PONE-D-24-47105Non-linear association of cardiometabolic index with gallstone disease in US adults: a cross-sectional studyPLOS ONE

Dear Dr. Li,

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.

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Academic Editor

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?

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: Partly

Reviewer #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: 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: No

Reviewer #2: No

Reviewer #3: 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

Reviewer #3: No

**********

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: This manuscript investigates the relationship between the Cardiometabolic Index (CMI) and gallstone disease (GSD) in U.S. adults. Using data from the National Health and Nutrition Examination Survey (NHANES) between 2017 and 2020, the study assesses whether CMI (a new composite indicator of obesity and lipid levels) associates non-linearly with GSD risk. The authors reveal that higher CMI correlates with an increased risk of GSD and propose that CMI might serve as a screening tool for GSD, with potential implications for clinical management.

In general, the manuscript is well-written and tables are clear. The authors use multiple ways (logistic regression, restricted cubic spline models, and subgroup analysis) to prove the positive correlation between CMI and GSD. The topic is beneficial to the clinical engagement and clearly suitable for publication in this journal. However, following issues need to be addressed before considering for publication.

1. This manuscript states they use logistics regression and restricted cubic spline models but haven’t provided any formulas or parameters deployed in this study. Need to address the rationale of choosing these two models for evaluating CMI – GSD correlation.

2. Lipid balance is crucial for gallstone disease, why choose CMI as indicator? Not [TG (mmol/L)/HDL-C (mmol/L)]? How does CMI compares to [TG (mmol/L)/HDL-C (mmol/L)] alone? And how does CMI compares to WHtR alone?

2. Lack visuals for logistics regression results and subgroup analysis.

3. Processed data (2825 out of 15,560) is not provided.

4. Although adjustments for multiple covariates were made, some potential confounders like diet habits, physical activity, and genetic predisposition are not accounted for. Discussing their potential impact on the results would improve the study's robustness.

5. Expand bias discussion (lack of other important factors as above). Address limitations of self-reported data -- could introduce recall bias. Highlight this as a limitation and consider suggesting longitudinal studies for validation.

6. Provide more insights on the subgroup analysis in the results, particularly regarding gender differences. Emphasize the clinical implications of gender-based variations in CMI's impact on GSD.

7. While the study indicates that CMI could be a screening tool, it may be helpful to discuss how CMI could complement existing GSD screening practices. Elaborate on how clinicians might integrate CMI in routine evaluations.

8. table 1: need to clearly indicate readers they are “logistic regression” models. The 4th “Q3” should be Q4.

9. figure 2 is too rough. It shows “figure 1” at the top left corner. Need more comprehensive captions explaining all elements including in the plot like the shade and cross-point. Enlarge x-axis and y-axis font size.

Reviewer #2: The present study demonstrates a nonlinear relationship between higher Cardiometabolic Index (CMI) and an increased risk of gallstone disease (GSD). However, there are several concerns regarding the methods used in the study that merit further consideration

Reviewer #3: This research is aligned with other research on cardiometabolic disease and liver disease such as GSD metabolic-associated fatty liver disease (MAFLD), applying different indices and statistical methods to test the association. The biological mechanism and underlying assumptions regarding the associations have been clearly defined previously, and possible co-variates/confounders have been identified, but the questions regarding which CM index is the most sensitive and specific clinical indicator for possible imminent liver disease in different populations residing in different environments and whether a valid universal threshold may be derived from the analyses if the association between the outcome and the index is not linear are not yet been answered. Although this study applied weighting in their analysis and adjusted for all relevant confounders in the multivariate logistic regression analyses, linearity was not observed. Restricted cubic spline analyses were thus performed to test for a ‘dose-dependent’ relationship, but failed to identify a threshold.

Some references that may be useful for the introduction, methodology or discourse are:

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis

Wang, Xin et al. Clinical Gastroenterology and Hepatology, Volume 22, Issue 8, 1586 – 1595

Zhang J, Liang D, Xu L, Liu Y, Jiang S, Han X, Wu H and Jiang Y (2024) Associations

between novel anthropometric indices and the prevalence of gallstones among

6,848 adults: a cross-sectional study. Front. Nutr. 11:1428488. doi: 10.3389/fnut.2024.1428488

Koyama, A. K., McKeever Bullard, K., Xu, F., Onufrak, S., Jackson, S. L., Saelee, R., Miyamoto, Y., & Pavkov, M. E. (2024). Prevalence of Cardiometabolic Diseases Among Racial and Ethnic Subgroups in Adults - Behavioral Risk Factor Surveillance System, United States, 2013-2021. MMWR. Morbidity and mortality weekly report, 73(3), 51–56. https://doi.org/10.15585/mmwr.mm7303a1

Duan S, Yang D, Xia H, Ren Z, Chen J, Yao S. Cardiometabolic index: A new predictor for metabolic associated fatty liver disease in Chinese adults. Front Endocrinol (Lausanne). 2022 Sep 16;13:1004855. doi: 10.3389/fendo.2022.1004855. PMID: 36187093; PMCID: PMC9523727.

Yan, L., Hu, X., Wu, S. et al. Association between the cardiometabolic index and NAFLD and fibrosis. Sci Rep 14, 13194 (2024). https://doi.org/10.1038/s41598-024-64034-3. https://rdcu.be/d0CD1

Song, Jimei, Yimei Li, Junxia Zhu, Jian Liang, Shan Xue, and Zhangzhi Zhu. "Non-linear Associations of Cardiometabolic Index with Insulin Resistance, Impaired Fasting Glucose, and Type 2 Diabetes among US Adults: A Cross-sectional Study." Frontiers in Endocrinology 15, (2024): 1341828. Accessed November 18, 2024. https://doi.org/10.3389/fendo.2024.1341828.

Lazzer, S., D'Alleva, M., Isola, M., De Martino, M., Caroli, D., Bondesan, A., Marra, A., & Sartorio, A. (2023). Cardiometabolic Index (CMI) and Visceral Adiposity Index (VAI) Highlight a Higher Risk of Metabolic Syndrome in Women with Severe Obesity. Journal of clinical medicine, 12(9), 3055. https://doi.org/10.3390/jcm12093055

DS Prasad, Zubair Kabir, JP Suganthy, AK Dash & BC Das. (‎2013)‎. Appropriate anthropometric indices to identify cardiometabolic risk in South Asians. WHO South-East Asia Journal of Public Health, 2 (‎3-4)‎, 142 - 148. World Health Organization. Regional Office for South-East Asia. https://iris.who.int/handle/10665/329790

Yan Zheng, Min Xu, Yanping Li, Adela Hruby, Eric B. Rimm, Frank B. Hu, Janine Wirth, Christine M. Albert, Kathryn M. Rexrode, JoAnn E. Manson, and Lu Qi. Gallstones and Risk of Coronary Heart Disease: Prospective Analysis of 270 000 Men and Women From 3 US Cohorts and Meta-Analysis

Arteriosclerosis, Thrombosis, and Vascular Biology Volume 36, Number 9 https://doi.org/10.1161/ATVBAHA.116.307507

Indices:

LAP

Ebrahimi, M., Seyedi, S. A., Nabipoorashrafi, S. A., Rabizadeh, S., Sarzaeim, M., Yadegar, A., Mohammadi, F., Bahri, R. A., Pakravan, P., Shafiekhani, P., Nakhjavani, M., & Esteghamati, A. (2023). Lipid accumulation product (LAP) index for the diagnosis of nonalcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Lipids in health and disease, 22(1), 41. https://doi.org/10.1186/s12944-023-01802-6

Triglyceride-glucose index:

Li, H., Zhang, C. Association between triglyceride-glucose index and gallstones: a cross-sectional study. Sci Rep 14, 17778 (2024). https://doi.org/10.1038/s41598-024-68841-6

Aksoy E, Ergenç Z, Ocak Ök, Ergenç H. Triglyceride-Glucose Index is a Reliable Predictor of Metabolic Disorder in Gallstones. Bezmialem Science. 2024 Jul;12(3):363-367. doi:10.14235/bas.galenos.2024.43043

Body roundness index (BRI):

Wei C, Zhang G. Association between body roundness index (BRI) and gallstones: results of the 2017-2020 national health and nutrition examination survey (NHANES). BMC Gastroenterol. 2024 Jun 5;24(1):192. doi: 10.1186/s12876-024-03280-1. PMID: 38840060; PMCID: PMC11155175.

The threshold for risk assessment:

Eastwood, S. V., Hemani, G., Watkins, S. H., Scally, A., Davey Smith, G., & Chaturvedi, N. (2024). Ancestry, ethnicity, and race: explaining inequalities in cardiometabolic disease. Trends in molecular medicine, 30(6), 541–551. https://doi.org/10.1016/j.molmed.2024.04.002

General comments

The strength of the manuscript lies in the accommodation of relevant confounders and the application of restricted cubic spline analyses as a novel approach to make sense of the non-linearity of the association between this specific outcome and index.

Consider making more detailed and stronger deductions from the observed results, e.g., the subgroup analyses that were conducted to test for interactions between CMI and specific covariates. What stood out was the preponderance of males rather than females in the highest quartile (62.16 vs 37.8%) and the increasing trend in male proportions across quartiles with a reversed trend in females. This may be highlighted as a novel finding.

Specific comments:

There are numerous syntax errors throughout that need attention.

The Lipid Accumulation Product (LAP) index is mentioned in a sub-title within the Results section. This is the only occurrence of the term. Please clarify its relevance, because the paragraph reports on the CMI and the formulas for the two indices’ calculation differ.

The first paragraph in the introduction addresses Gallstone disease in general. The references are rather outdated. Please consider replacing them or adding more recent references (some of which are included in the above list of references that may be of interest to the authors)

In the third paragraph of this section, the CMI is introduced. You may consider referring to other more recently applied indices and state why you chose the CMI. E.g., that it has better predictive potential, as alluded to in the discussion section You refer to some of these indices in the paragraph within the discussion section that starts with ‘The CMI, as an indicator to assess the degree of obesity and lipid levels…’, but referring to them in the introduction section reflects insight within this field.

This is difficult, but consider re-writing the Conclusion so that it captures the contribution of this study to the body of scientific knowledge more distinctly.

Thank you for choosing this journal for your submission. Best wishes for your future research!

**********

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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: No

Reviewer #3: Yes:  Rhena Delport

**********

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Submitted filename: Comments to Author.docx

PONE-D-24-47105R1Non-linear association of cardiometabolic index with gallstone disease in US adults: a cross-sectional studyPLOS ONE

Dear Dr. Li,

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 make revisions based on the comments of the reviewers.

Please submit your revised manuscript by May 03 2025 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 rebuttal 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 .

We look forward to receiving your revised manuscript.

Kind regards,

Qian Wu

Academic Editor

PLOS ONE

Journal Requirements:

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.

[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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

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

Reviewer #3: No

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: No

**********

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: regarding my previous comment #2, I would compare CMI to the lipid indicator alone to make the choice of CMI technically sound, rather than you "posit" CMI may be a better one. This comparision would be an impoartant evidence to support the comprehensive reflection of CMI. Especially, from the CMI formula, we can see its a combination of the lipid indicator and waist-to-height ratio. They should be most direct comparision that were not supposed to skip.

2.Lipid balance is crucial for gallstone disease, why choose CMI as indicator? Not [TG

(mmol/L)/HDL-C (mmol/L)]? How does CMI compares to [TG (mmol/L)/HDL-C

(mmol/L)] alone? And how does CMI compares to WHtR alone?

"Response: This is a very good suggestion. After synthesizing previous research

findings, we posit that compared to individual lipid indices or waist-to-height ratio

(WHtR), the cardiometabolic index (CMI) may provide a more comprehensive reflection

of human metabolic status. It is noteworthy that we will conduct comparative analyses

of these parameters in subsequent multicenter randomized controlled clinical trials to

more directly demonstrate the advantages of the CMI index."

Reviewer #2: The Author has answered all the comments. They also incorporated the corrections in the manuscript

Reviewer #3: Dear Authors

The following comments have not been addressed in your rebuttal:

General comments

The strength of the manuscript lies in the accommodation of relevant confounders and the application of restricted cubic spline analyses as a novel approach to make sense of the non-linearity of the association between this specific outcome and index.

Consider making more detailed and stronger deductions from the observed results, e.g., the subgroup analyses that were conducted to test for interactions between CMI and specific covariates. What stood out was the preponderance of males rather than females in the highest quartile (62.16 vs 37.8%) and the increasing trend in male proportions across quartiles with a reversed trend in females. This may be highlighted as a novel finding.

Specific comments:

There are numerous syntax errors throughout that need attention.

The Lipid Accumulation Product (LAP) index is mentioned in a sub-title within the Results section. This is the only occurrence of the term. Please clarify its relevance, because the paragraph reports on the CMI and the formulas for the two indices’ calculation differ.

The first paragraph in the introduction addresses Gallstone disease in general. The references are rather outdated. Please consider replacing them or adding more recent references (some of which are included in the above list of references that may be of interest to the authors)

In the third paragraph of this section, the CMI is introduced. You may consider referring to other more recently applied indices and state why you chose the CMI. E.g., that it has better predictive potential, as alluded to in the discussion section You refer to some of these indices in the paragraph within the discussion section that starts with ‘The CMI, as an indicator to assess the degree of obesity and lipid levels…’, but referring to them in the introduction section reflects insight within this field.

Consider re-writing the Conclusion so that it captures the contribution of this study to the body of scientific knowledge more distinctly.

**********

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: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

PONE-D-24-47105R2Non-linear association of cardiometabolic index with gallstone disease in US adults: a cross-sectional studyPLOS ONE

Dear Dr. Li,

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 make peer-to-peer modifications to the reviewer's comments.

Please submit your revised manuscript by Jun 08 2025 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 rebuttal 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 .

We look forward to receiving your revised manuscript.

Kind regards,

Qian Wu

Academic Editor

PLOS ONE

Journal Requirements:

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.

[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 #3: (No Response)

**********

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 #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: 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 #3: 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 #3: 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: All my concerns are well addressed. The authors have imporved the study with analysis details along with the critical corrections to the manuscript. I would recommend to publish this manuscript.

Reviewer #3: Thank you for submitting the revised manuscript.

Although all comments have been addressed suitably, there are still a few suggestions for consideration.

Specific comments:

“In contrast (line 98)to previous BRI and LAP indicators, CMI …” Please precede the acronyms with the full terms.

Line 276: Consider replacing ‘literatures’ with ‘reports’.

In Vancouver style, "P-value" should be written with a capital "P" and without a hyphen, as "P value".

General comment:

Line 309: Consider preceding the Conclusion with a summative statement regarding the clinical relevance of these findings, such as:

"However, the clinical relevance of identifying emergent GSD using the CMI is extended by acknowledging the significant relationship between GSD and CVD, probably due to common causal pathways, as established through meta-analysis and meta-regression." [ref. Hasan R, Allahbakhshi F, Shlyk AD, Allahbakhshi K. Gallstones as a predictor of elevated cardiovascular disease risk: A meta-analysis and meta-regression of over 7.4 million participants. PLoS One. 2025 Mar 19;20(3):e0314661. doi: 10.1371/journal.pone.0314661. PMID: 40106516; PMCID: PMC11922230.

Best wishes for your future research!

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Reviewer #1: No

Reviewer #3: No

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Non-linear association of cardiometabolic index with gallstone disease in US adults: a cross-sectional study

PONE-D-24-47105R3

Dear Dr. Li,

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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Qian Wu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #3: 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 #3: Yes

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

Reviewer #3: Yes

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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 #3: 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 #3: 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 #3: (No Response)

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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 #3: Yes:  Rhena Delport

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