PONE-D-24-07473Population-based cohort across stroke life course in India-The NIMHANS-NH-SKAN Stroke project :  Study ProtocolPLOS ONE

Dear Dr. Banandur,

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.

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Thank you for your submission. Please respond carefully to reviewer 2 comments. Additional comments are also provided to improve the manuscript and scientific rigor of the proposed study. 

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PLOS ONE

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Additional Editor Comments:

Thank you for this manuscript, the protocol is of an important study that would contribute to the understanding of stroke in India. However, we would like to suggest some changes for you to consider. These changes are suggested to improve the readability of the manuscript and to increase the rigor of the study in keeping with the reason we publish protocol papers.

Please carefully respond to the reviewer 2 comments, this will greatly improve the readability of the manuscript.

I want to raise some fundamental issues that may be good to incorporate or discuss in the manuscript

1. This is a cohort study- following up exposed but not diseased. In this, multiple exposure groups are described, including some novel risk/ exposed groups. An important consideration not discussed is lead time bias with regard to exposure. We cannot clearly know the onset of the exposure, detection of the risk factor is not the same as onset and this has bearing on interpretation of findings and hence should be discussed.

2. Please justify in some more detail why the cohort design is being used when the primary aim is to determine risk factors as opposed to the case control design. If however, the primary objective is to develop risk scoring and predictive calculators of incidence then this design is well justified. Please discuss this to justify the effort of a cohort study and the outcomes we can expect as readers.

In case developing predictive risk scores specific to our population is indeed an important objective, please describe in analysis how measurements upto 5 years will enable predictions for 10 year risk (the usual time frame for risk calculators). The 5 year duration seems to be less to fulfill the objective please provide some justification for this.

3. As risk prediction is an important aim of the study- please justify how urban poulation of Kolar and Bengaluru will enable applicability of the risk score across India.

4. Please do not name the health facilities for referral in the manuscript as it does not add to the understanding of the design; instead, please include a section on the setting and health care available that is more general and useful for readers not familiar with the Indian health care delivery system.

5. The description of the cohort study as retrospective and prospective is not clear- all cohort studies are prospective, all exposures have already occured. Kindly relook at description of the design. I also find the divison into stroke free and post stroke peiod rather artificial and inaccurate. There will be the population that were risk factor free to begin with but develop new risk factors or new combinations - it is rather dynamic something not addressed int the way the design is depicted. It is enough to mention that Follow up of cohort participants will be done till 12months after disease has occured.

6. Perhaps a section on the management of the cohort is useful- what efforts will be taken to keep the 2 lakh recruited participants within the cohort and minimise attrition. This increases accountability to the huge effort, time and money being invested in this research. The gains should justify the effort.

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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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: No

Reviewer #2: Yes

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

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: No

Reviewer #2: Yes

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

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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

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Reviewer #1: No

Reviewer #2: Yes

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6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an epidemiological study on stroke in Karnataka, involving NIMAHNS and other institutes. The aim is good and study worth perusing. However it fall outside my area of expertise hence I recommend that an epidemiologist should be consulted.

Reviewer #2: In this manuscript the authors describe a protocol for a population-based cohort study in the Karnataka state of India. I have following suggestions to improve the manuscript-

1. The abstract needs to be crisp. The background should list the importance of stroke as a public health problem, what are the current knowledge gaps that the study tries to fill and the key aims of the project.

2. It is unclear in the methods part of the abstract as to how the geographic areas (two districts) were selected for the study. Also, it is unclear if certain blocks from the two districts will be selected as the population of 200,000 doesn’t appear to be the population of the two districts.

3. Also, the authors should specify how the participants will be recruited in the cohort.

4. Please edit the sentence in the abstract- “is the first-of-its-kind, aims to fill critical gaps in epidemiological data concerning”

5. In the discussion part of the abstract the authors may want to use the words ‘important insights’ instead of ‘invaluable insight’. It is better to highlight the uniqueness of the study other than it is the largest cohort study and what specific insights this study will provide which have not been provided by many epidemiological and risk factors studies related to stroke in India.

6. The authors may want to remove these more generic statements in the abstract “This research has the potential to provide invaluable insights into stroke epidemiology, risk factors, and healthcare. The findings will carry significant implications for policy-making and health programming at both community and national levels.”

7. Introduction- “Stroke is one among the top five NCDs in the world (2)”, the authors may want to specify what do they mean by top five NCDs. For example they may specify that it is one of the top five leading causes of deaths worldwide.

8. In figure 1 specify how communities are selected i.e. how two wards in Bengalure and a block in Kolar district were selected.

9. It is unclear why “low risk group” is listed along with the risk factors and what does a bi-directional arrow between “physical activity” and “low risk group” suggests.

10. In figure 1, the second part may be better labelled as “stroke and post-stroke period” instead of just “post-stroke period”

11. Will medication-compliance be monitored in the post-stroke period?

12. In the methods part of the manuscript, please specify how the wards and sub-districts were selected.

13. Please provide a geographical map of study areas in two districts.

14. What processes will be in place to capture any missing stroke patients? The authors may want to specify. Do they have any idea about the potential percentage of patients who might be missed with their proposed method of enrolment?

15. In the “Ascertainment of exposure and outcome” section the authors mention that they will evaluate “tobacco dependence” Will they evaluate only tobacco dependence or tobacco use as well?

16. Kindly specify how current alcohol and tobacco use as mentioned in Table 3 will be defined.

17. In the same section the authors state that “certain neo-risk factors namely gambling, COVID-19 infection and vaccination, sleep (insomnia and obstructive sleep apnea), exposure to media, risk of cell phone addiction and Restless leg syndrome constitute exposures” . It will be good to provide operational definitions for each of these risk factors in an appendix.

18. Table 2 can be moved to an appendix.

19. Will blood be collected only for glucose and lipid estimations or other tests will also be done?

20. On page 33, the statement “Stroke will be examined for overall as well as type (thrombotic/hemorrhagic/SAH/CVT)” is unclear.

21. Table 3 has a back box. Why is it backed out?

22. Please check if all the references are formatted as per the journal’s requirements. I do not see them being appropriately formatted.

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Reviewer #1: No

Reviewer #2: No

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Population-based cohort across stroke life course in India-The NIMHANS-NH-SKAN Stroke project : A Study Protocol

PONE-D-24-07473R1

Dear Dr. Banandur,

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.

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Kind regards,

Dorothy Lall

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for thoughtfully responding to the comments. About including maps, please consider including as supplementary material, though not mandatory to include.

Reviewers' comments: