PONE-D-20-22385

Laboratory-Confirmed Influenza Infection and Acute Myocardial Infarction among United States Senior Veterans

PLOS ONE

Dear Dr. Young-Xu,

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 justify the rationale for conducting this study, as the concern raised by the reviewer and explain what this study adds further to the existing knowledge.

Please submit your revised manuscript by Oct 17 2020 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

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Aziz Rahman, MBBS, MPH, CertGTC, GCHECTL, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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

1. 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. In your Methods section please include the dates upon which authors accessed the clinical data sources used in this study.

3. Thank you for stating the following in the Competing Interests section:

"YYX has received research funding from Sanofi Pasteur, Sanofi, Pfizer, Genentech, Janssen, VIR Biotechnology, and the Office of Rural Health Resource Center-Eastern Region. SMM has received research funding from Assurex, GSK, Merck, Pfizer, Roche and Sanofi, and is/was a member of advisory boards for GSK and Sanofi. RVA, JKL, EWT and AC are employees of Sanofi Pasteur. The remaining authors have nothing to disclose."

We note that one or more of the authors have an affiliation to the commercial funders of this research study : Sanofi Pasteur.

3.1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

3.2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.  

Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

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

In your revised cover letter, 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) and who has imposed them (e.g., an ethics committee). 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 as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

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

5. Please upload a new copy of Figure 2 as the detail is not clear. Please follow the link for more information: https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/

[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: It is a well-written article, although it was adapted from a previous study with similar design. It is somewhat lacking in originality and appealing new findings. I believe further analysis and edits and could improve the quality of this paper.

1. In line number 135-137 and 143, the authors described Laboratory confirmed influenza as the exposure variable and acute MI hospitalization as the outcome variable for the purpose of this study. The authors concluded that they found “significant association between LCI and AMI among senior Veterans”. However, the have compared with the “control interval” which is 52 weeks before the index date (Influenza test date) and 51 weeks after the end of the risk interval (the first 7 days after the index date). In general, exposure should be prior to any outcome for measurement of an association between exposure and outcome. How AMI episode before the influenza test can be included for association analysis? I think there is proper explanation and authors could consider including this clearly in the methods section.

2. More than half of the patients had known high risk factors for CVD (table 1). It would be good to see if patients with the similar co morbidity were stratified and compared for AMI after LCI.

3. Fig 1 showing risk interval as “Dark shaded area” which conflicts with the description of this figure in line no 392-394.

4. This study included 30 episodes of previous AMI hospitalization during year prior to start of study window (Table 1). Excluding old MI episodes from the study could provide more insight.

5. Out of 391 influenza tests, we see a total 288 test by test type in Table 1. Where is other tests?

6. Among those tests, one is antibody test. Which antibody? Is it reliable to indicate an acute influenza infection?

7. Throughout the analysis, authors compared rural (115) with non-rural patients. It would be great if authors define rural in their description of the study design.

8. As the 96% episodes included in this study are “male’, gender is not a strong factor to include in the comparison (line 234, 306 and table 4).

9. Overall, it would be an added value if authors clearly describe what new knowledge were added by this manuscript.

Reviewer #2: 1. Please choose one heading for the introduction section in line 77, either introduction or background.

2. As this study is also exploring the mediating role of WBC and PC, I would suggest the inclusion of previous knowledge on WBC and PC count in relation to influenza and acute myocardial infarction in the introduction section and also in the discussion section.

3. Line 184-185: Is there any justification why age 75 years was taken as a cut-off point to dichotomise the age variable? Why did not the authors consider age as a continuous variable?

4. The aim of mediation analysis using a survival model (Table 4) is to adjust for potential variables. However, I would recommend elaborating the description of table 4 in the result section - what significant variables (including comorbidities) imply.

5. As this study has tried to examine the impact of age, please discuss what other studies have found in the discussion section as well.

6. Line 311 – 312: Please include the p-value here to make it clearer that there was no significant difference between the IR between those having vaccination record and without a vaccination record.

7. Line 333: 8.89 in model 1, not model 4. Please correct it.

8. In conclusion, line 373-374, the risk to the patient of older age might be misleading as no statistical significance was observed.

**********

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.

Laboratory-Confirmed Influenza Infection and Acute Myocardial Infarction among United States Senior Veterans

PONE-D-20-22385R1

Dear Dr. Young-Xu,

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 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,

Associate Professor Dr Muhammad Aziz Rahman,

MBBS, MPH, CertGTC, GCHECTL, PhD

Academic Editor

PLOS ONE