Response to Reviewers:

Manuscript reference number: PONE-D-26-17844

The burden and epidemiology of orofacial cleft and its socioeconomic associates in Iran from 1990 to 2023

Dear Dr. Beiki,

Thank you for giving us the opportunity to revise our paper for potential publication in PLOS ONE. We are grateful to the reviewers and the Editors for their constructive and positive comments on our paper. We have addressed each of the comments in our revision, which has further improved the article. Below we detail our changes and respond to each of the comments in turn.

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Response: Thank you for pointing this out. We implemented and considered the points.

Reviewer Comments to Author:

Reviewer: 1

Comments to Author

Title

The title appropriately identifies the topic and geographical scope but does not indicate that the study relies entirely on GBD-derived modeled estimates.

The phrase “socioeconomic associates” is vague and potentially misleading, as the analysis is limited to ecological SDI correlations rather than evaluation of socioeconomic determinants.

Response: Thank you very much for your valuable time and comments. To improve clarity and accurately reflect the scope and methodology of the study, we revised the title accordingly. It reads:

“The burden and epidemiology of orofacial clefts in Iran from 1990 to 2023: a Global Burden of Disease study with subnational socio-demographic index analysis”

Abstract

The abstract lacks sufficient methodological detail regarding how GBD estimates were obtained and analyzed.

Statements describing reductions as significant require clarification regarding statistical criteria.

The conclusion overstates policy implications related to maternal health programs despite no direct analysis of maternal risk factors.

Response: Accordingly, we revised the Methods section of the abstract to specify the GBD 2023 source, ICD-10 case definition, use of DisMod-MR 2.1 estimates, age-standardization, and uncertainty intervals. We also removed wording that could be interpreted as a formal significance claim and replaced it with neutral trend language. We moderated the conclusion to avoid direct causal implications about maternal health programs while still noting broader service-planning implications supported by the burden patterns observed.

Introduction

The rationale for conducting this study in Iran requires stronger justification beyond updating epidemiological estimates.

Response: We revised the introduction to emphasize that Iran has a large and geographically heterogeneous population, prior evidence has been mostly local or hospital-based, and no recent national and province-level time-trend assessment covering 1990–2023 had been available. We also clarified that the value of this study lies in informing subnational planning for cleft prevention, surgical access, and long-term rehabilitation.

The manuscript does not sufficiently explain the remaining knowledge gap considering multiple previous GBD-based OFC burden studies.

Response: We appreciate this important point. We clarified that although several GBD-based OFC studies have been published, they were primarily global or regional in scope and did not provide a long-term province-level assessment for Iran. We therefore strengthened the knowledge-gap statement to show that our study adds both temporal and subnational evidence for a country that has not been specifically characterized in recent GBD analyses.

The introduction lacks discussion regarding important distinctions between OFC subtypes and their epidemiologic implications.

Response: We revised the text to distinguish cleft lip with or without cleft palate from isolated cleft palate and to note that these subtypes differ in embryology, clinical course, treatment needs, and functional consequences. This helps justify why OFCs are an important congenital condition for epidemiologic monitoring, even when analyzed as a combined category in the GBD framework.

Methods

Definition of Condition

Combining all OFC phenotypes into a single category limits epidemiological interpretation because cleft palate and cleft lip with or without palate have different biological and clinical characteristics.

Response: We revised the Methods to make clear that the combined category was used because the GBD 2023 outputs for this analysis were available in that form, and we added a limitation stating that this approach does not allow subtype-specific inference.

The assumption of equal distribution among sequelae requires stronger justification because it may influence DALY estimation.

Response: We clarified that this was a simplifying assumption used within the GBD modeling framework when more granular sequela-specific data were unavailable. We also noted that this assumption may affect DALY estimates and should be considered when interpreting the results.

Mathematical Modeling

The manuscript reproduces GBD methodology but does not adequately clarify whether authors independently modeled estimates or extracted pre-generated outputs.

Response: We clarified that we did not independently re-estimate the GBD models. Instead, we extracted the finalized GBD 2023 outputs and used the published GBD framework to describe how those estimates were generated.

GBD assumptions are described extensively but their implications for interpretation in the Iranian setting are not discussed.

Response: We added text to emphasize that the results should be interpreted as ecological, population-level summaries rather than causal or individual-level socioeconomic effects.

Statistical Analysis

Details regarding smoothing spline models remain insufficient.

Response: We expanded the statistical analysis description to specify how the SDI relationship was assessed, what the models were used for, and how the smoothing was handled in R.

Model assumptions, smoothing parameters, and analytical procedures are not adequately described. The manuscript lacks reproducibility details including extraction parameters and analytical workflow.

Response: We added workflow details on extraction, organization, and analysis of the GBD outputs and clarified the software version used. It reads:

“For this analysis, SDI was treated as a continuous predictor and age-standardized OFC burden metrics were used as outcomes to explore potential non-linear patterns across provinces and over time. The smoothing spline curves were fitted in R using standard spline procedures, with the degree of smoothness selected automatically by the software to balance fit and parsimony. These analyses were descriptive rather than causal, and the observed SDI-burden patterns should be interpreted accordingly. The analytic workflow consisted of extracting the GBD outputs, restructuring them by location and year, calculating age-standardized rates and temporal changes, and then fitting the spline models.”

Results

Comparisons among Iran, MENA, and global estimates remain descriptive without formal comparative analyses.

Response: We agree that the comparisons across Iran, MENA, and global estimates are descriptive and were not based on formal hypothesis testing or pairwise comparative modeling. To avoid overinterpretation, we revised the text to present these findings as contextual comparisons rather than statistically tested differences.

Provincial variation is described extensively but remains observational and lacks spatial analytical methods.

Response: The provincial analysis in this study is descriptive and ecological in nature, based on GBD subnational estimates. We clarified this point in the Results and avoided language that might imply spatial clustering or spatial inference beyond the available data.

Age-related prevalence findings require cautious interpretation because prevalence in congenital conditions accumulates over time and may not reflect disease biology.

Response: We appreciate this important point. We revised the age-related section to avoid implying that prevalence patterns directly reflect disease occurrence at a given age. Instead, we clarified that prevalence in a congenital condition reflects accumulation over time, survival, and access to care, and therefore should be interpreted cautiously.

The higher DALY burden among females under five years is reported without exploration of possible explanations.

Response: We agree that this finding should be presented cautiously. Because the current analysis was descriptive, we did not attempt causal explanation in the Results. We revised the text to report the pattern without overinterpreting it and noted that possible explanations are better considered in the Discussion.

Discussion

Several interpretations attribute declining burden to improved surgical care, healthcare access, neonatal support, and health-system improvements despite these variables not being directly analyzed.

Response: We revised the Discussion to make clear that these factors are plausible explanations for the observed decline, but they were not directly measured in this study. We therefore changed the wording to present them as cautious interpretations rather than conclusions.

Explanations regarding referral patterns, healthcare inequalities, and reporting differences remain speculative.

Response: The revised text now identifies referral patterns, differential case ascertainment, and reporting completeness as possible contributors to provincial variation, while explicitly noting that these are hypotheses rather than directly tested explanations.

The discussion occasionally shifts from epidemiologic interpretation toward causal inference unsupported by presented data.

Response: We appreciate this important comment. We revised the Discussion to maintain an epidemiologic and descriptive focus throughout, removed causal language, and ensured that the interpretation remains aligned with the ecological and modeled nature of the data.

The markedly larger reduction in DALYs observed in Iran relative to global estimates warrants deeper discussion.

Response: We expanded the Discussion to compare Iran’s reduction with global and MENA trends more explicitly and to note that the larger decline may reflect a combination of improved survival, changes in disability patterns, and modeled estimation differences. We also clarified that this comparison should be interpreted cautiously because the estimates come from different geographic levels and modeling contexts. It reads:

“The larger decline in DALYs observed in Iran compared with global estimates (4) may reflect a combination of improving survival, changes in disability patterns, and differences in model-based estimation across geographic levels. However, this interpretation remains cautious because these factors were not directly tested in the present analysis (15).”

Ecological SDI findings should be interpreted cautiously to avoid ecological fallacy.

Response: As suggested, we revised the text to state clearly that the SDI analysis is ecological and descriptive, and that it cannot be interpreted as evidence of individual-level socioeconomic effects. It reads:

“This ecological association should be interpreted cautiously to avoid ecological fallacy, because province-level SDI does not necessarily represent the socioeconomic conditions of individual patients.”

Limitations

Important limitations are incompletely addressed.

Response: We agree and expanded the limitations substantially.

The study should explicitly discuss reliance on modeled rather than observed data.

Response: We added a direct statement that the analysis relies on GBD modeled estimates rather than primary observed registry data, and that this is an important limitation.

Limitations related to sparse provincial data, ecological analysis, inability to evaluate subtype-specific patterns, and inability to distinguish syndromic and non-syndromic OFCs should be acknowledged.

Response: We have added these limitations explicitly and noted that they constrain interpretation of provincial differences and prevent phenotype-specific and etiologic conclusions. It reads:

“Third, we could not evaluate the influence of specific risk factors at the provincial level within the GBD framework, so causal inferences about drivers of observed trends are limited. Fourth, because OFCs were analyzed as a combined category, we could not evaluate subtype-specific patterns for cleft lip with or without palate versus isolated cleft palate. Fifth, the GBD framework does not allow us to distinguish syndromic from non-syndromic OFCs, which limits etiologic interpretation. Sixth, the provincial and SDI analyses are ecological and should not be interpreted at the individual level. Nevertheless, the use of the most recent, internationally comparable GBD 2023 framework to produce a comprehensive, subnational picture of OFC burden for Iran across three decades provides useful context for understanding long-term trends and provincial inequalities. Future studies should compare GBD-derived estimates with Iranian congenital anomaly registry and hospital-based data when such data become available.”

Conclusion

The conclusion contains policy recommendations that extend beyond the presented analyses.

Response: We toned down the conclusion to focus more closely on the findings actually demonstrated in the study.

Statements regarding prevention strategies and healthcare interventions should be more closely aligned with observed epidemiological findings.

Response: We revised the conclusion to emphasize burden reduction, inequities, and the need for stronger surveillance and access to care, while avoiding overly specific preventive claims not directly supported by the analysis. It reads”

“Iran has experienced declines in OFC burden from 1990 to 2023, while national prevalence has remained relatively stable and provincial and age-specific disparities persist. The highest disability burden was among young children and was inversely associated with SDI, highlighting ongoing equity gaps in access to timely and comprehensive cleft care. These findings highlight persistent burden and inequity patterns that may inform future planning for surveillance, diagnosis, treatment access, and follow-up care. More specific prevention and health-system recommendations should be interpreted in light of future studies that directly examine risk factors, care pathways, and service availability.”

Figures and Tables

Figure 1 is visually crowded

Attachments

Attachment

Submitted filename: RTR PLOS ONE-Orofacial cleft.doc

Response to Reviewers:

Manuscript reference number: PONE-D-26-17844R1

The burden and epidemiology of orofacial clefts in Iran from 1990 to 2023: a Global Burden of Disease study with subnational socio-demographic index analysis

Dear Dr. Beiki,

Thank you for giving us the opportunity to revise our paper for potential publication in PLOS ONE. We are grateful to the reviewers and the Editors for their constructive and positive comments on our paper. We have addressed each of the comments in our revision, which has further improved the article. Below we detail our changes and respond to each of the comments in turn.

Reviewer Comments to Author:

Reviewer: 1

Comments to Author

The authors have addressed my comments satisfactorily and significantly improved the manuscript. The revised version is clearer, more balanced, and methodologically transparent.

Response: Thank you very much for reviewing the revised manuscript and your positive feedback.

Reviewer: 2

1. The manuscript should clearly distinguish whether the authors conducted any independent modeling or simply analyzed pre-existing IHME/GBD outputs. As currently written, this distinction is blurred. It needs to explicitly state that no new primary DisMod-MR 2.1 modeling was performed, and that the work is based on descriptive analysis of extracted GBD data rather than reproduction of the original modeling framework.

Response: Thank you so much for your time to review the revised manuscript and your valuable comments. We have revised the Methods to state that this study is based on a descriptive secondary analysis of finalized GBD 2023 outputs and that no new primary DisMod-MR 2.1 modeling was performed by the authors. We also clarified that the manuscript does not reproduce the original IHME modeling process but instead summarizes and interprets the available estimates for Iran and its provinces. It reads:

“We extracted the finalized GBD 2023 estimates and conducted a descriptive secondary analysis of these pre-generated outputs. No new primary DisMod-MR 2.1 modeling was performed in this study.”

“We did not independently re-fit the full GBD model. Instead, we extracted and analyzed the finalized GBD 2023 estimates as a descriptive secondary analysis.”

2. The aggregation of all orofacial clefts (ICD-10 Q35–Q37) into a single category conceals meaningful clinical and biological differences between subtypes such as cleft palate and cleft lip with or without cleft palate. While this grouping may be constrained by the structure of available GBD data, the manuscript should acknowledge that it reduces clinical granularity and may limit the interpretability and real-world applicability of burden estimates.

Response: We appreciate this point and agree that combining all OFC phenotypes into a single category reduces clinical granularity. We revised the manuscript to explain that this aggregation was necessary because the relevant GBD 2023 outputs were available only in combined form for Iran and its provinces. We also added text noting that this approach improves comparability across locations and years but limits phenotype-specific interpretation and real-world clinical applicability. It reads:

“Although OFC phenotypes differ in biological and clinical characteristics, they were analyzed as a combined category because this is how the GBD 2023 outputs were available for Iran and its provinces. This grouping improves comparability across years and locations, but it reduces clinical granularity and limits phenotype-specific interpretation and real-world applicability of the burden estimates. The equal-distribution assumption among sequelae was used within the GBD framework when more granular sequela-specific data were unavailable, and we acknowledge that this simplifying assumption may influence DALY estimation.”

3. The use of smoothing splines to model the relationship between SDI and burden metrics is not sufficiently described. Key details such as smoothing parameters, degrees of freedom, and model fit assessment are missing. The analysis should be explicitly framed as an exploratory, descriptive approach rather than inferential modeling, with clearer justification of how curve smoothness was selected to avoid the impression of arbitrary fitting.

Response: We appreciate your suggestion and have expanded the description of the SDI analysis in the Methods. We emphasize that the smoothing spline analysis was intended as an exploratory visualization of the relationship between SDI and age-standardized OFC burden metrics and was not designed as an inferential or predictive model. The spline curves were fitted using standard smoothing spline procedures in R, with the smoothing parameter selected automatically through generalized cross-validation, which balances model fit against complexity and helps avoid overfitting. We did not pre-specify the degrees of freedom or manually tune the smoothness parameter, as the objective was descriptive visualization rather than formal hypothesis testing or model optimization. Consequently, we did not perform additional assessments of model fit or sensitivity analyses, and the resulting curves should be interpreted as graphical summaries of non-linear ecological patterns rather than evidence of causal or statistically significant associations. It reads:

“Spline curves were fitted in R using standard smoothing spline procedures, with the smoothing parameter selected automatically by generalized cross-validation, allowing the algorithm to balance goodness of fit against model complexity and reduce the risk of overfitting. No degrees of freedom or smoothing parameters were manually specified or optimized, because the analysis was intended to provide descriptive visualization rather than formal statistical inference or prediction. Accordingly, no hypothesis testing or model-based causal interpretation was performed, and the observed SDI–burden relationships should be interpreted as population-level ecological patterns rather than individual-level associations.”

4. The observed inverse association between provincial SDI and DALYs is interpreted too strongly in places, risking ecological fallacy. Because the data are aggregated at the provincial level, these findings should not be extended to individual-level socioeconomic risk. The results should be framed strictly as area-level patterns rather than implying individual-level relationships.

Response: We revised the Results and Discussion to make clear that the inverse association between provincial SDI and DALY burden is an ecological, province-level pattern and should not be interpreted as evidence of individual-level socioeconomic risk. We also noted the risk of ecological fallacy and avoided wording that could imply causality at the individual level. It reads:

“The burden of OFCs, represented by the age-standardized DALY rate per 100,000 population, showed an inverse area-level association with the SDI.”

“Because these findings are based on ecological, modeled estimates, they describe population-level patterns rather than individual-level associations.”

“This ecological association should be interpreted cautiously to avoid ecological fallacy, because province-level SDI does not necessarily represent the socioeconomic conditions of individual patients.”

5. The manuscript highlights stable prevalence over time alongside a substantial reduction in DALYs and mortality, but this pattern is not well explained. A clearer interpretation is needed, likely involving improved survival, better long-term management, and the accumulation of treated individuals who continue to live with the condition, which maintains prevalence even as severity and mortality decline.

Response: We expanded the Discussion to better explain why prevalence may remain stable even when DALYs and mortality decline. The revised text now notes that in a congenital condition such as OFC, prevalence may accumulate across age groups because treated individuals survive longer, while disability burden and mortality may decrease with improved survival, earlier management, and better long-term care. This interpretation is now stated more clearly and cautiously. It reads:

“The decline in DALYs and deaths is consistent with a broader improvement in population health and may reflect improved survival, better long-term management, and reduced severity among affected individuals over time, but our study cannot determine the exact reason (22). In particular, in a congenital condition such as OFC, prevalence may remain stable because treated individuals continue to survive into later age groups, even as mortality and disability burden decline. Moreover, population health gains such as reductions in infant mortality and improved neonatal services can reduce OFC-related morbidity (23). Similarly, observed provincial inequalities may reflect differences in access, referral, ascertainment, and service availability, but the present analysis does not allow these mechanisms to be distinguished (18, 19). Accordingly, these factors should be considered plausible hypotheses rather than confirmed determinants of the observed trends.”

6. Several causal explanations for declining DALYs and mortality are stated too definitively. Since the GBD dataset does not directly measure healthcare access, prenatal screening, or underlying risk factors, these should be reframed as possible contributing hypotheses rather than confirmed drivers of change.

Response: We revised the Discussion to frame surgical advances, neonatal care, healthcare access, and system improvements as possible contributing hypotheses rather than confirmed drivers of change. We also added explicit caution that these factors were not directly measured in the present analysis, so causal inference is not possible from the current dataset. It reads:

“The larger decline in DALYs observed in Iran compared with global estimates (4) might be partially due to a combination of improving survival, changes in disability patterns, and differences in model-based estimation across geographic levels. However, this interpretation remains cautious because these factors were not directly tested in the present analysis. Also, these should be considered as possible contributing hypotheses rather than confirmed drivers of change (15).”

7. The policy recommendations extend beyond what can be justified by a descriptive epidemiological analysis. Specific clinical or preventive interventions should be avoided. Instead, conclusions should focus on higher-level public health implications such as strengthening congenital anomaly surveillance systems, improving registry completeness, and supporting broad resource allocation and health system planning.

Response: Thank you for your recommendations. We revised the conclusion to focus on the observed burden patterns, provincial disparities, and the implications for surveillance, registry completeness, resource allocation, and health-system planning. We removed or softened recommendations that went beyond what can be directly supported by the GBD data. It reads:

“Iran has experienced declines in OFC burden from 1990 to 2023, while national prevalence has remained relatively stable and provincial and age-specific disparities persist. The highest disability burden was among young children and was inversely associated with SDI, highlighting ongoing equity gaps in access to timely and comprehensive cleft care. These findings highlight persistent burden and inequity patterns that may inform future planning for surveillance, registry completeness, diagnosis, treatment access, and follow-up care. More specific prevention and health-system recommendations should be interpreted in light of future studies that directly examine risk factors, care pathways, and service availability.”

Attachments

Attachment

Submitted filename: R2 RTR PLOS ONE-Orofacial cleft.doc