PONE-D-24-01692FAST and Agile – the MASLD Drift: Validation of Agile 3+, Agile 4 and FAST Scores in 246 Biopsy-proven NAFLD Patients Meeting MASLD Criteria of Prevalent Caucasian OriginPLOS 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

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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: 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 retrospective study aimed to assess the effectiveness of three new, elastography-based

scoring systems for advanced fibrosis ≥F3 (Agile 3+), cirrhosis F4 (Agile 4), and

fibrotic NASH: NASH + NAS ≥4 + F≥2 (FAST score), in 246 patients with biopsy-proven

NAFLD meeting MASLD criteria. The authors concluded that Agile 3+ and Agile 4 are reliable, non-invasive tests for identifying advanced fibrosis or cirrhosis in MASLD patients, while FAST score demonstrates moderate performance in identifying fibrotic NASH. When compared to FIB-4 and LSM-VCTE, both Agile 3+ and Agile 4 performed better than FIB-4 and had a similar performance to LSM-VCTE, but with higher diagnostic accuracy, hence reducing the grey zone.

Comments are as follows

This study could be regarded as an external validation study. It enrolled patients mainly from Caucasian descents and was different from the original study.

1. Line 380. From our cohort of biopsy-proven NAFLD patients, out of 256 patients with reliable VCTE measurements, 246 (98.4%) met the criteria for MASLD definition, …..

The number of patients with reliable VCTE should be 250.

Reviewer #2: General comments

MASLD is a prevalent chronic liver condition with substantial clinical implications. This study aimed to assess the effectiveness of three new elastography based, scoring systems for advanced fibrosis ≥F3 (Agile 3+), cirrhosis F4 (Agile 4), and fibrotic NASH: NASH + NAS ≥4 + F≥2 (FAST score), in a cohort of biopsy-proven NAFLD meeting MASLD criteria. They included 246 Caucasian patients from Romania and confirmed the good performance of the Agile 3+ and Agile 4 scores in identifying >=F3 and F4, and the FAST score demonstrates a moderate performance in identifying fibrotic NASH.

Overall, this is a well-conducted study, and the manuscript is well-written. The results are clinically relevant and useful. Several issues are listed.

Major comments:

1. The patients in this study were enrolled from 2007 to 2023, which is a long period. The accuracy of the measurement of Fibroscan was a concern since the machine had been remodeled afterward. Please describe this issue and its limitations in the discussion.

2. Please compare the difference between the cut-off value proposed in this study and the recommended cut-off from the literature. After your analysis, what will be the cut-off value recommended for clinical suggestions?

3. Because the Agile 3+, Agile 4, and Fast scores identify populations with different fibrotic and inflammation statuses, the authors should provide an algorithm for patients to use the Agile and Fast score as a screening workflow for fibrosis and fibrotic NASH.

4. Please propose a recommendation for patients in the grey zone. Do they need additional monitoring to determine their real fibrosis status?

5. Because liver inflammation (ALT elevation) may impact the LSM-VCTE results. The authors are encouraged to do a subgroup analysis for the performance of the FAST score stratified by ALT levels (eg. ALT < 1x ULN vs. ALT >= 1X ULN).

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Reviewer #1: No

Reviewer #2: No

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FAST and Agile – the MASLD Drift: Validation of Agile 3+, Agile 4 and FAST Scores in 246 Biopsy-proven NAFLD Patients Meeting MASLD Criteria of Prevalent Caucasian Origin

PONE-D-24-01692R1

Dear Dr. Lupsor-Platon,

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.

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Kind regards,

Jee-Fu Huang, M.D., 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

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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: (No Response)

Reviewer #2: All of my comments are properly answered by the authors. I have no further questions. 

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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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