Determination method, determination device, and program for determining degree of progress of periodontal disease

Abstract

The present invention accurately determines the degree of progress of periodontal disease in a simple manner.　This determination method for determining the degree of progress of periodontal disease in a subject comprises a step S6 for determining the degree of progress on the basis of a saliva index measured from saliva of the subject and a blood index measured from the blood of the subject.

Description

Method, device and program for determining progression of periodontal disease

[0001] The present invention relates to a method, an apparatus, and a program for determining the progression of periodontal disease.

[0002] Periodontal disease is a condition in which bacteria infecting the oral cavity become a continuous source of bacterial exotoxins and inflammatory cytokines, adversely affecting various systemic diseases. For this reason, the Ministry of Health, Labour and Welfare is exploring early intervention through the introduction of universal dental checkups. However, current periodontal disease checkups rely on the skills of specialized technicians, such as periodontal pocket inspections and X-rays, and are not suitable for screening programs targeting more than 100 people per day. To address this issue, a new saliva testing technology has been developed in a joint research project (title: Development of a new oral care device aimed at preventing systemic diseases) conducted since April 2020 with Tohoku University and Fiber Medicine Co., Ltd.

[0003] In response to this, Patent Document 1 discloses a method for determining the stage of periodontal disease using the amount of occult blood, white blood cell count, total protein concentration, and ammonia concentration in a test sample obtained from the oral cavity as indicators, which makes it possible to easily determine the progression of periodontal disease without relying on the skills of a specialized surgeon. The invention described in Patent Document 1 is currently in practical use as a saliva testing device called SillHa (registered trademark).

[0004] International Publication No. 2017 / 175673

[0005] However, as in Patent Document 1, there is a problem in that the stage of progression of periodontal disease cannot be accurately determined using only a sample obtained from the oral cavity.

[0006] The present invention has been made in view of the above problems, and an object of the present invention is to easily and accurately determine the stage of progression of periodontal disease.

[0007] In order to solve the above problems, the present invention includes the following aspects. Item 1. A method for determining the stage of progression of periodontal disease in a subject, comprising the step of determining the stage of progression based on a saliva index measured from the subject's saliva and a blood index measured from the subject's blood. Item 2. The method according to Item 1, wherein the saliva index is the bacterial count of at least one of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Item 3. The method according to Item 2, wherein the saliva index is the bacterial count of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Item 4. The method according to Item 1, wherein the blood index is at least one of LDL, CRP, WBC, and HbA1c. Item 5. The method according to Item 4, wherein the blood index is LDL, CRP, WBC, and HbA1c. Item 6. Item 7. A determination method according to any one of Items 1 to 5, wherein in the step, the stage of progression is determined by logistic regression analysis using the saliva index and the blood index. Item 8. A determination device for determining the stage of progression of periodontal disease in a subject, comprising: a stage of progression determination unit that determines the stage of progression based on a saliva index measured from the saliva of the subject and a blood index measured from the blood of the subject. Item 9. A determination program for determining the stage of progression of periodontal disease in a subject, comprising: a determination program that causes a computer to execute a step of determining the stage of progression based on a saliva index measured from the saliva of the subject and a blood index measured from the blood of the subject.

[0008] According to the present invention, the progression of periodontal disease can be determined simply and accurately.

[0009] FIG. 1 is a flowchart showing the overall flow of a periodontal disease examination in an embodiment of the present invention. FIG. 2 is a block diagram showing the configuration of a determination device according to an embodiment of the present invention. FIG. 3 is a flowchart showing a specific flow of steps for determining the stage of progression of periodontal disease. FIG. 4 is a graph showing an ROC curve for a determination method according to an example of the present invention. FIG. 5 is a graph showing an ROC curve for a determination method according to a comparative example. FIG. 6 is a graph showing an ROC curve for a determination method according to a modified example of the present invention. FIG. 7 is a graph showing an ROC curve for a determination method according to a modified example of the present invention. FIG. 8 is a flowchart showing a specific flow of steps for determining the stage of progression of periodontal disease according to a modified example of the present invention.

[0010] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings. Note that the present invention is not limited to the following embodiment, and various modifications are possible without departing from the spirit of the present invention.

[0011] 1 is a flowchart showing the overall flow of a periodontal disease examination in this embodiment. In this embodiment, a case will be described in which a periodontal disease examination is performed as an option of a medical checkup such as a comprehensive medical checkup.

[0012] In step S1, saliva is collected from a person undergoing a health checkup (hereinafter referred to as a subject) using a saliva test kit. The saliva may be collected before or after the health checkup, or may be collected during the health checkup.

[0013] In step S2, the medical examination institution collects a saliva sample from the subject.

[0014] In step S3, blood is collected from the subject. Typically, blood is collected during a medical examination.

[0015] In step S4, the medical examination institution collects the subject's blood sample. The collected saliva and blood samples from the subject are sent to a testing institution.

[0016] In step S5, the testing facility analyzes the subject's saliva and blood. Specifically, the number of bacteria Porphyromonas gingivalis (P. g), Treponema denticola (T. d), and Tannerella forsythia (T. f) is measured from the saliva, and the values ​​of LDL (low-density lipoprotein), CRP (C-reactive protein), WBC (white blood cell count), and HbA1c (hemoglobin A1c) are measured from the blood. In this embodiment, bacterial DNA is collected from the saliva sample and the number of bacteria is measured using quantitative PCR. Note that the methods for analyzing the number of bacteria and the blood are not particularly limited.

[0017] The analysis results are sent to an analytical institution. Note that the saliva analysis and the blood analysis may be performed by different testing institutions.

[0018] In step S6, the analysis institution determines the progression of the subject's periodontal disease using the determination method according to this embodiment. In this embodiment, if the periodontitis stage is stage III or IV and the periodontitis grade is grade C according to the periodontitis classification established by the Japanese Society of Periodontology (https: / / www.perio.jp / file / news / info_191220.pdf), the periodontitis is determined to be progressing. Specific details of the determination method will be described later.

[0019] If the subject's periodontal disease is advanced (YES in step S7), the health checkup institution recommends that the subject visit a dental clinic or the like.

[0020] (Periodontal Disease Assessment) Fig. 2 is a block diagram showing the configuration of the assessment device 1 according to this embodiment. The assessment device 1 is used to assess the progression of periodontal disease in the subject in step S6 described above.

[0021] The determination device 1 can be configured as a general-purpose computer, and includes, as its hardware configuration, a processor such as a CPU or a GPU (not shown), a main memory device such as a DRAM or an SRAM (not shown), and an auxiliary memory device 2 such as an HDD or an SSD. The auxiliary memory device 2 stores a determination program P and the like.

[0022] The determination device 1 includes, as functional blocks, an index acquisition unit 3, a data cleaning unit 4, and a progress determination unit 5. These functional blocks are realized by the processor of the determination device 1 reading a determination program P into a main storage device and executing it. The determination program P may be downloaded to the determination device 1 via a communication network such as the Internet, or may be recorded in advance on a computer-readable non-transitory recording medium such as a CD-ROM or an SD card and installed into the determination device 1 via the recording medium.

[0023] FIG. 3 is a flowchart showing a specific flow of step S6 shown in FIG.

[0024] In step S61, the index acquisition unit 3 of the determination device 1 acquires saliva indexes and blood indexes from the analysis results sent from the analysis institution. The saliva indexes are the bacterial counts of P.g, T.d, and T.f. In this embodiment, the bacterial counts are expressed as copy number concentrations (copies / μl). The blood indexes are the values ​​of LDL, CRP, WBC, and HbA1c.

[0025] In step S62, the data cleaning unit 4 of the determination device 1 performs data cleaning on at least some of the saliva and blood indicators as needed. In this embodiment, data cleaning is performed on each of the P.g, LDL, and WBC values. Specifically, for P.g, the copy number concentration is converted to a logarithm with a base of 10. For LDL, if the LDL value is equal to or less than the reference value, it is converted to "1." If the LDL value is greater than 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 equal to or less than the reference value, it is converted to "1." If the WBC value is greater than the reference value, it is converted to a value obtained by subtracting the reference value from the WBC value.

[0026] In step S63, the progress determination unit 5 of the determination device 1 determines the progress of the subject's periodontal disease based on the data-cleaned saliva index and blood index. In this embodiment, the progress determination unit 5 determines the progress of the subject's periodontal disease by logistic regression analysis using the saliva index and blood index. An example of a logistic regression equation is shown below as equation (1).

[0027] P.g: logarithm (base = 10) of the number of bacteria in P.g (copies / μl) T.d: number of bacteria in T.d (copies / μl) T.f: number of bacteria in T.f (copies / μl) LDL: LDL value after data cleaning (mg / dl) CRP: CRP value (mg / dl) WBC: WBC value after data cleaning ( / μl) HbA1c: HbA1c value (mmol / mol) a to h: constants (regression coefficients) Note that although logarithm values ​​or values ​​after data cleaning are used, this is merely for convenience of calculation and is not limiting. Furthermore, using these values ​​is also included in using saliva indicators and blood indicators.

[0028] The progression determination unit 5 determines that the periodontal disease is progressing (severe periodontal disease) when Y obtained by the above formula is equal to or less than a predetermined threshold value (cutoff value).

[0029] (Summary) In the determination method according to this embodiment, the progression of periodontal disease is determined using both a saliva index measured from the subject's saliva and a blood index measured from the subject's blood. As shown in the examples below, this allows for more accurate determination of the progression of periodontal disease than the invention described in Patent Document 1, which uses only samples obtained from the oral cavity.

[0030] Furthermore, because blood indices are items that can be tested in a regular health checkup, they can be obtained from the results of the health checkup and do not depend on the skills of a specialist, as is the case with periodontal disease assessment in a dental checkup. Therefore, if the subject undergoes regular health checkups, the burden on the subject will not increase compared to the conventional assessment method described in Patent Document 1. The participation rate of health checkups in Japan is high, at 64%.

[0031] As described above, in this embodiment, the progression of periodontal disease can be determined simply and accurately.

[0032] (Additional Notes) The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Forms obtained by appropriately combining the technical means disclosed in the embodiments are also included in the technical scope of the present invention.

[0033] For example, in the above embodiment, the saliva indicator used for the determination was the bacterial count of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, but the bacterial count of at least one of these bacteria may also be used. Furthermore, the bacterial count of bacteria other than those mentioned above (for example, orange complex) may also be included in the saliva indicator.

[0034] In the above embodiment, the blood indices used for the determination were LDL, CRP, WBC, and HbA1c, but the blood indices may be at least any of these test item values. Also, values ​​of test items other than those mentioned above (e.g., neutrophil count, HDL, blood glucose level, etc.) may be included in the blood indices.

[0035] In the above embodiment, the progression of the subject's periodontal disease is determined by logistic regression analysis using saliva indexes and blood indexes, but the present invention is not limited to this. For example, the progression of the subject's periodontal disease may be determined using a known machine learning model using saliva indexes and blood indexes.

[0036] Examples of the present invention will be described below, but the present invention is not limited to the following examples.

[0037] In this example, 50 periodontal disease patients from the Department of Endodontics at Tohoku University Hospital and 50 periodontal disease patients from Midtown Clinic, a collaborative research institute of the present applicant, totaling 100 subjects, were used to determine the progression of their periodontal disease using the determination method according to the above embodiment. Specifically, saliva indices (P.g, T.d, and T.f bacterial counts) and blood indices (LDL, CRP, WBC, and HbA1c) obtained from each subject were read from a database, data cleaning was performed on each value of P.g, LDL, and WBC, and the progression of each subject's periodontal disease was determined by logistic regression analysis using the saliva indices and blood indices, and the accuracy of the determination was verified by cross-validation.

[0038] As a comparative example, the progression of periodontal disease was assessed for the same subjects as in the example using the saliva testing device Silha, which corresponds to the invention described in Patent Document 1. Specifically, the progression of periodontal disease for each subject was assessed using the indicators of occult blood, protein, leukocytes, and ammonia obtained from each subject, and the accuracy of the assessment was verified by cross-validation.

[0039] In both the Examples and Comparative Examples, periodontal disease was determined to be progressing when the stage of periodontitis was stage III or IV and the grade of periodontitis was grade C according to the classification of periodontitis established by the Japanese Society of Periodontology.

[0040] Figure 4 is a graph showing an ROC curve for the determination method according to this example, and Figure 5 is a graph showing an ROC curve for the determination method according to a comparative example. The AUC (P<0.001), sensitivity, and specificity of each determination method according to this example and the comparative example are shown in Table 1. Note that the sensitivity and specificity vary depending on the cutoff value set.

[0041]

[0042] As can be seen from Table 1, the AUC in this example is higher than any of the indexes in the comparative examples. Therefore, it was found that the method of this example can determine the progression of periodontal disease with higher accuracy than the conventional method described in Patent Document 1.

[0043] Supplements and variations of the above embodiment will be described. In the above embodiment, the bacterial counts of Porphyromonas gingivalis (P. g), Treponema denticola (T. d), and Tannerella forsythia (T. f) were exemplified as saliva indicator items (hereinafter referred to as "saliva indicator items" for convenience). However, as described above, the bacterial counts of at least one of these bacteria may be used as saliva indicator items for assessment. Similarly, in the above embodiment, LDL, CRP, WBC, and HbA1c were exemplified as blood indicator items (hereinafter referred to as "blood indicator items" for convenience). However, as described above, the values ​​of at least one of these test items may be used as blood indicator items for assessment. The method of the present invention can be realized by using at least one saliva indicator item and at least one blood indicator item. In this case, for example, the indicator items used may be used as explanatory variables (independent variables), and a logistic regression equation similar to the seven-item equation (1) described above may be formulated.

[0044] The inventors of the present application analyzed the influence of the seven items in the formula (1) described above based on the estimated regression coefficients, and found that "P.g" is a particularly important saliva index item, and "WBC" is a particularly important blood index item. Based on this finding, it is possible to use at least "P.g" as the saliva index item and "WBC" as the blood index item.

[0045] 6(a) to 6(g) are diagrams showing examples of results when using six items from the seven items, excluding "P.g," "T.f," "T.d," ​​"CRP," "WBC," "HbA1c," and "LDL." Looking at these results, it can be seen that the six items excluding "P.g" in (a) and the six items excluding "WBC" in (e) have lower AUCs than the others.

[0046] However, it is not necessary to use the saliva index item "P.g" and the blood index item "WBC", and it is not necessary to use either one of them, or both of them.

[0047] Furthermore, as a result of experiments conducted by the inventors of the present application, it was confirmed that, for example, including the blood index item "HbA1c" tends to result in a relatively high accuracy of determination. Therefore, for example, at least "HbA1c" may be used as a blood index item, but it is not necessary to do so.

[0048] 7(a) to 7(d) are diagrams showing examples of results when "P.g + WBC, HbA1c (total of three items)", "P.g + LDL, HbA1c (total of three items)", "T.f + WBC, HbA1c (total of three items)", and "P.g + HbA1c (total of two items)" are used, respectively. Looking at these results, it can be seen that the AUC is generally high.

[0049] Although not shown in the figures, it has been confirmed that sufficient accuracy can be obtained for determination accuracy with numbers and combinations other than those mentioned above, and any selected saliva index items and blood index items may be used.

[0050] As mentioned above, the saliva index may include the number of bacteria other than those mentioned above (for example, orange complex, etc.), and the blood index may include values ​​of test items other than those mentioned above (for example, neutrophil count, HDL, blood glucose level, etc.). In this case, it is still sufficient to use at least one saliva index item and at least one blood index item.

[0051] The determination device 1 may uniformly set the index items used for determination for all subjects, or may individually set the index items used for determination for specific subjects. This setting may be performed, for example, based on user input (input information) or on information about the subject stored in the storage unit. For example, the index items used to determine the progression of periodontal disease of a subject may be set based on information about the subject, including information about the subject, such as whether or not the subject has a disease such as diabetes, and attribute information about the subject, such as the subject's age (or generation) and gender. Furthermore, even if the index items used are the same, the determination may be performed using logistic regression equations with different regression coefficients.

[0052] For example, it is said that people with diabetes tend to have worsening periodontal disease. Therefore, for example, for subjects who are determined to have diabetes through interviews during a health checkup, the index items may be set to include at least the blood index item "HbA1c" associated with diabetes. Furthermore, for example, sample data of diabetic patients may be used to determine a logistic regression equation (regression coefficient) for diabetic patients. Then, if the target subject has diabetes, that logistic regression equation may be used.

[0053] It is also said that the incidence of periodontal disease increases with age. For this reason, for example, sample data of subjects of each age group may be used to calculate a logistic regression equation (regression coefficient) for each age group. Then, a logistic regression equation corresponding to the age of the subject may be used. Note that the same procedure may be performed for gender, for example.

[0054] 8 is a flowchart showing an example of the processing flow corresponding to FIG. 3 in this case. In step S60, the processing unit of the determination device 1 sets the index (index item) and / or logistic regression equation to be used for the determination. In this case, for example, the index (index item) and / or logistic regression equation (regression coefficient) to be used for the determination for the target subject may be set based on information about the target subject among information about the subject acquired and stored from a server of a health examination institution, etc. Then, the processing unit of the determination device 1 proceeds to step S61.

[0055] In step S61, the index acquisition unit 3 may acquire the index set in step S60 for the target subject. In step S63, the progress determination unit 5 may calculate Y for the target subject using the logistic regression equation set in step S60.

[0056] REFERENCE SIGNS LIST 1 Determination device 2 Auxiliary storage device 3 Index acquisition unit 4 Data cleaning unit 5 Progress determination unit P Determination program

Claims

1. A method for determining the stage of periodontal disease in a subject, carried out by a computer, comprising determining the stage of disease based on saliva indicators measured from the subject's saliva and blood indicators measured from the subject's blood.

2. The method according to claim 1, wherein the saliva indicator is the number of bacteria of at least one of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.

3. The method according to claim 2, wherein the saliva indicator is the number of bacteria of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.

4. The method of claim 1, wherein the blood index is at least one of LDL, CRP, WBC, and HbA1c.

5. The method of claim 4, wherein the blood indices are LDL, CRP, WBC, and HbA1c.

6. The method according to claim 2, further comprising: setting a saliva index to be used for determining the degree of progression from the saliva index.

7. The method according to claim 4, further comprising: setting a blood index to be used in determining the stage of progression from the blood indexes.

8. The method of any one of claims 1 to 7, wherein the determining step includes determining the stage of progression by logistic regression analysis using the saliva index and the blood index.

9. A determination device for determining the degree of progression of periodontal disease in a subject, comprising a progression determination unit that determines the degree of progression 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, the program causing a computer to determine the progression based on saliva indicators measured from the subject's saliva and blood indicators measured from the subject's blood.

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