-->PONE-D-25-65515-->-->Survival Disparities and Competing Mortality Risks in Offspring of Consanguineous Marriages in Yemen: A 26-Year Retrospective Cohort Analysis-->-->PLOS One

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Reviewers' comments:

Reviewer's Responses to Questions-->

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: -Regarding the treatment of "Healthcare Access" as a time-dependent covariate updated at follow-up contacts, there is a significant risk of reverse causality that should be pointed out. Families with severely ill children, such as those with Thalassemia, may engage in selective migration by moving closer to healthcare centers specifically to address the child's medical needs. If these high-risk families relocate to areas classified as having "High Access" and the child subsequently dies, this could inflate the mortality rate associated with better access, thereby diluting its observed protective benefit. I suggest clarifying how migration was handled in the analysis, specifically whether you assessed if families changed residence following a diagnosis; if this is not feasible with the current dataset, the potential for selective migration should be explicitly acknowledged as a limitation in the discussion.

-In your "Policy Implications", you suggest expanding newborn screening. Given the current economic burden, you calculated ($62.25 million), is this feasible? It would be compelling to see a "Cost per Case Detected" estimate if your data allows, or at least a stronger argument for how a war-torn health system can afford this.

-Did the rate of consanguineous marriage change over the 26-year study period? You adjusted for "Birth Cohort", but it would be interesting to know descriptively if the practice is declining, increasing, or stable in this region.

Reviewer #2: 1. Revision points for methodology: The methodology provides a structured approach to examining survival disparities; however, certain limitations suggest that revisions may be necessary to strengthen the validity of the findings. The retrospective cohort design is appropriate for analysing long-term trends, but the reliance on existing records raises concerns about missing data, inconsistent documentation, and potential misclassification of exposures or outcomes. Additionally, the study would benefit from a clearer explanation of how confounding variables were controlled, particularly socio-economic factors, maternal health indicators, and access to care, which play a key role in survival differences among children from consanguineous marriages. More detail on sampling strategy, inclusion–exclusion criteria, and data quality assurance would further improve methodological transparency.

2. Revision points for discussion: While the manuscript correctly highlights the importance of strengthening both basic and specialized healthcare infrastructure to reduce the mortality burden among high-risk offspring of consanguineous marriages, the discussion would be more comprehensive if it explicitly addressed barriers related to accessibility, affordability, and acceptability. In many fragile and conflict-affected settings—such as Yemen—geographic inaccessibility, prohibitive out-of-pocket expenditure, and socio-cultural norms significantly limit healthcare utilization even when infrastructure is improved. Evidence from Pakistan and Sudan shows that culturally embedded acceptance of consanguineous marriage constrains care-seeking and early-risk identification unless health interventions are aligned with community beliefs and delivered through culturally trusted channels (Bittles, 2001; Hamamy, 2012). Incorporating this perspective would strengthen the argument that system-level improvements must be paired with culturally sensitive community engagement strategies to meaningfully reduce mortality disparities in populations practicing consanguinity.

3. Page 35 : While the Priority Action Plan outlines immediate to long-term interventions, the authors should emphasize that prevention can begin even earlier—before marriage or before planning a pregnancy as an immediate targated action plan. . Pre-marital and pre-conception genetic counseling, community education, and culturally sensitive risk-communication strategies have been shown in countries such as Qatar and Jordan to significantly improve awareness and reduce high-risk consanguineous unions (Bener et al., 2019; Hamamy, 2012). Introducing this upstream, preventive layer would strengthen the model and highlight the importance of early engagement to reduce avoidable genetic and mortality risks.

References

Bener, A., Al-Maadid, S., & Al-Bast, D. (2019). Premarital screening and prevention of genetic disorders: Community perspectives from Qatar. Journal of Community Genetics, 10(2), 121–128.

Hamamy, H. (2012). Consanguineous marriages: Preconception consultation in primary health care settings. Journal of Community Genetics, 3(3), 185–192.

Bittles, A. H. (2001). Consanguinity and its relevance to clinical genetics. Clinical Genetics, 60(2), 89–98. https://doi.org/10.1034/j.1399-0004.2001.600201.x

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Reviewer #1: No

Reviewer #2: Yes: Dr. Priyanka Roy

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Survival Disparities and Competing Mortality Risks in Offspring of Consanguineous Marriages in Yemen: A 26-Year Retrospective Cohort Analysis

PONE-D-25-65515R1

Dear Dr. Ali,

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,

Serkan Yılmaz

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

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-->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 #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. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: (No Response)

Reviewer #2: The topic is highly relevant and addresses an important public health concern. The review comments have been appropriately incorporated, and the manuscript reflects a clear effort to strengthen the analysis and interpretation.This specific study "Survival Disparities and Competing Mortality Risks in Offspring of Consanguineous Marriages in Yemen: A 26-Year Retrospective Cohort Analysis" appears original.

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Reviewer #1: Yes: Munachimso Emesobum

Reviewer #2: Yes: Priyanka Roy

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