PONE-D-21-08970

Oral health and atrial fibrillation in the Hamburg City Health Study  ​

PLOS ONE

Dear Dr. Seedorf,

Thank you for submitting your manuscript to PLOS ONE. This is an interesting topics. Before sending out for external review, I would like to clarify some points. You may remove the patients with AF risk (i.e., HTN, DM, Stroke events, etc.) from the analyses. Then, you may see clear results without the statistical models.  Please analyze h-CRP and IL-6 as well. If the inflammatory markers do not play a role in AF, what would be potential mechanism? In addition, I do not think reference 25 would be a suitable to cite since these studies are  merely based upon insurance claims, not clinical data.

Please submit your revised manuscript by May 10 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

This is an interesting topics. Before sending out for external review, I would like to clarify some points. You may remove the patients with AF risk (i.e., HTN, DM, Stroke events, etc.) from the analyses. Then, you may see clear results without the statistical models. Please analyze h-CRP and IL-6 as well. If the inflammatory markers do not play a role in AF, what would be potential mechanism?

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PONE-D-21-08970R1

Oral health and atrial fibrillation in the Hamburg City Health Study  ​

PLOS ONE

Dear Dr. Seedorf,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process

Your paper was reviewed by three experts in the field. Although the topic seems to be interesting, several issues need to be clarified. Specifically, there are several confound factors need to be included to asses the PD status, and occurrence of AF needs to be validated. Please read the comments carefully, and address the issues accordingly. I would recommend the authors to consult statistical expert(s).

Please submit your revised manuscript by Aug 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I find it hard to justify the accuracy of the data collected without more information- Therefore I feel the article can be accepted if they provide more information about the data collected.

It would be useful if the authors shared data on how many patients were already diagnosed with AF, and how many they tested for AF who were diagnosed with unknown AF. Without this data it is hard to see a true representative of data- e.g the patient may have had good plaque control, was diagnosed with AF but since the diagnosis had then had not brushed teeth as much and resulted in poor plaque control. In a cross sectional study ideally the patient would not know they have AF, have poor plaque control and after investigation with ECG, has been diagnosed with unknown AF. If a patient was already diagnosed with AF in the medical was this information known to the researcher prior to the plaque index being carried out? This can introduce researcher bias. Also there is no cause or effect with this type of study as it is cross-sectional they cannot state oral health preventing AF based on their study. If there was an exclusion criteria for those who already had AF then can this be stated clearly in the methods

I have some other comments:

According to a recently published systematic review, only two small clinical studies had been looked at a potential association between PD and AF over the last fifty years [22].

Incorrect, this SR states two small clinical studies looking at acute infections, not PD, also here is a useful and recent citation

Sen S, Redd K, Trivedi T, Moss K, Alonso A, Soliman EZ, Magnani JW, Chen LY, Gottesman RF, Rosamond W, Beck J, Offenbacher S. Periodontal Disease, Atrial Fibrillation and Stroke. Am Heart J. 2021 May;235:36-43. doi: 10.1016/j.ahj.2021.01.009. Epub 2021 Jan 24. PMID: 33503409; PMCID: PMC8084947.

The examination was carried out by trained and certified study nurses.

Normally dentists are required to examine patients and diagnose PD, not nurses- if nurses then is diagnosis inaccurate? If nurses are trained then how are they trained to ensure accurate diagnosis are they performing the periodontal charts? more detail needed here.

Based on the measurements, a calculation of the decayed, missing and filled teeth (DMFT) index was performed and the plaque index (PI) of Silness-Löe (1964) was assessed

Would have liked to see more information in the methods about systematic and rigourous testing of scores- for example, were the plaque scores assessed by 2 different clinicians, if there was disagreement then would a third clinician be involved

Although (DMFT) index is a valid measurement tool it has disadvantages as people can lose teeth from trauma or for orthodontic treatment or tooth decay (eg not just from periodontitis).

The diagnosis of PD and the classification of severity were performed based on the criteria of Eke and Page [26]:

26. Chen SJ, Liu CJ, Chao TF, Wang KL, Chen TJ, Chou P, et al. Dental scaling and atrial fibrillation: a 241 nationwide cohort study. International journal of cardiology. 2013;168(3):2300-3. doi: 242 10.1016/j.ijcard.2013.01.192. PubMed PMID: 23453452.

Incorrect citation placed.

Assessment of cardiac variables

Authors have used a combined method of diagnosing for AF including self reporting and medical investigations with 24 hour ECG- 1) self reporting is considered inaccurate for diagnosing AF, diagnosing all patients medically would have been more accurate

Methods

would like to see a flowchart of patient journey and data which would make the results of the research more easily accessible and clear

Statistical analysis

adjusted for all confounders considered relevant (age, sex, body mass index, diabetes, smoking, and hs-CRP)

There are many more confounders considered relevant- please amend statement to adjusted for some confounders considered relevant

Figure 1 and figure 2 are not clearly labelled, figure 1 no label of unit measurement for y axis is it a percentage, figure 2 for me was not absolutely clear what the units of measurements were as the bar charts had numbers on the top but I do not know what they represented.

Reviewer #2: The authors present a cross-sectional study evaluating the relation between PD and AF. Patients were evaluated for PD using CAL, BOP, DMFTi and PI. AF was assessed using a 24-hour ECG monitoring or a single 12 lead ECG, according to risk, using the CHARGE-AF score. In addition, diagnosis was made using self-reported AF or medically diagnosed AF. Their results reflect what we already know about the epidemiologic patterns of AF, it increases with age and other risk factors such male gender and hypertension.

Overall, after adjustment for multiple confounders, there was no association between PD and AF; however, the authors found an association between markers of oral hygiene like plaque index and AF. They conclude that there might be an association between dental plaque accumulation and AF.

The article is interesting as it adds to the evidence of the link between PD and CVD; particularly the relationship between PD and AF still needs to be confirmed. The text is written in good English, methods and statistical analysis are clear, and results are presented appropriately.

Revisions

1. Could the authors explain the rational for using the CHARGE-AF score to decide if patients where having a 24-hrs ECG monitoring or not in the methods section.

2. Add the CHARGE-AF score for each group of PD as a part of the results.

3. The authors include the LVEF in different groups of PD as a part of their results. Do they have information of other echocardiographic parameters? It would be particularly interesting if they provide data on left atrium (volume, diameter), since it is a marker of FA risk.

4. This is a suggestion: Most of the data that shows an association between PD and cardiac structural and functional abnormalities detected with echocardiogram (mass, myocardial deformation), comes from studies in patients with diabetes mellitus, hypertension and chronic kidney disease. In all of these studies, there was a clear association between PD severity and left ventricular hypertrophy and abnormal ventricular function. (You can see: Periodontal Disease, Systemic Inflammation and the Risk of Cardiovascular Disease. Heart Lung Circ. 2018 Nov;27(11):1327-1334, for a description of some of these studies). In our laboratory, we have done some work in otherwise healthy subjects with different grades of PD using echocardiography, and we could not find an association between PD and LVH or abnormalities in LV function. Although the reasons can be diverse, there is a possibility that PD and the systemic inflammatory process that comes with it acts as a boost for CVD; perhaps, PD might not be enough to cause CV abnormalities, but when added to other types of stress to the CV system (Hypertension, DM) it can cause CVD.

Since AF is multifactorial, and abnormalities in cardiac structure and function can play a role, this can be important for your study. More than 50 of your study population have hypertension; perhaps, you can consider a last analysis including only those with HTN and divide them in those with none/mild PD and severe PD to look for an association between AF and PD, in unadjusted and adjusted analysis.

Reviewer #3: 1) Recent results from ARIC cohort study on PD-AF association not discussed

2) DMFT assessed, a measure primarily for Caries. Data not used for analysis

3) CRP and IL-6 are potential mediators, hence should not be adjusted for

4) Socioeconomic status is a potential confounder that is not assessed

5) Based on hypothesis oral care should be associated with less AF

6) Assessment of AF using questionnaire not a validated method

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Amaar Hassan

Reviewer #2: Yes: Edgar Francisco Carrizales-Sepúlveda

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-21-08970R2Periodontitis, dental plaque, and atrial fibrillation in the Hamburg City Health StudyPLOS ONE

Dear Dr. Seedorf,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Your revised paper was reevaluated by the previous reviewers. Though the quality of paper has been improved, one reviewer made some suggestions to further improve the analysis. Please read the comments carefully and address the issues accordingly. 

Please submit your revised manuscript by Nov 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: No further suggestions as the author has responded to all points and improved the overall validity of the article

Reviewer #2: The authors have made a great effort addressing the reviewers’ suggestions; the quality of the manuscript has improved.

Although the overall results of the study do not suggest an association between PD and AF, the study is still of relevance since it adds valuable information to the field, I think the paper is now ready to be considered for publication.

Reviewer #3: The reviewers comments have been addressed. I would suggest following changes:

1) Abstract conclusion starts with "no finding" first, and readers have to go sentences down to figure out what the positive findings of PI -->AF association

2) DMFT is an useful marker of oral health and dental caries. If the DMFT score is better in the group, please indicate that as a reason why it was not tested for association with AF. Alternately please include the analysis for readers to know that DMFT is not associated with AF

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Amaar Obaid Hassan

Reviewer #2: Yes: Edgar Francisco Carrizales-Sepulveda

Reviewer #3: Yes: Souvik Sen MD

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Periodontitis, dental plaque, and atrial fibrillation in the Hamburg City Health Study

PONE-D-21-08970R3

Dear Dr. Seedorf,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. I think this study will be an important reference regarding association between oral hygiene and AF. Congratulations!

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: Thank you for responding to all comments. All comments have been addressed including addition of DMFT data.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Souvik Sen MD