PONE-D-22-35678Analysis of Ancestry-Specific Polygenic Risk Score and Diet Composition in Type 2 DiabetesPLOS ONE

Dear Dr. Hardy,

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. Particularly, the authors need to clarify and discuss any potential bias generated by the data and its interpretation as detailed by Reviewer 2.

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We look forward to receiving your revised manuscript.

Kind regards,

Andreas Zirlik, MD

Academic Editor

PLOS ONE

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Additional Editor Comments:

Reviewer 1:

In short summary, this study found that individuals in the highest PRS tertile had higher T2DM risk in European Americans and African Americans. Protective effects were seen with combination of high carbohydrate, low protein intake and low PRS. African Americans benefited from increased physical activity by reduce harm of high protein diet.

Sections:

1. Disclosures:

a. In financial disclosures, the authors mention a grant from the NLHBI to the first author. As this grant (K01) can include salaries and only NLHBI-sponsored studies were accessed, this should also be mentioned as conflict of interest. Otherwise, the authors should explain why this should not be the case.

2. Introduction:

a. The authors should shortly state the clinical importance of their work at the end of the introduction and furthermore in the discussion and conclusion section.

3. Results:

a. Bonferroni adjustments: The authors make a Bonferroni adjustment for both African American and European Americans, i.e. deduce a significance level of .025. I would like the authors to explain why a Bonferroni adjustment was not done for testing between different tertiles (e.g. in Table 3), as this is also a case of multiple testing. However, I am aware that this topic can be interpreted differentially. This would reduce the number of reported significant associations in the tables significantly.

b. Tables 4 and 7 are quite hard to interpret as the information is somewhat ambiguous. The tables should be simplified or restructured to improve readability. Also, instructions of how to interpret the table should be given in the caption. For example, in Table 4, the authors compare tertiles within two groups, one with “High Carbohydrate and Low Protein Intake” and vice versa. Then, in the former group, the authors present data about Physical activity alone twice.

4. Conclusions:

a. “African Americans can benefit from increased physical activity to decrease the harmful effects of a high protein diet despite having a deleterious burden of high-risk alleles.” (This is a literal quote from the abstract).

This study only tested for associations, not causality, which should be stated in the paragraph listing the study’s limitations. The design of the study is a cross-sectional study that aims to examine the relationship between variables at one point in time, rather than to establish cause-and-effect relationships. Thus, for the next iteration of this work, the authors should rephrase this sentence such as “African Americans may benefit…” etc. as they did in the conclusions section in the main text.

b. The authors should elaborate on the clinical significance of this paper, i.e. hypothesis generation for future RCTs or direct clinical implications.

5. General remarks:

a. Length: The article is quite long and very technical. Perhaps, the authors can omit some of the presented text and tables and transfer them into the supplement.

b. Captions: In general, captions should be optimized to give the reader more guidance of how the data has been interpreted.

Misspellings and Errors:

1. Line numbers suddenly stop at line 250 without apparent reason.

2. Line 65: should be "...that affects 37.3M (11.3%) people in the U.S."

3. Line 99: "was associated". Replace with "has been associated".

4. In the last sentence of the main text should be changed from “..harmful high protein diet…” to “ A high level of physical activity may be protective in African Americans with T2DM who consume a harmfully high protein diet…”.

Reviewer 2:

The authors performed a retrospective study of the influence of a polygenic risk score (PRS), diet and physical activity on the occurrence of diabetes mellitus type 2 (T2DM). They showed in an analysis from many genetic studies that a PRS influenced the occurrence of DMT2. However, high carbohydrate and low protein intake were associated with reduced risk of T2DM.

This observational study contradicts the results of prospective interventional studies, probably due to bias: Since more than 15 years, low carbohydrate diet was led to improved glycaemic control in T2DM patients (also in randomized studies) [Nutr Metab (Lond). 2008; 5: 9.]. Therefore, national and international guidelines mainly recommended carbohydrate restriction in T2DM patients. (In the last years, there was a change towards the assessment of the quality of carbohydrates, but this is still a matter of debate). Consequently, all patients with T2DM in the last decades received recommendations to reduce carbohydrate intake and increase protein intake. Patients included in the genetic studies may also have received the same recommendation and therefore either (1) have changed their dietary habits or (2) at least report that they would have changed their dietary habits in interviews. This would have led to this carbohydrate “paradox” in this study. What do the authors think about this problematic bias? I encourage the authors to clearly state in the discussion that this is only a retrospective study with associations. I discourage the use of the word “protective” as the study has no longitudinal data included, therefore no “protective” behavioural factors can be derived from this data. Furthermore, the authors discuss the possibility of “ketogenic diet” with means a total cut of carbohydrates and clearly contradicts the results of this study.

Furthermore, the authors should describe the source data better: Were those cross-sectional or longitudinal data? (this should be already mentioned in the Methods section). How were patients included? Do the patients represent the same characteristics as the general population? Did patients receive compensation?

In general, the manuscript is well written, statistics and references are adequate. The manuscript is generally very long, the results section may be shortened.

Minor comments:

- The first half of the first paragraph at page 14 should be moved to the Methods section.

- The authors write that the ADA currently recommends a high carbohydrate, low protein diet with reference [9]. However, the reference [9] refers to the definition of T2DM, and does not recommend any dietary measure. In fact, this reference does not even contain the words “carbohydrate” or “protein”.

- The main endpoint (occurrence of T2DM) is not clear from the abstract.

- Specific steps and changed variables during data harmonization should be summarized in a supplemental table.

- Was multiple imputation performed for missing data?

[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: Yes

Reviewer #2: Yes

**********

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: No

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: In short summary, this study found that individuals in the highest PRS tertile had higher T2DM risk in European Americans and African Americans. Protective effects were seen with combination of high carbohydrate, low protein intake and low PRS. African Americans benefited from increased physical activity by reduce harm of high protein diet.

Sections:

1. Disclosures:

a. In financial disclosures, the authors mention a grant from the NLHBI to the first author. As this grant (K01) can include salaries and only NLHBI-sponsored studies were accessed, this should also be mentioned as conflict of interest. Otherwise, the authors should explain why this should not be the case.

2. Introduction:

a. The authors should shortly state the clinical importance of their work at the end of the introduction and furthermore in the discussion and conclusion section.

3. Results:

a. Bonferroni adjustments: The authors make a Bonferroni adjustment for both African American and European Americans, i.e. deduce a significance level of .025. I would like the authors to explain why a Bonferroni adjustment was not done for testing between different tertiles (e.g. in Table 3), as this is also a case of multiple testing. However, I am aware that this topic can be interpreted differentially. This would reduce the number of reported significant associations in the tables significantly.

b. Tables 4 and 7 are quite hard to interpret as the information is somewhat ambiguous. The tables should be simplified or restructured to improve readability. Also, instructions of how to interpret the table should be given in the caption. For example, in Table 4, the authors compare tertiles within two groups, one with “High Carbohydrate and Low Protein Intake” and vice versa. Then, in the former group, the authors present data about Physical activity alone twice.

4. Conclusions:

a. “African Americans can benefit from increased physical activity to decrease the harmful effects of a high protein diet despite having a deleterious burden of high-risk alleles.” (This is a literal quote from the abstract).

This study only tested for associations, not causality, which should be stated in the paragraph listing the study’s limitations. The design of the study is a cross-sectional study that aims to examine the relationship between variables at one point in time, rather than to establish cause-and-effect relationships. Thus, for the next iteration of this work, the authors should rephrase this sentence such as “African Americans may benefit…” etc. as they did in the conclusions section in the main text.

b. The authors should elaborate on the clinical significance of this paper, i.e. hypothesis generation for future RCTs or direct clinical implications.

5. General remarks:

a. Length: The article is quite long and very technical. Perhaps, the authors can omit some of the presented text and tables and transfer them into the supplement.

b. Captions: In general, captions should be optimized to give the reader more guidance of how the data has been interpreted.

Misspellings and Errors:

1. Line numbers suddenly stop at line 250 without apparent reason.

2. Line 65: should be "...that affects 37.3M (11.3%) people in the U.S."

3. Line 99: "was associated". Replace with "has been associated".

4. In the last sentence of the main text should be changed from “..harmful high protein diet…” to “ A high level of physical activity may be protective in African Americans with T2DM who consume a harmfully high protein diet…”.

Reviewer #2: The authors performed a retrospective study of the influence of a polygenic risk score (PRS), diet and physical activity on the occurrence of diabetes mellitus type 2 (T2DM). They showed in an analysis from many genetic studies that a PRS influenced the occurrence of DMT2. However, high carbohydrate and low protein intake were associated with reduced risk of T2DM.

This observational study contradicts the results of prospective interventional studies, probably due to bias: Since more than 15 years, low carbohydrate diet was led to improved glycaemic control in T2DM patients (also in randomized studies) [Nutr Metab (Lond). 2008; 5: 9.]. Therefore, national and international guidelines mainly recommended carbohydrate restriction in T2DM patients. (In the last years, there was a change towards the assessment of the quality of carbohydrates, but this is still a matter of debate). Consequently, all patients with T2DM in the last decades received recommendations to reduce carbohydrate intake and increase protein intake. Patients included in the genetic studies may also have received the same recommendation and therefore either (1) have changed their dietary habits or (2) at least report that they would have changed their dietary habits in interviews. This would have led to this carbohydrate “paradox” in this study. What do the authors think about this problematic bias? I encourage the authors to clearly state in the discussion that this is only a retrospective study with associations. I discourage the use of the word “protective” as the study has no longitudinal data included, therefore no “protective” behavioural factors can be derived from this data. Furthermore, the authors discuss the possibility of “ketogenic diet” with means a total cut of carbohydrates and clearly contradicts the results of this study.

Furthermore, the authors should describe the source data better: Were those cross-sectional or longitudinal data? (this should be already mentioned in the Methods section). How were patients included? Do the patients represent the same characteristics as the general population? Did patients receive compensation?

In general, the manuscript is well written, statistics and references are adequate. The manuscript is generally very long, the results section may be shortened.

Minor comments:

- The first half of the first paragraph at page 14 should be moved to the Methods section.

- The authors write that the ADA currently recommends a high carbohydrate, low protein diet with reference [9]. However, the reference [9] refers to the definition of T2DM, and does not recommend any dietary measure. In fact, this reference does not even contain the words “carbohydrate” or “protein”.

- The main endpoint (occurrence of T2DM) is not clear from the abstract.

- Specific steps and changed variables during data harmonization should be summarized in a supplemental table.

- Was multiple imputation performed for missing data?

**********

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: 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.

Attachments

Attachment

Submitted filename: PlosOne_T2DM_PRS.docx

PONE-D-22-35678R1Analysis of Ancestry-Specific Polygenic Risk Score and Diet Composition in Type 2 DiabetesPLOS ONE

Dear Dr. Hardy,

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 Jun 11 2023 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,

Andreas Zirlik, MD

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 #2: (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 #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: This retrospective study found that individuals within a higher PRS percentile had increased risk of developing T2DM. Furthermore, there was an association between a high protein low carbohydrate diet and risk of developing T2DM.

In my opinion, my posed questions have been sufficiently addressed. Especially the newly added captions to the figures enhance readability.

Reviewer #2: The authors made substantial improvements to the manuscript. However, I believe that the manuscript can still be optimized:

- As already mentioned in the first review, the main outcome has to be reported in the abstract. I therefore recommend to add this information to the Methods section of the manuscript.

- There is still missing information about data imputation in the manuscript (imputation by mean? Or median? Multiple imputation?)

**********

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

**********

[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.

Analysis of Ancestry-Specific Polygenic Risk Score and Diet Composition in Type 2 Diabetes

PONE-D-22-35678R2

Dear Dr. Hardy,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Andreas Zirlik, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: