PONE-D-23-40352Metabolic profiling during COVID-19 infection in humans: Identification of potential biomarkers for occurrence, severity and outcomesPLOS ONE

Dear Dr. Elabd,

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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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #3: Yes

Reviewer #4: 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: “Metabolic profiling during COVID-19 infection in humans: Identification of potential biomarkers for occurrence, severity and outcomes” by Elabd and co-workers studied the metabolic profiles of different groups of patients having different severity of covid 19. I recommend the editor to accept this publication after major revision on addressing the following queries.

1. As per Methods details blood sample are collected from covid patient between the year 2021 to 2022. When they analyze these samples using LC-MS in 2023 or between 2021 to 2022 immediately collecting after the blood sample collection?

If data is not collected immediately or after 1-2 month after the sample collection. How authors will justify the change in metabolites is due to severity of the covid 19 patient not due to ageing of the sample stored in refrigeration at -80°C?? Did the authors perform any control experiment to confirm any of the metabolites they found is due to sample aging or not??

2. In Table 1, authors mention % in front of symptom (like cough/fever etc.) each group. Does this % means, among the total number of patients in each group that percent of patients are with symptoms of cough, fever etc???

Reviewer #2: The review explains all the possible metabolites from blood samples which might be helpful in prediction of the stage of COVID -19 patients and severity of the disease. I have some concerns listed below:

1. When the authors categories the various stages of COVID-19 patients (section 2.1), They wrote that severity is considered with any of the following include low oxygen saturation level which they defined below 90 and respiratory distress whereas Critical Patients who need the mechanical ventilation.

My concern is that some patients might have low oxygen saturation and does use all CPAP and other oxygen flow ways. During that stage, some patients need more oxygen flow from outside and some might need less depending upon the lungs functioning. How can we compare when the patients are in early stages of virus and need less outside oxygen flow (may be 4 or 6) versus patients in late stages of disease and need more oxygen flow (may be 14). The latter patients might also be similar to critical ones.

Secondly, sometime during the ventilation, there is ventilated pneumonia associated with disease, how that can be ruled out.

2. What age group is used during data collection? As per I understand, Is the age graph is one which represented in supporting figure S2, if that is true, how can we compare metabolites samples from age group 20-30 years versus age group 70-80 years? Please comment on that.

3. During patient treatment on severity and critical stages of disease, there are many medications given to patients. How can we rule out some metabolites might alter in the blood because of that medication. Please comment.

Reviewer #3: Manuscript titled as "Metabolic profiling during COVID-19 infection in humans: Identification of potential

biomarkers for occurrence, severity and outcomes"

I would like to congratulate the authors for such a nice work.

Is written very well with consideration of all the possible analysis.

This leads to a great addition of data set in the field of this study.

As the results suggest a greater possibility for future analysis through experimentalist using the results suggested in this Manuscript.

I found all the analysis relevant and results were interpreted very nicely.

So I found the manuscript in acceptable state.

Reviewer #4: 1. Section 2.2-Sample Collection:

Please specify the type/kind of vacutainer used, in text.

2. Section 4- Discussion:

Page 2, Paragraph 1.. "Antibiotic administered..... acid [54]."

Please review the statement for accuracy and rephrase

if required. Does the infection cause the reduction

in gut microbiome diversity or the antibiotics?

Further, please change nsp15 endonuclease to nsp15 endoribonuclease.

3. The manuscript requires an overall editing in

terms of consistency and grammar for tenses. Also for

sub/super-scripts.

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Reviewer #1: No

Reviewer #2: Yes: Anupreet Kaur

Reviewer #3: Yes: Deepika Rai

Reviewer #4: No

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Attachments

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Submitted filename: Metabolic profiling during COVID_Review comments.docx

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Submitted filename: Comments.docx

Metabolic profiling during COVID-19 infection in humans: Identification of potential biomarkers for occurrence, severity and outcomes using machine learning.

PONE-D-23-40352R1

Dear Dr. Elabd,

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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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,

Anil Bhatia, Ph.D

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

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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

**********

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

**********

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 carefully addressed al queries. I recommend that the editor should accept the publication without any additional revision.

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: Yes: Sandeep Kumar

Reviewer #2: Yes: anupreet kaur

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Attachments

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Submitted filename: Review comment.docx