Method, device, and program for determining the progression of periodontal disease

Abstract

The present invention simply and highly accurately determines the progression degree of periodontal disease. A determination method of determining the progression degree of periodontal disease of a subject, the determination method including a step (S6) of determining the progression degree based on a saliva index determined from saliva of the subject and a blood index determined from blood of the subject.

Description

Technical Field

[0001] This invention relates to a method, apparatus, and procedure for determining the progression of periodontal disease. Background Technology

[0002] Periodontal disease is a condition in which oral infections become a continuous source of bacterial exotoxins and inflammatory cytokines, adversely affecting various systemic diseases. Therefore, the Japanese Ministry of Health, Labour and Welfare has planned nationwide dental checkups to promote early intervention. However, current periodontal disease checkups rely on the techniques of specialists performing procedures such as periodontal pocket examinations and Röntgen photography, which is insufficient for a health checkup program that targets more than 100 people per day. To address this technical issue, a new saliva examination technology has been developed through a joint research project initiated in April 2020 by Tohoku University, a fiber pharmaceutical company, and others (project title: Development of a Novel Oral Care Device for the Prevention of Systemic Diseases).

[0003] In contrast, Patent Document 1 discloses a method for determining the stage of periodontal disease using indicators such as the amount of occult blood, white blood cell count, total protein concentration, and ammonia concentration in a test sample obtained from the oral cavity. This allows for a simple determination of the progression of periodontal disease without relying on the skills of a professional practitioner. Currently, the invention described in Patent Document 1 has been commercialized as the SillHa (registered trademark), a saliva testing device.

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: International Publication No. 2017 / 175673 Summary of the Invention

[0007] The problem that the invention aims to solve

[0008] However, as in Patent Document 1, there is a problem that the degree of periodontal disease progression cannot be accurately determined using only samples obtained from the oral cavity.

[0009] The present invention was made in view of the above-mentioned problems, and its technical problem is to determine the degree of progression of periodontal disease simply and with high accuracy.

[0010] Solution for solving the problem

[0011] To address the aforementioned technical problems, the present invention includes the following solutions.

[0012] Project 1.

[0013] A method for determining the progression of periodontal disease in a subject, characterized in that,

[0014] The determination method includes the step of determining the degree of progress based on saliva indicators measured from the subject's saliva and blood indicators measured from the subject's blood.

[0015] Project 2.

[0016] According to the determination method described in Project 1, the characteristic is that the saliva index is the number of at least one of Porphyromonas gingivalis, Treponema denticulatum, and Forsythori.

[0017] Project 3.

[0018] According to the determination method described in Project 2, the characteristic is that the saliva index is the number of Porphyromonas gingivalis, Treponema denticulatum, and Forsythori.

[0019] Project 4.

[0020] According to the determination method described in Project 1, the blood indicator is at least one of LDL, CRP, WBC, and HbA1c.

[0021] Project 5.

[0022] According to the determination method described in Project 4, the blood indicators are LDL, CRP, WBC, and HbA1c.

[0023] Project 6.

[0024] According to the determination method of any one of items 1 to 5, in the step, the degree of progress is determined by using logistic regression analysis of the saliva index and the blood index.

[0025] Project 7.

[0026] A determining device for determining the progression of periodontal disease in a subject, characterized in that,

[0027] The determination device includes a progression determination unit, which determines the progression based on saliva indicators measured from the subject's saliva and blood indicators measured from the subject's blood.

[0028] Project 8.

[0029] A diagnostic procedure for determining the progression of periodontal disease in a subject, characterized by comprising the following steps performed by a computer:

[0030] The degree of progression is determined based on saliva parameters measured from the subject's saliva and blood parameters measured from the subject's blood.

[0031] Invention Effects

[0032] According to the present invention, the progression of periodontal disease can be determined simply and with high accuracy. Attached Figure Description

[0033] [ Figure 1 [ ] is a flowchart illustrating the overall process of periodontal disease examination according to an embodiment of the present invention.

[0034] [ Figure 2 [ ] is a block diagram illustrating the configuration of a determination device according to an embodiment of the present invention.

[0035] [ Figure 3 This is a flowchart illustrating the specific steps involved in determining the progression of periodontal disease.

[0036] [ Figure 4 [] is a graph representing the ROC curve related to the determination method of the embodiments of the present invention.

[0037] [ Figure 5 [] is a graph showing the curves related to the determination method of the comparative examples.

[0038] [ Figure 6 [] is a graph representing the ROC curve related to the determination method of the modified example of the present invention.

[0039] [ Figure 7 [] is a graph representing the ROC curve related to the determination method of the modified example of the present invention.

[0040] [ Figure 8 [ ] is a flowchart illustrating the specific steps of determining the progression of periodontal disease in a modified example of the present invention. Detailed Implementation

[0041] Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings. It should be noted that the present invention is not limited to the embodiments described below, and various modifications can be made without departing from its spirit.

[0042] (Overall process)

[0043] Figure 1 This is a flowchart illustrating the overall process of periodontal examination according to this embodiment. In this embodiment, the periodontal examination is explained as an option for health diagnoses such as comprehensive physical examinations.

[0044] In step S1, saliva is collected from the patient (hereinafter, the test subject) for health diagnosis using a saliva test kit. Saliva collection can be performed before or after the health diagnosis, or it can be performed during the health diagnosis.

[0045] In step S2, the medical examination institution collects the saliva sample from the test subject.

[0046] In step S3, blood is collected from the subject. Typically, blood collection is performed during a health checkup.

[0047] In step S4, the medical examination institution collects the blood sample from the test subject. The collected saliva and blood samples from the test subject are sent to the examination institution.

[0048] In step S5, the testing agency analyzes the subject's saliva and blood. Specifically, the counts of *Porphyromonas gingivalis* (Pg), *Treponema denticulatum* (Td), and *Forsythia suspensa* (Tf) are determined based on the saliva, and the values ​​of LDL (low-density lipoprotein), CRP (C-reactive protein), WBC (white blood cell count), and HbA1c (hemoglobin A1c) are determined based on the blood. In this embodiment, bacterial DNA is collected from the saliva sample, and the bacterial count is determined using quantitative PCR. It should be noted that the methods for analyzing the bacterial count and blood are not particularly limited.

[0049] The analysis results were sent to the analytical institution. It should be noted that saliva and blood analyses can also be performed by different testing institutions.

[0050] In step S6, the analysis mechanism uses the determination method of this embodiment to determine the degree of progression of periodontal disease in the subject. In this embodiment, according to the classification of periodontitis defined by the Japanese Society of Periodontology (https: / / www.perio.jp / file / news / info_191220.pdf), periodontitis is classified as stage III or IV, and if the periodontitis grade is grade C, it is determined that periodontal disease is progressing. The specific details of the determination method will be described later.

[0051] If the subject's periodontal disease is progressing (yes in step S7), the medical examination agency recommends that the subject visit a dental hospital or other facilities.

[0052] (Diagnosis of periodontal disease)

[0053] Figure 2 This is a block diagram showing the configuration of the determination device 1 in this embodiment. The determination device 1 is used to determine the degree of progression of periodontal disease in the subject in step S6 described above.

[0054] The determination device 1 can be constructed from a general-purpose computer. As a hardware component, it includes processors such as CPU and GPU (illustrations omitted), main storage devices such as DRAM and SRAM (illustrations omitted), and auxiliary storage devices 2 such as HDD and SSD. The determination program P is stored in the auxiliary storage device 2.

[0055] The determination device 1 includes an indicator acquisition unit 3, a data cleaning unit 4, and a progress determination unit 5 as functional blocks. These functional blocks are implemented by the processor of the determination device 1 reading the determination program P from the main storage device and executing it. The determination program P can be downloaded to the determination device 1 via a communication network such as the Internet, or the determination program P can be recorded on a computer-readable non-transitory recording medium such as a CD-ROM or SD card and installed on the determination device 1 via the recording medium.

[0056] Figure 3 It means Figure 1 The flowchart shows the specific process of step S6.

[0057] In step S61, the indicator acquisition unit 3 of the determination device 1 acquires saliva indicators and blood indicators from the analysis results sent by the analysis mechanism. The saliva indicators are the bacterial counts of Pg, Td, and Tf. In this embodiment, the bacterial count is expressed as copy number concentration (copies / μl). The blood indicators are the values ​​of LDL, CRP, WBC, and HbA1c.

[0058] In step S62, the data cleaning unit 4 of the determination device 1 performs data cleaning on at least a portion of the saliva and blood indicators as needed. In this embodiment, data cleaning is performed on the values ​​of Pg, LDL, and WBC. Specifically, for Pg, the copy number concentration is converted to a logarithmic value with a base of 10. For LDL, if the LDL value is below a reference value, it is converted to "1"; if the LDL value is above the reference value, it is converted to a value obtained by subtracting the reference value from the LDL value. Similarly, for WBC, if the WBC value is below the reference value, it is converted to "1"; if the WBC value is above the reference value, it is converted to a value obtained by subtracting the reference value from the WBC value.

[0059] In step S63, the progression determination unit 5 of the determination device 1 determines the progression of the periodontal disease of the subject based on the cleaned saliva and blood indicators. In this embodiment, the progression determination unit 5 determines the progression of the periodontal disease of the subject by using logistic regression analysis of the saliva and blood indicators. An example of the logistic regression formula is shown in the following equation (1).

[0060] [Formula 1]

[0061]

[0062] Pg: The logarithm of the number of bacteria in Pg (copies / μl) (base = 10).

[0063] Td: The number of bacteria in Td (copies / μl).

[0064] Tf: The number of bacteria in Tf (copies / μl).

[0065] LDL: LDL value (mg / dl) after data cleaning.

[0066] CRP: CRP value (mg / dl).

[0067] WBC: WBC value ( / μl) after data cleaning.

[0068] HbA1c: HbA1c value (mmol / mol).

[0069] a~h: constants (regression coefficients).

[0070] It should be noted that logarithmic values ​​or cleaned data values ​​are sometimes used, but this is merely for computational convenience and is not a limitation. Furthermore, the use of these values ​​includes the use of saliva and blood indicators.

[0071] If the progression determination unit 5 determines that periodontal disease is progressing (is severe periodontal disease) when Y obtained by the above formula is below the prescribed threshold (cutoff value).

[0072] (summary)

[0073] In the determination method of this embodiment, the degree of periodontal disease progression is determined using both saliva indicators measured based on the subject's saliva and blood indicators measured based on the subject's blood. Therefore, as shown in the embodiments described later, the degree of periodontal disease progression can be determined with high accuracy compared to the invention described in Patent Document 1, which uses only samples obtained from the oral cavity.

[0074] Furthermore, blood indicators are items that can be checked in routine health checkups, and therefore can be obtained based on the results of the health checkup, unlike periodontal disease assessment in dental examinations which relies on the skill of a professional practitioner. Therefore, for individuals who regularly undergo health checkups, the burden on the individual will not increase compared to the existing assessment method described in Patent Document 1. It should be noted that the health checkup rate in Japan is as high as 64%.

[0075] As described above, in this embodiment, the progression of periodontal disease can be determined simply and with high accuracy.

[0076] (Additional Notes)

[0077] This invention is not limited to the above-described embodiments. Various modifications can be made within the scope of the claims. The methods obtained by appropriately combining the technical means disclosed in the embodiments are also included within the technical scope of this invention.

[0078] For example, in the above embodiments, the saliva index used for determination is the number of Porphyromonas gingivalis, Treponema denticulatum, and Forsythoriium, but it can also be the number of at least one of these bacteria. In addition, the number of bacteria other than those mentioned above (e.g., Orange Species Complex, etc.) can also be included in the saliva index.

[0079] In the above embodiments, the blood indicators used for determination are LDL, CRP, WBC, and HbA1c, but may also be at least one of these test values. In addition, values ​​of test items other than those mentioned above (e.g., neutrophil count, HDL, blood glucose level, etc.) may also be included in the blood indicators.

[0080] In the above embodiments, the progression of periodontal disease in the subject is determined by logistic regression analysis using salivary and blood indicators, but the present invention is not limited thereto. For example, the progression of periodontal disease in the subject can also be determined using a known machine learning model that uses salivary and blood indicators.

[0081] Example

[0082] The following describes embodiments of the present invention, but the present invention is not limited to the following embodiments.

[0083] In this embodiment, 100 patients were selected as subjects: 50 periodontal disease patients from the Department of Endodontics at Northeastern University Hospital and 50 periodontal disease patients from the city center outpatient clinic (a joint research institution of the applicant). The progression of periodontal disease in the subjects was determined using the determination method described above. Specifically, saliva indicators (Pg, Td, and Tf bacterial counts) and blood indicators (LDL, CRP, WBC, and HbA1c) obtained from each subject were retrieved from the database. The values ​​of Pg, LDL, and WBC were cleaned. The progression of periodontal disease in the subjects was determined using logistic regression analysis of the saliva and blood indicators. The accuracy of the determination was verified by cross-validation.

[0084] Furthermore, as a comparative example, using the saliva examination device Silha, which corresponds to the invention described in Patent Document 1, the progression of periodontal disease was determined with the same subjects as in the embodiment. Specifically, the progression of periodontal disease in each subject was determined using indicators such as occult blood, protein, white blood cells, and ammonia obtained from each subject, and the accuracy of the determination was verified by cross-validation.

[0085] In the examples and comparative examples, in the classification of periodontitis prescribed by the Japanese Society of Periodontology, if the periodontitis is in stage III or IV and the periodontitis grade is grade C, it is determined that the periodontitis is progressing.

[0086] Figure 4This is a graph representing the ROC curve related to the determination method of this embodiment. Figure 5 This is a graph showing the ROC curves related to the determination method of the comparative examples. Table 1 shows the AUC (P < 0.001), sensitivity, and specificity of each determination method for this embodiment and the comparative examples. It should be noted that the sensitivity and specificity vary depending on the cutoff value set.

[0087] [Table 1]

[0088]

[0089] According to Table 1, in this embodiment, the AUC is higher than any index of the comparative example. Therefore, it can be seen that the determination method of this embodiment can determine the degree of periodontal disease progression with high accuracy compared with the existing determination method described in Patent Document 1.

[0090] Supplements and variations to the above embodiments are described.

[0091] In the above embodiments, examples of salivary indicators (hereinafter referred to as "saliva indicator items" for convenience) include the number of Porphyromonas gingivalis (Pg), Treponema denticulatum (Td), and Forsythoracic bacteria (Tf). As mentioned above, the number of at least one of these bacteria can also be used as a salivary indicator item for determination.

[0092] Similarly, in the above embodiments, examples of blood indicators (hereinafter referred to as "blood indicator items" for convenience) include LDL, CRP, WBC, and HbA1c. As mentioned above, the value of at least one of these test items can also be used as a blood indicator item for determination.

[0093] The method of the present invention can be achieved by using at least one saliva indicator and at least one blood indicator. In this case, for example, the indicator used can be used as explanatory variables (independent variables), and the logistic regression formula can be formulated in the same way as Equation (1) for the seven items mentioned above.

[0094] The inventors of this application analyzed the influence of Equation (1) for the above 7 items based on the estimated regression coefficients, and found that the saliva indicator "Pg" and the blood indicator "WBC" are particularly important. Based on this insight, at least "Pg" as a saliva indicator and "WBC" as a blood indicator can be used.

[0095] Figure 6 (a) ~ Figure 6(g) is a graph showing an example of the results when six items other than “Pg”, “Tf”, “Td”, “CRP”, “WBC”, “HbA1c”, and “LDL” are removed from the seven items respectively.

[0096] Observing these results, it can be seen that: (a) with the removal of 6 items other than "Pg" and (e) with the removal of 6 items other than "WBC" have lower AUCs compared to the others.

[0097] However, it is not necessary to use the saliva marker "Pg" and the blood marker "WBC". You can omit either one or both.

[0098] Furthermore, the inventors of this application conducted experiments and confirmed that, for example, if the blood indicator "HbA1c" is included, the determination accuracy tends to be higher. Therefore, for example, "HbA1c" can be used as a blood indicator, or it can be omitted.

[0099] Figure 7 (a) ~ Figure 7 (d) is a graph representing an example of the results when the options are set as "P.g + WBC, HbA1c, a total of three items", "P.g + LDL, HbA1c, a total of three items", "T.f + WBC, HbA1c, a total of three items", and "P.g + HbA1c, a total of two items".

[0100] Observing these results, we can see that the overall AUC has increased.

[0101] It should be noted that although the illustrations are omitted, it can be confirmed that sufficient accuracy can be obtained for quantities and combinations other than those mentioned above, and any choice of saliva and blood indicators can be used.

[0102] Furthermore, as mentioned above, the bacterial counts of bacteria other than those described above (e.g., Orange microbiota complex) can also be included in the saliva indicators, and the values ​​of other test items (e.g., neutrophil count, HDL, blood glucose level) can also be included in the blood indicators. In this case, what remains unchanged is that at least one saliva indicator and at least one blood indicator are required.

[0103] The judgment device 1 can set the judgment indicators uniformly for all subjects, or it can set the judgment indicators individually for specific subjects. This setting can be based on user input (input information) or on information related to the subject stored in the storage unit.

[0104] For example, indicators for determining the progression of periodontal disease in a subject can be set based on subject-related information, including whether the subject has diseases such as diabetes, and the subject's age (or age group) / gender. Furthermore, even if the same indicators are used, logistic regression with different regression coefficients can be used for the determination.

[0105] For example, people with diabetes are considered to have a tendency for periodontal disease to worsen. Therefore, for subjects diagnosed with diabetes through interviews during health checkups, the test items can be set up in a way that includes at least the blood indicator "HbA1c" which is associated with diabetes.

[0106] Furthermore, for example, logistic regression (regression coefficients) can be derived using sample data from diabetic patients. Moreover, logistic regression can be used when the subjects being tested have diabetes.

[0107] Furthermore, it is said that the incidence of periodontal disease increases with age. Therefore, for example, sample data from subjects in each age group can be used to calculate the logistic regression (regression coefficient) by age group. Moreover, the logistic regression corresponding to the age group of the subjects can be used.

[0108] It should be noted that, for example, the same treatment can also be applied to gender.

[0109] Figure 8 This indicates that in this case, the same as... Figure 3 A flowchart of an example of the corresponding processing flow.

[0110] In step S60, the processing unit of the determination device 1 sets the indicators (indicator items) and / or logistic regression formulas for determination.

[0111] In this case, for example, based on the subject-related information stored from the server of the medical examination institution, indicators (indicator items) and / or logistic regression (regression coefficients) can be set for the subject to make judgments.

[0112] Furthermore, the processing unit of the determination device 1 causes the processing to proceed to step S61.

[0113] In step S61, the index acquisition unit 3 can acquire the index set in step S60 from the subject of the test.

[0114] In step S63, the progress determination unit 5 can use the logistic regression formula set in step S60 to calculate Y for the subject of the test.

[0115] Explanation of reference numerals in the attached figures

[0116] 1: Determining device;

[0117] 2: Auxiliary storage device;

[0118] 3: Indicator Acquisition Department;

[0119] 4: Data Cleaning Department;

[0120] 5: Progress Assessment Department;

[0121] P: Judgment procedure.

Claims

1. A method for determining the progression of periodontal disease in a subject, performed by a computer, the method comprising: The degree of progression is determined based on saliva parameters measured from the subject's saliva and blood parameters measured from the subject's blood.

2. The determination method according to claim 1, wherein, The salivary index is the number of at least one of Porphyromonas gingivalis, Treponema denticulatum, and Focaccia foetida.

3. The determination method according to claim 2, wherein, The saliva indicators are the bacterial counts of Porphyromonas gingivalis, Treponema denticulatum, and Focaccia fossa.

4. The determination method according to claim 1, wherein, The blood indicators are at least one of low-density lipoprotein (LDL), C-reactive protein (CRP), white blood cell count (WBC), and hemoglobin A1c (HbA1c).

5. The determination method according to claim 4, wherein, The blood indicators are LDL, CRP, WBC, and HbA1c.

6. The determination method according to claim 2, wherein, The determination method includes setting a saliva index for determining the degree of progress based on the saliva index.

7. The determination method according to claim 4, wherein, The determination method includes setting blood indicators for determining the degree of progression based on the blood indicators.

8. The determination method according to any one of claims 1 to 7, wherein, The determination includes using logistic regression analysis of the saliva and blood indicators to determine the degree of progress.

9. A determining device for determining the progression of periodontal disease in a subject. The determination device includes a progress determination unit, which determines the progress level based on saliva indicators measured from the subject's saliva and blood indicators measured from the subject's blood.

10. A program for determining the progression of periodontal disease in a subject, said program causing a computer to perform: The degree of progression is determined based on saliva parameters measured from the subject's saliva and blood parameters measured from the subject's blood.

Images