Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

Thanks for submitting your manuscript to the Healthcare Journal. This paper investigates the levels of HDL-C and LDL-C on atherosclerotic cardiovascular disease risk. The idea is not novel, but outcome is still relevant. Some considerations should be addressed before acceptance. 1) Introduction is poorly written, missing properly citations about ZEM solutions. What is in the methods, should be added in the introduction. 2) Conclusion is too big and part should be added to discussion. 3) Discussion should be properly cited. Overall, the English is good, but the writing needs some work for proper reading and data interpretation.  

Author Response

We thank the reviewers for their insightful and constructive comments. We have revised the manuscript accordingly and addressed all points raised. Changes have been highlighted in the revised manuscript (we have used tracked changes), and a clean version has also been provided. A detailed, point-by-point response is presented below.

 

Reviewer One

This paper investigates the levels of HDL-C and LDL-C on atherosclerotic cardiovascular disease risk. The idea is not novel, but outcome is still relevant. Some considerations should be addressed before acceptance.

1) Introduction is poorly written, missing properly citations about ZEM solutions. What is in the methods, should be added in the introduction.

Thank you. We have expanded the Introduction to provide a clearer description of the modelling framework and included key data sources used in constructing the model. We also clarified that the large patient-level dataset is available in the supplementary material.

 2) Conclusion is too big and part should be added to discussion.

Thank you. The Conclusion has been shortened and key elements have been moved to Discussion.

3) Discussion should be properly cited. Overall, the English is good, but the writing needs some work for proper reading and data interpretation.  

Thank you for this comment. The Discussion has been revised to improve clarity and readability. Several sentences were simplified and transitions between paragraphs were improved to facilitate interpretation of the results. In addition, we added further references throughout the Discussion to support the interpretation of our findings and to better contextualize them within the existing literature.

Reviewer 2 Report

Comments and Suggestions for Authors

• The study is entirely based on a simulation framework (NHM) rather than observed cohort data, which makes the findings model-dependent, not data-driven.

• The projections are derived from previously published risk equations and assumptions, so the results largely reflect established knowledge about LDL-C and ASCVD rather than providing new evidence

• No measures of statistical uncertainty, such as confidence intervals, probabilistic sensitivity analysis, or parameter variation, were reported. This makes the projected estimates of QALY and life expectancy meaningless.

• No external validation or calibration of the model outputs against real-world cohort data was conducted. 

• The inverse association between LDL-C and lifetime stroke events appears to be a consequence of competing mortality and survivorship bias within the simulation rather than a novel biological insight.

• The novelty of focusing on the HDL-C/LDL-C ratio is limited, as the causal role of LDL-C and the risk stratification value of lipid ratios are already well established in epidemiological and genetic studies

• Potential confounders such as socioeconomic status, nutritional factors, physical activity, and medication adherence were not included in the models.
• The HDL-C/LDL-C risk categories are not linked to clinical guideline thresholds.

Author Response

We thank the reviewers for their insightful and constructive comments. We have revised the manuscript accordingly and addressed all points raised. Changes have been highlighted in the revised manuscript (we have used tracked changes), and a clean version has also been provided. A detailed, point-by-point response is presented below.

Reviewer Two

• The study is entirely based on a simulation framework (NHM) rather than observed cohort data, which makes the findings model-dependent, not data-driven.

We do recognize that a formal external validation against longitudinal cohort datasets was not performed in the present analysis. To address this, we have expanded/changed the Limitations section to clarify this aspect and to highlight that several key outputs of the model (LE estimates and cumulative MI risk) were compared with published epidemiological studies and showed close agreement. We inserted that future research will focus on formal validation of the NHM framework using real-world cohort and registry data. All data and R code used in this study is included in the supplementary material.

  

• The projections are derived from previously published risk equations and assumptions, so the results largely reflect established knowledge about LDL-C and ASCVD rather than providing new evidence

Yes, the projections in this study are based on previously published epidemiological risk equations describing the relationship between LDL-C and ASCVD. In fact, the aim of our study was not to generate new causal evidence regarding lipid biology, but rather to integrate established risk relationships within a multi-disease simulation framework in order to quantify the cumulative lifetime burden of ASCVD across different HDL-C/LDL-C risk strata. To clarify we revised the Discussion section to emphasize that the novelty of the study lies in the integrated lifetime projections of cardiovascular outcomes, incorporating competing mortality risks and long-term disease trajectories which are difficult to capture in conventional cohort studies.

• No measures of statistical uncertainty, such as confidence intervals, probabilistic sensitivity analysis, or parameter variation, were reported. This makes the projected estimates of QALY and life expectancy meaningless.

Thank you for this important comment. Our work reports point estimates of projected outcomes and does not include formal measures of statistical uncertainty such as PSA. We have added a paragraph to   Limitations clarifying that the projections represent model-based estimates derived from established risk equations and that uncertainty around input parameters may influence the magnitude of the results. Future work will incorporate probabilistic sensitivity analyses and parameter variation to better quantify uncertainty around projected life expectancy and QALY estimates.

• No external validation or calibration of the model outputs against real-world cohort data was conducted. 

Thank you for this comment. We are aware that a formal external validation / calibration of longitudinal cohort datasets was not conducted in the present study. To mitigate this point, we have explicitly stated this limitation in the manuscript and clarified that several projected outcomes were compared with epidemiological estimates reported in the literature (including life expectancy in familial hypercholesterolemia and cumulative LDL exposure–related myocardial infarction risk). These comparisons provide indirect support for the plausibility of the model outputs. In addition, we have made patient-level simulation outputs available in the supplementary material to facilitate future external validation efforts.      

• The inverse association between LDL-C and lifetime stroke events appears to be a consequence of competing mortality and survivorship bias within the simulation rather than a novel biological insight.

The reviewer is correct that the inverse association between LDL-C and lifetime stroke events in our results reflects competing mortality and survivorship effects within the simulation framework rather than a biological protective effect of elevated LDL-C. We have revised the Discussion section to clarify that this pattern arises from competing cardiovascular mortality (particularly myocardial infarction) in higher-risk groups, which reduces the likelihood of surviving to ages at which stroke incidence increases. We have also ensured that this interpretation is consistently reflected in the manuscript to avoid any implication of a causal protective effect.

 

• The novelty of focusing on the HDL-C/LDL-C ratio is limited, as the causal role of LDL-C and the risk stratification value of lipid ratios are already well established in epidemiological and genetic studies

Thank you for this comment, we do agree that these are well established in epidemiological and genetic studies. The aim of our research was not to demonstrate a new causal relationship, but to integrate these established risk relationships within a multi-disease simulation framework in order to quantify their cumulative impact on lifetime cardiovascular outcomes. We did revise the Discussion section to emphasize that the novelty of the study lies in the lifetime modelling of ASCVD burden across HDL-C/LDL-C risk strata, incorporating competing mortality risks and long-term disease trajectories.

• Potential confounders such as socioeconomic status, nutritional factors, physical activity, and medication adherence were not included in the models.

  Part of these related factors are discussed in the Limitations section, however, we have revised this section to more explicitly acknowledge that these variables were not directly incorporated into the current model.  

• The HDL-C/LDL-C risk categories are not linked to clinical guideline thresholds.

Thank you, that is true. Clinical guidelines typically define treatment thresholds based on absolute LDL-C levels rather than lipid ratios. To clarify the rationale for our approach, we have added an explanation in the Methods section indicating that the HDL-C/LDL-C ratio categories were selected to represent progressively worsening lipid profiles and are consistent with ranges observed in epidemiological studies. The use of lipid ratios in the model provides an integrated representation of lipid balance and allows exploration of the combined effects of HDL-C and LDL-C on lifetime cardiovascular outcomes.

Reviewer 3 Report

Comments and Suggestions for Authors

Abstract:

In the abstract, no background of the study is provided. The sentence structure of the study's aim should be improved to increase readability and clarity and to avoid confusion for future readers. Additionally, no information has been provided on the validation of the National Health Model of projected and expected outcomes.

Introduction:

This section has clearly defined the prevalence and burden of cardiovascular diseases. But it should provide some literature on the pathophysiology of these diseases to enhance the conceptual clarity.

Material and methods:

In the methodology section, it is stated that triglyceride levels were also included in the system, even though the study aims to examine the relationship between HDL-C, LDL-C, and atherosclerotic cardiovascular disease (ASCVD) risk. It is not clearly stated why triglyceride levels were also included. No justification is provided for the cutoff values of LDL-C/HDL-C ratio. Additionally, I suggest adding details on model calibration to the methodology.

Results:

The results section is well structured and comprehensively evaluates the outcomes, with clear tables and graphs.

Discussion:

In the result section, it is written that “the very high-risk group (HDL-C/LDL-C ≦ 0·25) resulted in an average LDL-C 148 lower than in the other elevated risk groups.” But there is no clarification of these findings in the discussion. Other than that, this section is a bit too lengthy for me. It covers many details that obscure the study's main findings. It may lead to confusion for future readers.

 

Author Response

We thank the reviewers for their insightful and constructive comments. We have revised the manuscript accordingly and addressed all points raised. Changes have been highlighted in the revised manuscript (we have used tracked changes), and a clean version has also been provided. A detailed, point-by-point response is presented below.

Third reviewer

• Abstract: In the abstract, no background of the study is provided. The sentence structure of the study's aim should be improved to increase readability and clarity and to avoid confusion for future readers. Additionally, no information has been provided on the validation of the National Health Model of projected and expected outcomes.

  Thank you for these comments. The Abstract was revised to include a brief background statement describing the importance of lipid abnormalities in ASCVD and the rationale for examining HDL-C/LDL-C ratios. Also,  we have added  sentence in the Methods section of the Abstract explaining that the NHM projections are based on epidemiological risk equations and that model outputs were assessed for plausibility through comparison with published epidemiological studies.

• Introduction: This section has clearly defined the prevalence and burden of cardiovascular diseases. But it should provide some literature on the pathophysiology of these diseases to enhance the conceptual clarity.

Thank you for the comment and proposal. In the revised manuscript, we expanded the Introduction to provide additional context on the pathophysiology of atherosclerotic cardiovascular disease, including the role of cholesterol-rich lipoproteins in atherosclerotic plaque formation and progression. Relevant references describing the mechanisms of lipid retention and atherogenesis have been incorporated to strengthen the conceptual background of the study.

• Material and methods: In the methodology section, it is stated that triglyceride levels were also included in the system, even though the study aims to examine the relationship between HDL-C, LDL-C, and atherosclerotic cardiovascular disease (ASCVD) risk. It is not clearly stated why triglyceride levels were also included. No justification is provided for the cutoff values of LDL-C/HDL-C ratio. Additionally, I suggest adding details on model calibration to the methodology.

Thank you, we have clarified the rationale for the HDL-C/LDL-C ratio thresholds in the Methods section. Specifically, we note that the selected categories represent progressively worsening lipid profiles and approximate lipid patterns commonly observed in epidemiological studies of cardiovascular risk. We also clarify that current clinical guidelines primarily focus on absolute LDL-C thresholds, while lipid ratios are used here as integrated indicators of lipid-related risk.

• The results section is well structured and comprehensively evaluates the outcomes, with clear tables and graphs.

Thank you

• Discussion: In the result section, it is written that “the very high-risk group (HDL-C/LDL-C ≦ 0·25) resulted in an average LDL-C 148 lower than in the other elevated risk groups.” But there is no clarification of these findings in the discussion. Other than that, this section is a bit too lengthy for me. It covers many details that obscure the study's main findings. It may lead to confusion for future readers.

We have revised the Discussion to clarify the interpretation of the lipid ratio findings. In particular, we added an explanation for the observation that the very high-risk group exhibited slightly lower mean LDL-C levels than some intermediate groups, noting that this reflects the ratio-based stratification in which very low HDL-C levels drive the unfavorable HDL-C/LDL-C ratio. In addition, the Discussion section has been revised to improve readability and to focus more clearly on the main findings of the study.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thanks for resubmitting the paper. Although I see some progress, the paper still lacks definitions of its sections and should be better written. The reading is not flowing. Please, take your time and rewrite it. Thanks 

1) Rewrite and clarify paragraph line 73-75.

2) The aim of the study is to correlate HDL-c/LDL-C ratio, but its importance hasn't been mentioned in the introduction. It's all been inappropriately in the Methods section. 

The 3) should be rewrite the paper. There are a lot of corrections to be made through the text. It’s hard to mention every single change. 

Author Response

Thanks for resubmitting the paper. Although I see some progress, the paper still lacks definitions of its sections and should be better written. The reading is not flowing. Please, take your time and rewrite it. Thanks 

1) Rewrite and clarify paragraph line 73-75.

Answer: Thank you for this comment. We rewrote the relevant paragraph in the Introduction to improve clarity and better link the role of simulation modelling to the objectives of the study. The revised text now more explicitly explains how patient-level simulation integrates epidemiological evidence, disease progression, and competing mortality risks to estimate lifetime cardiovascular burden.

2) The aim of the study is to correlate HDL-c/LDL-C ratio, but its importance hasn't been mentioned in the introduction. It's all been inappropriately in the Methods section. 

Answer: We agree and have revised the Introduction accordingly. We added a dedicated paragraph introducing the HDL-C/LDL-C ratio as an integrated marker of lipid imbalance, reflecting the combined contribution of atherogenic and protective lipoprotein fractions to cardiovascular risk. In parallel, we shortened the corresponding explanation in the Methods section to ensure that the rationale for the ratio is presented primarily in the Introduction, while Methods focuses on its operational definition.

3) should be rewrite the paper. There are a lot of corrections to be made through the text. It’s hard to mention every single change. 

Answer: 

We thank the reviewer for this important observation. We carefully revised the manuscript to improve clarity, readability, and internal consistency. Specifically:

• the Introduction was streamlined to remove repetitive wording and improve logical flow,
• the Results section was revised to ensure a clear separation between descriptive findings and interpretation,
• interpretative content (e.g. stroke paradox and survivorship bias) was moved from Results to the Discussion,
• several sections, including myocardial infarction and ischaemic heart disease results, were rewritten for improved clarity and structure,
• language, formatting, and typographical consistency were systematically improved across the manuscript.

We believe that these revisions have substantially improved the overall readability and coherence of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

NA.

Author Response

Response: We thank Reviewer 2 for the additional evaluation. In response to the general concern regarding clarity and presentation, we carefully revised the manuscript throughout to improve readability, internal flow, section transitions, and overall language. We also clarified the study rationale in the Introduction, simplified the Results section by removing interpretative statements, and improved consistency of terminology across the manuscript.