PONE-D-21-25486Migraine Patients Visiting Chinese Medicine Hospital: Protocol for a Prospective, Registry-Based, Real-World Observational Cohort StudyPLOS ONE

Dear Dr. Guo,

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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: Partly

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: Partly

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: No

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Reviewer #1: Yes

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: Thanks for giving me the opportunity to review the manuscript titled "Migraine Patients Visiting Chinese Medicine Hospital: Protocol for a Prospective, Registry-Based, Real-World Observational Cohort Study". Migraine has indeed been acknowledged as one of the most burdensome disorders, and treatment and prevention should be considered as an important health priority. Although I acknowledge some of the the limitations of RCT in the evaluation of treatment effectiveness in some cases, these design remain the only research design, in which causal relations between the randomized exposure (i.e. treatment) and outcome (e.g. quality of life) can be evaluated and established. The authors state that "the research evidence obtained from previous explanatory RCTs and systematic reviews need to be updated with more observational real-world evidence" to accommodate some issues that arise when conducting an RCT, such as "Such design may not reflect the complexity of migraine and its comorbidities (34), nor reflect the real-world practice of CHM which is commonly tailored according to individual’s syndrome differentiation (35)".

The step from RCT to observational trials to address all issues within an RCT-design is rather drastic, and the existence of pragmatic trials is ignored. Might I suggest the authors to consider the following publication on the use of pragmatic trials:

Ford, I., & Norrie, J. (2016). Pragmatic trials. New England journal of medicine, 375(5), 454-463.

Notwithstanding the limitations of RCT, observational studies have a tendency to yield highly biased estimates. Inferring on the effectiveness of CHM (as stated in the objectives of the authors "evaluate the effectiveness and safety of individualized CHM for adult migraine in a real-world setting;" will be a tough - if not impossible - challenge based on the method that was presented in the protocol of the authors. Registries can indeed uncover patterns and help in understanding health care seeking behaviour of certain groups. They can also help in understanding and exploring potential trends, but lack the ability to infer on causal relations. Frameworks around causal inference in observational studies have been suggested (see Causal Inference, What If by Robins and Hernan), but require a solid theoretical hypothesis. I would suggest the authors to consider creating a DAG, in which they represent the theoretical background on how there study might infer on a causal relation between exposure-outcome.

In the data-analyses, the authors state "Multiple imputation will be carried out to deal with missing data". However,

there is no information on the methodology that will be used to reach this goal. Which packages will be used?

Why do you rely on the Missing at Random (MAR) hypothesis? What if the data is rather NMAR? The section also lacks references. The authors refer to the "Apriori Algorithm", but no reference is added with a description of this algorithm.

In summary: Although registries can provide important insights, they limit the ability to infer on effectiveness.

I would suggest the authors to consider a pragmatic trial or - in case a pragmatic trial is infeasible - I would suggest the authors to focus more on patterns in healthcare behaviour.

Reviewer #2: Dear authors,

It is necessary to describe in detail the nature of CHM that will be used in this research, to connect it with previous research on animal models or in the laboratory research. It is necessary to show the chemical composition of the drug, the chemical formula of the drug, the site of action of the drug, the mechanism of action of the drug, the potential interactions of CHM with drugs for various comorbidities.

Introduction

I ask the authors to remove the part of the sentence which says that according to the latest classification, the division of migraine in relation to menstruation was made (this statement is not contained in the current classification).

Explain what is meant by a poor prognosis in patients with comorbidities.

The sentence "Currently there is no cure for migraine" is unnecessary.

List all groups of drugs, and western groups of drugs and western treatments for migraine. It is not enough to list only NSAIDs, triptans, CCB, beta blockers.

Are these drugs also used for comorbidity or just for migraine. If yes, for which comorbidities and provide references that confirm these claims.

OBJECTIVES

STUDY DESIGN

The dose of the medicine that the patients will take be determined on the basis of what references? What previous studies have confirmed the effectiveness of that dose and not some other dose of the drug? On the basis of which studies the administrative methods, courses, forms of CHM will be determined and which previous studies have confirmed that it is the best method, course, form?

Is it correct to collect data for patients who were not in the study during the entire planned period?

INTERVENTIONS

It is necessary to describe in detail the nature of CHM that will be used in this research, to connect it with previous research on animal models or in the laboratory. It is necessary to state the chemical composition of the drug, the chemical formula of the drug, the site of action of the drug, the mechanism of action of the drug, the potential interactions of CHM with drugs for various comorbidities. Are these medications used for an acute migraine attack or to prevent an attack or both?

DATA COLLECTION

TREATMENTS, EXAMINATIONS AND DIAGNOSES:

Chinese medicine syndrome diagnosis - I would ask the authors to explain the meaning of this term in more detail.

SAMPLING METHOD AND SAMPLE SIZE

The number 400 is based on the number of views in which time period? Explain in more detail the selection of this number of patients.

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Reviewer #1: Yes: Robby De Pauw

Reviewer #2: No

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Migraine Patients Visiting Chinese Medicine Hospital: Protocol for a Prospective, Registry-Based, Real-World Observational Cohort Study

PONE-D-21-25486R1

Dear Dr. Guo,

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.

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Kind regards,

Sarah Michiels

Academic Editor

PLOS ONE

Journal Requirements:

1. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 

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 #2: Partly

**********

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 #2: Yes

**********

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 #2: 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 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 #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

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 #2: Thank you for the answers. Keep in mind my comments when conducting research. I suggest that the paper should be accepted.

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7. 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 #2: No