Dear Dr. Olayinka,

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We look forward to receiving your revised manuscript.

Kind regards,

Taiwo Opeyemi Aremu, MD, MPH, PhD

Academic Editor

PLOS One

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Additional Editor Comments:

• Please make the description of eligible study designs fully consistent across the manuscript, reconciling the abstract (observational only) with the Methods section (observational and interventional).
• Make the description of language restrictions fully consistent across all sections, ensuring that the abstract reflects the policy of including studies "in any language" and briefly describing how non‑English articles will be translated and checked.
• Provide a clear operational definition of "asymptomatic malaria" and ensure this definition underpins its use as an exclusion criterion.
• Clarify and standardize what you mean by "associated factors," explicitly listing the prespecified factors (e.g. demographic, socioeconomic, environmental, clinical) and explaining how these will be analyzed (e.g. as covariates in subgroup or meta‑regression analyses).
• Clarify for outcomes such as discharge, mortality, and complications how you will ensure that these outcomes are attributable to malaria (e.g. restriction to lab‑confirmed clinical malaria, handling of co‑morbidities and mixed‑cause deaths) and define any time frames used.
• Justify the choice of excluding studies with fewer than 100 participants and, if feasible, pre‑specify a sensitivity analysis including these smaller studies to assess their impact.
• Make explicit in the Methods that full search strings for all databases are provided in a supplementary file (e.g. "Search string for the study‑malaria") and ensure that the example PubMed strategy in the text matches the supplementary material.
• Please strengthen the Data Synthesis and Statistical Analysis section by adding appropriate methodological references for the random‑effects model, the use of R ("meta" and "metafor" packages), and key measures such as I² and prediction intervals.
• Add supporting methodological references for the Assessment of Publication Bias and Sensitivity Analysis (e.g. Egger’s test, funnel plots, trim‑and‑fill, leave‑one‑out analyses) and briefly clarify how results from these procedures will be interpreted.
• Provide a more detailed, prespecified plan for subgroup analyses and any meta‑regression (e.g. listing subgroup variables, minimum number of studies per subgroup/covariate, and the basic modelling approach).
• Consider adding an explicit "Strengths and limitations" subsection that also summarizes the main anticipated limitations of the planned review (e.g. heterogeneity of definitions, risk of publication/language bias, hospital‑based data).
• Please revise the manuscript carefully for formatting, structure, and English language clarity (e.g. consistent terminology, numbering, headings) so that it meets PLOS ONE's readability and presentation standards.

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

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: Partly

Reviewer #2: Partly

Reviewer #3: 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??>

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: No

Reviewer #3: 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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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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: I noticed a couple of inconsistencies that should be clarified. For example, the abstract says only observational studies will be eligible, but the eligibility criteria section later mentions both observational and interventional studies. Similarly, the abstract limits inclusion to studies published in English, while the eligibility criteria section states that studies in any language will be included.

Some points also need more detail. The cutoff of 100 participants for exclusion is mentioned, but the rationale for this threshold isn’t explained. The secondary outcomes are also a bit vague. For instance, “associated factors” isn’t clearly defined, and for outcomes like discharge, mortality, and complications, it’s not clear how the authors will ensure these outcomes are directly attributable to malaria.

In the exclusion criteria, “asymptomatic malaria” should be explicitly defined to avoid ambiguity.

For the search strategy, I’d suggest adding a supplementary file that lists all search strings used across databases. That would make the process more transparent and reproducible for readers.

In the methods section, some areas like Data Synthesis and Statistical Analysis and Assessment of Publication Bias and Sensitivity Analysis don’t have any supporting references. Even if these are common methods, citing references would strengthen the protocol. I also don’t see where the subgroup analysis methodology is clearly and detailedly stated.

An “Expected Limitations” section would help.

Finally, there are many formatting and arrangement issues throughout the manuscript that don’t meet standards, which may lead to difficulty in reading for readers.

Reviewer #2: Dear Authors,

Well done for the effort in drafting this protocol.

Please address the concerns below.

Abstract: Line 26-28

Clarify how your study design will fill the gap (i.e. unknown exact burden).

Methods:

Line 32 reads "Eligible studies will be observational and published in English from inception till June 30, 2025."

Lines 105-107 also reads "Study design (S): This review will include quantitative observational and interventional studies, including cross-sectional, cohort, case-control, and longitudinal studies, conducted in Nigeria and

published in any language."

First statement has observational studies (no indication of interventional studies) and language restriction. The second statement has interventional studies and no language restriction.

Reconcile the two statements and include the necessary justifications.

Exclusion criteria:

What happens to studies involving adult malaria in your systematic search?

Line 116 reads "4. Studies with a sample size of fewer than 100 participants."

Justify clearly (with reference, if any) why you will exclude studies with specifically less than 100 sample size.

Line 119 reads "6. Studies on asymptomatic malaria."

What do you mean by asymptomatic malaria? Justify its exclusion.

Provide clarity in the two sentences below.

144 ... "Level 1 would involve screening of identified studies for the

145 study design quantitative observational and interventional studies would be accepted."

151 ... "The screened will be done

152 independently by two reviewers..."

In lines 176-177, citation is required for the statement "The NOS tool evaluates observational studies based on three key domains: selection of study groups, comparability, and ascertainment of outcomes or exposures."

All statements under authors’ contributions (lines 271-278) appear to suggest that search, data extraction, and analysis have already been carried on. Please rectify.

Reviewer #3: Thanks for your impactful study. Comments:

The abstract initially states inclusion of English-language studies only, while later sections state “any language” with translation plans.

Please ensure full consistency across the abstract, methods, eligibility criteria, and search strategy. The revised “no language restriction” approach is methodologically appropriate, but it must be reflected uniformly throughout the manuscript.

Given the wide variation expected across Nigerian geopolitical zones, diagnostic methods, healthcare levels, and time periods, heterogeneity is likely to be substantial.

Please predefine thresholds for when meta-analysis will not be performed due to excessive heterogeneity and clarify how such situations will be handled.

The protocol states that odds ratios will be pooled for associated factors. However, observational studies may report heterogeneous effect measures (OR, RR, HR).

Please clarify plans for handling different effect sizes (e.g., conversion methods, separate meta-analyses, or narrative synthesis).

The protocol addresses an important gap and has the potential to produce valuable evidence for malaria control policy in Nigeria.

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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.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Burden, risk factors, and clinical outcomes of pediatric malaria in Nigeria: A systematic review and meta-analysis protocol

PONE-D-25-56196R1

Dear Dr. Olayinka,

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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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,

Taiwo Opeyemi Aremu, MD, MPH, 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 #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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 #2: I am satisfied with the responses and revised version. Methodological inconsistencies in the original submission have been addressed by the authors.

Reviewer #3: Thanks for revised version and answer the concerns. This protocol addresses an important gap by aiming to synthesize national estimates of pediatric malaria burden, associated factors, and outcomes in Nigeria. The methodology is generally sound, with predefined subgroup and meta-regression analyses and clear outcome attribution; however, some issues require clarification. The concept of “burden” should be more precisely defined (prevalence vs. broader measures such as hospitalization and mortality), and the rationale for including interventional studies in prevalence pooling needs stronger justification. Overall, the study is relevant and well structured.

**********

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

Reviewer #3: No

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