PONE-D-21-38060Serum Cystatin-C is linked to increased prevalence of diabetes and higher risk of mortality in diverse middle-aged and older adultsPLOS ONE

Dear Dr. Tarraf,

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Academic Editor

PLOS ONE

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Additional Editor Comments:

The strength of this study is the size of the cohort; however, as the reviewers point out there are a number of deficiencies in how it is presented and needs authors' attention.

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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: Yes

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: No

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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: Excellent job in analyzing this large data, this would be considered a well done manuscript for future references. I do have few points as below:

1. Line 51: No mention of diabetes as a risk factor of cardiovascular disease and death, while knowing that cardiovascular disease is the most common cause of death in patients with diabetes, hence relevant to noticed increased relative risk of death among patients with elevated Cystatin-C.

2. Line 59: Hba1c better to written (henceforth) as HbA1c or HbA1c.

3. Authors could spend more time discussing and possibly explaining the reason of elevated Cystatin-C and increased risk of diabetes and death in terms of pathophysiology.

Reviewer #2: Whilst the study has an advantage of a relatively large sample size and longitudinal design, it lacks originality and novelty. An extensive literature on the associations of Cystatin C with mortality and DM risk including various ethnic groups already exists (examples of some of those studies not referenced in the manuscript:

Shlipak MG, Wassel Fyr CL, Chertow GM, Harris TB, Kritchevsky SB, Tylavsky FA, Satterfield S, Cummings SR, Newman AB, Fried LF. Cystatin C and mortality risk in the elderly: the health, aging, and body composition study. J Am Soc Nephrol. 2006 Jan;

Peralta CA, Lee A, Odden MC, Lopez L, Zeki Al Hazzouri A, Neuhaus J, Haan MN. Association between chronic kidney disease detected using creatinine and cystatin C and death and cardiovascular events in elderly Mexican Americans: the Sacramento Area Latino Study on Aging. J Am Geriatr Soc. 2013

Sabanayagam C et all. Serum cystatin C and prediabetes in non-obese US adults. Eur J Epidemiol. 2013 Apr;

K. Sahakyan et all. Serum Cystatin C and the Incidence of Type 2 Diabetes Mellitus, Diabetologia 2011)

The manuscript does not read well in sections, particularly the results section, which needs to be presented in a clearer manner. Also, I would suggest placing the tables with the description of the findings within Results Section rather than Statistical Analyses. There are a number of small errors/typos throughout this this manuscript which needs correcting such as:

Line 132- error in eGRF categories

HDL categories- discrepancy in description on text/table 1

Table 1- units of measure in the table

Line 240 - unclear what authors mean by “lower association”

Duplication of reference: 11=13

Line 257 - Cystatin-C was associated with higher odds of diabetes and ??mortality at baseline

Please justify the choice of covariates on statistical grounds (unless biologically plausible mechanism linking covariate to the dependant variable exists) and provide the cut-off points for the categorical variables where missing.

The authors might want to take advantage of the availability of the Cystatin C data at three time points and apply more complex statistics such as repeated measures GLM to allow more robust longitudinal analysis.

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Reviewer #1: No

Reviewer #2: No

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Serum Cystatin-C is linked to increased prevalence of diabetes and higher risk of mortality in diverse middle-aged and older adults

PONE-D-21-38060R1

Dear Dr. Tarraf,

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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Kind regards,

Aloysious D Aravinthan, MBBS, FRCP, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Authors have addressed the reviewers' comments to my satisfaction.

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)

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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 #1: Yes

Reviewer #2: Yes

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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

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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 #2: 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: Excellent job in analyzing this large data, this would be considered a well done manuscript for future references

Reviewer #2: (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 #1: No

Reviewer #2: No

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