Response to ReviewersRevised Manuscript with Track ChangesManuscript

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Additional Editor Comments (if provided):Journal Requirements:

At this stage, the following Authors/Authors require contributions: Lydia Trippler, Said Mohammed Ali, Mohammed Nassor Ali, Ulfat Amour Mohammed, Khamis Rashid Suleiman, Naomi Chi Ndum, Saleh Juma, Shaali Makame Ame, Fatma Kabole, Jan Hattendorf, and Stefanie Knopp. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

The list of CRediT author contributions may be found here: https://journals.plos.org/plosntds/s/authorship#loc-author-contributions

Reviewers' comments:

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: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

- Yes

-Is the study design appropriate to address the stated objectives?

- Yes

-Is the population clearly described and appropriate for the hypothesis being tested?

- Yes

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

- yes

-Were correct statistical analysis used to support conclusions?

- Yes

-Are there concerns about ethical or regulatory requirements being met?

- No

Reviewer #2: (No Response)

Reviewer #3: (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: -Does the analysis presented match the analysis plan?

- Yes, it does

-Are the results clearly and completely presented?

- Yes

-Are the figures (Tables, Images) of sufficient quality for clarity?

- Yes

Reviewer #2: (No Response)

Reviewer #3: (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: -Are the conclusions supported by the data presented?

- Yes the conclusion is supported by the data, especially poverty is related to continual transmission of schistosomiasis

- Are the limitations of analysis clearly described?

- Yes, especially on the number of participants excluded in the analysis

- Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

- Yes, especially as we move towards 2030 goals of eliminating schistosomiasis

-Is public health relevance addressed?

- Yes, on the control of schistosomiasis in low prevalence areas and how integratied approach can help to maintain low prevalence

Reviewer #2: (No Response)

Reviewer #3: (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: None

Reviewer #2: (No Response)

Reviewer #3: (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: The paper is good and described the impact of multiple intervention implemented to control schistosomiasis in areas with low prevalences. The work is relevant and deserve to be published. Furthermore, the research assess how poverty can contribute to continual transmission of this disease. To reach eradication goals, poverty must be addressed

Reviewer #2: This is a Research Article by Dr. Trippler and colleagues reporting on the SchistoBreak study performing a 4-year prospective adaptive intervention trial for Schistosoma haematobium elimination in low prevalence settings in Pemba, Tanzania. The authors applied a multi-disciplinary intervention (bi/annual MDA, snail control, behavioral change activities) to “hotspot” locations (defined as >3% school based prevalence or >2% household prevalence by urine microscopy) and surveillance / monitoring (with some directed test-and-treat) in non-hotspots based on annual repeated cross-sectional prevalence surveys across 20 locations. They found that while Schistosoma haematobium prevalence remained low with the multi-disciplinary intervention in hotspot locations, there was not elimination of transmission and prevalence remained overall the same. This is an important article reporting on a well conducted and impressive study on a pressing topic of elimination in the field of schistosomiasis. I would like to congratulate the authors and their team for completing this study. I hope my comments can be helpful and constructive.

Major comments:

--The definition of “hotspot” is highly variable in the literature of Schistosoma and beyond and the authors definition is different from others (e.g., WHO). For their purposes, it makes sense. However, it would be helpful to clarify in the Methods the justification for their definition, and also explicitly state that urine microscopy was used for the prevalence measurement. Furthermore, some additional Discussion on alternative hotspots definitions could be helpful (i.e., most are often used in the context of “control” rather than “elimination”). My final point is that this binary classification of hotspot when the prevalence threshold is so low is probably prone to random variation (i.e., a few positive participants may change the classification); when considering imperfect diagnostic sensitivity, drug efficacy, etc, it would be helpful to have some comments from the authors on the robustness of this classification, so that some fluctuation in number of hotspots is not over-interpreted.

--The study would benefit from additional discussion on other explanations for why this well-conducted and thought-out intervention did not eliminate transmission. For example, are participants traveling and getting infected elsewhere outside the implementation unit? Praziquantel efficacy is imperfect. Are we sure that all participants were treated in the prior MDA (given the design is a repeated cross-sectional and not the same cohort of individuals)? Did they all accept treatment? Animal reservoir? Size of transmission network?

Minor comments (most are just suggestions/optional):

--Abstract: In Principal findings, why not report 95% CI instead of the counts?

--Some discussion on generalizability of these findings (Pemba island) to other settings would be helpful.

--Were there differences in timing of the relationship between MDA and the prevalence survey that could explain some variation in year to year results?

--Were any participants tested with CAA or PCR? If not, would add this as a limitation (e.g., the prevalence threshold is based on a diagnostic test with imperfect sensitivity).

--Data visualization: Could add color legend to Figure 3. I found Figure 4 hard to understand, and perhaps some more explanation in the legend could help.

--Is there any other cause of the microhematuria in this population?

--Apologies if I missed this, but a figure plotting the resurgence of prevalence in nonhotspots given surveillance/monitoring would be quite helpful, as well as any unique features in those locations.

--The authors looks at risk factors for individual infection, but what about risk factors for being a hotspot IU vs non-hotspot IU?

Thank you for the opportunity to review this important work.

Reviewer #3: The authors provide a valuable contribution to the dearth of evidence for "integrated management" that the WHO is driving. It is incredibly noteworthy that the “integrated” approach did nothing. There is so little evidence to back this drive from the WHO across so many diseases, and it is nice to see an attempt to provide some evidence towards this.

My major qualm with this paper is that I am not sure I agree with your use of the term hotspot. You can have a persistent transmission hotspot where prevalence is still in your “low prevalence” threshold…your groupings are almost operating on different units of observation…And in some way I think this is why you see your hotspots coming back and going away in a way that to me fundamentally just seems quite random. There is no difference between these groups, the whole dataset is a low but consistent force of infection with some noise.

Figure 7 maps - it would help if these were zoomed out so that it is easier to see where your IUs fall in terms of the whole island.

Line numbers would make your feedback easier.

When you say you left out those with missing values for the PCA – how many did you start with and how many did you omit? Your sample sizes are not clear to me, I see you “aimed for 250 and 80 houses” but this isn’t a clear number of participants…I see now it is in your results section, I would find this easier to process in the methods section so I can appraise your methods more efficiently.

It would be nice to see your PCA output so that we can see the clustering of PCA1.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachments

Attachment

Submitted filename: Minor observations.docx

Dear Dr Knopp,

We are pleased to inform you that your manuscript 'Adaptive integrated intervention approaches forschistosomiasis elimination in Pemba: a 4-year intervention study and focus on hotspots' 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.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Jennifer A. Downs, M.D., Ph.D.

Academic Editor

PLOS Neglected Tropical Diseases

Jong-Yil Chai

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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