PONE-D-24-44751The Etiology of Attention Deficit Disorder with Hyperactivity: A systematic review protocolPLOS ONE

Dear Dr. Yanru,

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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: Yes

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: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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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.

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

Reviewer #1: The protocol of this systematic review aims to explore the etiologies of Attention Deficit Hyperactivity Disorder (ADHD), which holds significant clinical importance and research value. The overall structure of the protocol is clear, and the methods are relatively detailed. However, there are still some aspects that need improvement.

1. The retrieval strategies for each database should be elaborated in detail, rather than just providing an example of the search strategy for PubMed. This can ensure the repeatability of the retrieval process and also facilitate other researchers to evaluate the rationality of the retrieval.

2. Please supplement the Sensitivity analysis. Regarding the issues of loss of original research information and subjective influence, explain how to reduce their impact and improve the reliability of research results through rigorous methodologies (such as adopting standardized data extraction and quality assessment methods, conducting sensitivity analysis, etc.) and quality assessment (such as evaluating the background and conflict of interest of the authors of systematic reviews and meta - analyses, and testing the stability of research results, etc.).

3. Refine the classification operation of the health ecological model: Elaborate on the specific factors included in each category (macro - environment, interpersonal relationships, individual congenital characteristics, behavioral lifestyles, and socioeconomic status) in the health ecological model, and provide specific operation guidelines for classification. For example, in the macro - environment category, clarify the definition criteria of urban or rural environments (such as population density, infrastructure, etc.). At the same time, explain how to ensure the accuracy and consistency of classification during the data extraction and analysis process.

4. Please supplement the publication bias analysis.

Reviewer #2: Dear Authors,

Thank you for the opportunity to review this protocol for an umbrella review on the etiology of ADHD. The manuscript presents a well-structured protocol with several strengths, including comprehensive database coverage, clear adherence to established guidelines, and appropriate methodological frameworks. The topic is highly relevant and the proposed review has the potential to provide valuable insights into ADHD etiology.

However, I have some concerns that should be addressed to enhance the protocol's methodological rigor.

A critical point relates to the time frame restriction. The exclusion of systematic reviews and meta-analyses published before January 2019 appears arbitrary and needs justification. While this recent cut-off would likely prevent overlap among included reviews, it might exclude valuable high-quality evidence from older, more focused reviews. The authors should either provide a clear rationale for this restriction or consider expanding the time frame. In the latter case, they would need to address how overlapping studies will be managed, for instance using the corrected covered area index or the meta-umbrella package (https://mentalhealth.bmj.com/content/26/1/e300534).

There is also some confusion regarding the quality assessment methodology. The protocol states that GRADEpro GDT will be used to evaluate the quality of included studies. However, GRADEpro is designed to assess the certainty of evidence for specific outcomes within systematic reviews, not the methodological quality of the reviews themselves. The authors should clarify how they plan to use GRADEpro for evaluating certainty of evidence for specific outcomes, while specifying which tools will be used to assess the methodological quality of the included reviews.

Furthermore, there is ambiguity in the analysis plan. The statement suggesting that a new systematic review or meta-analysis will be conducted on risk factors ("We will do a systematic or meta-analysis on at least one clearly established risk factor...") appears inconsistent with the umbrella review methodology described elsewhere in the protocol. This needs to be clarified to avoid confusion about the intended analytical approach.

Finally, the manuscript would benefit from English language editing. For instance, several sentences inappropriately begin with "And", and there are some typographical errors (e.g., "PROSERP" instead of "PROSPERO").

These revisions would strengthen what is already a promising protocol. I look forward to seeing the final version and eventually the results of this important work.

Best regards,

Antonio Di Francesco

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Reviewer #1: No

Reviewer #2: Yes: Antonio Di Francesco

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The Etiology of Attention Deficit Disorder with Hyperactivity: A systematic review protocol

PONE-D-24-44751R1

Dear Dr. Yanru,

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,

Carmen Concerto

Academic Editor

PLOS ONE