PONE-D-19-21107

Glycated albumin as a diagnostic tool in diabetes: an alternative or an additional test?

PLOS ONE

Dear Dr. Camargo,

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.

==============================

ACADEMIC EDITOR: Minor revisions requested

==============================

We would appreciate receiving your revised manuscript by Nov 08 2019 11:59PM. 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,

Petter Bjornstad

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 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.

Additional Editor Comments (if provided):

[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: No

**********

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

**********

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 entitled “Glycated albumin as a diagnostic tool in diabetes: an alternative or an additional test?” by Chume et al. presents an evaluation of the diagnostic use of glycated albumin (GA) as a diagnostic tool for type 2 diabetes in a cohort of individuals from a single tertiary center in Brazil. IRB approval was endorsed and a participant consent process was completed for participation in this study. Overall, the study was well-developed and detailed. The experiments were well-conducted and the analysis was appropriate to evaluate the stated main study question.

TITLE and ABSTRACT:

1. As with the remainder of the paper, would recommend changing all notations of “patients” to either “participants” or “subjects” to follow people first language.

2. It would be helpful to characterize your study population in the results section of the abstract, if possible (i.e. number of participants, average age, BMI, etc.) to allow the reader a frame of reference.

3. Your conclusion statement that GA should be used as an adjunctive test instead of an alternative test to HbA1c or OGTT is somewhat confusing as you state in your introduction that either fasting plasma BG, HbA1c, or 2h OGTT can be used to diagnose T2D – why is GA different than HbA1c if you have come to the conclusion that “GA showed overall diagnostic accuracy similar to HbA1c in the diagnosis of DM” – how did you come to that conclusion?

4. In your abbreviations, I would label DM as "type 2 diabetes mellitus" instead of simply "diabetes mellitus" as you do not refer to other forms of diabetes mellitus such as type 1 diabetes mellitus in this manuscript. You should also define OGTT as an "oral glucose tolerance test" in this section.

INTRODUCTION:

1. Would consider splitting the first paragraph into two paragraphs given the paragraph length.

2. Would recommend adding a hypothesis statement in addition to the aim statement at the end of the “Introduction” section.

METHODS:

1. Why was HbA1c used only for descriptive purposes and comparison with GA if ADA criteria state that T2D can be diagnosed with a FPG ≥126 mg/dL, 2hG on OGTT ≥200 mg/dL, HbA1c ≥6.5%, or random plasma glucose ≥200 mg/dL with symptoms of hyperglycemia? Should it also be used to define participants with T2D if going by true ADA T2D diagnosis criteria? It seems like you use it to diagnose T2D in the results section (i.e. table 2) so the methods section should reflect that.

RESULTS:

1. The average BMI in this paper was noted to 28.9 +/- 6.3 kg/m2 which falls in the overweight category with a large percentage of study participants also being obese, how do you think that impacts your results for GA utility as you have rightly previously stated that both age and obesity are factors that impact GA levels?

2. It’s unclear what separating out clinical and laboratory characteristics of the cohort by the upper tertile of GA values adds to the data given you only reference the equilibrium threshold of 14.8% and the value of 16.8% as the cut off that demonstrates a similar sensitivity/specificity as HbA1c. Why did you select 16.0%? Would it make more sense to select 14.8% or 16.8%?

DISCUSSION:

1. You mention briefly that the HbA1c, GA, and OGTT tests do not reflect the same participants when a diagnosis is made of T2D. I think this is a really important point and it would be good to explore that more as the use of OGTT and HbA1c are currently both accepted for a diagnosis of T2D even though in your population, they only overlapped in terms of a diagnosis of T2D by both measures in 24/86 of the participants. Why do you think that is? It seems like that number would only decrease if combining HbA1c, OGTT, AND GA so what comments do you have about why all three of these measures are detecting T2D in completely different individuals? And does that mean that we should accept a diagnosis of T2D if any one of these tests is positive or if all 3 are positive? Or is one test superior to all of the others? If adding GA as an adjunctive test to the diagnosis of T2D, how would we interpret positive vs. negative results in terms of our diagnosis and management?

CONCLUSIONS:

1. What comments do you have about the generalizability of these results as this study was completed at a single center in Brazil?

2. It would also be worth mentioning that because this study was completed in a population at high risk (i.e. they were referred for an OGTT due to some predisposing factor), results about GA can only really be interpreted if obtained in a similar high-risk population (i.e. one with a high pre-test probability) rather than as a general population screening tool.

Reviewer #2: The authors examined the utility of glycated albumin as a screening tool for diabetes mellitus. Similar work has been performed in other (mostly Asian) populations, and found GA to be useful in some conditions. This report verifies the potential utility of GA as a secondary screening measure in Brazilian patients with high risk of developing DM who were seen at a tertiary hospital. It is promising work in an important area.

My biggest concern is that this is a study cohort with a relatively broad age range, and GA is well known to increase with age. Therefore, it might be worth adjusting these analyses for age, or investigating different cut points for different age groups.

Below are my other comments:

1. In the abstract results (line 43), please include the sensitivity and specificity information for the HbA1c cutoff, so readers can easily compare it to the reported GA cutoff.

2. When comparing paired areas under the ROC curve (e.g. two diagnostic tests on the same group), it is better to use DeLong’s test rather than t-tests.

3. Post-test probability should be calculated directly rather than estimated graphically.

4. Please explain why in table 1 the group is divided by upper tertile of GA, rather than at the equilibrium cut point 14.8% or high specificity cut point 16.8%.

5. Ethnic difference between groups should be assessed with Fisher’s exact test rather than chi-squared, though this is unlikely to make much of a difference. Please also remove the “trended toward significance” language.

6. Line 242 – Please clarify that some of the other studies (e.g. Chan et al.) also suggest GA as a secondary screening tool, not as a primary diagnostic test.

7. Figure 2 – it looks to me as if the HbA1c curve has been smoothed but the GA has not, though this might not be correct.

8. Figure 3 – I find this figure confusing. Please either clarify the legend or remove the figure.

9. Figure 4 – I don’t think this figure is necessary, but it doesn’t detract from the paper either.

10. Please include all CIs in the text as well as figures.

**********

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: Tim Vigers

[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.

Glycated albumin as a diagnostic tool in diabetes: an alternative or an additional test?

PONE-D-19-21107R1

Dear Dr. Camargo,

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. Congratulations!

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,

Petter Bjornstad

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 #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: Fantastic work with your responses to questions from the reviewers. A few errors that were noted that should be corrected before the manuscript makes it into print are as follows:

INTRODUCTION:

1. Type 2 DM mellitus (DM) on page 4 line 61 should be changed to type 2 diabetes mellitus (DM) for clarity. This should also be reflected on page 4 line 67 where it should read DM instead of DM type 2 (due to previous definition).

TABLE 1:

1. All fields with mean +/- SD should include a +/- and not just a + in this table.

DISCUSSION:

1. Page 21 line 352 should state "enrollment" instead of "enrolment."

Reviewer #2: (No Response)

**********

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