PONE-D-25-04963Association of U09.9 Long COVID documentation with clinical outcomes among Veterans with diabetesPLOS ONE

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PLOS 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

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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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: No

Reviewer #2: Yes

Reviewer #3: No

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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

Reviewer #3: 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: This is an interesting and well-written paper on a relevant topic. However, a number of issues should be addressed to improve its quality:

General:

- The whole manuscript should be reviewed and if necessary revised according to STROBE guidelines. For example, the study’s design should be indicated with a commonly used term in the title or the abstract.

- International units for height and weight should be used throughout the manuscript and in all tables, e.g. kg instead of pounds.

- Suggest to separate the lower and upper limit of confidence intervals with ";" or "," instead of "-" to make them better readable in case the limits are negative.

- In the spirit of Open and Reproducible Science, the statistical analysis code should be made available in an online repository together with a data dictionary, and the respective URL should be mentioned in the Methods section.

Title:

- Suggest to remove "U09.9" from the title

Abstract:

- "10/1/2021-10/1/2023" is somewhat ambiguous to an international readership and should therefore be revised to e.g. "1 October 2021 - 1 October 2023".

- The data source and the location of the patients included (whole US?) should be mentioned.

- "Veterans were 69.7 years old". Does this refer to 1 Oct 2021?

- The term "index date" needs to be explained.

- All abbreviations such as IRR, CI, OR, VA need to be explained at first appearance, also in the Abstract.

- In the CI of mortality, 8.87 seems to be a typo.

- "These associations do not appear to be mediated through effects on weight or glycemia." This is not supported by the results shown in the Abstract.

Introduction:

- How can the difference in the prevalence of Long-COVID in US veterans (5% vs. 1%) be explained?

- The sentence mentioning reference 6 seems to imply that this reference already contains work from these authors on Long-COVID in insulin users compared to non-users. Is this intended?

- Please explain the term "Veterans". Is this retired military staff? Were all of them engaged in military operations (outside the US), or does this include also e.g. IT personnel?

Methods:

- "Participants were also required to be active in VA care, defined by the presence of ≥1 inpatient or outpatient visit in the prior 12 months." Does this mean that participants were on average less healthy than non-participants (as some of the latter maybe did not need VA care)?

- "For individuals without Long COVID documentation the index date was defined as a random date during a month in which a visit or laboratory test was recorded." This sounds quite arbitrary. Which visit or test was chosen if there was more than one month with a visit or test?

- How was the index date distributed, and what was the median observation period after the index date in individuals with and without Long-COVID? If some differences occur between groups, it might be advisable to add a sensitivity analysis addressing this issue.

- "We collected data..." seems somewhat misleading, as the data had already been collected routinely as I understand it. Should this possibly read "We extracted data..."?

- A reference should be added to the Charlson comorbidity index. A short explanation of this index would be helpful in order to interpret differences in this index between groups.

- What was the rationale to calculate mean HbA1c BEFORE the index date?

- What is a CPT code?

- "11/22/24" should be revised to make as mentioned in a similar comment above.

Results:

- The text would be better readable if veterans without U09.9 were used as reference group and not vice versa (as currently done in the main text).

- The text should be specific in that vaccine doses refer to SARS-CoV-2 vaccinations.

Discussion:

- What is EHR?

- The authors should discuss why they did not differ between type 1 and type 2 diabetes and how this might have affected the results.

- How comes that the participants had a weight loss on average? Would it not be expected to observe an average weight gain over time?

- Is it realistic that only around 2.5% diabetic patients uses insulin? How does this compare to the rate of insulin-dependent diabetes in the US?

- Which associations are referred to by the term "null associations"?

- "These associations do not appear to be mediated through effects on weight or glycemia." Again, this sentence strikes me as this has actually not been shown, which could have been done e.g. by comparing crude and adjusted effect estimates.

Table 1:

- It should be mentioned which tests were used to derive the p-values. However, it appears questionable to report p-values in this table anyway, as also rather irrelevant differences between groups became statistically significant just because of the large sample size.

- It should be mentioned that the % refer to column percent.

- What is the meaning of "Residence: None"? Were approx. 30% of the Veterans homeless?

- Does mean HbA1c refer to before or after the index date? If before, it appears somewhat confusing to present this together with other clinical outcomes which seem to refer to the observation period after th index date.

Table 2:

- It should be mentioned that all covariates were mutually adjusted in each model.

Table 3:

- It should be mentioned that these estimates were adjusted for the same covariates as in Table 2.

Reviewer #2: Review.

Association of U09.9 Long COVID documentation with clinical outcomes among Veterans with diabetes

Abstract;

1. Its inclusive of the objective, relevant methods and key findings.

Introduction

1. The introduction is clearly written and straightforward.

Methods:

1. Are clear and relevant to the study purpose.

Results

1. These are clearly reported in relation to the study objective.

Discussion

1. The discussion starts by summarizing the most important findings. This is good for the reader.

2. The findings are clearly related to other previous related studies.

Remark.

This is generally informative and well written manuscript.

Reviewer #3: The study evaluated the long-COVID clinical outcomes, including mortality, dialysis, glycemia status, and the number of primary care visits in patients with diabetes. The authors found that individuals with long Covid did not have an increased risk of higher HbA1C, weight gain, and mortality, while other clinical outcomes were more likely in them.

The study benefits from a large population of 1.8 million participants. However, the methodology and presentation need significant improvements. Overall, I hope addressing the following comments helps with the manuscript.

1. In the abstract, the OR for mortality in the last line of abstracts result is wrong. Please recheck other variables in the manuscript globally.

2. The term, the impact of long COVID on “glycemia”, used in abstract, highlights, and main text could be changed to better reflect the alterations. I suggest a more precise wording, such as hyperglycemia or glycemia alterations, changes, etc.

3. I suggest adding the study period to the abstract method section.

4. In the abstract, “veterans were 69.7” years needs to be modified.

5. The authors aimed to evaluate the metabolic status of patients with long Covid. However, the full spectrum of metabolic unhealthy was not included, this could significantly limit assessment of the metabolic health.

6. In the method section, it is stated that prior positive Covid test documentation was not necessary, particularly due to the high prevalence of the population with positive rates. Was the prevalence of patients with no prior positive Covid test and a positive long Covid diagnosis checked? How was the potential misclassification assessed?

7. In the method section, I suggest adjusting for hypertension, dyslipidemia, and baseline eGFR as well.

8. In the method section, please determine the timeframe for follow-up. What was the median follow-up period post-index date? How were the variations in follow-up duration between groups accounted for? (For instance, some patients may have had a longer follow-up time for HbA1c changes.)

9. Continuing in my previous question, I suggest providing sensitivity analyses excluding patients with short follow-up periods or insufficient HbA1c data and patients with imputed BMI.

10. In the method section, why was only current insulin use considered as an interaction term? Other medications could potentially modify the effect of Long COVID on metabolic outcomes.

11. Please provide further details on the BMI imputation. How were the robustness and representativeness evaluated?

12. The study is considerably under referenced, and in some instances, the presentation could get better. For the effect of COVID-19 on kidney function, there are multiple large-scale studies with long follow-ups, although not necessarily under the long-covid term. I recommend integrating them into the corresponding section from the discussion.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Association of U09.9 Long COVID documentation with clinical outcomes among Veterans with diabetes

PONE-D-25-04963R1

Dear Dr. Wander,

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,

Gaetano Santulli, MD, PhD

Academic Editor

PLOS ONE

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 #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 #1: Yes

Reviewer #3: Yes

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

Reviewer #1: 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 #1: No

Reviewer #3: No

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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 #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 #1: The authors have sufficiently addressed all my issues. -----------------------------------------------

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 #1: No

Reviewer #3: No

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