From the Emergency Department to Follow-Up: Clinical Utility of Biomarkers in Mild Traumatic Brain Injury

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Overall, the authors presents a well organized narrative review of blood biomarkers' utility in mild TBI.  It is a significant topic and relevant to emergency medicine, especially as point-of-care biomarkers come into the forefront of clinical practice.  There are improvements to be made.  In general, I would write more clearly into text and into all Table legends or titles what diagnosis the sensitivity/specificity is for (ICH, or any TBI?); Tables report diagnostic accuracy statistics but do not specify the diagnosis.  It seems the authors switch often in the diagnosis used and this is not always clearly written.

Other specific comments:

Abstract

line 19 repeats. I would remove "ubiquitin c-terminal hydrolase-L1,"

Introduction

Lines 38-43 are unclear with listing the criteria. I recommend rewording or putting criteria in parentheses or improving the punctuation to make more clear which criteria line up with which number.

Methods

line 99 - should read "underlying each marker" and delete the " 's".

line 103 - Nfl is used as abbreviation. Capitalization should be consistent throughout manuscript (previously wrote NFL).

Results

Lines 157-158: "GFAP can be detected in peripheral blood via mass spectrometry and proximity extension assays, though not currently by conventional immunoassays".  I'm not sure this is accurate.  Can authors clarify what current methods are used for GFAP detection in mTBI? Are the SIMOA platform and Abbot Point-of-Care TBI Blood test not immunoassays? 

Lines 251-252.  Similarly, UCHL1 is measured in mTBI with immunoassays above.

Table 2 could have improved "Study Type" descriptors.  For example, I have no idea what "mTBI Biomarker" or "Clinical Rules" mean as study types.

Line 368-370: Similarly to above, this is definitely an inaccurate statement. There are numerous studies published on S100B in TBI using ELISA methods: "While S100B is detectable in blood using mass spectrometry, it is not consistently identified through traditional immunoassays or proximity extension assays."

Line 381: Please define "ICI".

Lines 374-393: Can authors specify what the reported sensitivities and specificities are for (ICH, any TBI, surgery, etc.)?  It is not clear in the text what the authors are reporting the sensitivity and specificity for.  Usually it is to detect ICH, but this is not written.

Line 416: Reference #47 is not a Frontiers paper as cited in text.

Line 422:  The reference in text (Persson et al. (2016)) does not match the cited reference #48.

Line 429:  The reference in text (Asken et al. (2021)) does not match the cited reference #49.

Line 429:  The reference in text (Zetterberg et al) does not match the cited reference #50.

Table 4: I would remove columns that are blank (Sensitivity, NPV, AUC).

Line 549: Citation 61 was published in 2023 per the Reference, not 2022 as written in text.

Author Response

Please see the attachment

Thank you for your thorough review of this manuscript. Below are our detailed responses, and the related revisions and corrections are clearly highlighted in the resubmitted files. The improvements made thanks to your suggestions have significantly enhanced the quality of this study especially regarding the updates to the tables and the platforms used to measure the biomarkers.

Comments 1: In general, I would write more clearly into text and into all Table legends or titles what diagnosis the sensitivity/specificity is for (ICH, or any TBI?); Tables report diagnostic accuracy statistics but do not specify the diagnosis.  It seems the authors switch often in the diagnosis used and this is not always clearly written.
Response 1: Thank you for pointing this out. Adding a clear indication of what each statistical data point refers to within the tables has indeed made them significantly more complete and informative.

Comments 2: Line 19 repeats. I would remove "ubiquitin c-terminal hydrolase-L1.
Response 2: Thank you for pointing this out. We have corrected the error.

Comments 3: Lines 38-43 are unclear with listing the criteria. I recommend rewording or putting criteria in parentheses or improving the punctuation to make more clear which criteria line up with which number.
Response 3: Thank you for pointing this out. We have removed that section to make the introduction more concise.

Comments 4: Line 99 - should read "underlying each marker" and delete the " 's".
Response 4: Thank you for pointing this out. We have corrected the error.

Comments 5: Line 103 - Nfl is used as abbreviation. Capitalization should be consistent throughout manuscript (previously wrote NFL).
Response 5: Thank you for pointing this out. We have corrected the error.

Comments 6: Lines 157-158: "GFAP can be detected in peripheral blood via mass spectrometry and proximity extension assays, though not currently by conventional immunoassays".  I'm not sure this is accurate.  Can authors clarify what current methods are used for GFAP detection in mTBI? Are the SIMOA platform and Abbot Point-of-Care TBI Blood test not immunoassays? 
Response 6: Thank you for pointing this out. We completely agree with your observation. Unfortunately, it was an error on our part, which has now been corrected.

Comments 7: Lines 251-252.  Similarly, UCHL1 is measured in mTBI with immunoassays above.
Response 7: Thank you for pointing this out. We are fully in agreement with your observation. Unfortunately, this was an oversight on our part, which has since been corrected.

Comment 8: Table 2 could have improved "Study Type" descriptors.  For example, I have no idea what "mTBI Biomarker" or "Clinical Rules" mean as study types.
Response 8: Thank you for pointing this out. We have improved the description of the study accordingly.

Comment 9: Line 368-370: Similarly to above, this is definitely an inaccurate statement. There are numerous studies published on S100B in TBI using ELISA methods: "While S100B is detectable in blood using mass spectrometry, it is not consistently identified through traditional immunoassays or proximity extension assays.
Response 9: Thank you for pointing this out. We completely agree with your observation, and regret the oversight, which has now been corrected.

Comment 10: Line 381: Please define "ICI".
Response 10:  Thank you for pointing this out. We have substituted the acronym with the complete word for clarity.

Comment 11: Lines 374-393: Can authors specify what the reported sensitivities and specificities are for (ICH, any TBI, surgery, etc.)?  It is not clear in the text what the authors are reporting the sensitivity and specificity for.  Usually it is to detect ICH, but this is not written.
Response 11: We have specified that they refer to intracranial lesions following mild traumatic brain injury.

Comments 12: Line 416: Reference #47 is not a Frontiers paper as cited in text.
Response 12: Thank you for pointing this out. We have corrected the error.

Comments 13: Line 422: The reference in text (Persson et al. (2016)) does not match the cited reference #48.
Response 13: Thank you for pointing this out. The error has been corrected.

Comments 14: Line 429:  The reference in text (Asken et al. (2021)) does not match the cited reference #49.
Response 14: Thank you for pointing this out. The error has been corrected.

Comments 15: Line 429:  The reference in text (Zetterberg et al) does not match the cited reference #50.
Response 15: Thank you for pointing this out. The error has been corrected.

Comments 16: Table 4: I would remove columns that are blank (Sensitivity, NPV, AUC).
Response 16: Thank you for pointing this out. We have removed the columns that were left empty from the table.

Comments 17: Line 549: Citation 61 was published in 2023 per the Reference, not 2022 as written in text.
Response 17: Thank you for pointing this out. The error has been corrected.

Reviewer 2 Report

Comments and Suggestions for Authors

The language needs major corrections. Please read and check the manuscript for grammar errors (e.g., "additional individual lifetime risk of cancer-related mortality," etc.).
Abstract: Your manuscript does not provide any information about the statistical studies and the content of the studies conducted regarding the biomarkers you selected. Please briefly mention them.
Introduction: 
The introduction provides information about TBI, but not the mechanism of the disease. Furthermore, no references are provided until lines 39-45.
In this section, not enough information is given about the biomarkers selected, and it is not clear from your manuscript why these markers are mentioned.
In your manuscript, the purpose of the study is given at the end of the introduction, but the originality of your work is not emphasized.
Choose a graphical summary to summarize your work and provide general information.
Results:
The information given in the conclusion section should be provided in the introduction section.
If the results section is written too complexly, simplify it and provide content appropriate to the headings. Furthermore, the parameters and types of analysis to be examined should be explained in detail in the introduction or the materials and methods section.
The discussion section is written like the discussion section. Read it again and make the necessary corrections.
Discussion:
The discussion section is superficial and could have been written in more detail. There are similarities with the conclusion section. Please be careful to include the necessary information in the correct sections. 

Comments on the Quality of English Language

The language needs major corrections. Please read and check the manuscript for grammar errors (e.g., "additional individual lifetime risk of cancer-related mortality," etc.).
Abstract: Your manuscript does not provide any information about the statistical studies and the content of the studies conducted regarding the biomarkers you selected. Please briefly mention them.

Author Response

Please see the attachment

Thank you for your thorough review of this manuscript. Below are our detailed responses, and the related revisions and corrections are clearly highlighted in the resubmitted files. In particular, thanks to your suggestions, I have made the discussion section much more elaborate and informative.

Comments 1: Abstract: Your manuscript does not provide any information about the statistical studies and the content of the studies conducted regarding the biomarkers you selected. Please briefly mention them.
Response 1: Thank you for pointing this out. I have revised the abstract by incorporating the statistical section as requested.

Comments 2: Introduction: 
The introduction provides information about TBI, but not the mechanism of the disease. Furthermore, no references are provided until lines 39-45.
In this section, not enough information is given about the biomarkers selected, and it is not clear from your manuscript why these markers are mentioned.
In your manuscript, the purpose of the study is given at the end of the introduction, but the originality of your work is not emphasized.
Choose a graphical summary to summarize your work and provide general information.
Response 2: Thank you for pointing this out. I have improved the introduction as requested, making it more informative. I encountered some difficulties in managing the graph, so I preferred to enhance the introduction without including a summary graph in the text.

Comments 3: Results:
The information given in the conclusion section should be provided in the introduction section.
If the results section is written too complexly, simplify it and provide content appropriate to the headings. Furthermore, the parameters and types of analysis to be examined should be explained in detail in the introduction or the materials and methods section.
The discussion section is written like the discussion section. Read it again and make the necessary corrections.
Response 3: Thank you for pointing this out. I have revised the Introduction and the Materials and Methods sections as requested, making the results more focused while also ensuring that adequate attention is given to the biological aspects.

Comments 4: Discussion:
The discussion section is superficial and could have been written in more detail. There are similarities with the conclusion section. Please be careful to include the necessary information in the correct sections. 
Response 4: Thank you for pointing this out. I have revised the Discussion section to make it more informative and aligned with the aims of the paragraph. Additionally, I have included an extra table to further support and strengthen the arguments presented.

Comments 5: The language needs major corrections. Please read and check the manuscript for grammar errors (e.g., "additional individual lifetime risk of cancer-related mortality," etc.).
Response 5: Thank you for pointing this out. I'm sorry that the quality of the written English was not satisfactory. I hope that with the revised version of the manuscript, it will now meet the standards and objectives set by the journal.

Reviewer 3 Report

Comments and Suggestions for Authors

This review is well-written and provides substantial information ablout the markers involved with inflammation and differences in among them. The manuscript is worth publishing however it has some references issues. Authors are requested to add refrences at places where outcomes of other studies are mentioned without citing the article, example line 61, add refrence and many other places similarly. 

Author Response

Please see the attachment.

We sincerely appreciate the time and effort you dedicated to reviewing this manuscript. Our detailed responses are provided below, and the corresponding revisions and corrections have been clearly marked using track changes in the resubmitted files.

Comments 1: Authors are requested to add refrences at places where outcomes of other studies are mentioned without citing the article, example line 61, add refrence and many other places similarly. 
Response 1: Thank you for pointing this out. In the text, we have aimed to place references at the end of each result or statement to avoid redundant repetition of the same citation within a single sentence. Nevertheless, we have made the necessary revisions where explicitly requested.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

In section 3.1.4. Detection in Blood and Biomarker Potential:

I think it is an oversight to omit the i-STAT Alinity point-of-care platform/i-STAT TBI CARTRIDGE as one way to measure GFAP, of which there is substantial literature published in mild TBI cohorts.

Author Response

Thank you for dedicating your time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files. 

Response 1. I think it is an oversight to omit the i-STAT Alinity point-of-care platform/i-STAT TBI CARTRIDGE as one way to measure GFAP, of which there is substantial literature published in mild TBI cohorts.
Comments 1: Thank you for pointing this out. I have revised the paragraph as requested, also incorporating reference to UCH-L1.

Reviewer 2 Report

Comments and Suggestions for Authors

Accept in corrent form

Author Response

Thank you for dedicating your time to review this manuscript. 

Response 1. Accept in corrent form.
Comments 1: Thank you very much for your valuable contribution. I am pleased that you have accepted the study in its current format.