Diagnosis support program, diagnosis support system and diagnosis support device

Abstract

To support a diagnosis on an infection focus in an in-vitro diagnosis.SOLUTION: A diagnosis support program is a program for supporting a diagnosis on an infection focus of a bacillus collected from an analyte. The diagnosis support program causes a computer to execute an information acquiring function, a collating function and a determining function. The information acquiring function acquires extracellular vesicles information related to extracellular vesicles including bacterial decomposition products of the bacillus. The collating function collates the extracellular vesicles information with in-vivo station information. The determining function determines information showing the correlation between the extracellular vesicles and the infection focus based upon the collation result.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The embodiments disclosed in the present specification and drawings relate to a diagnostic support program, a diagnostic support system, and a diagnostic support device. [Background technology]

[0002] Infectious diseases may be suspected as the etiology of patients with fever of unknown origin. In order to diagnose infectious diseases, in vitro diagnostics are generally used to identify the causative bacteria. However, it is known that while such in vitro diagnostics can identify the causative bacteria (identify the type of bacteria), they cannot identify the infection focus of the causative bacteria. The infection focus is the site where the causative bacteria is produced. The infection focus is also called the host cell and the cell of origin. The site can be an organ, tissue, etc. within the body.

[0003] For example, while direct microscopic diagnosis of pathogens, immunological diagnosis, and genetic diagnosis can identify the causative bacteria, it is difficult to accurately identify the host tissue. The inability to identify the infection focus can lead to the inability to treat the underlying disease or to delays in treatment. Therefore, when performing in vitro diagnosis on patients with fever of unknown origin who are suspected of having an infectious disease, there is a need for support in diagnosing the infection focus of the causative bacteria. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2023-73798 Summary of the Invention [Problem to be solved by the invention]

[0005] One of the problems to be solved by the embodiments disclosed in this specification and the drawings is to support the diagnosis of an infection focus in in vitro diagnosis. However, the problems to be solved by the embodiments disclosed in this specification and the drawings are not limited to the above problem. Problems corresponding to the effects of each configuration shown in the embodiments described below can also be positioned as other problems. [Means for solving the problem]

[0006] A diagnostic assistance program according to an embodiment is a program for assisting in the diagnosis of a bacterial infection focus collected from a subject. The diagnostic assistance program causes a computer to execute an information acquisition function, a matching function, and a determination function. The information acquisition function is a function for acquiring extracellular vesicle information related to extracellular vesicles containing bacterial degradation products of the bacteria. The matching function is a function for matching the extracellular vesicle information with in vivo localization information. The determination function is a function for determining information indicating the association between the extracellular vesicles and the infection focus based on the matching result. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a diagram illustrating an example of the configuration of a diagnosis support system. [Figure 2] FIG. 2 is a schematic diagram showing how extracellular vesicles are released into the blood. [Figure 3] FIG. 3 is a diagram schematically illustrating an example of the location information stored in the location information database. [Figure 4] FIG. 4 is a flowchart illustrating the procedure of a diagnostic method using the diagnosis support system. [Figure 5] FIG. 5 is a flowchart illustrating a procedure of the diagnosis support process performed by the diagnosis support system. [Figure 6] FIG. 6 is a diagram showing an example of a diagnostic support screen displayed by the diagnostic support system. DETAILED DESCRIPTION OF THE INVENTION

[0008] Hereinafter, an embodiment of a diagnosis support device will be described in detail with reference to the drawings. In the following description, components having substantially the same functions and configurations are designated by the same reference numerals, and redundant description will be given only when necessary.

[0009] (Embodiment) FIG. 1 is a diagram showing the configuration of a diagnostic support system 1. The diagnostic support system 1 includes a diagnostic support device 10, a molecular information database 30, a bacterial species database 40, and a localization information database 50. The diagnostic support device 10 is connected to the molecular information database 30, the bacterial species database 40, and the localization information database 50 via a network 20. The diagnostic support device 10 can transmit and receive various types of information to and from the molecular information database 30, the bacterial species database 40, and the localization information database 50 via the network 20. Note that the various types of data handled in this specification are typically digital data.

[0010] The network 20 is, for example, a LAN (Local Area Network). Connection to the network 20 may be either a wired connection or a wireless connection. Furthermore, as long as security is ensured by a VPN (Virtual Private Network) or the like, the connection line is not limited to a LAN. Connection to a public communication line such as the Internet may also be possible.

[0011] The molecular information database 30, the bacterial species database 40, and the localization information database 50 may be located inside the diagnosis support device 10 or may be provided on the cloud.

[0012] The molecular information database 30 is a database that stores information (hereinafter referred to as molecular information) about molecules contained in extracellular vesicles (EVs) collected from a subject. The molecular information is an example of extracellular vesicle information about extracellular vesicles. Extracellular vesicles are, for example, exosomes. In this embodiment, a case where exosomes are used as extracellular vesicles will be described.

[0013] Exosomes are tiny vesicles approximately 100 nm in diameter found in the body. They have a lipid bilayer membrane structure containing nucleic acids and proteins. Exosomes are secreted from cells, released into the bloodstream, and transport between distant organs. They function to transport substances and transmit information. Proteins or glycoproteins are contained within the lipid bilayer membrane, and nucleic acids such as DNA are known to be attached to the periphery. In other words, exosomes contain molecules such as proteins and nucleic acids. The types and combinations of molecules contained in exosomes are specific to the site where the exosomes are produced. Therefore, information about the molecules contained in exosomes can be used to provide information about the site where the exosomes are produced. Hereinafter, molecules contained in exosomes that are unique to exosomes or specific to the site where the exosomes are produced are referred to as specific molecules.

[0014] Here, "site" refers to an organ, organ, tissue, etc. of a subject. Organs include, for example, organs. Organs include, for example, the brain, lung, breast, esophagus, stomach, rectum, colon, liver, pancreas, bladder, prostate, cervix, or ovary. Tissues are subclassifications of the above organs. For example, lung tissue includes lung non-small cell, small cell, glandular, squamous, large cell, etc.

[0015] Specific molecules include, for example, nucleic acids, enzymes, membrane proteins, scaffolding proteins, single molecules, chaperone proteins, etc. Specific molecules include molecules that have a relationship with exosomes (hereinafter referred to as exosome-associated molecules) and molecules that have a relationship with the site where they are produced (hereinafter referred to as site-associated molecules).

[0016] Exosome-associated molecules are molecules that can be linked to the fact that the tissue to be detected is an exosome. The combination of specific molecules contained in the extracellular vesicles varies depending on the site where the exosomes are produced. Exosome-associated molecules are molecules whose presence in exosomes is predetermined depending on the site where the exosomes are produced. The combination of exosome-associated molecules present in exosomes varies depending on the site where the exosomes are produced. Examples of exosome-related molecules include enzymes such as GAPDH, PK, ATPase, PGK, and enolase; cytoskeletal proteins such as actin, myosin, vimentin, tubulin, cofilin, profilin, and fibronectin; signaling molecules such as EGF-R, HIF-1a, CDC42, PI-3K, ARF1, and Rab5b; chaperone proteins such as HSP70, HSP90, HSP60, and HSC70; tetraspanins such as CD9, CD63, and CD81; integrins such as α6β4, α6β1, and αvβ5; MHC class I molecules, class II molecules; multivesicular molecules such as TSG101, clathrin, ubiquitin, and Alix; and lipid rafts such as flotillin-1.

[0017] Site-associated molecules are molecules that can be linked to the site where the tissue to be detected is produced. Site-associated molecules are molecules whose presence or absence varies depending on the type of site. Examples of site-associated molecules include exosomal microRNAs (miRNAs) such as miR-30c, miR-34a, and miR-181c, messenger RNAs (mRNAs) such as MMP-1, and DNA.

[0018] As described above, molecular information is information about molecules contained in extracellular vesicles detected from blood collected from a subject. The molecular information includes the types of specific molecules contained in the collected exosomes. The molecular information may also include the amount of each specific molecule. The extracellular vesicles may be collected from sources other than blood. For example, the extracellular vesicles may be collected from urine, saliva, or pleural effusion.

[0019] The molecular information is, for example, analytical information obtained by liquid biopsy. The molecular information may be any information containing information about molecules contained in extracellular vesicles, and may be analytical results obtained using an analytical method other than liquid biopsy.

[0020] Additionally, bacterial degradation products (hereinafter referred to as bacterial degradation products) are produced within the cells of the infection focus through decomposition or metabolic processes. Bacterial degradation products are components of bacteria. Bacterial degradation products are packaged in extracellular vesicles and released into the blood. Figure 2 is a schematic diagram showing how extracellular vesicles are released into the blood. Extracellular vesicles containing bacterial degradation products are released into the blood. If the bacteria are not subsequently decomposed or if degradation cannot keep up, the bacteria themselves are also released from the cells. When extracellular vesicles are collected, exosomes containing bacterial degradation products may be detected. Therefore, if the collected exosomes contain exosomes containing bacterial degradation products, the molecular information will also include information about the molecules contained in the bacterial degradation products.

[0021] Bacterial degradation products are released from cells before the bacteria are released from the cells. Therefore, exosomes containing bacterial degradation products are generated before the bacteria are released into the blood. Therefore, exosomes containing bacterial degradation products can be detected earlier than the time when bacteria can be detected in the blood.

[0022] The bacterial species database 40 is a database that stores information (hereinafter referred to as bacterial species identification information) for identifying types of bacteria (hereinafter referred to as bacterial species). As the bacterial species database 40, for example, known databases such as domestic and international medical databases and chemical databases can be used.

[0023] Bacterial species-specific information is information that associates the type of bacteria with a combination of molecules contained in extracellular vesicles containing bacterial decomposition products. For example, the bacterial species-specific information is a correspondence table that associates the type of bacteria with a combination of molecules contained in extracellular vesicles containing bacterial decomposition products. The types of molecules and the combinations of molecules are specific to the type of bacteria contained in the extracellular vesicles. Therefore, information about molecules contained in extracellular vesicles can be used as information about the type of bacteria. Hereinafter, molecules contained in extracellular vesicles containing bacterial decomposition products that are specific to a type of bacteria are referred to as bacterial species-related molecules.

[0024] Bacterial species-associated molecules are molecules whose presence in exosomes containing bacterial lysates is predetermined depending on the type of bacteria. The combination of bacterial species-associated molecules present in exosomes varies depending on the type of bacteria. For example, the bacterial species-associated molecules present in exosomes containing bacterial lysates of Mycobacterium tuberculosis are known to be LpqH (Mycobacterium tuberculosis Lipoprotein), LAM (lipoarabino mannan), and PDIM (phithiocerol dimycoserosites).

[0025] The localization information database 50 is a database that stores in vivo localization information. Here, the living body is, for example, a subject. The in vivo localization information is information that indicates the types and combinations of specific molecules present in each site in the living body. For example, the in vivo localization information is a correspondence table that associates combinations of site-related molecules present inside the organs and tissues of the subject. The localization information database 50 can be, for example, a publicly known database such as a domestic or international medical database or chemical database.

[0026] FIG. 3 is a diagram schematically illustrating an example of in vivo localization information. In FIG. 3, the in vivo localization information is information that defines the combination of site-related molecules present in each organ of the human body. In FIG. 3, for each site, such as "lung," "heart," or "muscle," specific types that may be contained in exosomes produced in that organ are stored. The specific molecules to be stored may include site-related molecules that may be present in that site, and both site-related molecules and exosome-related molecules that may be present in that site may be stored.

[0027] The diagnostic support device 10 acquires molecular information obtained by analyzing molecules contained in extracellular vesicles from a molecular information database 30 via a network 20, and acquires bacterial species identification information from a bacterial species database 40. The diagnostic support device 10 estimates the type of bacteria contained in the extracellular vesicles by comparing the combination of bacterial species-related molecules contained in the molecular information with the bacterial species identification information, and presents the estimated bacterial species as a candidate for an infectious disease, thereby assisting the user in making a diagnosis.

[0028] The diagnostic support device 10 also acquires in vivo localization information from the localization information database 50 via the network 20. The diagnostic support device 10 compares the combination of specific molecules included in the molecular information with the in vivo localization information to estimate the site where extracellular vesicles containing bacterial degradation products have been produced, and presents the estimated site as a candidate site for infection by the causative bacteria, thereby assisting the user in making a diagnosis.

[0029] Next, the configuration of the diagnosis support device 10 will be described. The diagnostic support device 10 includes a memory 11, a communication interface 12, a display 13, an input interface 14, and a processing circuit 15. Although the diagnostic support device 10 will be described below as a single device that executes multiple functions, the multiple functions may be executed by separate devices. For example, the functions executed by the diagnostic support device 10 may be distributed and installed on different console devices or workstation devices.

[0030] The memory 11 is a storage device such as an HDD (Hard Disk Drive), an SSD (Solid State Drive), or an integrated circuit that stores various information. The memory 11 may also be a portable storage medium such as a CD (Compact Disc), a DVD (Digital Versatile Disc), or a flash memory, in addition to an HDD or SSD. The memory 11 may also be a drive device that reads and writes various information from and to semiconductor memory elements such as flash memory and RAM (Random Access Memory). The storage area of ​​the memory 11 may be located within the diagnostic support device 10 or in an external storage device connected via a network.

[0031] The memory 11 stores programs executed by the processing circuit 15, various data used in the processing of the processing circuit 15, etc. As the programs, for example, programs that are installed in advance on a computer from a network or a non-transitory computer-readable storage medium and cause the computer to realize each function of the processing circuit 15 are used. The memory 11 is an example of a storage unit.

[0032] The communication interface 12 is a network interface that controls transmission of communications with the molecular information database 30, the bacterial species database 40, the localization information database 50, and other external devices via the network 20.

[0033] The display 13 displays various types of information. For example, the display 13 outputs medical information generated by the processing circuitry 15, a GUI (Graphical User Interface) for receiving various operations from an operator, etc. For example, the display 13 is a liquid crystal display or a CRT (Cathode Ray Tube) display. The display 13 is an example of a display unit.

[0034] The input interface 14 accepts various input operations from the operator, converts the accepted input operations into electrical signals, and outputs them to the processing circuitry 15. For example, the input interface 14 accepts input of medical information, input of various command signals, etc. from the operator. The input interface 14 is realized by a mouse, keyboard, trackball, switch buttons, a touch screen integrating a display screen and a touchpad, a non-contact input circuit using an optical sensor, a voice input circuit, etc., for performing various processes in the processing circuitry 15. The input interface 14 is connected to the processing circuitry 15 and converts input operations received from the operator into electrical signals and outputs them to the control circuit. Note that, in this specification, the input interface is not limited to those equipped with physical operating components such as a mouse and keyboard. For example, an electrical signal processing circuit that receives electrical signals corresponding to input operations from an external input device provided separately from the device and outputs the electrical signals to the processing circuitry 15 is also an example of an input interface. The input interface 14 is an example of an input unit.

[0035] The processing circuitry 15 controls the overall operation of the diagnostic support device 10. The processing circuitry 15 is a processor that executes an information acquisition function 151, a matching function 152, a decision function 153, and a display control function 154 by calling and executing programs in the memory 11. In other words, the processing circuitry 15 functions as a processing unit that executes programs for realizing the information acquisition function 151, the matching function 152, the decision function 153, and the display control function 154.

[0036] 1, the information acquisition function 151, the matching function 152, the decision function 153, and the display control function 154 are described as being implemented by a single processing circuit 15. However, the processing circuit may be configured by combining multiple independent processors, and each processor may execute a program to implement each function. Also, the information acquisition function 151, the matching function 152, the decision function 153, and the display control function 154 may be implemented as individual hardware circuits. The above description of each function executed by the processing circuit 15 applies to the following embodiments and modifications.

[0037] Although the diagnosis support device 10 is described as a single console that executes multiple functions, the multiple functions may be executed by separate devices. For example, the functions of the processing circuitry 15 may be distributed and installed in different devices.

[0038] The term "processor" used in the above description refers to a circuit such as a central processing unit (CPU), a graphics processing unit (GPU), an application-specific integrated circuit (ASIC), a programmable logic device (e.g., a simple programmable logic device (SPLD)), a complex programmable logic device (CPLD), and a field programmable gate array (FPGA). When the processor is a CPU, for example, the processor realizes its function by reading and executing a program stored in a memory circuit. On the other hand, when the processor is an ASIC, for example, the program is not stored in a memory circuit, but the function is directly incorporated into the processor circuit as a logic circuit. Note that each processor in this embodiment is not limited to being configured as a single circuit, but may be configured as a single processor by combining multiple independent circuits to realize its function. Furthermore, multiple components in FIG. 1 may be integrated into a single processor to realize its function. The above description of "processor" also applies to the following embodiments and modifications.

[0039] The processing circuit 15 acquires extracellular vesicle information related to extracellular vesicles containing bacterial degradation products of bacteria collected from a subject using the information acquisition function 151. In this embodiment, in the information acquisition function 151, the processing circuit 15 acquires molecular information from the molecular information database 30 as extracellular vesicle information. Molecular information is an example of extracellular information. Furthermore, the processing circuit 15 acquires bacterial species-specific information from the bacterial species database 40 and acquires in vivo localization information from the localization information database 50 using the information acquisition function 151. The processing circuit 15 that realizes the information acquisition function 151 is an example of an information acquisition unit.

[0040] The processing circuit 15 compares the extracellular vesicle information with the in vivo localization information using the matching function 152. For example, in the matching function 152, the processing circuit 15 compares a combination of specific molecules included in the extracellular vesicle information with a combination of specific molecules stored in the in vivo localization information, and obtains the comparison result as a matching result. The processing circuit 15 also compares the extracellular vesicle information with the bacterial species-identifying information using the matching function 152. For example, in the matching function 152, the processing circuit 15 compares a combination of bacterial species-associated molecules included in the extracellular vesicle information with a combination of bacterial species-associated molecules stored in the bacterial species-identifying information, and obtains the comparison result as a matching result. The processing circuit 15 that realizes the matching function 152 is an example of a matching unit.

[0041] The processing circuit 15 determines information indicating the association between extracellular vesicles and an infection focus based on the comparison result using the determination function 153. The information indicating the association between extracellular vesicles and an infection focus is, for example, information regarding a candidate infection focus of the pathogenic bacteria. In this case, in the determination function 153, the processing circuit 15 searches for a site where the combination of specific molecules included in the extracellular vesicle information matches the combination of specific molecules stored in the in vivo localization information, and determines the site where the combination matches as a candidate infection focus of the pathogenic bacteria. The processing circuit 15 that realizes the determination function 153 is an example of a determination unit.

[0042] Furthermore, the processing circuit 15 determines information indicating the association between extracellular vesicles and types of bacteria based on the comparison results using the determination function 153. The information indicating the association between extracellular vesicles and types of bacteria is, for example, information about candidate bacteria. In this case, in the determination function 153, the processing circuit 15 searches for bacterial species whose combination of bacterial species-associated molecules included in the extracellular vesicle information matches the combination of bacterial species-associated molecules stored in the bacterial species identification information, and determines the bacterial species with the matching combination as a candidate pathogenic bacteria.

[0043] The processing circuitry 15 generates a screen for assisting diagnosis (hereinafter referred to as a diagnostic assistance screen) using the display control function 154, and displays the generated diagnostic assistance screen on the display 13. In the display control function 154, the processing circuitry 15 displays the names of candidate infection foci on the display 13 as information indicating the association between extracellular vesicles and infection foci. In addition, in the display control function 154, the processing circuitry 15 may further display the names of candidate pathogenic bacteria as information indicating the association between extracellular vesicles and the type of bacteria. The processing circuitry 15 that realizes the display control function 154 is an example of a display control unit.

[0044] Next, a diagnostic method using the diagnostic support system 1 will be described. FIG. 4 is a flowchart showing an example of the procedure of the diagnostic method. Here, as an example, a case will be described in which the type of bacteria that is infecting a patient suspected of having fever of unknown origin and the infection focus of the causative bacteria are diagnosed. Note that the procedure described below is merely an example, and each step can be modified as much as possible as appropriate. Furthermore, steps in the procedure described below can be omitted, replaced, or added as appropriate depending on the embodiment.

[0045] (Diagnosis support processing) (Step S101) When diagnosing a patient with an infectious disease, first, blood is collected from the patient to obtain the patient's blood.

[0046] (Step S102) Next, exosomes are isolated from the collected blood and the isolated exosomes are collected. Known methods can be used to isolate and collect exosomes. For example, a commercially available exosome isolation kit can be used to isolate exosomes.

[0047] (Step S103) Next, the collected exosomes are analyzed to obtain information about the specific molecules contained in the exosomes. For example, liquid biopsy technology can be used to analyze the exosomes. If the collected exosomes contain exosomes that contain both bacterial digests and specific molecules, the liquid biopsy analysis results will include information about the specific molecules as well as information about the bacterial species-related molecules contained in the bacterial digests. The analysis results are stored in the molecular information database 30 as molecular information about the extracellular vesicles.

[0048] (Step S104) Next, using the acquired molecular information, a diagnosis support process is executed by the diagnosis support system 1. The diagnosis support process is a process for supporting the diagnosis of an infectious disease in a patient suspected of having fever of unknown origin.

[0049] Next, the operation of the diagnostic support processing executed by the diagnostic support system 1 in step S104 will be described. Fig. 5 is a flowchart showing an example of the procedure of the diagnostic support processing. Note that the processing procedure in each process described below is merely an example, and each process can be modified as appropriate as possible. Furthermore, steps in the processing procedures described below can be omitted, replaced, or added as appropriate depending on the embodiment.

[0050] (Diagnosis support processing) (Step S201) In the diagnostic support process, first, the processing circuitry 15 acquires molecular information from the molecular information database 30 using the information acquisition function 151. At this time, the processing circuitry 15 acquires, as molecular information, the results of a liquid biopsy analysis of extracellular vesicles collected from the patient's blood. The molecular information includes the types of specific molecules (including exosome-related molecules and site-related molecules) detected from the extracellular vesicles and the types of bacterial species-related molecules.

[0051] (Step S202) Next, the processing circuit 15 reads out bacterial species-specific information from the bacterial species database 40 using the matching function 152, and matches the read-out bacterial species-specific information with the bacterial species-related molecules included in the molecular information. At this time, the processing circuit 15 compares the combination of bacterial species-related molecules included in the molecular information with the combination of bacterial species-related molecules corresponding to the type of bacteria.

[0052] Thereafter, the processing circuit 15 uses the determination function 153 to estimate the species of the pathogenic bacteria causing the fever of unknown origin based on the bacterial species comparison result and determines the estimated species as a candidate pathogenic bacteria. For example, if there is a bacterial species included in the bacterial species identification information that matches the combination of bacterial species-related molecules included in the molecular information, the processing circuit 15 determines that species as a candidate pathogenic bacteria. On the other hand, if there is no bacterial species included in the bacterial species identification information that matches the combination of bacterial species-related molecules included in the molecular information, the processing circuit 15 determines that the candidate pathogenic bacteria is unknown.

[0053] The bacterial species determined as a candidate for the pathogenic bacteria may be one or more bacterial species. Furthermore, the bacterial species determined as a candidate for the pathogenic bacteria need not be a bacterial species with a perfect match in the combination of species-related molecules. For example, among the bacterial species included in the bacterial species identification information, a bacterial species that includes all of the species-related molecules included in the molecular information may be determined as a candidate for the pathogenic bacteria. Furthermore, for each bacterial species, the match rate between the species-related molecules specified in the species identification information and the species-related molecules included in the molecular information may be calculated, and a bacterial species with a match rate equal to or greater than a predetermined value may be determined as a candidate for the pathogenic bacteria.

[0054] (Step S203) Next, processing circuitry 15 reads in vivo localization information from localization information database 50 using matching function 152, and matches the read in vivo localization information with the specific molecules included in the molecular information. In this case, processing circuitry 15 compares the combination of site-associated molecules included in the molecular information with the combination of second specific molecules corresponding to the site of an organ, tissue, etc.

[0055] Thereafter, the processing circuit 15 uses the determination function 153 to estimate the infection focus of the pathogenic bacteria based on the site matching result and determine the estimated infection focus as a candidate infection focus. For example, if there is a site included in the in vivo localization information that matches a combination of site-associated molecules included in the molecular information, the processing circuit 15 determines that site as a candidate infection focus of the pathogenic bacteria. On the other hand, if there is no site included in the in vivo localization information that matches a combination of site-associated molecules included in the molecular information, the processing circuit 15 determines that the candidate infection focus of the pathogenic bacteria is unknown.

[0056] The site determined as a candidate for a focus of infection may be one site or multiple sites. Furthermore, the site determined as a candidate for a focus of infection does not have to be a site with a perfectly matching combination of site-associated molecules. For example, among sites included in the in vivo localization information, a site that contains all of the site-associated molecules included in the molecular information may be determined as a candidate for a focus of infection. Furthermore, for each site, the matching rate between the site-associated molecules defined in the in vivo localization information and the site-associated molecules included in the molecular information may be calculated, and a site with a matching rate equal to or greater than a predetermined value may be determined as a candidate for a focus of infection.

[0057] If the candidate infectious disease of the patient is unknown in the process of step S202, the process of step S203 may be omitted.

[0058] (Step S204) The processing circuitry 15 generates a diagnostic support screen for assisting diagnosis using the display control function 154, and displays the generated diagnostic support screen on the display 13. At this time, the processing circuitry 15 displays the candidate pathogenic bacteria determined in the processing of step S202 and the candidate infection focus determined in the processing of step S203 on the diagnostic support screen. Note that in addition to the candidate pathogenic bacteria and the candidate infection focus, the diagnostic support screen may also display the analysis results of the liquid biopsy and detailed information on the matching results.

[0059] FIG. 6 is a diagram showing a specific example of a diagnostic support screen. The example in FIG. 6 shows an example of a prediction result when the molecular information includes the molecules LpqH (Mycobacterium tuberculosis Lipoprotein), LAM (lipoarabino mannan), PDIM (phithiocerol dimycoserosites), miR146a, and miR150. In the example in FIG. 6, the combination of bacterial species-related molecules (LpqH, LAM, PDIM) included in the molecular information matches the combination of bacterial species-related molecules for "Mycobacterium tuberculosis" stored in the bacterial species-specific information. Therefore, "Mycobacterium tuberculosis" is predicted to be the causative bacterium, and "Mycobacterium tuberculosis" is displayed as a candidate for the causative bacterium. Furthermore, in the example in FIG. 6, the combination of site-related molecules (miR146a, miR150) included in the molecular information matches the combination of site-related molecules for "lung" stored in the in vivo localization information. Therefore, "lung" is predicted to be the infection focus of the causative bacterium, and "lung" is displayed as a candidate for the infection focus. If the candidate pathogenic bacteria or infectious disease is unknown, the diagnosis support screen will display "Unknown."

[0060] The effects of the diagnosis support system 1 and the diagnosis support device 10 according to this embodiment will be described below.

[0061] The diagnostic support system 1 according to this embodiment includes a diagnostic support device 10. The diagnostic support device 10 acquires extracellular vesicle information about extracellular vesicles containing bacterial degradation products of bacteria collected from a subject, compares the extracellular vesicle information with in vivo localization information, and determines information indicating an association between the extracellular vesicles and an infection focus based on the comparison results. The information indicating the determined association can be displayed on a display 13.

[0062] The extracellular vesicles are, for example, exosomes. Bacterial degradation products are bacterial components produced by the degradation or metabolism of bacteria within the tissues of an infected focus. The extracellular vesicle information includes, for example, analytical information obtained by liquid biopsy, and includes information about molecules contained in the extracellular vesicles. The molecules contained in the extracellular vesicles are, for example, proteins or nucleic acids.

[0063] The in vivo localization information includes, for example, information associating a part of the subject with a combination of specific molecules present within the part. The part is, for example, an organ, tissue, or tissue. The information indicating the association between the extracellular vesicles and the infection focus is, for example, information regarding a candidate infection focus of the pathogenic bacteria. The diagnostic support device 10 searches for a part where the combination of specific molecules included in the extracellular vesicle information matches the combination of specific molecules stored in the in vivo localization information, determines the part where the combination matches as a candidate infection focus of the pathogenic bacteria, and displays the determined candidate infection focus on the display 13.

[0064] The diagnostic support device 10 according to this embodiment utilizes the fact that different combinations of specific molecules exist in different regions of organs, tissues, and the like. By comparing the in vivo localization information of specific molecules present in each region stored with the analysis results of extracellular vesicles, the diagnostic support device 10 can estimate the focus of infection and display the estimated candidate focus of infection. In other words, host information and biologically derived information can be obtained from blood extracellular vesicles containing bacterial degradation products as information regarding the focus of infection of the pathogenic bacteria, and the host cells and cells of origin in the body can be estimated and displayed. This makes it possible to present information useful for diagnosing the location of the focus of infection.

[0065] The diagnostic support system 1 of this embodiment also includes a bacterial species database 40 that stores bacterial species-specific information for identifying bacterial species. The bacterial species-specific information is, for example, information that associates bacterial species with combinations of bacterial species-related molecules contained in extracellular vesicles containing bacterial decomposition products. The extracellular vesicle information also includes bacterial information related to the bacterial decomposition products contained in the extracellular vesicles. Therefore, the diagnostic support device 10 compares the bacterial species-specific information with the bacterial information, and determines and displays candidate bacterial species as information indicating the association between the bacterial decomposition products contained in the extracellular vesicles and the bacterial species. With this configuration, the diagnostic support device 10 can also estimate and display the bacterial species of the causative bacteria.

[0066] Furthermore, extracellular vesicles containing bacterial degradation products are released into the blood before the bacteria themselves are released into the blood. Therefore, extracellular vesicles containing bacterial degradation products can be collected from a subject before bacteria are detected in the blood. Obtaining extracellular vesicle information before bacteria are detected in a subject and estimating possible infection foci can be used for early diagnosis.

[0067] Molecular information may be used to determine whether extracellular vesicles have been collected. In this case, it is determined whether exosome-associated molecules specific to exosomes are included in the molecular information. If the exosome-associated molecules are not included in the molecular information, the patient is prompted to collect extracellular vesicles again, thereby assisting in accurate diagnosis.

[0068] According to at least one of the embodiments described above, it is possible to assist in the diagnosis of an infection focus of an infectious agent in in vitro diagnosis.

[0069] Although several embodiments have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be implemented in various other forms, and various omissions, substitutions, modifications, and combinations of embodiments can be made without departing from the spirit of the invention. These embodiments and their modifications are included within the scope and spirit of the invention, as well as within the scope of the invention and its equivalents as defined in the claims. [Explanation of symbols]

[0070] 1...diagnostic support system, 20...network, 30...molecular information database, 40...bacterial species database, 50...localization information database, 10...diagnostic support device, 11...memory, 12...communication interface, 13...display, 14...input interface, 15...processing circuit, 151...information acquisition function, 152...matching function, 153...decision function, 154...display control function.

Claims

1. A program for assisting in the diagnosis of a bacterial infection focus collected from a subject, comprising: An information acquisition function for acquiring extracellular vesicle information regarding extracellular vesicles containing bacterial degradation products of the bacterium; A collation function for collating the extracellular vesicle information with in vivo localization information; A determination function that determines information indicating the association between the extracellular vesicles and the infection focus based on the matching result; A diagnostic support program that causes a computer to execute the above.

2. The extracellular vesicles can be collected from the subject before the bacteria is detected; The information acquisition function is a function of acquiring information about the extracellular vesicles before the bacteria are detected in a subject. The diagnostic support program according to claim 1 .

3. The bacterial decomposition product is produced by the decomposition or metabolism of bacteria in the tissue of the infection focus. The diagnostic support program according to claim 1 .

4. Further comprising a display control function for displaying information indicating the association between the extracellular vesicles and the infection focus on a display unit. The diagnostic support program according to claim 1 .

5. The in vivo localization information includes information associating a site of the subject with a combination of specific molecules present at the site. The diagnostic support program according to claim 1 .

6. The site is an organ, tissue, or organ. The diagnostic support program according to claim 5 .

7. the specific molecule is a protein or a nucleic acid; The combination of the specific molecules contained in the extracellular vesicles varies depending on the site where the extracellular vesicles are produced. The diagnostic support program according to claim 5 .

8. The information indicating the association between the extracellular vesicles and the infection focus is a candidate infection focus from which the extracellular vesicles containing the bacterial lysis products have been released. The diagnostic support program according to claim 5 .

9. The determination function is a function of searching for a site included in the in vivo localization information that matches a combination of specific molecules included in the extracellular vesicle information, and determining the matching site as a candidate for the infection focus. The diagnostic support program according to claim 8.

10. The extracellular vesicle information includes bacterial information regarding bacterial degradation products contained in the extracellular vesicles, the matching function is a function of further matching the bacteria information with bacterial species identification information for identifying the type of bacteria, The determination function is a function of further determining information indicating the association between the extracellular vesicles and the type of bacteria. The diagnostic support program according to claim 1 .

11. the bacterial species-identifying information is information that associates the type of bacteria with a combination of bacterial species-associated molecules contained in the extracellular vesicles; The combination of the bacterial species-associated molecules contained in the extracellular vesicles varies depending on the site where the extracellular vesicles are produced, The information indicating the association between the extracellular vesicles and the type of bacteria is a candidate for the type of bacteria, The determination function is a function of searching for a type of bacteria included in the bacterial species identification information that matches a combination of bacterial species-related molecules included in the extracellular vesicle information, and determining the matching type as a candidate for the bacterial species. The diagnostic support program according to claim 10.

12. Further comprising a display control function for displaying information indicating the association between the extracellular vesicles and the type of bacteria on a display unit. The diagnostic support program according to claim 11.

13. The extracellular vesicles are exosomes. The diagnostic support program according to claim 1 .

14. The extracellular vesicle information includes analysis information obtained by liquid biopsy. The diagnostic support program according to claim 1 .

15. An apparatus for assisting in the diagnosis of a bacterial infection focus collected from a subject, comprising: an information acquisition unit that acquires extracellular vesicle information regarding extracellular vesicles containing bacterial degradation products; A collation unit that collates the extracellular vesicle information with in vivo localization information; A determination unit that determines information indicating an association between the extracellular vesicles and the infection focus based on the matching result; A diagnostic support device comprising:

16. The diagnosis support device according to claim 15; a location information database for storing the in vivo location information; A diagnostic support system comprising:

17. A diagnostic assistance device configured to execute the diagnostic assistance program according to any one of claims 1 to 14 in a processing unit.

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