Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trend in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" 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:

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[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,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

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: methods are well explained and appropriate for this study

Reviewer #2: Information on the objectives of the study is clear, ethical approval was obtained. See full comments below in the Methods section.

Reviewer #3: The objectives of the study are clearly articulated with a clear testable hypothesis stated.

The study design is appropriate to address the stated objectives.

The population is clearly described and appropriate for the hypothesis being tested.

Since all the population is included in the study, there is no sample size issue.

The statistical analysis is corrected for supporting the conclusions.

But: (1) Please include the diagnosis criterion of leprosy for better under standing. (2) Please clarify the mobile population for analysis since it could be a confounding factor for the result. (3) Is there any policy change for leprosy which could influence the detection of leprosy. (4) The method of Seasonal-Trend decomposition procedure based on Loess (STL) can be described more clearly for better understanding by readers.

Reviewer #4: This is an interesting exercise made possible by the comprehensive SINAN database in Brazil. The authors have given much emphasis to the statistical analysis of trends. I believe the statistical approach is generally valid and the analysis well-performed, but there are some unclarities:

1) Please provide the definition used in Brazil for hyper endemic. For international use, consider to just state 'highly endemic' and use this term as well in the title, instead of 'hyper endemic'.

2) There is quite some 'fog' in relation to disability grade, its registration and the way it was dealt with in the analysis. Lines 152-154 are unclear; e.g. what does 'below expectations' mean. Also the sentence in lines 188-190 is unclear. What total number? And how does this translate in the results? There I see a breakdown by disability grade and 'not registered'. With the great uncertainty with regard to the indicator disability grade, why do you not just take 'grade 0' and 'joint grade 1 and 2' in the trend analysis, and ignore the 'not evaluated'?

3) I think very important information is missing necessary for interpreting trends, namely operational changes in the leprosy control program, or for that matter the health system in general. The total leprosy detection over the ten years is rather spiky. It comes down between 2008 and 2012, increases and decreases steeply between 2012 and 2016, and then increases again to reach possibly a plateau. The health system (or other operational changes) during this time need to be described in some detail in the methods section under a separate heading. This is essential context to understand and interprete the trends.

Reviewer #5: There is too much background information in the methods – make this more concise, especially the parts about the “study design and research scenario”. Also, in English, we generally don’t say “Research scenario”. I would say “Study Design and Setting”.

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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: well presented and relevant information provided

Reviewer #2: The result section is clearly written. I would suggest to use not only colours, but also a different line appearance in the table to make them more clear for readers who are printing the tables in black/white. Please also see my comments below on the Results section.

Reviewer #3: The analysis presented matches the analysis plan.

The results are clearly and completely presented.

But: A standardized population need to be provided and calulated for the age and gender groups.

Reviewer #4: With regard to the case characteristics (table 1) there is some unclarity about operational classification and clinical form. PB (26.67%) seems to be the sum of I and TT clinical forms (26.88%), but not just the same. In the sentence starting on line 237 it states: "... there was a predominance of multibacillary cases (73.33%), followed by borderline cases (57.00%)". But borderline cases are part of MB...

With regard to presentation of trends, I would first like to see the figure 'Detection total' separately with under the time line some bars or arrows indicating important operational changes in time. See for instance the figure A in the following article for inspiration https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(20)30065-4. In that way the overall trend is placed in context of the most important operational factors influencing the trend.

Table 2 summarizes the main findings of the trend figures 2-5. You could therefore consider to place all these figures in an appendix.

In table 2, make sure to give the full name of the abbreviation AMPC. Furthermore, as reader I need help to understand the importance of the figures under AMPC. Under the heading Trend you state Increasing or Decreasing. But is there a way to indicate a measure of increase or decrease, for instance through a p-value? And how do you establish the importance of a trend. When is the trend such, that you want to highlight it as an important result and discuss its implications. And when is it just some irrelevant 'noise'.

Reviewer #5: 1. I don’t think G0D (as opposed to G1D and G2D for grade 1 and grade2) is an accepted acronym for “no disability” and it’s confusing to say that G0D is decreasing – G0D in effect is “NO disability”. I would use a different way of describing it because if you read it quickly you may think that some disability is decreasing whereas what you are saying is that people presenting without disability is actually decreasing among many groups which is very concerning.

For all “G0D”, I would substitute “No disability”

2. I know that Asian descent for race translates to “amarelo” in Portuguese, but many English language readers would find “Yellow” offensive, so I would change that to Asian descent.

3. Lines 237-238: You wouldn’t really say “followed by borderline cases”, since they are part of two different categories, just state these separately.

Figures overall seem ok, but would change the G0D label as per above.

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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 #2: In the discussion, I am missing the role of leprosy prevention as post-exposure chemoprophylaxis with a single dose of rifampicin (SDR-PEP) for contacts of leprosy contacts, in combination with contact screening / active case finding. This is a very important strategy for decreasing the number of new cases / case detection delay / disability etc. For example in Brazil, a current research project is ongoing studying advanced chemoprophylaxis regimen (PEP++). But the evidence from e.g. COLEP & LPEP regarding SDR-PEP is clear and it is also included in the WHO Leprosy Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. You could add this as reconmendation.

Including 1 study limitation may be a bit limited.

Reviewer #3: The conclusions are supported by the data presented.

The limitations of the study are addressed.

Public health relevance is addressed.

The authors need to discuss in more detail to help readers understanding the result.

Reviewer #4: To start with, cut the discussion by at least 50%. It is far too long and therefore unclear. In the discussion state first what you consider the really most important findings of your study. Which trends are really relevant in terms of being unexpected, undesired and amendable to health care interventions?

After stating the most important findings, only then start with some explanation and interpretation. Make clear that you are discussing everything against the Brazilian background. You use the term 'global' at a certain point, but I understand it to mean Brazil as a whole and not the world. Here it is also important to take into account the operational factors, that you have now incorporated in the new figure 1.

Much of the disparities are due to delayed detection, which may apply more strongly to e.g. women and people in the working age. This is also related to stigma. Try to bring that together in the discussion more comprehensively, instead of just going along the different groups (gender, age and disability) in order of appearance in analysis.

Whereas the general discussion text should be much shorter, the paragraph on strengths and weaknesses should be a more detailed.

Finally, the conclusion is very general. Can you make it a bit more specific, based on your findings? Just one or two sentences more.

Reviewer #5: 1. Line 288 Again, do not say “grade 0 disabilities” are decreasing. That’s misleading. Grade 0 means there is no disability, so you shouldn’t describe it like that. You should say that the rates of new diagnosis without disability is decreasing.

2. Gender differences – I think you are missing discussion of a potentially big reason for differences in gender that has been proposed – that women are not seeking care for their leprosy, possibly due to more PB in women than men so underrecognition or possibly due to stigma (reference: Factors preventing early case detection for women affected by leprosy: a review of the literature. Price VG.Glob Health Action. 2017 Jan-Dec;10(sup2):1360550. doi: 10.1080/16549716.2017.1360550.PMID: 28853325 )

3. The discussion is too long – you should summarize the different age time series more succinctly and in 1-2 paragraphs and not just repeat your results.

4. There is no discussion on the limitations of this study – one big thing, which you can tell from the figures, is that the number of children with grade 2 disability is actually quite small so it may not be able to tell a clear trend. However, the fact that there are any G2D in children is concerning, and at odds with the WHO goals for zero disability in children < 15 (you should mention these goals in the discussion).

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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 #2: ABSTRACT:

32-35: First sentence in abstract is quite long, change this into 2 sentences to increase readability.

35-36: Second sentence in abstract is incorrect. Start the sentence with e.g. “This is a …”

45-46: In the abstract it is stated “Regarding detection according to gender, there was a decrease among women”, but “by evidencing a increasing trend of leprosy cases among women” (47-48). This seems contradictive, please make some changes. It should also be ”aN increasing trend”.

INTRODUCTION:

60: In introduction, I would advise to change “which lead to physical disabilities” into “which can lead to physical disabilities”.

61: Please remove “skin contact” in “skin contact or other means cannot be excluded”, the evidence for skin contact is low (i.e. using a tattoo needle in a leprosy patch and next tattooing another person with the same needle is risky, but not normal skin contact and rare of course) and stating it like this can sound stigmatizing for some people.

65: Reference numbers should be placed before/after (depending on reference style) punctuation marks. In this case: before a comma (,) or full stop/period (.), not in the middle of a sentence. Please move [2,3] to after “imagined”.

67: “In 2016, according to WGHO data, 143 countries…” -> This data is a bit outdates, especially because your data reflected in the time series study is ranging from 2008-2018. Please use WHO data from 2018 (or even 2019) here.

72: It seems like you are referring to both North and South America, so it should be continentS.

77: “preventing cases with grade of disability” should be “preventing cases with disabilities”.

79: Please remove the capital at “The Plan” -> “The plan” or even better, change it to “The strategy”.

89: Place a comma after “2010-2012”.

102-107: This is also the case because you cannot count ‘undetected cases’.

105: “disabilitie” should be “disability”.

111: the word “public” is missing: “define public policies” -> “define public health policies”.

113: the word “tools” is missing: “more sensitive is the time series” -> “more sensitive tools is the time series”.

METHODS

129: when including such an exact number as 3,266,538 km2, I would suggest to remove the word “approximately”.

138: Explain shortly what Gini index is.

140. full stop is missing after “[17,18]”

140-141: capital usage is incorrect, please check. I would suggest to remove most of the capitals used in this sentence.

145-146: same point regarding the capitals, I would suggest to remove most of the capitals used in this sentence.

153-154: which expectations are meant here? Where does 75.00% come from?

STUDY POPULATION AND INFORMATION SOURCES

164: I do understand why you included this (race/skin color), and the explanation on this in the discussion is very clear and correct. But when people are reading this in the Methods section, it is a bit in your face. Registering this data should be avoided or happen very carefully from an ethical perspective, as it may sound like ethical profiling / offensive / discriminatory to some people. The colors as outlined here (“white, black, yellow, mixed, and indigenous”) is not ethical preferred. Starting with white is tricky (also now with Black Lives Matter), alphabetical order would be better. I would include information that people had to register their own race (instead of the health professionals / researchers registering it, because it is hard to judge whether someone is mixed or black for example). I would remove it completely from the article. If you want to leave it in, I would suggest to more clearly explain also in the Methods section that this is registered in the national leprosy system and that this is outdated or not found to be ethical anymore and why this data can still be important and change/remove this listing of skin tones.

181/189/192/212/214/215: Grade of Disability is sometimes written with capitals and sometimes without, I would suggest to write it without capitals. I also prefer “disability grade” over “grade of disability”.

202-206: I would use “” or ‘’ for the words you are defining: ‘Trend’, ‘Seasonality’, ‘noise’.

RESULTS:

229 & Table & 321: see comments above about “race/skin color”

235 & 262: Delete “Source: Authors”. If there is no other source included, it is clear it is from the authors.

238/240/241-242/245/Table 2/260/262/264/268/268/271/274/354/372: See comment above: “Grade of Disability” -> “disability grade”.

243: full stop missing after “Fig”.

Table 2: “General Population”-> “General population”.

Fig. 2/3/4/5: It may be nice to use strips/dots for one of the lines in the graphs (e.g. the red one) besides a color difference, so people who print it black & white can still see the color difference.

279 & 339 & 434: I would suggest a different word here, as “behavior“ is more suitable for humans/animals, go for e.g. “trend” here instead.

280 & 289: “and or” should be “and/or”.

297: remove “the” before “: disability”.

299: Remove “The” before “literature”.

300: Maybe add reference here, as “literature” sounds like plural.

308: Possibly remove “various”.

310: you could replace “published works” by simply staying “studies”.

311: what is meant here by “risky situations”? It this referring to getting infected? As prolonged contact is needed, I would not call this “risky situations” (also sounds a bit stigmatizing), or is it referring to possible damage to the hands because of work related accidents or so? I would delete “risky situations” or rephrase and explain it.

313-314: at least 2 references seem to be missing, as you are talking about evidence from the 90ies and current policies.

343: add the word “the” between “regarding” and “detection”.

343 & 354: add “years of age” after “15”.

348-349: word repetition “carry out”, if you like, change for executed/organized…

357 & 377: reference location not correct (should be at end of sentence or before comma).

357-360: what do you mean here by the statement that “early exposure” leads to disabilities? Because of the length of the exposure/infection period (although, they were still children at time of diagnosis, so it cannot be decades for example) or is it because their bodies were still developing biologically at that age. Or both?

362: I would change “academic performance” into “school performance”, as “academic” often refers to university level.

383: delete commas around “as well as”.

384: “incapacity” –> “incapacities”.

400: change the word “scenario” into “setting”.

400: you may like to add “registration at health care level/national surveillance system”.

402: you may like to add “lack of adherence”.

408: “a way of” sounds a bit informal, you could replace it for “a method of”.

421-422: change “does not behave in a homogenous way” into “disease trend is not homogenous”.

427: what is meant by “promotion actions”? Awareness raising? Self care? Please explain.

431 & 432: I don’t think “State” should be capitalized here.

432: “State protection” has a double definition (also a negative one), I would replace it for “state support”.

434: 432-435: references are missing, as you are referring to multiple studies and WHO reports.

435: delete “which is true”, as you need to have verified all these studies/data to know for sure.

435: a decrease in new cases can also be caused by a lack of active case finding activities, and this, is not always a ‘positive’ finding.

445: usually, multiple limitations (at least 2) are named.

Say something on post-exposure prophylaxis (PEP) as prevention strategy for leprosy (see my comment above) in the discussion section.

REFERENCES:

Reference 1 (457) and reference 5 are the same, though 2 difference websites are used. Please replace reference 1 with number 5 (2018 WHO is the correct reference for the WHO Leprosy Guidelines).

Reviewer #4: The first paragraph of the introduction is rather outdated. Please use 2019 WHO data and also refer to the latest WHO strategic document for leprosy.

Reviewer #5: The paper needs some work before publication, especially in its length, which I think can be shortened, and in the English / writing in certain places. I found a few typos as well. It needs a thorough review for English language editing, spelling, typos before publication. I also didn't see cover letter or summary which was unusual.

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Reviewer #1: Yes: Carlos Franco-Paredes

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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

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: I enjoyed reading this and reviewing this manuscript. It is a master piece in social sciences in medicine and it reveals the fallacy of the academic imperlalism by the "experts" drinking latte in European countries dictaing polices in coutnries where leprosy is a major public health concern. This publication is a clear demonstration of the poor decision meaking of public health organizations. The only thing that the elimination campign of leprosy did, was the elimination of attention to major chronic infectious disease that causes severe disability. It was an honor to review this paper.

Reviewer #2: Very nice article and an important topic. Please make some editorial changes (see full comments), and pay extra attention to capital usage. Also, be careful with the section on race/skin color (especially in the Methods section) as this is a sensitive topic. See if you can add another limitation and add chemoprophylaxis for leprosy in your recommendations. Also please do check the reference list again and add a few extra references in the text (see comments).

Reviewer #5: This study is a straightforward analysis of epidemiologic data on leprosy from the SINAN data base and uses a time series analysis that really studies the trends over time of the 3 key epidemiologic indicators for leprosy: 1. New case detection rate, 2. Pediatric cases, 3. New grade 2 disability. Using a hyperendemic city is a really nice way to not only show concerning trends in this area, but to model ways that we can study other geographic areas. These findings are very important because it shows that the decreasing incidence does not tell the whole study and that different age / sex can be impacted differently and may need different control strategies. The paper needs some work before publication, especially in its length, which I think can be shortened, and in the English / writing in certain places.

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Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" 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 pay particular attention to reviewer's 2 comments and make sure that their concerns are addressed appropriately.

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,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

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: OK

Reviewer #2: TITLE:

- "hyperendemic" is written with space in the rest of the manuscript, but without in the title

INTRODUCTION:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- Please include the latest version oif the WHO Global Leprosy Strategy (2021-2030).

- I would delete: "Also, regarding the inequality related to age, it is known that when there is a delay in diagnosis, children that who had contact with index cases can also become ill [1112], which is an important gap to be filled."

METHODS:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- You could think of adding a definition table with an overview of the disability grades (what is G0D, G1D, G2D)

- Capital usage still not fully correct

- This sentence is unclear: "Regarding the disability gradethe grade of disability, health units evaluated a mean of 56.24% of new cases with a disability at the time of diagnosis, below expectations, which was listsed as should be at least 75.00% according to SINAN [235, 26]."

- I donnot understand this sentence because of the level of English, you can maybe also delete it: "For the construction of time series of the cases with disability grade we considered all the number of cases with disability grade (G0D, G1D, G2D, and not evaluated)."

- This is also quite vague, could it be deleted? "... even for a very long time series and large amounts of trend and seasonal smoothing, a very small amount of trend smoothing, and seasonal components that are not distorted by aberrant behavior in the data ability to decompose time series with missing values"

- This should not be in the methods section, but in the discussion (is already included there). Also, the word 'dubious' is too strong/incorrect: "Finally, we mention that the notification forms are filled out by third parties, so dubious data may be provided."

Reviewer #3: The objectives of the study are clearly articulated with a clear testable hypothesis stated. The study is design appropriate to address the stated objectives. The population is clearly described and appropriate for the hypothesis being tested. The sample size is sufficient to ensure adequate power to address the hypothesis being tested.

Reviewer #4: See attachment

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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: OK

Reviewer #2: - Changes made were appreciated.

- 'ignored' is too strong in table 1, go for: 'not classified / incorrect / incomplete' instead

Reviewer #3: The analysis presented matches the analysis plan. The results are clearly and completely presented.

Reviewer #4: See attachment

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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: OK

Reviewer #2: DISCUSSION:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- Improvements can be made regarding: item order in the discussion, repetition, level of English.

- I would suggest to delete this, as it seems less relevant (not clearly explained how this affects the leprosy programme) and the discussion word count is too high: "In the state of Mato Grosso, in 2015, the “National Campaign for Leprosy, Geohelminthiasis and Trachoma” was initiated, which mobilized local health services to execute carry out actions related to the active search for cases, focusing on schoolchildren, aged from 5 to 14 years. The campaign was carried out in approximately 915 schools in 65 municipalities (including Cuiabá), to examine and treat more than 291..200 thousand students and possibly their possible contacts [242]. It is estimated that the campaign may have had an impact in the region studied, reflecting the peak of detection verified in the study for this age group. No further policies were encountered in public archives to influence the detection of leprosy in the region duringh the time period."

CONCLUSION:

- See my suggested changes and comments in the text file attached.

Reviewer #3: The conclusions are supported by the data presented. The limitations of the study are clearly described.

Reviewer #4: See attachment

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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: OK

Reviewer #2: revision needed

Reviewer #3: (No Response)

Reviewer #4: I have made some edits to the text (attached, visible with track changes). That is easier for me than repeating everything in this form one by one.

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

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: OK

Reviewer #2: Improvements were made and are much appreciated. Nevertheless, the manuscript still need to be revised. Especially the discussion needs attention, the text order should be changed and repetition should be avoided. Both the introduction and discussion section can be shorter and more to the point. The newly written text segments need improvents regarding the level of English.

Reviewer #3: (No Response)

Reviewer #4: The paper has improved well after a thorough revision. There are still some small issues that I have addressed directly in the revised manuscript with track changes visible. This is not intended as a full language edit, but just to improve on some relatively important matters with regard to language and explanation.

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

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: Carlos Franco-Paredes MD

Reviewer #2: No

Reviewer #3: No

Reviewer #4: 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, 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.

Attachments

Attachment

Submitted filename: Revised Manuscript with Track Changes_corrJHR.docx

Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" 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,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

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

Reviewer #2: - The changes made after last round were a great imporvement.

- The methods section can still be shortened, see if you can delete some sentences, this will make it easier to read.

- I suggested in the Word document to move a text section from the 'Methods' to the 'Discussion'.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

Reviewer #4: (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: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

Reviewer #4: (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: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file. These were especially focused on the level or English.

Reviewer #4: (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

Reviewer #2: Minor revision, mainly editorial, English language and references. Especially the methods section can be shortened. See my suggestions & comments in the Word file.

Reviewer #4: (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: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- If possible, further shorten the 'Methods'-section.

- Describe where the raw data can be found for reproducibility reasons (see my comment/addition in 'Ethics'-section).

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

- Please check the references, some are incorrect in the text and inconsistent in the reference list.

Reviewer #4: I am happy with all revisions made.

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

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: Carlos Franco-Paredes

Reviewer #2: No

Reviewer #4: 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, 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.

Attachments

Attachment

Submitted filename: Revised Article with Changes Highlighted_reviewers comments+changes v3.docx

Dear Mr Martoreli Júnior,

We are pleased to inform you that your manuscript 'Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases. However, Reviewer 2 still had a few more recommendations to improve the manuscript a little more. Please make sure to address the comments from Reviewer 2 when preparing your mansucript for publication.

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,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

Deputy Editor

PLOS Neglected Tropical Diseases

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

Make the minor changes indicated by the reviewer:

"The manuscript has improved a lot and is, in my opinion, almost ready to be published. Some relatively minor final comments:

- Please check punctuation marks and paces use throughout the manuscript. Examples: remove comma in sentence 51; parenthesis in sentence 143 should be placed after 'referrals' instead of 'rehabilitation'; remove full stop in sentence 317; remove space in sentence 325 & 397.

- In table 'Table 1 - Disability grade and his characteristics', the word 'claw' at hands & feet at G2D can be seen as stigmatizing language. Better is 'contractures' or 'claw hand deformity'

- The reference for 'WHO disability grading for leprosy' (part of Table 1) is: https://apps.who.int/iris/handle/10665/42060

- The level of English could be improved at sentence 291-2: 'care should be taken to reveal the identity of the index patient when implementing this preventive therapy in contacts, especially outside the patient's family.'. I would like to propose to change that into: 'revealing the identity of the index patient when implementing this preventive therapy for contacts should be handled with care and only after gaining consent, especially when this takes place outside the patient's family'.

- In sentence 397, the English could be improved by removing 'between the sum of them'."

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: Adequate

Reviewer #2: (No Response)

Reviewer #3: The objectives of the study were articulated with a clear testable hypothesis stated. The study design is appropriate to address the stated objectives. The population is described and appropriate for the hypothesis being tested. The sample size is sufficient to ensure adequate power to address the hypothesis being tested. There are concerns about ethical or regulatory requirements being met.

**********

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: Presented well

Reviewer #2: (No Response)

Reviewer #3: The analysis presented matches the analysis plan. The results are clearly and completely presented.

**********

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: Relevant and concordant to previous sections

Reviewer #2: (No Response)

Reviewer #3: The conclusions are supported by the data presented. The limitations of analysis are described.

**********

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)

Reviewer #3: Accept

**********

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: The manuscript has improved a lot and is, in my opionion, almost ready to be published. Some relatively minor final comments:

- Please check punctuation marks and paces use througout the manuscript. Examples: remove comma in sentence 51; parenthesis in sentence 143 should be placed after 'referrals' instead of 'rehabilitation'; remove full stop in sentence 317; remove space in sentence 325 & 397.

- In table 'Table 1 - Disability grade and his characteristics', the word 'claw' at hands & feet at G2D can be seen as stigmatizing language. Better is 'contractures' or 'claw hand deformity'

- The reference for 'WHO disability grading for leprosy' (part of Table 1) is: https://apps.who.int/iris/handle/10665/42060

- The level of English could be improved at sentence 291-2: 'care should be taken to reveal the identity of the index patient when implementing this preventive therapy in contacts, especially outside the patient's family.'. I would like to propose to change that into: 'revealing the identity of the index patient when implementing this preventive therapy for contacts should be handeled with care and only after gaining consent, especially when this takes place outside the patient's family'.

- In sentence 397, the English could be improved by removing 'between the sum of them'.

Reviewer #3: (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: No

Reviewer #2: No

Reviewer #3: No