Peer Review History

Original SubmissionSeptember 12, 2019
Decision Letter - Xianwu Cheng, Editor

PONE-D-19-25704

Phenotypic and lifestyle determinants of HbA1c in the general population – the Hoorn Studies

PLOS ONE

Dear Dr Wisgerrhod

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.

We would appreciate receiving your revised manuscript by April 30. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

4. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following

competing interests: at the time this article was written, Marjan Alssema was employed

by Unilever which manufactures and sells consumer food products. All other authors

declare that they have no potential conflict of interests relevant to this article."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

Additional Editor Comments (if provided):

None.

[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: The manuscript is technically reasonable, the data is reliable, and appropriate and rigorous statistical analysis is performed, but the conclusions need to be further proved. The manuscript is presented in an intelligible fashion and written in standard English, but the author failed to provide important factors such as hemoglobin and serum alanine aminotransferase in the manuscript. Needs further research and reveals.

Reviewer #2: General Comments

This is a very important and interesting study. The replication element of the study greatly increases its impact. It is important to determine the relation between the potential determinants of HbA1c and HbA1c itself.

Specific comments

Methods

A breakdown of Ethnicity of the participants would be very helpful – sorry if I missed this

Results

Please can a Figure be included to display the results of the multivariate regression analysis as described in Table 2. This always aids data appreciation from a reader perspective.

**********

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: Dr. Adrian Heald

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments
Attachment
Submitted filename: Comment to Authors(PONE-D-19-25704).doc
Revision 1

Reviewer #1:

Summary:

This manuscript by Willem et al. entitled “Phenotypic and lifestyle determinants of HbA1c in the general population – the Hoorn Studies” is aimed at understanding the relevance of phenotypic and lifestyle factors to HbA1c, in the general population. The data of both cohorts, independent of FPG and 2hPG, higher age, female sex, larger waist circumference, and smoking were associated with a higher HbA1c level. Larger hip circumference, higher BMI, higher alcohol consumption and vitamin C intake were associated with a lower HbA1c level. FPG and 2hPG together explained 41.0% (HS) and 53.0% (NHS) of the total variance in HbA1c. The authors fully describe the relationship between lifestyle, blood glucose levels and glycated hemoglobin in NHS and HS. There are several concerns to consider.

Major:

This study is simply a description and fails to give a reasonable explanation. The results of BMI related to increased hip circumference and low-grade glycated hemoglobin are interesting, but there is no explanation. In general, glycated hemoglobin is a non-independent diagnostic standard for diabetes. In this study, as a key point to explore, the actual or predictive role of glycated hemoglobin changes in the model population should be more revealed. At present, I cannot appreciate the value of the information provided by the research to clinical or public nutrition research. I hope researchers can further discuss and reveal the significance of the research.

Response: We thank the reviewer for careful reading of the paper and for addressing these important points. We will respond to these in a point-by-point answer below.

1.The trend of BMI results in HS from Q1 to Q4 is inconsistent. Can this result be adopted?

Response: the trend over quartiles BMI in the HS cohort is indeed slightly inconsistent. This inverse association of BMI with HbA1c is partly due to the model being multivariate and including hip and waist circumference as well as fasting and post-load glucose. This will make closely related estimates somewhat unstable. Therefore, we avoided to speculate on the importance of this slightly inconsistent association over BMI quartiles.

2. Hemoglobin and serum alanine aminotransferase are important factors affecting glycated hemoglobin, which are not shown in the analysis results, can they be explained?

Response: Hemoglobin and serum alanine aminotransferase were indeed considered potential determinants of HbA1c in addition to glucose measures. These factors were added to the multivariable model of the HS cohort in a stepwise procedure. However both did not appear statistical significant determinants at level P< 0.10 and were therefore not presented in Table 2. Serum alanine transferase indeed was an important determinant, that was excluded in the final model with a p-value of 0.25, while hemoglobin was already excluded earlier in the analysis.

3. Can I know the results about the investigator's medication history?

Response: the medication history for blood glucose lowering medication was considered in the study. All study participants with diabetes and thus also those who were using blood glucose lowering medication were excluded from the analysis. This is indicated more clearly now on page 5 line 98 and 106.

4. The author's study showed a negative correlation between the amount of alcohol consumed and the content of glycated hemoglobin, which means that increased drinking in healthy people is beneficial to prevent blood sugar rising. Can I understand it this way?

Response: The study shows an inverse association between alcohol intake and glycated hemoglobin in two independent cohorts, but causality cannot be concluded from observational studies. The finding is not unique. Several observational studies have reported an inverse association between alcohol consumption and HbA1c or insulin resistance (refs 35-37). Moreover, moderate alcohol consumption is shown to reduce HbA1c and insulin resistance in multiple intervention studies as summarized in a meta-analysis (Schrieks IC, diabetes care). Therefore, this finding is consistent with other studies, but the mechanism is currently not resolved. We have now indicated this briefly in the discussion section of the paper as follows; ‘The same is true for alcohol consumption which has been associated with a lower HbA1c level and improved insulin resistance in previous observational and intervention studies, but not particularly with HbA1c independent of glucose [35-37]. The mechanism by which alcohol would improve insulin sensitivity is currently not resolved.’

5. The author further explains the significance of the findings for metabolic or cardiovascular disease will be appreciated. (The significance of the study is unclear because the glycated hemoglobin in the study fluctuates within the normal range)

Response: The main relevance of the paper is related to the use of HbA1c levels for the diagnosis of diabetes. Since disagreement in diagnosis by HbA1c and glucose is observed in other studies, it is important to understand the contributing factors to HbA1c beyond glucose. Increased HbA1c levels are associated with future CVD incidence. This association is also apparent among individuals with levels of HbA1c in the normal range (Khaw KT (2004) Ann Intern Med 141: 413-420 and Di Angelantonio E (2014) Jama-J Am Med Assoc 311: 1225-1233). The author is right that this point was not particularly articulated in the paper. Therefore we added this sentence in the introduction section:

“HbA1c has also been shown to be a more accurate marker than measures of glucose for future risk of diabetes complications, such as micro vascular complications and cardiovascular disease (CVD), in individuals with type 2 diabetes [4]. In addition, higher HbA1c is associated with higher risk for CVD and total mortality [5, 6]. This increased CVD and mortality risk with higher HbA1c is already seen at levels in the normal range [5, 6].

6. The conclusion that women's hemoglobin is higher than men's is also worthy of our attention. It would be greatly appreciated if the author could further analyze the pre- and post-menopausal women. (Because previous studies have shown that estrogen treatment can increase glycated hemoglobin levels)

Response: This is an interesting suggestion. The current findings were in contrast with other studies where a higher HbA1c was found in men [REF 15]. And a study were HbA1c was lower in women before menopause as compared to men [REF 31]. However, in previous studies, no adjustment was made for glucose levels. As explained in the discussion section line 263, similar to these previous studies, we also observed a higher HbA1c level in men when we did not correct for glucose. In the current study, the higher HbA1c levels in women were consistently found in both cohorts, in which age, and hence the proportion of postmenopausal women, was different. This suggests that the observed higher HbA1c levels, at similar glucose concentration, were not specific for postmenopausal women or women using estrogen treatment. In addition, in both cohorts only a small proportion of women was premenopausal with 5.5% in the HS and approximately 15% in NHS. We considered that the subsample of premenopausal women was too small to conduct a stratified analysis.

Reviewer #2: General Comments

This is a very important and interesting study. The replication element of the study greatly increases its impact. It is important to determine the relation between the potential determinants of HbA1c and HbA1c itself.

Specific comments

Methods

A breakdown of Ethnicity of the participants would be very helpful – sorry if I missed this

Response: In the HS cohort, only Caucasians were part of the cohort. In the NHS only 4.5% of individuals were non-Caucasian. We considered that the subsample of non-Caucasians was too small for a subanalysis.

Results

Please can a Figure be included to display the results of the multivariate regression analysis as described in Table 2. This always aids data appreciation from a reader perspective.

Response: thank you for the suggestion. We are not sure how this would add to the current information since a Figure does not provide specific numbers. Therefore, we prefer the data being presented in a Table.

Attachments
Attachment
Submitted filename: Response to Reviewers.doc
Decision Letter - Xianwu Cheng, Editor

Phenotypic and lifestyle determinants of HbA1c in the general population – the Hoorn Study

PONE-D-19-25704R1

Dear MSc Wisgerhof 

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All original concerns have been addressed by the authors.

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: 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: The authors have shown a lot of effort to improve the manuscript and this should be well appreciated. I found the authors have addressed all my comments carefully by adding more materials in the text. As a result, I now recommend the current form can be accepted for publication without further modification.

Reviewer #2: Please can you accept this excellent paper

I already emailed your office twice to say "ACCEPT"

Kind regards

Dr. Adrian Heald

**********

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: Dr. Adrian Heald

Formally Accepted
Acceptance Letter - Xianwu Cheng, Editor

PONE-D-19-25704R1

Phenotypic and lifestyle determinants of HbA1c in the general population – the Hoorn Study

Dear Dr. Wisgerhof:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. 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.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Associate Prof. Xianwu Cheng

Academic Editor

PLOS ONE

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .