Dear Dr. Kaur,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 06 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Zewdu Gashu Dememew, M.D

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

3. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

4. Please include a separate caption for each figure in your manuscript.

5. 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 Authors,

Congratulation to come up with quite relevant protocol for publication.

Please just attend to the relevant comments and suggestions given from peer reviews. Fortunately, a lot of reviewers were interested in the review of your protocol.

Good luck!

Zewdu

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Partly

Reviewer #8: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Partly

Reviewer #8: Yes

Reviewer #9: Partly

Reviewer #10: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: No

Reviewer #8: Yes

Reviewer #9: Yes

Reviewer #10: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

Reviewer #9: No

Reviewer #10: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: India remains the leading contributor to global burden of tuberculosis and it is obvious that in order to reduce global TB burden we need to reduce TB burden in India. At the same time in order to achieve END-TB goals in India we need to address TB diagnostics and treatment issues, including TB gaps in case finding, in every region and district in India, what will eventually result in reduction of incidence and mortality of TB in whole country.

The manuscript provides lots of information and is a great example of national TB program activities in India.

Few comments:

1. Are volunteers involved in active case finding provided with personal respiratory protection (FFP2/FFP3 respirators) since they might be exposed to lots of presumptive TB patients?

2. Does the protocol involve active contact tracing or it is not a part of the study, but has already been implemented by NTP in India? To clarify, there is and will be information on cases already registered in the district and contacts from those cases will be known to the NTP identifying certain households as focus of TB infection and they should be targeted for LTBI/TB diagnostics. Will that work be done within the proposed protocol?

3. Following previous question – what are the follow-up actions if TB case , especially smear positive highly contagious, is identified throughout the study in the household ? will the be a return visit for LTBI screening and possible LTBI treatment?

4. Will rifampicin resistance/MDR be tested in cases throughout the study? Will treatment for DR TB be provided for those patients?

Reviewer #2: My general comments:

In general, the authors presented a study protocol (a quasi-experimental pre-post study) for active case finding and treatment of tuberculosis (TB), focusing on inhabitants aged >15 years residing in the Senapati District, Manipur, India. This study aims to engage the Student and Women Organizations (SAWOs) in augmenting the TB case finding and treatment, based on clinical symptoms, chest xray and sputum testing (using rapid molecular test-CBNAAT). The rationale for this study is very good.

My first concern is that the active case finding (ACF) and treatment for TB elimination and engaging organizations to enhance the effectiveness of ACF is a novel idea. This has been performed and published by Australian Research Teams (Guy B.Marks, Greg J.Fox et al., https://www.nejm.org/doi/full/10.1056/NEJMoa1902129). My suggestion is that the authors should reconsider the word “novel community-led strategy revolutionizing…”. I think “scaled up” is better term.

My second concern is the significance of the gold standard for testing TB so that the comparison outcomes (TB case notification rate, adherence rate, and treatment outcome) between the intervention and control arms are more accurate. The rapid molecular test CBNAAT has been reported to have a sensitivity of 63% to 75% ((https://pmc.ncbi.nlm.nih.gov/articles/PMC10654686/), indicating that approximately 25% to 37% of TB cases would be missed if only using the rapid molecular test CBNAAT. From my clinical and research knowledge, there will be a certain proportion of TB patients with trace calls by molecular TB testing ( about 50%-60% reveals negative TB culture). I think that there should be included TB culture (MGIT), regarding the true TB population with false negative CBNAAT and/or normal chest xray.

I highly believe that the TB culture (MGIT method…), applied for negative TB molecular testing with clinical and radiological findings consistent with tuberculosis, will ensure that the overall outcome comparisons between intervention and control arms are best accurate.

Reviewer #3: In this study protocol, the authors intend to study the impact of student and women organisations in improving TB case notifications. India has committed to end TB by 2025, this research seems to be late whereas such an intervention should have been a part of the program. Also, the protocol paper comes at a time when the sample collection is nearing completion.

Notwithstanding the above, as far as the protocol is concerned, there are a few issues that the authors need to clarify and address:

Details of the district including the health infrastructure both public and private, community-based organisations working for TB etc need to be elaborated for the reader to have an understanding the necessity of the intervention.

In the data from national program shared in Table 1 on TB notifications, adherence and outcomes it is observed that the program has achieved >100% of the target. It is strange that the authors mention they by this intervention achieve 80% success in the targets. The fact that the program has achieved more than the research proposes makes this study redundant.

The exclusion of the highly vulnerable populations such as mobile population/visitors, institutional populations (schools, colleges, offices, prisons, defence establishments, hospitals, nursing homes, hostels) and areas where survey operations are considered not to be feasible like insecurity areas is not clearly explained as large numbers of TB cases can be missed by such exclusion. The aim is to achieve a “comprehensive” approach to TB elimination.

Additionally, the authors have restricted the term “comprehensive approach” to the cascade of TB care whereas “comprehensive” would entail involvement of ALL stakeholders in the TB cascade such as private health care providers, NGOs/CBOs, TB champions etc.

Baseline assessment need to include anthropometric and nutrition data which are the current focus of all TB programs.

As per recommendation after symptom screening, X-ray screening comes next and then microbiological examination. This especially in a community setting and with the recent emphasis on asymptomatic sub clinical TB.

Linkages with the NTEP need to be elaborated in more detail in line 250.

Since the study is nearing completion, it would be good to provide interim data on achievement so far.

Lines 340, 341 mentioning direct costs, the authors mention doctor’s consultation fees, x-ray and sputum exam expenses - Where does this come in? cases are directly referred to NTEP!

Line 421, there is a mention of barriers to access to health care – was this studied in the study area what were the findings, if not this should be part of the study protocol.

Line 422, authors mention that the study addresses the social and behavioural factors that influence disease transmission as well as treatment outcomes by involving community members as active participants in TB control activities. What were these factors the authors wish to study? Were TB champions also involved in the process?

Line 435, the authors mention about the comprehensive approach. However, what they describe is the cascade of care and not a comprehensive approach which would entail involving all stakeholders in the process of ACF as mentioned above. Authors can refer to the many publications in the Indian context.

Reviewer #4: The objectives of the study protocol are clearly stated and ethically sound. Description of the research stages well described.

Would it be possible to mention the population size (15 y.o and above) of the Senapati district as according to the protocol approximately 316 volunteers will be involved to the activities ( 1 person per 150 households; 47,411 households in total) and later how many people were reached by volunteers, please?

On the implementation of the ACF phase, I would suggest to write more about Infection control measures for volunteers while making the screening, collecting sputum samples and packing specimens for the transportation to the laboratory. How the transportation of the specimen will be organized ( who transport, how, the distance to the nearest CB-NAAT point)

Although the study is ongoing, it is a second round of the ACF, I am looking forward seeing the results of the study!

Reviewer #5: The novelty of the concept may appear limited, as community systems for TB case finding have been previously documented in countries such as Ethiopia, South Africa, and Kenya, which the authors may wish to reference. Additionally, patient support group initiatives in Kerala bear some resemblance to this proposal, though these are more specifically targeted towards diagnosed patients.

A key contribution of this research could lie in its quantification of community systems—a measurement that has not yet been fully developed.

The authors should also consider providing a rationale for the target adjustments made by the National TB Program (NTP) over the years. This will support accurate impact estimation, as target adjustments are often subjectively set. Collaborating with WHO and the NTP team could help establish a reliable baseline, as solely relying on NTP targets might lead to skewed analysis.

Reviewer #6: This study is important highest TB burden country and the study is well designed and recommend to accept for publication.

Reviewer #7: 1. Methodology section is incomplete

2. CRF components to be mentioned in the methodology section

3. Difference between ACF by NTEP and ECF executed by this project to be mentioned in detail. Also the uniqueness and novelty of the study in terms of community engagement and its difference from the existing community outreach programs by NMC to be mentioned in detail

4. Target population to be defined precisely

5. Any similar studies done in other countries or other programs may be quoted as reference

Reviewer #8: Major Comments

Page 3, Line 33-36: The introduction needs better contextualization of the TB burden in Manipur. Specific local challenges could be highlighted in more detail, beyond the general statement about India's TB burden. This would strengthen the rationale for the study.

Page 4, Line 77-84: The study timeline is mentioned to be extended by 6 months due to disruptions, but the impact of these disruptions on study outcomes is not fully discussed. Please elaborate on how these events might affect the findings, participant retention, or data collection.

Page 5, Line 107-110: The TB burden in Senapati district is noted as unknown, yet a similar neighboring district's TB burden is cited. Consider providing more data or clarifying why exact prevalence estimates are unavailable. This would support the choice of study site and methodology.

Page 15, Line 373-374: The methodology lacks detail on how potential confounders will be identified and controlled in the logistic regression analysis. Please specify the strategies for confounder identification and handling, as this is crucial for the robustness of the results.

Minor Comments

Page 2: A more detailed definition of the role of Student and Women Organizations (SAWOs) would benefit readers unfamiliar with these groups.

Page 7, Line 158: Typo in 'volunteers give written consent' - 'give' should be 'gave'. Please correct verb tense consistency.

Reviewer #9: The protocol does indeed present a novel approach to TB case finding and overall TB control in Senapati District of Manipur,India.

The use of student and women local organisations offers an opportunity for ownership of the intervention by the community and some assurance of sustainability after project life

The protocol is presented soundly and manages to put across activities that will carried out during project life.

However,the authors could consider the following to make the protocol more clearer and avoid confusion with the readers;

For example,line 196-198 talks about village mapping and assigning of unique identification numbers to participants according to the designated area. It will be helpful for the authors to describe and show how this process will be implemented

Line 215-217 talks about screening tools…the authors should state that a symptom screening tool will be used other and state any other tool will be used if any

Line 393-399,the authors describe payments/stipends that will be given to the volunteers.

• An honorarium of ₹500 per month

• mobile recharge of ₹700 per quarter

• NTEP schemes NTEP ;

informant incentive (₹500/-

Patient support incentive;₹1000 for drug sensitive TB patients and ₹5000 for MDR-TB

It would helpful for the authors to provide context and justification for these payments and how they circle back to sustainability after project life.

Overally,this protocol could benefit from a copy editor to make readability and flow of the protocol better.

Reviewer #10: The manuscript describes an interesting approach to TB case finding in a vulnerable and a violence prone area in East India. The effort to undertake it is laudable. This reviewer offers the following comments.

1. At the onset it would be desirable to know why 64% of TB symptomatics do not seek treatment. The Project should aim to elicit some responses from the TB cases detected in the study to guide mitigation strategies in the location context.

2. The method section needs to elaborate on the approach to handling of asymptomatics between the 2 phases of intervention

3. It is unclear as to who has designed the costing tool and how is the costing data going to be analyzed. The researcher team needs to be well trained in eliciting responses to costing questions which would be best undertaken in the paper format.

4. The methods section also needs to describe the deployment of human resources for each household and estimate the time taken to complete the activities for identification of TB cases at the household level. Would be useful for future studies using a similar approach.

5. It should be clarified as to what were the selection criteria if any for the SAWO volunteers

6. The interim time period between the 2 intervention phases of 6 months appears on the lower side. A period of 12 months may have been more productive. In between the SAWO volunteers could be engaged in community health education activities to supplement case finding.

7. Fig.1 is indicative of good outcome indices. Would the present initiative be able to better these outcomes significantly. If any other foreseen tangible benefits to the community are identified, it would be helpful to mention them.

8. Reasons for refusal to participate in the survey should also be recorded and analysed.

We look forward to the results arising from this approach which maybe further strengthened by observations on its sustainability.

9. In the section on exposure to risk factors (line 118), the level of undernutrition in the community needs mentioning in view of the low SES and the high prevalence of TB.

10.Taking as an example the questionnaire on TB KAP Section 2 and 3 words like "drug resistant TB", virus, bacteria, fungi (Section 2) and "public health problem" (section 3) should be replaced in a way that is understood by the local population.

**********

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: Yes:  Thanh Tat Nguyen

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes:  Shibu Vijayan

Reviewer #6: No

Reviewer #7: Yes:  Dr.Krithikaa Sekar

Reviewer #8: No

Reviewer #9: No

Reviewer #10: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org

Attachments

Attachment

Submitted filename: Peer Review-Manuscript PONE-D-24-38779.docx

Attachment

Submitted filename: comment.docx

Breaking barriers for TB elimination: A novel community-led strategy revolutionizing Tuberculosis case finding and treatment support in Senapati District Manipur-A quasi-experimental pre-post study protocol

PONE-D-24-38779R1

Dear Dr. Harpreet Kaur and team,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Zewdu Gashu Dememew, M.D, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #7: Partly

Reviewer #9: Yes

Reviewer #10: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #3: No

Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #9: Yes

Reviewer #10: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #3: The authors have addressed all the comments satisfactorily within the constraints of geography, timing, resources and other limitations as indicated in their responses.

Reviewer #4: All questions of reviewers has been answered in an understandable manner. Looking forward on the study results! Good luck!

Reviewer #7: This is a well written manuscript. However, I would like to suggest a few revisions to the manuscript

1. As you had mentioned, SAWOs are already engaged in healthcare community engagement activities and in various welfare programs provided by the government. Hence, this idea may not be entirely "novel" as this is an extension of NTEP activities. So the word "novel" in the title may be reconsidered and alternate terminologies like "repurposed" or "redesignated" may be used.

2. Indicators for monitoring and evaluation of the study may be mentioned methodology section

3. Sample size or Expected prevalence does not compensate for the missed out vulnerable population, who are also the residents of the district. Hence the same may be mentioned.

Thanks and Regards

Dr. Krithikaa Sekar

Reviewer #9: The authors have responded to all the highlighted concerns sufficiently.I have no further concerns with the protocol.

Reviewer #10: The authors have adequately responded to the questions posed by this Reviewer. Some details in Methods could have been added in this protocol paper to guide future studies but hopefully the authors will do so in subsequent publications of the results

**********

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 #3: Yes:  Dr. Yatin Dholakia

Reviewer #4: Yes:  MD Aiymgul Duishekeeva, Kyrgyzstan

Reviewer #7: Yes:  Krithikaa Sekar

Reviewer #9: No

Reviewer #10: No

**********