-->PONE-D-25-66321-->-->Association between serum 25-hydroxyvitamin D levels and early vascular aging in young and middle-aged adults-->-->PLOS One

Dear Dr. Hu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 04 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Myadagmaa Jaalkhorol, MD,PhD

Academic Editor

PLOS One

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Additional Editor Comments:

Reviewer 1

The authors conducted a cross-sectional study in men and women aged 18–60 years undergoing health examinations to investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and early vascular aging (EVA) assessed by brachial–ankle pulse wave velocity (baPWV). They report a significant inverse association between 25(OH)D and EVA below a threshold of 17.9 ng/mL, whereas no significant association was observed above this threshold. Although the findings are interesting, several important concerns exist regarding the consistency between the study population and the concept of EVA, as well as the validity of the diagnostic criteria used.

Major Comments

1. The authors state that EVA is “a significant autonomous predictor of cardiovascular risk among individuals in their youth and middle age” (L52) and cite reference [3] in support of this statement. However, reference [3], as indicated by its title, addresses early vascular aging in children and adolescents, which does not correspond to the “youth and middle-aged” population studied here. It is unclear whether the current study population should be considered as having EVA according to this definition. Please clarify this issue and provide more appropriate references supporting the relevance of EVA in young and middle-aged adults.

2. The authors state that “evidence regarding its relationship with EVA remains limited” (L59). However, the study population comprises adults aged ≥18 to <60 years, and numerous previous studies have examined the association between vitamin D status and cardiovascular disease or vascular function in middle-aged populations. Please cite appropriate literature and more clearly justify the novelty and significance of the present study.

3. With regard to cardiovascular disease prevention by vitamin D supplementation, many intervention studies, including well-designed randomized controlled trials, have already been conducted. As the authors themselves note, “recent large-scale trials have not conclusively demonstrated cardiovascular benefits of vitamin D supplementation” (L61). In this context, the authors should more clearly articulate the scientific and clinical rationale for conducting the present cross-sectional study.

4. EVA is defined as baPWV exceeding the mean +2 standard deviations for individuals of the same age and sex. More detailed justification for this cutoff is required. In particular, the source of the reference values embedded in the Omron device should be clearly described, and relevant validation studies demonstrating the applicability of this definition in Chinese populations should be cited.

Minor Comments

5. Because this is a cross-sectional study, causal relationships between serum 25(OH)D and EVA cannot be inferred. In the Discussion and Conclusion, causal wording (e.g., “protective effect,” “benefits”) should be replaced with more cautious terms such as “association” or “correlation.”

6. The method used to select study participants should be described more clearly. In addition, the authors should state whether a priori sample size estimation was performed and provide the rationale for the sample size.

7. The Methods section should specify how the threshold value of 17.9 ng/mL was determined, including the algorithm or statistical procedure used.

8. The authors present ROC curves and AUC values to support the “clinical utility” of the threshold. However, the validity of diagnostic performance evaluation based on cross-sectional data is questionable. The purpose of the ROC analysis should be clarified.

9. In Table 2 and Figure 1, the reported odds ratios (e.g., OR = 0.98) appear to represent the change per 1 ng/mL increase in 25(OH)D. This should be explicitly stated in footnotes. Because a 1 ng/mL change may have limited clinical relevance, the authors are encouraged to additionally present estimated ORs per 10 ng/mL increase.

10. Regarding the finding that the association was significant only in men, potential explanations beyond hormonal status, fat distribution, and lifestyle factors—such as differences in sample size between men and women—should also be discussed.

11. If the authors suggest potential implications for vitamin D supplementation, they should carefully consider and acknowledge that randomized controlled trials have not demonstrated clear cardiovascular benefits.

12. In Table 1, “Famale” should be corrected to “Female.”

Reviewer 2

1. Would you explain why participants from different seasons were essential?

2. The sample size looks enough, but do you have any assumptions that Q1 was equal to Q3, while Q4 is the highest?

3. Can you explain the result of HbA1c? It was 5.70 in the total group, but 5.70 in the control and 5.75 in the EVA group. Why is the total group the same as the control group?

4. In line 177, I could not understand the "three models". Please write that they are Q1, Q2, and Q3.

5. In line 178, EVAwere was type error.

6. In line 213, drinking status is a little bit confusing. Please clarify whether it is alcohol drinking or a water intake habit.

7. In the discussion (line 243), the "older age groups" statement is unclear. Please clarify whether it is above 60 or others.

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

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. 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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. 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

**********

-->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: The authors conducted a cross-sectional study in men and women aged 18–60 years undergoing health examinations to investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and early vascular aging (EVA) assessed by brachial–ankle pulse wave velocity (baPWV). They report a significant inverse association between 25(OH)D and EVA below a threshold of 17.9 ng/mL, whereas no significant association was observed above this threshold. Although the findings are interesting, several important concerns exist regarding the consistency between the study population and the concept of EVA, as well as the validity of the diagnostic criteria used.

Major Comments

1. The authors state that EVA is “a significant autonomous predictor of cardiovascular risk among individuals in their youth and middle age” (L52) and cite reference [3] in support of this statement. However, reference [3], as indicated by its title, addresses early vascular aging in children and adolescents, which does not correspond to the “youth and middle-aged” population studied here. It is unclear whether the current study population should be considered as having EVA according to this definition. Please clarify this issue and provide more appropriate references supporting the relevance of EVA in young and middle-aged adults.

2. The authors state that “evidence regarding its relationship with EVA remains limited” (L59). However, the study population comprises adults aged ≥18 to <60 years, and numerous previous studies have examined the association between vitamin D status and cardiovascular disease or vascular function in middle-aged populations. Please cite appropriate literature and more clearly justify the novelty and significance of the present study.

3. With regard to cardiovascular disease prevention by vitamin D supplementation, many intervention studies, including well-designed randomized controlled trials, have already been conducted. As the authors themselves note, “recent large-scale trials have not conclusively demonstrated cardiovascular benefits of vitamin D supplementation” (L61). In this context, the authors should more clearly articulate the scientific and clinical rationale for conducting the present cross-sectional study.

4. EVA is defined as baPWV exceeding the mean +2 standard deviations for individuals of the same age and sex. More detailed justification for this cutoff is required. In particular, the source of the reference values embedded in the Omron device should be clearly described, and relevant validation studies demonstrating the applicability of this definition in Chinese populations should be cited.

Minor Comments

5. Because this is a cross-sectional study, causal relationships between serum 25(OH)D and EVA cannot be inferred. In the Discussion and Conclusion, causal wording (e.g., “protective effect,” “benefits”) should be replaced with more cautious terms such as “association” or “correlation.”

6. The method used to select study participants should be described more clearly. In addition, the authors should state whether a priori sample size estimation was performed and provide the rationale for the sample size.

7. The Methods section should specify how the threshold value of 17.9 ng/mL was determined, including the algorithm or statistical procedure used.

8. The authors present ROC curves and AUC values to support the “clinical utility” of the threshold. However, the validity of diagnostic performance evaluation based on cross-sectional data is questionable. The purpose of the ROC analysis should be clarified.

9. In Table 2 and Figure 1, the reported odds ratios (e.g., OR = 0.98) appear to represent the change per 1 ng/mL increase in 25(OH)D. This should be explicitly stated in footnotes. Because a 1 ng/mL change may have limited clinical relevance, the authors are encouraged to additionally present estimated ORs per 10 ng/mL increase.

10. Regarding the finding that the association was significant only in men, potential explanations beyond hormonal status, fat distribution, and lifestyle factors—such as differences in sample size between men and women—should also be discussed.

11. If the authors suggest potential implications for vitamin D supplementation, they should carefully consider and acknowledge that randomized controlled trials have not demonstrated clear cardiovascular benefits.

12. In Table 1, “Famale” should be corrected to “Female.”

Reviewer #2: 1. Would you explain why participants from different seasons were essential?

2. The sample size looks enough, but do you have any assumptions that Q1 was equal to Q3, while Q4 is the highest?

3. Can you explain the result of HbA1c? It was 5.70 in the total group, but 5.70 in the control and 5.75 in the EVA group. Why is the total group the same as the control group?

4. In line 177, I could not understand the "three models". Please write that they are Q1, Q2, and Q3.

5. In line 178, EVAwere was type error.

6. In line 213, drinking status is a little bit confusing. Please clarify whether it is alcohol drinking or a water intake habit.

7. In the discussion (line 243), the "older age groups" statement is unclear. Please clarify whether it is above 60 or others.

**********

-->6. PLOS authors have the option to publish the peer review history of their article (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 #1: No

Reviewer #2: Yes: Jambaldorj Jamiyansuren

**********

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

PONE-D-25-66321R1

Association between serum 25-hydroxyvitamin D levels and early vascular aging in young and middle-aged adults

PLOS One

Dear Dr. Hu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 28 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Myadagmaa Jaalkhorol, MD,PhD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Decision: minor revision

The Authors are requested to address each comment made by the two Reviewers and submit a revised manuscript highlighting the lines where the corrections / additions have been made. The Authors should also mention in detail what changes (if any) have been made while replying to each of the Reviewers' comment. Please state the page number and lines where the corrections / additions have been made. Please do not say "this has been addressed in the revised manuscript" only.

When your revision is ready, the original submitting author, ru Hu, must upload a revised manuscript and a point-by-point response. To view any reviewer reports, editor feedback, and the instructions for submitting your revision, please visit your submission details page.

Reviewer B. Minor revision

The authors have revised the manuscript in response to the reviewers’ comments and suggestions, and the clarity of the description has improved substantially. Most of the revisions are acceptable. However, the following issue should still be addressed.

The authors used the built-in reference values of the Omron device to define EVA. They state that these reference values were derived from approximately 12,000 healthy Chinese subjects. However, detailed information about the reference population is limited and appears to be obtained from technical specifications and device manuals rather than from published scientific articles. Consequently, neither the readers nor the authors can determine from which population the reference subjects were drawn, who selected them, how they were selected, how health information was obtained, or how reliable the information was.

In addition, the authors added references #4 and #18 as supporting evidence for the use of these reference values. However, these studies report the validity of baPWV in predicting cardiovascular disease risk and do not demonstrate that the built-in reference values represent valid normal reference values for the Chinese population. Therefore, this issue represents an important limitation of the present study and should be clearly acknowledged in the Limitations section.

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

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

-->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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->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

**********

-->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: The authors have revised the manuscript in response to the reviewers’ comments and suggestions, and the clarity of the description has improved substantially. Most of the revisions are acceptable. However, the following issue should still be addressed.

The authors used the built-in reference values of the Omron device to define EVA. They state that these reference values were derived from approximately 12,000 healthy Chinese subjects. However, detailed information about the reference population is limited and appears to be obtained from technical specifications and device manuals rather than from published scientific articles. Consequently, neither the readers nor the authors can determine from which population the reference subjects were drawn, who selected them, how they were selected, how health information was obtained, or how reliable the information was.

In addition, the authors added references #4 and #18 as supporting evidence for the use of these reference values. However, these studies report the validity of baPWV in predicting cardiovascular disease risk and do not demonstrate that the built-in reference values represent valid normal reference values for the Chinese population. Therefore, this issue represents an important limitation of the present study and should be clearly acknowledged in the Limitations section.

Reviewer #2: Thank you for submitting your manuscript to this journal. I hope this manuscript can attract other researchers and can bring valuable citations to the journal.

Good luck.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (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 #1: No

Reviewer #2: Yes: Jambaldorj Jamiyansuren

**********

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Association between serum 25-hydroxyvitamin D levels and early vascular aging in young and middle-aged adults

PONE-D-25-66321R2

Dear Dr. Hu,

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,

Myadagmaa Jaalkhorol, MD,PhD

Academic Editor

PLOS One

Additional Editor Comments (optional):

Dear Dr. ru Hu,

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