PONE-D-22-02756Effect Modification by Age and Comorbidities on the Association Between Periodontitis and Female Breast Cancer: A Population-based Case-control StudyPLOS ONE

Dear Dr. Chen,

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. There are some issues that have been raised from the reviewers regarding the statistical analyses and the structure and content of the discussion that should be addressed.

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Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. 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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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3. 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: No

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4. 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: No

Reviewer #2: Yes

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5. 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: Introduction

Page 4. Did the prevalence of periodontitis increase because of changes in definitions? This has often been the case in other countries.

Page 4. There are many other cohort studies on periodontitis and breast cancer that are not referenced (e.g. Farhat et al CEBP 2021, Jia et al CEBP 2020, and earlier meta-analysis of 11 studies: Shao et al 2018). Also, the Sfreddo et al study referenced is not a cohort study. Please edit the last paragraph of the introduction to reflect this. The discussion (first paragraph) also needs to be revised since the association between periodontal disease and breast cancer risk has previously been reported in Taiwan using the same dataset (PMID: 26280747); please explain the differences/overlap between the two studies in the discussion section.

Methods

This is not a traditional case-control study; based on the selection of all breast cancer cases during a 10-year period and selection of controls from a large cohort database for comparison, this would be better described as a retrospective population-based cohort study.

It appears that all incident breast cancer cases identified through the NHIRI between 2003 and 2013 were included in this analysis. It is unclear if the breast cancer cases that are not in the NHRI database would have detailed data on claims for periodontal disease or other co-morbidities and if these were also included. A figure would help between understand the selection process including exclusions that were made and available data available for each step.

Statistical analysis – please provide details on how the tests for interactions were conducted.

Would it be possible to differentiate different types of breast cancers? E.g. invasive vs non-invasive?

Also, given the strong association between urbanization and breast cancer, it would be useful to examine whether the periodontal disease and breast cancer is modified by this variable (this could be added to Table 5).

Discussion

The discussion could be improved. Prior results from existing studies on this topic are not provided (e.g., range of RRs to compare magnitude of association, quality of periodontal disease measurement). It would also be helpful to point out some limitations in prior studies, and what this study adds to the literature (given that there are over 10 papers on this topic). A better synthesis of the literature is needed.

Typos (tables and “CRT” in discussion) and English grammar need to be corrected throughout.

Reviewer #2: This study explored the effect of periodontitis on female breast cancer using a population based case control study. The paper is reasonably well written though I have some comments which the authors might consider to improve their study.

Introduction

Page 4 final paragraph – "small sample size" is somewhat relative – I would state the sample sizes of these studies

Page 5: "...while Sfreddo et al. [21] found there was a significant association between periodontitis and breast cancer" - Presumably this is a positive association? Please clarify in the text

Materials and methods

Page 7 "Potential confounders included level of urbanization". Presumably this is a city / regional level variable in the dataset?

"Sensitivity analyses were conducted based upon age (<65 years, ≥65 years) and CCI" – further elaboration required.

"We tested the differences in the continuous variables through use of the Student’s t-test and the categorical variables by using the Pearson’s χ2 test" What is the motivation for this and define the specific variables?

Logistic regression model – presumably maximum likelihood was used to estimate the model parameters, but it would be good to state this explicitly.

There is a strong case for modelling the dose response relationship as a continuous response. Arbitrarily creating categories is statistically inefficient and at worst can be misleading. I would advise modelling each explanatory variable of interest for the dose response as a continuous term. This can easily be achieved in SAS using a spline. A good choice would be a restricted cubic spline with the number of knots selected based on prior knowledge or beliefs (3-5 knots is often sensible – see Harrell F. (2015) Regression Modelling Strategies). The dose response adjusted for covariates can be presented as a smooth curve with confidence intervals. Odds ratios can still be obtained from this curve between specific points of interest. You might also consider modelling the CCI this way. Even if this approach is not adopted, the authors might consider mentioning this as a limitation.

Details of the interaction term (later referred to in subsequent sections) in the logistic regression models are missing. This is critical since the primary interest (according to the title of the paper) is effect modification necessitating interaction terms.

Perhaps the authors might consider making dataset and SAS code used available as SI

Results

Page 9 "After adjusting for age and index date"…this implies that age and index date were covariates in the regression model – this does not appear to be the case according to the statistical analysis section as it stands.

It would be nice to have some supportive figures (e.g. partial effect plots) summarizing the statistical models.

Discussion

First paragraph talks about several studies one by one – it would be preferable to integrate this as continuous prose and convey the message that your work is supportive of these previous studies.

"In this study, one important finding is that the risk of breast cancer is modified by both age and comorbidities" - this statement is redundant since it is a repetition of the first sentence of the paragraph.

Table 3 – It seems patient is the statistical unit as opposed to an adjustment variable as currently indicated at the foot of the table. Also urban should be "urbanization".

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-02756R1Effect Modification by Age and Comorbidities on the Association Between Periodontitis and Female Breast Cancer: A Population-based Case-control StudyPLOS ONE

Dear Dr. Chen,

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.

Please submit your revised manuscript by Aug 18 2022 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,

Antonis Valachis

Academic Editor

PLOS ONE

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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.

Additional Editor Comments:

Although the authors have adequately respond to several of the reviewers' comments, there are some issues that need to be clarified before the manuscript be accepted for publication. Please, read the additional comments from the reviewers carefully and address all the remaining issues.

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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

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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

********** 

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

Reviewer #1: Yes

Reviewer #2: 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: No

Reviewer #2: 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 #1: Yes

Reviewer #2: 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: The authors have not addressed the comment on how their study was different from the previous study published on periodontal disease and cancer using the same Taiwan database (and also fail to mention this previous study) "A population-based study on the associations between chronic periodontitis and the risk of cancer" Shiu-Dong Chung et al.

Since breast cancer is a female cancer, stating that they studied females (vs both sexes) makes little sense as obviously prior studies on breast cancer risk were in women only. Please mention this study in the Introduction and this study should not be referred to as the "first" case-control on periodontal disease that is population based (as it is not).

This is not a retrospective case-control study. Retrospective case-control studies are studies that recruit cancer patients and ask about their past exposures; the exposure here is measured prior to the development of the disease. So, this is a retrospective cohort study, because the cohort exists and the analysis is conducted on a sample of the cohort retrospectively. Alternatively, you can call it a nested case-control study, which is nested in a cohort population.

Figure 1 – can you clarify what is meant by “unsured amount” given that half of the population is excluded for this reason (+ missing data) can you justify whether this was a reasonable exclusion and whether it might have caused some selection bias (in other words, how did the excluded population differ from the one included)?

Table 5. The title needs to be modified to clearly describe that the ORs presented are for the comparison of periodontal disease vs no periodontal disease stratified on age, CCI and urbanization. Many readers will misinterpret these results otherwise.

I don’t think the figures add any value, especially the ones that are based on categorial comparisons.

Please edit the abstract for grammar "assess that periodontitis" change to "assess whether periodontitis"

Reviewer #2: I enjoyed re-reviewing this interesting study and was pleased that the authors considered many of my suggestions. I only have two minor comments:

-Response to Reviewers - Reviewer #2: Point 12. The authors responded that "The variable of level of urbanization is an individual level variable based on individual’s residence region in the dataset." I believe this should be termed an ecological level variable since it describes properties of the region, and not each person.

Perhaps a very slight re-wording will suffice.

-The conclusion section looks a little peculiar with just one sentence. I would add a few more sentences or integrate into the discussion depending on the requirements of the journal.

Overall this is now essentially ready for publication and will be a valuable contribution to the literature.

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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: No

Reviewer #2: No

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Stratified Analysis of the Association Between Periodontitis and Female Breast Cancer Based on Age, Comorbidities and Level of Urbanization: A Population-based Nested Case-control Study

PONE-D-22-02756R2

Dear Dr Chen,

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Academic Editor

PLOS ONE