Dear Dr. Marks,

Thank you very much for submitting your manuscript "Diagnostics to support the eradication of yaws – Development of Two Target Product Profiles" 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.

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,

Justin D Radolf

Guest Editor

PLOS Neglected Tropical Diseases

Richard Phillips

Section Editor

PLOS Neglected Tropical Diseases

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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: Accept

Reviewer #2: The methods are robust

Reviewer #3: Fongwen et al, describe a strategy by which WHO's diagnostic technical advisory group for neglected tropical diseases (DTAG) assembled and charged a working group to develop target product profiles (TPPs) for new diagnostic tools to aid with the eradication of Yaws. The manuscript summarizes the work done by the working group and how it resulted in two separate TPPs, which are described in the paper.

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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: Minor revision. Figure 1 quality needs to be improved.

Reviewer #2: the results are clear

Reviewer #3: The authors provide a summary of the working group's recommendations in two Tables. The first table includes recommendations for the development of new diagnostic tools for diagnosis Yaws and table two provides guidance for how to develop testing strategies for azithromycin resistance (Table 2). There is no statistical analysis, since the paper is purely a description of the process by which the working group came up with their recommendations for testing for Yaws and for defining azithromycin resistance. The tables are clear in their present format, results are purely descriptive and aligned with the purpose of this manuscript.

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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: Minor revision, WHO reassured crteria should be moved to the dicussion.

Reviewer #2: the conclusions reflect an appropriate analysis of the data

Reviewer #3: Based on the existing literature and epidemiology of Yaws, the working group made certain assumptions about Yaws diagnostics and T. pallidum subs. pertenue azithromycin resistance in low and high risk populations and at different time periods in their respective journey towards eradication. The recommended TPPs have not yet been tested in any of the populations described. As a result this paper is not meant to be data driven and is purely hypothetical based on a number of well established assumptions.

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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: Accept

Reviewer #2: (No Response)

Reviewer #3: I recommend the authors add a statement in the discussion indicating that the recommendations will need to be validated in real life situations.

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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: This is a well-written manucsript describing target product profiles needed for yaws eradication efforts worldwide. I have minor comments for the authors to consider.

1. Neglected Tropical Diseases should be abbeviated in the Abstract

2. Line 6 of the abstract: The second "and" should be deleted

3. The first and third sentences in the introduction seem contradictory with regard to endemicity of yaws in the tropics

4. Page 5: Since azithromycin resistance is a major concern, it's important to mention in which geographical location/s resistance has been reported.

5. Page 5: Suggest changing "one of which" to "the latter"

6. Page 6: Methods section, "The seven members" should read "The seven member"

7. Figure 1: The text is illegible.

8. Page 9: Suggest adding POC before lateral flow assays.

9. I suggest moving the statements on WHO reassured criteria to the discussion.

Reviewer #2: This revised submission is clear and concise.

Reviewer #3: Fongwen et al, provide a description of the process followed by the working group in coming up with two different target product profile development strategies which will ultimately result in control and eradication of Yaws. The manuscript is well written and the objectives are clear. Whether or not the proposed TPPs are feasible for high risk settings will require extensive field work. The bar which is set for diagnostics in Table 1 and Table 2 is very high and thus may not be achievable in real world situations.

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Reviewer #1: No

Reviewer #2: Yes: Dr L Claire Fuller

Reviewer #3: Yes: Juan C Salazar

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 see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

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. Marks,

Thank you very much for submitting your manuscript "Diagnostics to support the eradication of yaws – Development of Two Target Product Profiles" 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.

The authors have addressed reviewer comments but the manuscript has some textual issues that should be addressed. As one example "latter????" on page 5. I also noted other typos (e.g., Ref 6) on p5. Please proof read carefully.

""

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,

Justin D Radolf

Guest Editor

PLOS Neglected Tropical Diseases

Richard Phillips

Section Editor

PLOS Neglected Tropical Diseases

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

The authors have addressed reviewer comments but the manuscript has some textual issues that should be addressed. As one example "latter????" on page 5. I also noted other typos (e.g., Ref 6) on p5. Please proof read carefully.

""

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 see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

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. Marks,

We are pleased to inform you that your manuscript 'Diagnostics to support the eradication of yaws – Development of Two Target Product Profiles' 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,

Justin D Radolf

Guest Editor

PLOS Neglected Tropical Diseases

Richard Phillips

Section Editor

PLOS Neglected Tropical Diseases

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