Dear Dr Baron,

Thank you very much for submitting your manuscript "Impact of accessibility to rabies centers on human Rabies post-exposure prophylaxis rates in Cambodia and prediction of future needs using spatio-temporal Bayesian regression modelling" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

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

[1] A letter containing a detailed list of your responses to the 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.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. 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,

Mauro Sanchez, ScD

Associate Editor

PLOS Neglected Tropical Diseases

Guilherme Werneck

Deputy Editor

PLOS Neglected Tropical Diseases

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

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: In this manuscript, the authors investigate the relationship between travel time to rabies treatment centers and the rate that individuals receive post-exposure prophylaxis (PEP) to prevent rabies in Cambodia. They first use a Bayesian regression model to fit the relationship between travel time and PEP rate using data reported from 2000-2016. They find an inverse relationship between travel time (accessibility) and PEP rate, as expected. Then they use this fitted relationship to estimate how much PEP would increase if additional testing facilities had been built in each province or district in 2017 (under 3 different scenarios). They conclude by identifying the 5 provincial capitals where they would recommend adding an additional treatment center.

What I liked about the manuscript was the creative approach the authors use to identify high-risk areas in the absence of reliable human disease risk or burden data. There are also several aspects of the rationale and methods that need to be addressed or clarified before publication, which I have described below.

1) Throughout the manuscript it was hard to follow what the authors meant by the different scenarios, and which ones they were referring to (table ST2 helped). I suggest (1) including at least one main table or diagram that describes the analytical approach clearly and (2) being explicit throughout the results and discussion section about which scenario and model (district or province) you are referring to. It would also be helpful to explicitly describe which model/scenario is used to recommend new treatment centers (and why that one was chosen).

2) It would be helpful to have more details on how new treatment centers were placed in scenarios 2-4. In scenario 3 and 4, were the centers from scenario 2 that currently exist included (it appears this way from the figures)? In scenario 4, were the centers randomly place or were they placed within the largest city or existing health facilities/clinics? Do lines 215-216 refer to scenario 3, and was this the scenario used for final conclusions? Please clarify these points in the text.

3) Why were Bayesian regression models chosen for identifying locations for a new treatment center? Since the goal is reducing travel time, why not just put a new center in a location that would maximally reduce travel time in either total hours or population-weighted in person-hours? Would this change the results? It looks like this might be what was done in “Section 3.2 Population accessibility”, but that section includes no corresponding methods or figures so it’s hard to follow.

4) What was the purpose of estimating the number of animals tested? This analysis doesn’t directly address the objectives of the study and isn’t included in the discussion. I suggest either removing it or making the rationale for doing it very clear (and then also including it in the discussion and conclusions).

5) On lines 517-520 you mention that there was no evidence for seasonality. Can you show this data in an SI figure or include a reference? You could also consider explicitly fit a non-linear model to confirm that seasonality isn’t captured here, and/or consider including a metric of seasonality in a model to test this (for example, including a monthly rainfall fixed effect). Though, I do not expect this to impact the overall conclusions.

Reviewer #2: Methods

The methods chosen seem to have been carefully considered and I support the decision to use an INLA model, because of the widely available options to incorporate spatial and temporal dependency of the data. The authors managed to explain the four different scenarios very well and have scientifically sounds approach. However, I feel that the description is not always clear and the objectives become a little bit fuzzy after the very clear introduction. If indeed the goal of this paper is to estimate the spatial distribution of the risk of dogbite among all provinces and districts of Cambodia, then the explanation of the methods would have to be restructured.

I would consider merging the estimates of dogbite patients and the estimates of positive animal samples so that you can say something about the proportion of rabid dogbites among people bringing in a sample along with their need for PEP.

In addition, the methods lack an explanation on data cleaning or incomplete bite reports. I would expect that not all patients were bitten by dogs or animals capable of transmitting rabies, so this raises the question how many reports had to be removed because of that. In addition, I was wondering how many bite reports couldn’t be linked to the right administrative boundaries because of incompleteness or misspelling. Maybe this could be elaborated in the Supplementary material.

Population data is the main denominator for the outcomes of your estimates, make sure to use one that is reliable across all years. I would also suggest comparing the estimates made in this study to the widely available open datasets from for instance WorldPop or the CIESN/facebook team. This would give you more precise input data about the location of your data for the eventual demographic estimates. I would also suggest you to have a look at the R package wopr (https://github.com/wpgp/wopr) to support the estimates you make for the population data as described in lines 162-165. Find below some additional points of feedback:

Line 216-218: “The accessibility rasters were aggregated for each province and district polygon by extracting the median travel time from patient residence province or district to PEP center or provincial capital value.”

This sentence is a bit hard to follow, I would suggest rewriting to: The accessibility measure was aggregated by means of extracting the median travel time per province or district. This could ultimately be linked to the patient’s record (i.e. the district or province of residence).

Paragraph 2.2.1: I would advise you to use a constrained (using building footprints) gridded population dataset as input data (https://www.worldpop.org/methods/top_down_constrained_vs_unconstrained). It allows you to have more accurate information on the actual location of population and thus the population living beyond the travel time catchments you are indicating (i.e 60 and 120 min). The calculations you make involve two aggregated measures (namely aggregated travel time and aggregated population counts) while in fact you have finer scale spatial data available to deal with the calculations in a more precise manner.

Paragraph 2.2.3: This paragraph is not very clear to me and my feedback links back to the more general point raised before “to consider merging the estimates of dogbite patients and the estimates of positive animal samples”. To me it does not seem logical to predict the number of dogs that would be brought in for testing. This would make sense if your goal is to scale up your FAT testing capacity, but not to predict the risk of rabid dogbites. In my opinion it would make more sense if you use the number of positively tested samples among the patients that brought in a sample, as a proxy for the number of rabid dog bites and thus potentially averted deaths by the use of PEP. In a recent article written by Rajeev et al (2021), dogbites in Madagascar were used in a decision tree model to estimate the risk of a rabid dogbite in a Bayesian MCMC model. If this is also your aim, I would consider redoing a part of your model here and re-describe your goal and method here.

Line 252-254: Sentence “In an aggregated logistic regression..” is a bit challenging to read I would suggest to rewrite.

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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: Results

The results presented reflect the methods introduced before and are clearly lined out in text and figures. However, I find paragraph 3.3. challenging and would suggest to restructure and rewrite this. Below you can find a more detailed description.

Line 279-280: Were all these patient reports complete? How many were available at the province level and how many at the district level?

Paragraph 3.2: For the statistics about access to PEP I would highly suggest you to use a gridded population dataset instead of the aggregated counts. See example Rajeev et al. (2021). This would really increase the validity of your estimates. Proportionally calculating people’s access to care without taking into account their exact location leads to too much uncertainty of your estimates.

Line 355-356: Can you compare the provincial and district models? Since not all input data was collected at the district level, I would also expect a less powerful model output on district level because not all bite reports can be brought back to this level.

Paragraph 3.3: It’s a well written paragraph but it remains unclear to me what exactly you want to model and to communicate to your audience. I think the main goal is to understand the distribution of rabies risk and thus the need to improve the spatial availability of PEP in high risk regions. To me it seems therefore that you would like to report 1) on the number of patients estimated to have missed out on PEP because of poor access, which would be your predicted number of patients minus the reported number of animal bite patients 2) the estimated risk of a patient being bitten by a rabid animal, which would be the probability of an animal to be rabid times the number of reported animal bites.

The increase in PEP patients to me seems a bit as an indirect measure. Because it represents the estimated total number of patients based on access to PEP centers over the last years. So reporting onthe regions where the difference between reported and predicted bite victims is highest would be the most important outcome, that is where you are missing access.

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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: 6) In either the introduction/rationale or discussion/future work it would be helpful to understand whether building new treatment centers is the best way to prevent deaths due to rabies, compared with using those funds to make treatments free, increase awareness, vaccinate dogs, or some combination thereof, and how you might integrate that information with the results from this type of analysis.

Reviewer #2: Discussion & conclusion

Again, well written and provides a good overview of the results but would be more tangible with reports on measures as “averted deaths”, “human burden of diseases”, “proportion of rabid positive bites”

Line 431: “bite injuries” instead of “bites injuries”

Paragraph 4.2: The authors mention an important limitation of the accessibility layer used in paragraph 4.4, reflecting the static usage of the layer which is likely to have changed over the years because of improvements in the road network. However, the way accessibility is measured in this study brings another uncertainty to the estimates. The widely used malaria atlas friction layer makes large scale assumptions on road networks and travel speeds on different landcover types, which in fact might be different for your target population, namely people who seek access to care. In the paper published by Weiss et al (2018) https://www.nature.com/articles/nature25181. You can find back the travel speeds applied to each country. I would highly suggest you to have a look and check whether they seem reliable for your target population.

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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: - In the title, “prediction of future needs” is misleading since that is not actually what is done in this study, and I suggest removing or rephrasing.

- In Fig 2, it would be helpful to see results in both absolute and relative terms since the numbers, especially since the overall are so small.

- If Fig 3b, the “missing” label seems incorrect.

- In Fig 4, please include a panel for scenario 4.

- A lot of my comments require adding additional clarity or details. Since the manuscript is already long, some of the more descriptive text and discussion could be made more concise or removed.

Reviewer #2: Figures:

Overall great figures, but would suggest to clip the estimated travel times to the country borders.

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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: (No Response)

Reviewer #2: Thank you for the opportunity to review this interesting paper on the effect of accessibility to PEP providing health centers on bite patient estimates to support rabies control strategies. The authors have written a very good piece and the scope of the work fits well with the PLoS NTD audience. Rabies research faces a lot of challenges regarding data availability and the authors applied thorough methods to estimate the number of actual bite victims in comparison to the reported bite victims in Cambodia. However, some of the methods and results have to be adapted to further improve the validity of the outcomes.

My main concerns are related to the population data in combination with the accessibility measures. Aggregated population counts in combination with aggregated measures of accessibility, create more uncertainty in the predictions and outcomes mentioned in the results. Since the travel time rasters are gridded I would highly suggest the authors to also use a gridded population dataset that provides information on the location of the population, like the WorldPop constrained dataset.

In addition, the way the results are written make it hard to follow the actual goal of the paper, which in my opinion is to estimate the risk of a rabid animal bite. I would consider a stronger emphasis on the number of patients estimated to be missed by the PEP clinics (estimated patients – reported patients) and the number of estimated rabid positive bites (number of positive samples * estimated animal bites). A visual representing the aimed outcomes or a decision tree model would maybe help guide the reader in understanding the results better. I provide more detail below.

The paper would also greatly benefit from a detailed read through to improve grammar. There are quite some inconsistencies with missing words or words that are plural and miss and s at the end.

Finally, the accessibility measures that are adapted from the global friction surfaces as provided by the Malaria project introduce uncertainty on actual travel times of the target population, because speeds on roads and landcover types have been set-up in a global studuy, not always reflecting the local context realistically.

Yet, the paper provides useful insights into an important NTD in a context that lacks recent research. The paper has high potential for publication when the feedback provided is taken into consideration.

All the best with the suggestions and I’m looking forward to reading an improved version of the paper!

--------------------

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Reviewer #1: No

Reviewer #2: No

Figure Files:

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Attachments

Attachment

Submitted filename: PNTD-D-21-00896.pdf

Dear Dr Baron;

Thank you very much for submitting your manuscript "Impact of accessibility to rabies centers on human rabies post-exposure prophylaxis rates in Cambodia and identification of optimal future center locations using spatio-temporal Bayesian regression modelling" for consideration at PLOS Neglected Tropical Diseases. 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.

After reviewing the revised version you have submitted, we would like to ask you to address the points raised by the reviewers to allow your work to be deemed suitable for publication. I suggested that your go through all comments provided below and provide special consideration to changing the title your manuscript as indicated by reviewer 1 and carry out a thorough revision of grammar and spelling.

We look forward to receiving your revised version and congratulate the team on a careful work in addressing previous comments.

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,

Mauro Sanchez, ScD

Associate Editor

PLOS Neglected Tropical Diseases

Guilherme Werneck

Deputy Editor

PLOS Neglected Tropical Diseases

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

Dear Dr Baron and co-authors;

After reviewing the revised version you have submitted, we would like to ask you to address the points raised by the reviewers to allow your work to be deemed suitable for publication. I suggested that your go through all comments provided below and provide special consideration to changing the title your manuscript as indicated by reviewer 1 and carry out a thorough revision of grammar and spelling.

We look forward to receiving your revised version and congratulate the team on a careful work in addressing previous comments.

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: I thank the authors for adding Table 1 in response to my comments. It is very helpful, but I suggest editing the text for "scenario 5" to reflect the description in the text of the methods because it's currently unclear. For example, the description could read something like: "21 scenarios with four PEP centers, where each scenario includes the three current PEP centers (Phnom Penh, Battambang and Kampong Cham) and one additional center added in each of the 21 provincial capitals." In addition, I'm unsure what "as scenario 1,2, and 3" means for the Source.

Lines 314-315. "The result of this analysis was not significant". Please be more specific about what you were specifically testing here, and what was "not significant".

Reviewer #2: Thank you very much for the opportunity to review a revised version of this manuscript. The paper was already very interesting and good at the first round of review, but the authors did an outstanding job at further improving the study. I would like to thank the authors for their detailed feedback on the comments raised and have no additional technical comments for consideration in this new round of revisions. The authors improved the explanation of the different scenarios substantially by adding an extra table and also further highlighted the limitations of the input data. I find the paper fit for publication after some small improvements of grammar and spelling. I think the paper would even further improve after a native english speaker could read over it.

--------------------

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: I'm a bit confused about why Scenario 5 gets introduced first in section 3.2. Shouldn't lines 460 to 471 belong in the last paragraph of the results where Table ST4 is referenced? If I am missing something here then it would be helpful to have further description of the rationale of this scenario in both sections of the results.

Reviewer #2: Yes

--------------------

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: Their conclusions are supported and in their revisions the authors have added additional limitations and public health context important for understanding the implications.

Reviewer #2: Yes

--------------------

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: The title of the manuscript is still a bit misleading. In this paper, the authors examine associations between accessibility and yearly PEP patient rates (and use that fitted relationship to predict optimal new PEP center locations), rather than causally assessing the "impact". I suggest replacing "impact" with "association between". Alternatively, the title could be rephrased to read something along the lines of: "Accessibility to rabies centers and human Rabies post-exposure prophylaxis rates in Cambodia: a spatio-temporal analysis to identify optimal locations for future centers".

Reviewer #2: I think the paper would even further improve by having a native speaker go over the text once. I started to notice some tiny mistakes in the abstract (see below), but then focussed more on the bigger picture of the paper and the content.

Title

“in Cambodia and identification of optimal future center locationsusing spatio-temporal Bayesian regression modelling” add space between locations & using.

Abstract

Line 34: “to inform the selection future PEP center locations in high-risk areas” suggest to change sentence to “to inform the selection of future PEP center locations in high-risk areas”

Line 35: “accessibility to rabies centers on the yearly rate of PEP patient in the population and generate a risk map” suggest to add and “s” behind patient > PEP patients

Line 38: “patients as outcomes” remove “s” behind outcome.

Line 39: “Secondary exposure variables consisted in” change to “consisted of”

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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: Overall, the authors have done a thorough job of responding to my comments and my remaining comments are mostly editorial.

Reviewer #2: Strong study with a very important societal impact in a rabies endemic country. Authors have been able to produce reliable estimates of human rabies and dogbite burden that can aid prioritization and allocation of resources. Figures and tables support the findings of the studies and the improvements made by the authors help guide the reader through the paper. Well done and I look forward to seeing the rest of the research coming alive!

--------------------

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Reviewer #1: No

Reviewer #2: 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.

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Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your 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

References

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.

Dear Dr Baron,

We are pleased to inform you that your manuscript 'Accessibility to rabies centers and human rabies post-exposure prophylaxis rates in Cambodia: a Bayesian spatio-temporal analysis to identify optimal locations for future centers' 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,

Guilherme L Werneck

Deputy Editor

PLOS Neglected Tropical Diseases

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

I want to thank the authors for providing adequate answers to the reviewers and revising the manuscript accordingly.