Dear Dr. Richardus,

Thank you very much for submitting your manuscript "Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis" 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,

Linda B Adams

Associate Editor

PLOS Neglected Tropical Diseases

Gerson Penna

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: Yes to all questions above

Reviewer #2: This is a well defined and organized study

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

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: Table 1: No explanation is given for the acronym ‘RAND-36’ or its equivalence with the SF-36

Table 5: People with Grade 1 disabilities also face participation restrictions and suffer from depression. Grade 2 disability is a frequent cause of depression and of severe participation restrictions. A recent systematic review found that up to 50% of persons affected by leprosy suffer from depression and/or anxiety. This is insufficiently captured in the proposed health state descriptions.

Reviewer #2: Results are clear and well analyzed

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

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: Line 358-65: the authors are advised to consider rephrasing the proposed health state descriptions since ‘daily activities’ is often taken to mean activities of daily living, i.e. the activity component of the ICF, rather than the participation component. Furthermore, an explicit reference to poor mental wellbeing (or mental health) is recommended.

Reviewer #2: The conclusions are logical and supported by the analysis

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

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: Discussion

I miss a discussion of the impact of the number of people counted in the DALY calculation (based on new cases only?) and the duration of the disability (only counted during MDT?). If these are not included appropriately, this will also significantly affect the resulting estimates.

Line 313-4: This may indicate that the SF-36 is not the most appropriate instrument to quantify the experience of depression and anxiety, which are found to be very common among persons affected by leprosy. It would be appropriate to note this in the light of the findings in the below two studies.

Line 316-8: see also Somar et al (2020). The impact of leprosy on the mental wellbeing of leprosy-affected persons and their family members - a systematic review.

Also Van Dorst et al (2020): ref 3 and

Bow-Bertrand et al (2019). An exploration into the psychological impact of leprosy in Sirajganj, Bangladesh.

Line 332: It may be worth noting that this has been found also for other NTDs, e.g.

Bailey F, Mondragon-Shem K, Haines LR, Olabi A, Alorfi A, Ruiz-Postigo JA, Alvar J, Hotez P, Adams ER, Vélez ID, Al-Salem W. Cutaneous leishmaniasis and co-morbid major depressive disorder: A systematic review with burden estimates. PLoS neglected tropical diseases. 2019 Feb 25;13(2):e0007092.

Bailey F, Eaton J, Jidda M, van Brakel WH, Addiss DG, Molyneux DH. Neglected tropical diseases and mental health: Progress, partnerships, and integration. Trends in parasitology. 2019 Jan 1;35(1):23-31.

Line 343: I would challenge this statement. HRQOL based weights may do a better job than the previous methods, but the SF-36 may still underestimate the impact, especially on social and work participation and on mental health, since it has not been designed to measure these based on the ICF and DSM frameworks. The very common impact on family members is not taken into account either.

Reviewer #2: Probably has too many tables and seems overly technical

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

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: The DALY weights for leprosy are an important topic since revision has been overdue for a long time!

Reviewer #2: The authors present here a meta-analysis of leprosy disability weighting estimates, with particular emphasis on patient input. They suggest that leprosy is among the more “neglected of the neglected tropical diseases” in that the current antiquated disability estimates erroneously suggest a false low burden of disease in most populations, that can incorrectly skew distribution of health resources or bely the benefits of new intervention programs. This results mainly from a lack of patient input on psychological and social issues and a traditional reliance of physical impairment scores.

It is mind boggling that a disease so widely known, feared and stigmatized around the world, would not somehow include patient input on mental health and social impacts of their disease. Yet, among the more than 2000 manuscripts reviewed in this analysis only 14 included standardized patient input and among those only 8 also had robust enough data to be re-analyzed in this study. Perhaps not surprisingly, they observe that individuals with grade 0 and 1 disabilities also suffer mental health and social deficiencies and the resulting true burden of those disabilities are 4-20 times greater than previously understood.

This is an important contribution to bring leprosy more into the modern world. Based on solid statistical analysis the authors responsibly offer new disability definitions that can change the paradigm of disability estimation and disease burden in leprosy. The language of the paper is somewhat technical and the total number of tables could easily be halved.

In revision the authors should consider:

Line 222: “a” few

Lines 346-349: poorly phrased. As written implies the revised weights are not different from before. Should say they 'are similar to each other'

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

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: Wim H van Brakel

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.

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, 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/plosntds/s/submission-guidelines#loc-materials-and-methods

Dear Drs. Richardus and Chandran,

We are pleased to inform you that your manuscript 'Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you may 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,

Linda B Adams

Associate Editor

PLOS Neglected Tropical Diseases

Gerson Penna

Deputy Editor

PLOS Neglected Tropical Diseases

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