PONE-D-23-25506Prediction of Future Visceral Adiposity and Application to Cancer Research: The Multiethnic Cohort StudyPLOS 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: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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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

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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

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5. Review Comments to the Author

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

Reviewer #1: Wilkens et al. present an interesting study in which they evaluate the prediction value of a previously developed VAT score by the authors, by enhancing it with additional data. The results they present are interesting and can be of interest in big cancer research and epidemiological studies. However, some sections of the paper are a bit confusing to follow at times, and are lacking some information, and I feel that some changes are necessary.

Abstract

In the introduction of the abstract you talk about the past score with 9 biomarkers but in this study you are enhancing it with others, maybe you can mention it somehow.

In your conclusion you say it could help predict in incident diseases, but really you only looked at breast and CC cancer, I think this sentence should be rewritten, since it could be misleading.

Introduction

- Line 40: please include something such as the “previously developed vat score” to improve understanding

- Line 44: could be worth briefly explaining why you chose these two indexes and methodological differences (either here or in the discussion)

Materials & methods:

- A flow chart of the patients included, data obtained at each time point, etc. would be helpful to understand the process better.

- Line 96: did they report height as well? Please specify better what you mean when you discuss “their anthropometry data” (weight, height, waist circumference…).

- Was the anthropometry after 10 years self-reported or collected by a trained professional? It should be clearly stated.

- A list of the 48 biomarkers in supplementary information will make it easier for the reader to know what has been tested.

- I think this section would benefit from a subsection of (other)variables included to clearly specify what other data (other than diet, anthropometry and blood biomarkers) were employed and how they were collected.

- What statistical program/package was employed? Threshold of significance? This section needs improving.

Results:

- In Table 1, why is education there if it is not discussed later, used to adjust and has been published before? Not sure if it is relevant.

- Table 1 footnotes need improving: HEI, VAT…

- Table 3/results: please include n of participants

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Discussion:

- Sentence 290-293: I think you should specify that you have previously shown this correlation, how it is written it seems you found this correlation in this study.

- Line 297-299: I think this is an important point and should be discussed further. Where and in which populations could this score be applied realistically? What clinical advantage would it give vs. other scores? Since this is the title of the paper (application to cancer research) I think it deserves a bit more discussion.

- I think the final message should be a bit clearer (in line with previous comment).

Although the paper is well-written, sometimes it is a bit confusing, some minor English/typos revision is needed. Examples (but not exhaustive list):

- Abstract: “9” should be spelled out.

- Full stop after “studies” in line 9.

- Line 76: collected from (instead of on)

- Line 105: As previously described, as described elsewhere, etc.. this occurs throughout the paper, needs to corrected.

- Line 206: pre/peri-menopausal? (now per-mernopausal)

- Line 121, 217, 255: remove the “:”, full stop instead or connector or similar. This is repeated throughout the paper.

- Line 233: (0.62, 0.55) needs R2, men, women….

Reviewer #2: The manuscript presents an intriguing analysis that delves into the predictive capabilities of VAT (visceral adipose tissue) scores, derived from a combination of demographics, anthropometric measures, and blood biomarkers, in relation to cancer risk. The study evaluates three VAT prediction models (original, refit, and enhanced) and their associations with incident breast and colorectal cancer within the Multiethnic Cohort (MEC). The manuscript's strength lies in the inclusion of a diverse cohort that meticulously represents various racial and ethnic groups, enhancing the generalizability of the findings. The balanced representation across sexes and ethnicities and prospective design augments the robustness of the study.

First, the study exhibits several strengths, including the use of MRI-quantified VAT, prospectively collected blood biomarkers, and balanced representation across diverse demographic groups. Moreover, the nested case-control analysis provides valuable insights into cancer associations. One remarkable aspect of this study is the comparison of VAT prediction scores with the conventional measures, BMI, and other published VAT prediction models (VAI and METS-VF). The findings suggest that the VAT scores outperform these conventional metrics in terms of predicting VAT and its associations with cancer risk, particularly breast cancer.

Furthermore, the varying prediction performance between men and women and the influence of factors like menopausal status and nutrition underscore the need for further investigation into interactions and the role of diet quality in body fat distribution. This study provides a foundation for exploring these intricate relationships, and examining potential interactions between VAT, predictive variables, and demographic characteristics could be a valuable next step in future studies.

In addition to exploring interactions, future research could focus on addressing the reasons behind the lack of a BMI-independent association with colorectal cancer and its prognosis. These findings may also prompt the evaluation of other cancer sites and their relationships with VAT scores to provide a comprehensive understanding of obesity-related cancer risks.

The manuscript contributes to our understanding of VAT prediction models and their associations with cancer risk. It opens the door to further investigations into interactions, temporal aspects, and the development of more practical prediction models. The findings underscore the importance of considering VAT as a valuable metric for assessing cancer risk beyond BMI.

Considerations:

1) Elastic Net Regression: The use of LASSO twice, first on past data and then on more recent data, allows for the development of prediction models that take into account the influence of various predictors and changes over time. While LASSO is a widely used regularization technique, the manuscript might benefit from considering the incorporation of Elastic Net regression or at least discussion as a possible next step. Elastic Net combines both L1 (LASSO) and L2 (ridge) regularization, striking a balance between feature selection and model fitting. This technique offers the advantage of simultaneously addressing issues related to variable selection and multicollinearity for a possibly more interpretable model.

2) Variable Selection: It is crucial to elaborate on the rationale behind variable selection for the VAT prediction models. As LASSO automatically selects variables, discussing the clinical significance of the included variables and their impact on VAT prediction would enhance the depth of the manuscript.

3) Graph: The tables, although informative, could benefit from a visual representation, such as, a SHAP plot of the LASSO regression coefficients of variable importance or a single graph overlaying ROC curves by sex and model type.

4) Inconsistent Associations: The manuscript observes a significant positive association between predicted VAT and breast cancer risk but not colorectal cancer. A comprehensive technical exploration of the potential reasons for these inconsistencies, involving a deep dive into the biological mechanisms, pertinent factors, or possible reasons for lack of association is warranted.

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Reviewer #1: No

Reviewer #2: Yes: Linda M. Polfus, PhD

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Prediction of Future Visceral Adiposity and Application to Cancer Research: The Multiethnic Cohort Study

PONE-D-23-25506R1

Dear Dr. Wilkens,

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,

Omar Yaxmehen Bello-Chavolla, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All queries have been adequately addressed.

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 #2: All comments have been addressed

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 #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

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 #2: 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 #2: 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 #2: Authors addressed comments/concerns regarding revision of Figure 1 and clarification of previous study data elements contributing to this work. Advise to accept manuscript.

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 #2: Yes: Linda M. Polfus, PhD

Reviewer #3: No

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