer device, storage device or hard copy.
[0036]
Patient information is typically entered into the computer device 11. In view of the knowledge base 12 and the entered patient information on the plurality of different methylation states at selected sites of the DNA of cells with known diseased or medical conditions and / or healthy cells, the computer device 11 may Includes a knowledge base 13 containing a number of specialized rules for assessing a disease or medical condition or selecting a type based on the methylation status of the selected site.
The list (preferably a rank list) is a computer device that provides information about the methylation status of the selected site in the patient's DNA, the selected site in the DNA of a cell with a known disease or medical condition and / or healthy cells. Generating knowledge or medical conditions based on methylation status at selected sites in a patient's DNA based on multiple expert rules for assessing or selecting types I do.
This rank list shows all known illnesses or medical conditions of the patient and is displayed at 14. In one aspect of the invention, the displayed information is used to manually determine the preferred treatment for the patient, in light of the patient information, and to manually generate advisory information. Based on the information displayed at 14, it is applied to the patient at need 15.
[0037]
The method displayed in FIG. 1 further includes a knowledge base 16 including a plurality of different therapies for the diseased cell or medical condition and a disease or medical condition based on the methylation status of selected sites in the patient's DNA. In light of the type selected, a knowledge base 17 comprising a plurality of technical rules for the evaluation or selection of the choice of a suitable treatment for the patient is included.
The list (preferably a rank list) is based on a knowledge base 16 containing a plurality of different therapies for diseased cells or medical conditions and the disease or medical condition based on the methylation status of selected sites in the patient's DNA in a computer device. In accordance with the selected type of the patient, the information is generated based on the knowledge base 17 including a plurality of technical rules for evaluating or selecting a suitable treatment selection for the patient.
The ranked list shows all possible treatments for the sick or medically ill patient, which is displayed at 18. In another embodiment of the invention, the displayed information is then used to manually determine the preferred treatment for the patient in order to manually generate the advisory information in light of the patient information. Based on the information displayed at 18, it is applied to the patient at need 15.
[0038]
The method of the present invention further includes knowledge based on the advisory information 19. A list of suitable advisory information for the preferred treatment is then generated based on the knowledge base of the advisory information and a list showing all possible known treatments and displayed at 111. The advisory information indicates that it is clinically effective to administer a non-contraindicated drug and / or perform a corresponding therapy that is compatible with the warning or condition that isolates the patient from contraindicated drugs prior to administering the corresponding therapy. Contains information. Based on the information displayed at either 14, 18 or 111, at 15 a treatment for the patient is applied. The progress of this procedure is monitored by monitoring the patient's (cellular) methylation status at all times by taking an intermediate sample from the patient and following the procedure described above.
In another aspect of the invention, the information displayed at any of 14, 18, or 111 is used to apply prophylactic treatment to the patient to prevent an outbreak of the disease.
[0039]
Treatments for diseases (medical conditions), simplified or improved according to the invention, have a very wide choice and are suitable for selection and treatment. Such diseases and medical conditions include, but are not limited to, the following: Heart disease (including, but not limited to, congestive heart failure, hypertension, hyperlipidemia), lung disease (including, but not limited to, chronic obstructive pulmonary disease, asthma, pneumonia, cystic fibrosis, pulmonary tuberculosis) ), Neurological disorders (Alzheimer's disease, Parkinson's disease, epilepsy, multiple neurological sclerosis, amyotrophic lateral sclerosis, or psychosis such as ALS, schizophrenia and brain syndrome, neurosis including anxiety, depression and manic depression Disease), hepatitis (including hepatitis B and C), urinary tract infection (inflammation), sexually transmitted diseases, cancer (including, but not limited to, breast, lung, prostate, and colon cancer). It should be appreciated that the prevention of the progression or onset of the above-mentioned diseases or medical conditions is improved by the present invention.
[0040]
The patient's disease is known, for example, an HIV-1 infection (acquired immune definition syndrome, or acquired immunodeficiency syndrome or AIDS), or the known disease has been administered a combination of treatments. For example, the present invention is useful for some medical conditions. Whether the list of suitable treatments is multiple treatments (eg, 2, 10, or 15 or other), combination therapies (eg, those incorporating two or more therapeutic agents), The invention is particularly useful where the potential for drug interaction is increased and / or the choice of optimal treatment is multifactorial due to its complexity.
Among other things, advisory information can be automatically generated for non-recommended treatments. These multiple steps can be repeated in any sequence in an interactive manner that provides the user with the assurance that all treatment choices will be made with due care. The terms Therapy and therapeutic treatment regimen are interchangeable terms herein and are described herein by the route of administration (eg, oral, intravenous, intramuscular, subcutaneous, arterial, intraperitoneal, intrathecal). Regardless of the disease, it is used pharmaceutically or pharmacologically for any disease (chronic or acute medical condition, disease, etc.). In addition, it is understood that the present invention is not limited to facilitating or improving disease treatment. The present invention is used without limitation in facilitating or improving the treatment of patients in various medical conditions. The term also includes prophylactic treatments used to prevent the occurrence of acute illness.
[0041]
(Description of system)
The present invention consists of a specialized system that provides physicians (or other health care professionals) with treatment of patients with illnesses, such as known or unknown infections, to assist with decisions. The system of the present invention analyzes the methylation status of selected sites in a patient's DNA, provides this information to other knowledge bases, calculates treatment choices and / or selects prophylactic treatments and all relevant Information to be given to those selections. A professional system is a computer program that is capable of simulating the judgment and behavior of a human or organism having specialized knowledge and experience in a particular field, known in the art and also known as AI. Other specialized systems systematically include a set of rules to provide a familiarized experience and each special condition and knowledge base input to the program. Other specialized systems are known as neuronal networks (NNs) that can actively adapt information and knowledge. Other specialized systems are well known in the art and need not be described here.
For example, the choice of antibacterial and / or antiretroviral therapy (combination of antiretroviral agents) takes into account many specialized system rules and treatment history, current status and experimental values of a given patient one after another. It is derived theoretically using a knowledge base consisting of functions. The system of the present invention supports entry, storage, and analysis of patient data regarding the methylation status of selected sites in a patient's DNA in a large central database. The system of the present invention describes the design philosophy of the structure of the microprocessor and the custom reporting capabilities designed to support patient care management and trial activities for clinical drugs such as screening, patient tracking and support. It has flexible data to operate. The system of the present invention provides healthcare professionals (including physicians), clinical research scientists and, perhaps, a high standard of care, while at the same time providing the most effective treatment and / or prophylactic treatment for individual patients. It will be used by health care organizations seeking the lowest cost treatment options for patients as well as treatments.
[0042]
A system 20 embodying the present invention is shown in FIG. System 20 comprises two major components 21 and 22. The first component 21 can analyze the methylation status of selected portions of the DNA of the patient sample 30. This component automatically processes the sample to be analyzed during the analysis, for example, with a PCR device, a mass spectrometer and / or electrophoresis, a component that can convert the generated information into a computer readable signal. Robot. The second component 22 can generate and display information regarding the type of illness of the patient and / or information regarding individual (prophylactic) treatments for the patient.
The second component part 22 includes the following knowledge bases. The first knowledge base 23 comprises information on a plurality of different methylation statuses of selected sites of DNA of known diseased or medical conditions and / or DNA of healthy cells, and the second knowledge base 24 comprises , Consisting of a number of specialized rules that evaluate and select the type of disease or treatment based on the methylation status of selected sites in the patient's DNA, the third knowledge base 25 is ranked by effect (eg, Or a plurality of different and / or prophylactic therapies for diseased or medical condition cells, ranked by system rules) or a fourth knowledge base 26. Consists of a plurality of specialized rules for evaluating and selecting a treatment for a diseased cell or medical condition, and a fifth knowledge base 27 comprises Consisting useful advisory information in the treatment of patients subjected in different configurations. Optionally, the second component comprises a knowledge base of the patient's treatment history and additional patient information (not previously shown).
[0043]
Patient information is preferably stored in a database and updated (programmed). The knowledge base and patient information are updated by an input / output system 28 consisting of a keyboard (and / or mouse) and a video monitor. Note that while the knowledge base and patient information are shown in separate blocks, the knowledge base and patient information can be combined (eg, expert rules and advisory information can be combined into a single database).
To implement the method, at least two of blocks 23-27 generate a list of any of the patient's illnesses or preferred treatments and corresponding advisory information from the information provided by the blocks. Supplied to the inference engine.
[0044]
The inference engine is implemented as hardware, software, or a combination thereof. Inference engines are known, and variations thereof are used to practice the invention. For example, but not limited to, US Pat. No. 5,263,127, Brabash et al (Method for fast rule execution of experts systems), US Pat. No. 5,720,009, Kirk et al (Metho et al.). for rule execution in an expert system using equivalence class to group data objects, U.S. Pat. No. 5,642, accession scheme, Paillet (product education) Kim (High perform It has been described in nce max-min circuit for a fuzzy inference engine).
In the high-speed inference engine, the results of the input data are continuously updated and input as new data. Regarding the involvement of the knowledge base and the patient information in the block, the inference engine is in a separate block from the knowledge base and the patient information, or is combined in a normal program or a routine program. Alternatively, an external knowledge base can be used as well. The information generated in the inference engine can be displayed via an input / output system. Based on the displayed information, the person subscribing to the patient's medical surveillance regime is selected and a patient therapy is applied. At any time, feedback information about the type of disease, the success of the treatment and the preferred medication can be added via the input / output system. Optionally, this data can be provided from an external source 40 (eg, a remote server).
It should be noted that the advisory information generated for the preferred treatment will vary from case to case based on differences in the patient information provided.
[0045]
(System design concept)
The present invention can implement a system including the first component 21 capable of analyzing the methylation status of a patient's DNA. The device takes DNA from a patient sample provided to the component and performs several analyzes to obtain the methylation status of selected sites in the patient. These analysis steps are known to the expert in the field, such as bisulfite treatment, DNA amplification cycle and hybridization reactions by polymerase chain reaction (PCR) experimental design, DNA sequencing, spectroscopy or fluorescence measurement, etc. Consists of All parts of the first device are usually connected and installed as automated as possible to avoid human error and create a high throughput environment.
[0046]
The data generated in the first component is provided to a second component that can perform calculations using the provided data to generate information related to treatment of the patient as described below. The second component may be implemented as a system running on a stand-alone computing device. The present invention is implemented as a system in a client-server environment. As the expert knows, the client application is a request program in a client-server relationship. A server application is a program that waits for a request from a client program on the same or another computer and processes it completely. Client-server environments include the Internet and private networks such as the often cited intranet, local area networks (LANs) and wide area networks (WANs), neural networks (NN), virtual private networks (VPNs), Includes public networks such as frame relay or direct telephone connections. A client or server application includes a computer host client and server application, or other device configured to implement program code embodied in computer usable media performs a number of functions. It is understood that the present invention operates as a means for performing the numerous operations of the present invention. In a preferred embodiment of the present invention, the results of the client calculation can be returned to the server as a report.
FIG. 3 illustrates a client-server environment 30 according to a preferred embodiment of the present invention. The illustrated client-server environment 30 includes a central server 32 that can be accessed by at least one local server via a computer network 36, such as the Internet. Many computer network transport textbooks can be used for communication between the central server 32 and the local server 34, not limited to TCP / IP.
[0047]
(Central server)
The central server 32 includes a central database 38 using Microsoft RTM, a SQL server application program, version 6.5 (Microsoft, Redmond, Wash.) Or the like. The central server 32 confirms that the local server 34 operates with the latest knowledge-based version. The central server 32 stores all patient data and methylation pattern data and procedures, and performs various administrative functions that add and derate local servers and users to the system (20, FIG. 2). Central server 32 also delegates before local server 34 is available to the user. Patient data and / or data on the methylation status of selected sites of the patient's DNA, referred to herein as methylation patterns, is preferably provided to a central repository of patient data and methylation data, Stored in server 32. However, it is understood that patient data may be stored on local server 34 or local storage media. Patient data and methylation patterns and therapy data can be stored on a local server or, for example, on a large scale, analyzing patient samples in a laboratory and supplying methylation patterns to a central server for multiple methylation patterns from multiple patients. Can be provided to a central server from a central device that creates
[0048]
(Local server)
Each local server 34 provides a typical service to multiple users within a geographic area. Each local server 34 includes an inference engine, one or more knowledge bases, and server applications such as a local database 39. Each local server 34 performs an artificial intelligence process for implementing the present invention. When the user initiates the operation of the local server 34 via the client 35, the user is identified by his identification and password, as in the prior art. Once verified, the user has access to the system (20, FIG. 2) and certain administrative rights are given to the user.
Each local server 34 contacts the central server to verify that the latest version of the knowledge base and applications are requesting the local server 34. If not, the request to the local server 34 is downloaded from the central server 32 to a current, verified knowledge base and / or application before a user session is set up. Once the user initiates operation of the system (20, FIG. 2) and a user session is established, all data and artificial intelligence processes operate on the local server.
In a preferred embodiment, each local server database 39 is implemented via Microsoft RTM, a SQL server application program, version 6.5. The primary purpose of each local server database 39 is to store the identifiers of various patients, confirm security, and justify user access to the system. However, it is understood that both the central and local databases 38, 39 are hosted for the central server 32.
[0049]
(Local client)
Each local client 35 includes a client application program consisting of a graphical user connection device (GUI) and a middle layer program that communicates with the local server 34. The program code of the client application program is implemented entirely on the local client 35 or partially on the local clients 35 and 34, respectively. As described below, the user supplies the patient sample to the system (20, FIG. 2) and the first component (21, FIG. 2) of the system (20, FIG. 2) in the client 35 and selects it. Specifically, information is exchanged with each other by inputting (or accessing) patient data displayed in the GUI. The client 35 then proceeds to the local server 34 and to analyze the information generated by the system (20, FIG. 2) and / or entered via the GUI regarding the methylation status of the selected site in the patient's DNA. Contact each other.
[0050]
The computer program code for performing the operations of the present invention is preferably JAVA®. RTM. , Smalltalk, or C ⁺⁺ It is written in a programming language-oriented manner. However, the computer program code that implements the operations of the present invention may also include commonly used "C" programming languages, translated languages such as Perl, or functional (or four generation) programming such as Lisp, SML, Forth. It is also written in the language.
Middle-layer applications, such as client applications, continuously provide users with online information and alert the user immediately when a contraindicated or antagonistic drug or medical treatment is incorporated into the patient's current treatment. An inference engine is included in the local server 34 where it can be found.
[0051]
(Inference engine)
Inference engines are known in the art and need not be described further here. Each knowledge base used by the inference engine according to the present invention is a collection of rules and methods written by a panel of clinical advisors of physicians and scientists of disease treatment. The knowledge base has subject rules, goal rules, and system generated rules. Objective rules are based on the industry setting facts about the treatment of illnesses by drug application, and are obtained from information on drug manufacturers and from review of publications.
In the goal rule, the present invention is set up to protect the user from being recommended for a new treatment choice if no strict data has been entered for the patient. However, the present invention prevents a health care provider, such as a physician, from recording his or her treatment decisions even though the system (20, FIG. 2) indicates why the treatment is harmful to the patient. It is understood that there is no. The present invention gives the health care manager the ultimate authority on patient care.
Thematic rules are based on expert opinion, observation, and experience. Subject rules are typically developed from information and best practices based on the opinions of the majority of experts in the field. Such expert opinion is based on findings from the literature published or published in the field, their own routine clinical experience, research or clinical trials of approved or unapproved drugs. Many experts have thus corrected personal prejudice.
A system-generated rule is tracked by a system that has been given a known or constant treatment over a period of time, resulting in a condition that has improved, stabilized, or worsened. Derived from the results of patients In infectious diseases, there are a huge number of available combinations, so the databases and rules that generated this system are derived from them and encompass data other than the purpose or subject rule database.
[0052]
【Example】
The following non-limiting examples illustrate various aspects of the present invention. These examples are only for the objects shown and are not intended to limit the invention.
(Example 1)
Methods used to treat the occurrence of acute illness
A body sample of an acutely ill patient, who is completely unknown or poorly identifiable, is collected by a physician's lab or hospital healthcare professional. In the context of the present invention, the term "acute illness that cannot be fully identified" generally refers to those diagnosed as having, for example, an unspecified type of cancer that affects the patient. Further examples are acute viral infections or commonly defined bacterial infections. A patient sample containing the DNA of the patient's cells is examined. Basically, any type of patient sample containing DNA can be used in the method of the invention. Samples include either specialized tissue, such as a single type of blood cell, a single type of hepatocyte or a single tumor, or a non-specific tissue, such as skin, brain or other organs. The sample, along with other information about the patient, is then exported to a central laboratory for analysis of the methylation status of selected sites in the patient's DNA. Optionally, the sample is methylated at a selected site in the patient's DNA, consisting of the two different components described above, either in a physician's lab or, for example, in a central laboratory of a hospital. It can be analyzed with the device. The information on the methylation patterns of the individual patients is then provided to a computer device either in the physician's lab or in a hospital or in a central laboratory. Optionally, this information is provided from a remote server or server to a local client for further use or analysis.
In another method of the invention, a tissue sample can be obtained from a selected group of patients, the purpose of which is to generate malignancies due to specific microorganisms or viruses, such as, for example, Neisseria or high communicable virosis. Is to monitor.
[0053]
The information about the methylation pattern of the patient is then compiled into a list of precisely defined individual patient illnesses or appropriate treatments and corresponding individual advisory information from the information supplied from that block. Are processed on a computing device by an inference engine using at least two of the information in blocks 23-27 (FIG. 2).
The patients are then individually treated based on the advisory information generated and displayed on the device. Treatment involves the combination of a particular type of drug or active compound in the drug used as part of the treatment used, which accompanies the individual needs and the patient's drug therapy, which is specific to the patient's disease type. Individual therapies are used, with individual additional, modified treatments that address the problem, such as contraindications.
[0054]
(Example 2)
(Example of preventive treatment)
A tissue sample from a healthy or unidentified or non-acute infectious disease or other disease, such as the earliest cancer, may be obtained by a responsible physician's lab or hospital healthcare professional. Collected. A sample containing the patient's DNA is examined. Thus, the sample contains either special tissues such as cells of a single type of blood cells, cells of a single type of hepatocytes or single tumors, or non-specific tissues such as skin, brain or other organs. The sample, along with the patient's other information, is then sent to a central laboratory for analysis of the methylation status of the selected site in the patient's DNA. Optionally, the sample comprises methylation status at selected sites of the patient's DNA, consisting of the two different components described above, either in a physician's lab or, for example, in a central laboratory of a hospital. It can be analyzed with the device. The methylation information is then provided to a computer device either in the physician's lab or, for example, in a hospital central laboratory. Optionally, this information is provided from a remote server or server to a local client for further use or analysis.
Information about the patient's methylation pattern can then generate a risk assessment, which has not yet been accurately identified and defined, for the individual patient's illness or for the individual to suffer an acute illness in the future, In blocks 23-27 (FIG. 2), the individual statistical risk of the patient is calculated, generating a list of any suitable treatments and corresponding individual advisory information from the information supplied from that block. Is processed on the computing device by the inference engine using at least two pieces of information. The statistical risk is calculated based on a comparison between a knowledge base containing information on the methylation status of healthy cells and information on the methylation status of the patient's DNA. A conclusion is drawn on the basis of the differences found between these two methylation patterns. In addition, factors that influence the conclusion of such statistical analysis include, for example, information on initial treatment or acute medication.
The patients are then individually treated based on the advisory information generated and displayed on the device. Prophylactic treatment is specific to the type of illness and uses individual treatments to prevent the outbreak of the illness and / or reduce the risk of such occurrence. One example of prophylactic treatment is the special diet, which limits the negative effects of diabetes, allergic reactions, cancer or other illnesses, and is most effective in the early stages. Prophylactic treatment is used with additional, individual, altered treatments that address the individual needs and problems that accompany the patient's medication, such as hypersensitivity or allergy.
The foregoing is an illustration of the present invention and is not to be construed as limiting the invention. Although several specific illustrations of the present invention have been set forth, in the state of the art, many of the changed instances are illustrative embodiments, and it will be readily understood that they do not depart from the novelty and advantages of the present invention. Can be evaluated. Accordingly, such variations are included within the scope of the invention as defined by the claims. Therefore, the above description is an exemplification of the present invention, and the disclosed special examples are not to be construed as limiting the present invention, and changes in the disclosed examples and other specific examples are not included in the appended claims. It is included in the range. The invention is limited by the following claims, with equivalents of the claims contained therein.
[Brief description of the drawings]
FIG.
FIG. 2 illustrates the process of the present invention, including the mechanical work of data entry for specific sites of methylation, therapeutic and prophylactic treatment of DNA in a patient.
FIG. 2
1 is a schematic diagram of a system or apparatus of the present invention.
FIG. 3
Fig. 3 is an illustration of a client / server work environment, in which the system of Fig. 2 is operated according to an embodiment of the present invention, wherein the central server is accessible by at least one local server via a computer network such as the Internet And that each local server is accessible by at least one client.

Claims (50)

A method for guiding the selection of a treatment for a patient who is ill or in a medical condition, the method comprising: (A) inputting information about the methylation status of a selected site in a patient's DNA into a computer. The information is based on a first knowledge base consisting of information on a plurality of different methylation statuses of selected sites of DNA in cells of known disease or medical condition and / or healthy cells, A second knowledge base consisting of a number of expert rules for assessing and selecting the type of disease or treatment relating to the methylation status of the selected site, (B) the methylation status of the selected site in the patient's DNA, The computer generates a list or rank list of diseases or medical conditions based on the information on the second knowledge base. In addition, a third knowledge base consisting of multiple treatments for diseased or medical cells, and a fourth knowledge base consisting of multiple specialized rules for the evaluation and selection of treatments for diseased or medical cells. Knowledge base, and
2. A computer generated rank list of preferred treatments for said patient based on (C) the information generated in step (B) and the third and fourth knowledge bases. The method described in. 3. The method according to claim 2, wherein the treatment is a prophylactic treatment. 3. The method of claim 2, further comprising:
A fifth knowledge base consisting of advisory information having different components of said different treatments useful for treating a patient, and (D) information generated in step (C) and the fifth knowledge base of claim 2. Generating advisory information for one or more therapies in the ranked list based on the computer. The method of claim 2, further comprising steps (E) and (F).
(E) input of a user-defined therapy for the disease or medical condition not included in the third knowledge base, and (F) for combination of one or more user-defined therapies. Generating advisory information on said computer. The patient information comprising gender, age, weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy and hypersensitivity information is used to determine the methylation status of the selected site of DNA. The method of claim 1, wherein the method adds to the information. 2. The method of claim 1, wherein the patient information preferentially includes treatment information. The method of claim 1, wherein the patient information preferentially comprises patient information stored on a computer. 5. The method of claim 4, wherein the advisory information includes a warning to isolate the patient from contraindicated drugs and information that it is clinically effective to perform the corresponding therapy prior to the implementation of the corresponding therapy. Method. The method of claim 1, wherein the computer comprises a sixth knowledge base consisting of previously treated patients, and wherein the advisory information comprises previously performed treatment information, wherein the advisory information is retrieved from the sixth knowledge base. The method according to claim 1, wherein the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urinary tract infection (inflammation), hepatitis or HIV infection. 2. The method of claim 1, wherein the dosage information is recommended and adjusted if necessary by the patient information. The method of claim 1, further comprising the step of: (G) accessing information about one or more treatments from drug references via the computer. A method for treating a patient having a disease or medical condition, comprising the following steps.
(A) collecting a DNA-containing sample from the patient; (B) analyzing cytosine methylation at a selected site of DNA contained in the sample; (C) methylating a selected site of patient DNA. Status data, thereby providing a first knowledge base consisting of said data, relating to a plurality of different methylation statuses of selected sites of DNA of cells in known disease or medical condition and / or healthy cells. A second knowledge base consisting of information, a third knowledge base consisting of a plurality of expert rules for the evaluation and selection of a type of disease or medical condition based on the methylation status of selected sites in the patient's DNA, and (D) Generation of a rank list of a disease or medical condition based on the data of the first knowledge base, the second knowledge base, and the third knowledge base. 15. The method of claim 14, wherein the data is provided on a computer. Furthermore, a fourth knowledge base consisting of a plurality of different treatments for diseased cells or medical conditions, and a plurality of expert rules for the evaluation and selection of treatments for diseased cells or medical conditions. A fifth knowledge base consisting of
15. The method of claim 14, further comprising: (E) generating a rank list of preferred treatments for the patient based on the information generated in step (D) of claim 14 and the fourth and fifth knowledge bases. Method. 17. The method of claim 16, wherein the therapy is a prophylactic treatment. Further, a sixth knowledge base consisting of advisory information useful for treating a patient having different components of said different therapies, and (F) a step (E) and a sixth knowledge base of claim 14. Generating advisory information for one or more special treatments in the ranked list based on the obtained information, (G) to the patient in a disease or medical condition based on the advisory information generated in step (F). 17. The method of claim 16, comprising providing the one or more special treatments. 17. The method according to claim 16, further comprising the following (H) and (I).
(H) input of a user-defined therapy for the disease or medical condition not included in the fourth knowledge base and (I) advice for one or more user-defined combination therapies. Generation of strategic information. The patient information comprising gender, age, body weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy and hypersensitivity information is converted to the methylation status of the selected site of DNA. The method of claim 14, wherein the information about is added. 15. The method of claim 14, wherein the patient data preferentially includes treatment information. 15. The method of claim 14, wherein the patient data preferentially comprises patient information stored on a computer. The claim wherein the advisory information includes warning that the patient should not take medications that are contraindicated for the patient prior to the corresponding treatment, and that the execution of the corresponding treatment is clinically effective. Item 19. The method according to Item 18. 19. The method of claim 18, comprising a seventh knowledge base consisting of a patient's history of treatment, and the advisory information obtained from the seventh knowledge base, including information on previously performed treatments. 15. The method according to claim 14, wherein the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urinary tract infection (inflammation), hepatitis or HIV infection. 15. The method of claim 14, wherein a dosage dose information is recommended and adjusted, if necessary, by said patient information. 15. The method of claim 14, further comprising the step of accessing information about one or more therapies from drug references via the computer. A system for guiding the selection of a therapy for a patient having a disease or medical condition, the system comprising: (A) a selected site of DNA of a known disease or medical condition and / or DNA of a healthy cell; A first knowledge base consisting of information on a plurality of different methylation statuses of the patient, a second knowledge base comprising a plurality of expert rules for assessing and selecting a type of disease or medical condition regarding the methylation status of a selected site in a patient's DNA. (B) means for providing the computer with information on the methylation status of the selected site in the patient's DNA, (C) methylation status of the selected site in the patient's DNA in the computer. Means for generating a ranked list of diseases or medical conditions from information about the first knowledge base and the second knowledge base. , Therapy selection guide system for patients with a disease or medical condition. Furthermore, a third knowledge base consisting of a plurality of different and / or prophylactic treatments for diseased or medical condition cells, evaluation and selection of treatment methods for diseased or medical condition cells. 29. A fourth knowledge base comprising a plurality of expert rules for: and (D) in the computer for the patient based on information generated in the third knowledge base and the fourth knowledge base. 29. The system of claim 28, comprising: means for generating a list of preferred treatments or a ranked list. Further, a fifth knowledge base consisting of advisory information having different components of said different treatments useful in treating the patient and (E) advisory information about one or more treatments in said ranked list. 29. The system of claim 28, comprising generating means on said computer. And (F) input means for a user-defined therapy for the disease or medical condition not included in the third knowledge base; and (G) one or more user-defined 30. The system of claim 29, comprising means for generating advisory information for a therapy. The patient information including gender, age, body weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy and hypersensitivity information is obtained for the methylation status of the selected site of DNA. 29. The system of claim 28, adding to the information of 29. The system of claim 28, wherein the patient information preferentially includes treatment information. 29. The system of claim 28, wherein the patient information preferentially includes patient information stored on a computer. The advisory information warns the patient not to take medications that are contraindicated before starting the corresponding treatment, and information that it is clinically effective to perform the corresponding treatment. 29. The system of claim 28, comprising: 29. The system of claim 28, wherein the computer comprises a sixth knowledge base that includes a patient's treatment history, the advisory information including previously performed treatment information derived from the sixth knowledge base. . 29. The system of claim 28, wherein the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis or HIV infection. 29. The system of claim 28, wherein the dosage information is recommended and adjusted, if necessary, by said patient information. 29. The system of claim 28, further comprising: (H) means for accessing, via said computer, information regarding one or more therapies from standard reference materials for drugs. A computer program for guiding the selection of a treatment for a patient with a disease or medical condition, said computer program comprising a readable computer program code means, wherein a computer usable storage medium is formed in the medium. And the readable computer program code means includes the following (A), (B), (C) and (D).
(A) A first knowledge base consisting of information on a plurality of different methylation statuses of selected sites in DNA of cells of known disease or medical condition and / or healthy cells, of selected sites in patient DNA. A second knowledge base containing multiple expert rules for the assessment or selection of a type of disease or medical condition related to methylation status, a plurality of different and / or prophylactic treatments for diseased cells or medical conditions A third knowledge base comprising a plurality of specialized rules for the evaluation or selection of a treatment for a diseased cell or medical condition, comprising a different component of said different treatment, Readable computer program code means for generating a fifth knowledge base containing advisory information useful for treating a patient And (B) readable computer program code means for providing information about the methylation status of the selected site in the patient's DNA, (C) based on information about the methylation status of the selected site in the patient's DNA. Readable computer program code means for generating a ranked list of illnesses or medical conditions; and (D) readable computer program code means for generating, in a computer, a ranked list of preferred treatments for the patient. 41. The computer program of claim 40, further comprising: (E) readable computer program code means for generating, by the computer, advisory information about one or more treatments in the ranked list. Further, (F) readable computer program code means for entering a user-defined therapy for the disease or medical condition not included in the third knowledge base, (G) one or more users 41. The computer program according to claim 40, comprising readable computer program code means for generating, by the computer, advisory information for a defined combination therapy. The patient information including gender, age, body weight, hemoglobin information, neuropathy information, neutrophil information, pancreas, liver function, renal function, drug allergy and hypersensitivity information is obtained for the methylation status of the selected site of DNA. 41. The computer program according to claim 40, wherein the computer program is added to the information of. 41. The computer program of claim 40, wherein the patient information preferentially includes treatment information. 41. The computer program of claim 40, wherein the patient information preferentially includes patient information. The advisory information warns the patient not to take medications that are contraindicated before starting the corresponding treatment, and information that it is clinically effective to perform the corresponding treatment. 41. The computer program according to claim 40, comprising: The readable computer program code means generates a sixth knowledge base including a history of treatment of the patient, and the previously performed treatment information obtained from the sixth knowledge base. 41. The computer program of claim 40, comprising readable computer program code means for generating the advisory information contained. 41. The computer program according to claim 40, wherein the disease or medical condition is heart disease, lung disease, neurological disease, cancer, diabetes, urethral infection (inflammation), hepatitis, or HIV infection. 41. The computer program of claim 40, wherein dose information is recommended and adjusted if necessary by the patient information. 41. The computer program of claim 40, further comprising: (H) readable computer program code means for accessing information about one or more therapies from a standard drug reference via the computer. .

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