PONE-D-23-41606Association between Atrial fibrillation and Gastroesophageal reflux disease in a population-based cohort study (the HUNT study)PLOS ONE

Dear Dr. Drca,

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 Mar 08 2024 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,

Dong Keon Yon, MD, FACAAI, FAAAAI

Academic Editor

PLOS ONE

Journal requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Additional Editor Comments:

Thank you for submitting your manuscript. The reviewers and I believe it is of potential value for our readers. However, the reviewers have raised a number of very important issues, and their excellent comments will need to be adequately addressed in a revision before the acceptability of your manuscript for publication in the Journal can be determined. We cannot guarantee that your revised paper will be chosen for publication; this would be solely based on how satisfactorily you have addressed the reviewer comments.

# Please receive the English editing service.

# Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with age as underlying time scale.

Please cite the statistical guideline (DOI: https://doi.org/10.54724/lc.2023.e8).

# Please add the sentence.

"A two-sided P less than 0.05 considered significance." -> in Method.

# Reference is too short to draw the conclusion.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

**********

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: No

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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: This study aimed to investigate the longitudinal association between GERD and AF using data from the HUNT Study.

I have the following comments:

1: It should be clear in the title that the authors investigated the association between GERD (exposure) and AF (outcome). The title (association between AF and GERD) may give the impression that the authors applied AF as an exposure and GERD as an outcome.

2: Lines 57-61: A reference is needed.

3: Line 66: GERD was already spelled out previously.

4: Line 87: > 30% of participants were excluded for having missing data about GERD. The sociodemographic and clinical data should be compared between those who were excluded and those who were included. The potential discrepancy might have affected the representativeness.

5: Line 88: I recommend the authors to reconsider their complete case analysis approach. They may consider imputation or dummy variable analysis.

6: Line 103: ICD-10 code I48 includes atrial flutter. This should be clarified.

7: The authors have provided data about cholesterol levels and CRP in Table 1, yet they did not adjust for these variables in the regression analysis. This should be reconsidered.

8: BP cut-off for hypertension is either 140/90 mmHg per the European guidelines or 130/80 mmHg per the US guidelines. The application of 130/85 mmHg should have a reference.

9: Table 3: The authors do not have to stratify results by age using the value of median. Age results are usually stratified based on clear definitions, older adults versus young and middle-aged adults for example, with a cut-off of 60 or 65 to define older adults.

10: The main limitation of this study is that GERD was self-reported. Was that diagnosis validated in the HUNT Study or any other studies with similar socio-demographic characteristics? This is a very important point that should be further discussed.

11: GERD and AF have so many common risk factors such as age, obesity, smoking, diabetes, dyslipidemia, heavy alcohol consumption, and dyslipidemia. Stratifying the results by these confounders is essential. The authors may consider performing interaction analyses as well.

12: Lines 210-216: This explanation is not based on scientific evidence. Further, participants aged 54 are not older adults. You may consider this explanation after the analysis is stratified by a different age group cut-off.

13: I recommend adding a 3rd GERD category (any) involving those with any GERD symptoms. Given that the authors have no data about GERD endoscopy or medication history, it is so presumptive to accept that the symptom severity suggested by the participants truly reflected their medical condition.

14: Lines 217-221: To test this hypothesis, the authors should revise their data to see whether GERD patients really improved their lifestyle within the following years.

15: Line 236-238: The conclusion gives the impression that there is a kind of association but not so strong, while no association could be attained. I recommend rephrasing this section.

16: GERD is associated with certain foods and drinks, stress and anxiety, pregnancy, NSAIDs, hormonal therapies, and gastric ulcers. These variables were not controlled in this study. The authors should raise this point in their limitation section.

Reviewer #2: Thank you for the opportunity to review this manuscript. This study investigates the association between conscious levels of gastroesophageal reflux symptoms and the risk of atrial fibrillation in individuals aged 20 years and older. The findings reveal a lack of evidence supporting this association and indicate different trends in this association between younger and older participants. The manuscript is well written, and the sample size is notably large. The ethical information and competing interests have been reported.

The reviewer has several comments.

Major comments:

In general, reports of gastroesophageal reflux disease and atrial fibrillation are not uncommon. Therefore, the content of differences compared to previous findings (interaction with age) becomes more important, which reflects the new information of this research field.

Regarding stratified analysis on age grouping, my perspective is that instead of using the median age to stratify, it is preferable to use age intervals that hold clinical significance. The median age only represents the current demographic of the data in wave 3 of the HUNT study. Using age intervals that have clinical significance, such as 20-39 years, 40-64 years, and 65 years and above, can enhance the applicability of the findings to clinical practice. Individuals aged 20-39 are generally considered to have low risks of cardiovascular diseases and atrial fibrillation (as the authors mentioned in line 182, 210), while the elderly population aged 65 and above exhibits significantly elevated risks of them. In contrast, conscious symptoms of gastroesophageal reflux disease are more common in younger individuals, while older individuals usually have fewer conscious symptoms, but more severe conditions and complications (lead to more misclassifications and possibly null association).

The age interaction is a clever entry point. My suggestion is to present more age-related information, such as the proportion of conscious symptoms in different age groups, and to add more content discussing why individuals of different ages may have different findings. I know the authors have already discussed this aspect, but I feel the content is a bit limited. It would be better to add more information, and mention this interaction in the Abstract and Introduction sections.

Moreover, it is preferable to show the interaction effect between age and gastroesophageal reflux disease levels alongside this stratified analysis.

Another suggestion is to use self-reported/ conscious symptoms of gastroesophageal reflux disease to describe exposure in title and other sections. My concern is that this study identified a weak association, which may be due to self-reporting rather than objective measurement (as the authors mentioned in line 228). Using a precise description can accurately convey the findings.

Minor comments:

1. Atrial fibrillation is the outcome of interest, so it is preferable to put it to the back and change the title to: Association between gastroesophageal reflux disease and incident atrial fibrillation…, or use a similar expression of your preference.

2. The expression “(n = 1,221)” in line 106 is unclear. It is preferable to add details and rephrase it as follows: During the follow-up, 1,221 cases of atrial fibrillation (AF) were diagnosed, or use a similar expression, or delete it because you have already mentioned it in line 141 of the Result section.

3. The expression “Degree of reported symptoms…” in Table 1 is not a column name for participants characteristics, so it is preferable to put it on the top of Never/ A little / Much columns. Besides, these numbers in Never/ A little / Much columns have a same column distance, it is preferable to make related numbers (eg. female n 11,363 and % 58.6) close together or merge them, such as 11,363 (58.6%), which is easier to understand. It is better to change the expression “Age at HUNT3” to “Age at baseline”, I think it's easier to understand. The above is my personal suggestion; the authors can choose to modify it based on their own judgment.

4. All continuous variables are presented as mean ± standard deviation in Table 1, which is not appropriate. For continuous variables with a normal distribution, presenting them with a mean and standard deviation is acceptable. However, for variables with a non-normal distribution, such as C-reactive protein, it is more appropriate to display them with an interquartile range, as the standard deviation is not a meaningful statistical measure for variables with non-normal distribution.

**********

6. 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: No

Reviewer #2: 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.

Gastroesophageal reflux disease symptoms and risk of atrial fibrillation in a population-based cohort study (the HUNT Study)

PONE-D-23-41606R1

Dear Dr. Drca,

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.

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Dong Keon Yon, MD, FACAAI, FAAAAI

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This is an excellent paper.

Reviewers' comments: