Dear Dr Demers,

Thank you very much for submitting your manuscript 'Managing disease outbreaks: The importance of vector mobility and spatially heterogeneous control' for review by PLOS Computational Biology. Your manuscript has been fully evaluated by the PLOS Computational Biology editorial team and in this case also by independent peer reviewers. The reviewers appreciated the attention to an important problem, but raised some substantial concerns about the manuscript as it currently stands. While your manuscript cannot be accepted in its present form, we are willing to consider a revised version in which the issues raised by the reviewers have been adequately addressed. We cannot, of course, promise publication at that time.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

Your revisions should address the specific points made by each reviewer.

In particular, I agree with the reviewers that while the paper derives several interesting insights, it is in its current form too long, too inaccessible, and too much focused on technical aspects. The revised version should therefore fundamentally streamline the manuscript, shift technical parts into a supplementary material and place much more emphasis on the biological/epidemiological utility of the results. 

Please return the revised version within the next 60 days. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by email at ploscompbiol@plos.org. Revised manuscripts received beyond 60 days may require evaluation and peer review similar to that applied to newly submitted manuscripts.

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- Figures uploaded separately as TIFF or EPS files (if you wish, your figures may remain in your main manuscript file in addition).

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We are sorry that we cannot be more positive about your manuscript at this stage, but if you have any concerns or questions, please do not hesitate to contact us.

Sincerely,

Roger Dimitri Kouyos

Associate Editor

PLOS Computational Biology

Rob De Boer

Deputy Editor

PLOS Computational Biology

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Authors conducted a study on “Managing disease outbreaks: The importance of vector mobility and spatially heterogeneous control.” Their approach seems novel and exciting in mathematical epidemiology. Also, their study can provide a critical/useful tool for cost effectiveness analysis of vector-borne infectious diseases. However, some critical points from mathematical and epidemiological aspects should be considered for publication in PLOS Computational Biology.

Major comments

It is insufficient for the validity of controlling only R0 (the basic reproduction number less than unity) in their spatial model. In general, the basic reproduction number for a single-patch mathematical model is the key indicator whether outbreaks will occur or not. However, it is not clearly shown whether it would be the case for multi-patch models.

For example, multi-patch models for vector-borne diseases with human movement showed disease persistence even though R0 is less than 1 in each patch (JTB 2009, The Effects of Human Movement on the Persistence of Vector- Borne Diseases). The results highlight human movement can cause the disease persistence even when R0 < 1.

Authors should provide extensive analysis on the final size relation (the total number of infected and the basic reproduction number) and furthermore, the effects of vector mobility on the final size relation should be discussed as well.

Therefore, the authors should carefully validate if it is sufficient to control only the basic reproduction number.

Reviewer #2: This paper presents a mathematical model aimed at answering a set of very interesting questions about optimization of mosquito control methods and their impact on mosquito-borne disease. Overall, this work is very interesting, timely, and useful; however, I worry that the paper in its current form is far too dense and without a focused direction, and I found it difficult to extract major points from this work. I have included a few comments below that I hope will be of aid to the authors.

1. In Methods II, the authors walk carefully through the process of how the basic reproductive number was obtained. This section was perhaps the most dense of the methods section and it read as material more appropriate for a theoretical biology or applied mathematics journal. Would it be possible to break this section down into key points and leave details to the appendices? If this approach was taken, the authors could focus on the R0 expressions obtained (such as those in equation 23) and explain the importance of each. The authors could then follow up with the hopping scenario-specific discussions of R0.

2. Related to the hopping scenarios: It would be interesting to get the authors' perspectives on how each of these scenarios relates to different mosquitoes and mosquito borne disease. It seems like finitely slow hopping is the only realistic scenario of the three. These scenarios are mathematically interesting, but are they biologically relevant?

3. I think interpretation of the results would benefit from a table of parameter descriptions in the main text. The table could include only those parameters that are important to reading and understanding figures.

4. It would also be worthwhile to have more clear reasoning behind the choice of metrics in figures. For instance, why do the authors present the metric on the vertical axis in Fig 6? What is the value of looking at omega/mu_0 in Figs 8-9? Are there other metrics that would perhaps be easier to interpret biologically for these results?

5. What are they key results here? There were a number of interesting figures presented in the results; however it was difficult to parse the major points from the work as it is presented.

6. I think this work is very interesting and useful overall, but I worry that there is too much information presented here, which distracts from the intended message of the paper.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

Dear Dr. Demers,

Thank you very much for submitting your manuscript "Managing disease outbreaks: The importance of vector mobility and spatially heterogeneous control" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. 

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Roger Dimitri Kouyos

Associate Editor

PLOS Computational Biology

Rob De Boer

Deputy Editor

PLOS Computational Biology

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A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have improved the paper; the paper is well written, with clear structure and careful explanations throughout. However, the authors have not attempted to show a relationship between the basic reproduction number, R0 and the final epidemic size (the one issue raised in the previous comments). The authors still need to carry out at least one simple case, which supports optimizing R0 is equally good as optimizing the final epidemic size.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

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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

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you 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. For instructions see http://journals.plos.org/ploscompbiol/s/submission-guidelines#loc-materials-and-methods

Dear Dr. Demers,

We are pleased to inform you that your manuscript 'Managing disease outbreaks: The importance of vector mobility and spatially heterogeneous control' has been provisionally accepted for publication in PLOS Computational Biology.

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 Computational Biology. 

Best regards,

Roger Dimitri Kouyos

Associate Editor

PLOS Computational Biology

Rob De Boer

Deputy Editor

PLOS Computational Biology

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