Response to ReviewersRevised Manuscript with Track ChangesManuscript

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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If you did not receive any funding for this study, please simply state: u201cThe authors received no specific funding for this work.u201d

Reviewers' comments:

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods :

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Results :

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Conclusions :

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Summary and General Comments :

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: This is an interesting epidemiological study that analysed 11 years of surveillance data in Malaysia to investigate the transmission factors of HFMDs, and is well suited to the scope of PLOS Neglected Tropical Diseases. Firstly, I would like to congratulate the authors for piecing together and evaluating an extensive data set. Overall, I very much enjoyed reading this manuscript. The manuscript is well written, proper statistical methods of analysis have been carried out and well explained. I do have a few comments that I hope will help improving the manuscript, or maybe just give the authors food for thoughts.

L174-207: The authors' multivariate analysis is commendable for employing an indicator that precisely quantifies the spread of infectious diseases through the evaluation of Rt. Nevertheless, there remains a concern that the results might vary depending on the methodology used to input the explanatory variables. Ensuring the robustness of the primary findings through comprehensive sensitivity analyses would enhance their reliability. For instance, meteorological factors such as mean temperature, relative humidity, and precipitation could exhibit lag delayed effects. Additionally, it is important to question the assumption of linearity in the exposure-response relationship, thereby justifying the use of a linear mixed-effects regression model.

L174-207: The evaluation of the predictive capability of statistical models is essential. Empirical validation requires an assessment of the model's fit to the data and the control of time-series trends.

L363: While the authors have assumed a Gaussian distribution, it would be prudent to assess the fit against alternative distributions, such as quasi-Poisson or negative binomial, to ensure the most appropriate model is employed.

L385: The examination of delayed effects of meteorological factors should consider a broader range of lags. Given the incubation period of HFMD, an evaluation extending up to 7 to 14 days would be advisable.

L391: If R-INLA is used, it should be evaluated using multiple indices, not just WAIC. For example, it may be necessary to thoroughly examine models with increased complexity regarding input variables and model structure, such as the deviance information criterion and average cross-validation log score.

Dataset and code sharing: It may be a good idea to include the dataset used in this study and the code to reproduce the results in the supplementary materials, so that third parties can reproduce the study. Also, although we were unable to access the Github repository provided by the authors (and so were unable to evaluate its contents), is there a reason for this?

Discussion: It is suggested that a section detailing the study's limitations be included, highlighting three to five key limitations and providing a concise summary of potential avenues for future research.

Reviewer #2: This paper delves into the epidemiological traits of HFMD in Malaysia and scrutinizes the influence of meteorological factors on its prevalence. As a comprehensive study, it holds considerable significance. Nevertheless, there are a few areas for improvement:

1. The dataset spans from 2009 to 2019. Incorporating data from 2020 to 2024 would enrich the analysis, particularly by illuminating the impact of the COVID-19 pandemic on HFMD trends.

2. Conducting a genetic evolutionary analysis of prevalent enteroviruses in Malaysia, such as EV-A71, could provide deeper insights into the virus's mutations and potential implications for HFMD.

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.

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Reviewer #1: Yes:  Keita Wagatsuma

Reviewer #2: Yes:  Yuefei Jin

Figure resubmission:Reproducibility:--> -->-->To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols-->?>

Dear Dr Pons-Salort,

We are pleased to inform you that your manuscript 'Spatio-temporal dynamics of hand, foot and mouth disease in Malaysia, 2009 – 2019' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS Neglected Tropical Diseases

David Safronetz

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

***********************************************************

Thanks for addressing all the editor’s and reviewers' comments. Congratulations on the excellent work!

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Improved

Reviewer #2: (No Response)

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Improved

Reviewer #2: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Improved

Reviewer #2: (No Response)

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Accept

Reviewer #2: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Since the authors have earnestly addressed my comments and concerns, I would like to accept this manuscript. I look forward to their future research endeavors and commend the valuable contribution of this study in evaluating the potential application of spatiotemporal statistical models to the transmission dynamics of infectious diseases.

Reviewer #2: (No Response)

**********

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:  Keita Wagatsuma

Reviewer #2: No