PONE-D-22-00397Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis in a North American cohortPLOS ONE

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"The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061713, U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U24DK061730). Additional support is received from the National Center for Advancing Translational Sciences (NCATS) (grants UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR002649). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. All FibroScan® 502 Touch systems were provided to the NASH CRN Investigators by Echosens™ through a Clinical Trial Agreement with the NIDDK."

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"Dr. Manal Abdelmalek: None for this project. Dr. Abdelmalek has served as a consultant to Merck, Bristol Myers Squibb,  Novartis, Novo Nordisk, Hanmi, TaiwanJ , Madrigal and NGM Bio.  Her institution has received grant support from Allergan, Intercept, Boehringer-Ingelheim, Bristol Myers Squibb, Madrigal, Novo Nordisk, NGM Bio, Novartis, Viking, Hanmi, TARGET NASH, Celgene, and Genentech.  She receives royalties from Elsevier and Up-to-Date

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Dr. Rohit Loomba: There are none for this paper. Dr. Loomba serves as a consultant or advisory board member for 89bio, Alnylam, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myer Squibb, Cirius, CohBar, DiCerna, Galmed, Gilead, Glympse bio, Intercept, Ionis, Metacrine, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sagimet and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Pfizer, pH Pharma, and Siemens.  He is also co-founder of Liponexus, Inc. Dr. Loomba receives funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (R01DK106419, 1R01DK121378, R01 DK124318, P30DK120515), and DOD PRCRP (CA170674P2). 

Dr. Brent Neuschwander-Tetri: None for the project. Consultant or advisor for Akero, Alimentiv, Allergan, Alnylam, Amgen, Arrowhead,  Axcella, Boehringer Ingelheim, BMS, Durect, Enanta, Fortress, Gelesis, Genfit, Gilead, HepGene, High Tide, HistoIndex, Intercept, Ionis, LG Chem, Lipocine, Madrigal, Medimmune, Merck, Mirum, NGM, NovoNordisk, pH-Pharma, Sagimet, Siemens, Theratechnologies, 89Bio; Institutional research grants: Allergan, BMS, Cirius, Enanta, Genfit, Gilead, Intercept, Madrigal, NGM

Dr. Arun Sanyal: None for this project. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect Inversago and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Conatus, Nimbus, Salix, Tobira, Takeda, Jannsen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, Surrozen. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Novartis. He receives royalties from Elsevier and UptoDate.

Dr. Mohammad Siddiqui: Dr. Siddiqui is a consultant for Pfizer and is on an advising board for AMRA.

Dr. Norah Terrault: Dr. Terrault received institutional grant support from Gilead Sciences, Roche-Genentech and GSK, and consulting for Gilead Sciences, Saol Therapeutics and Moderna.

Dr. Raj Vuppalanchi: Dr. Vuppalanchi received a one-time consultant fee from EchoSens on spleen stiffness measurement.

No conflicts of interest: Jeanne Clark, Srinivasan Dasarathy, Mark Fishbein, Paula Hertel, David Kleiner, Arunkumar Krishnan, Mariana Lazo, Arthur McCullough, Laura Miriel, Emily Mitchell, James Tonascia, Mark Van Natta, Laura Wilson, Tinsay Woreta"

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Reviewers' comments:

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Comments to the Author

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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?

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Reviewer #1: Yes

Reviewer #2: Yes

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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: The article by Woreta TA et al entitled ‘ Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis in a North American cohort ‘ describes the validation of the non-invasive FASTscore to stratify patients with non-alcoholic fatty liver disease based on the presence of the histological features NAS>=4 and fibrosis. The paper uses a well-characterised cohort of 585 US patients with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network (NASH CRN) Adult Database (D2) cohort study. The paper validates the previously reported FAST score (Newsome P et al 2020 Lancet Gastro&Hep) with similar rule-in and rule-out cut-offs. Patients in this study were enrolled based on the availability of FibroScan with LSM and CAP, aminotransferase levels and a centrally read liver biopsy within a timeframe of 6 months. The paper is well written and timely, and provides interesting insights in the performance of the score in an independent cohort. Only a few minor comments came to mind which are described below.

Minor comments

The description of the ‘derivation cohort’ in the Material & Methods is confusing and gives the impression that the 350 patients are part of the entire study cohort of 585 patients. The data and results of the derivation cohort have already been published. If the authors aim to perform a kind of meta-analysis comparing different cohorts then this should be clearly stated and explained in detail. If the aim is to validate an already published/established score, then the authors should focus on the new cohort and leave the description of a previously published cohort out of the M&M and results.

The nomenclature of ‘derivation cohort’ in the context of validating an established non-invasive score is rather confusing as nothing is being derived in this manuscript.

The abbreviation NAFLD is used for the ‘umbrella’ term non-alcoholic fatty liver disease as well as for non-alcoholic fatty liver (NAFL). I would recommend to use NAFLD and NAFL.

The definition used for at risk NASH and main outcome for this study changes slightly throughout the manuscript. In the abstract and p11, the authors define it as ‘NAS of 4 or higher and fibrosis stage of 2 or higher’. On p13, it is defined as ‘NAS 4 or higher with at least 1 point in each category and a fibrosis stage 2 or higher’, so NASH + NAS>=4 + F>=2. Presumably the latter definition has been used. This should be clarified and adjusted where necessary.

Not clear which statistical test was implanted to compare ROC curves? DeLong test? This should be clearly described in the M&M.

Reviewer #2: I’ve read with great interest the manuscript “Validation of the accuracy of the FAST score for detecting patient with at risk nonalcoholic steatohepatititis in a North American Cohort”. This study represents a validation study in which the FAST score was validated in a multi-racial North American NASH population, and confirms the diagnostic performance in this well-defined NAFLD cohort, as well as in several subgroups based on weigth and race.

The study is relevant, since good performing non-invasive tests are warranted for detection at risk NASH patients as well as inclusion for clinical studies. The methodology and statistics used are adequate and presented in detail, and the conclusion is presentered adequately.

However, since the original validation study (ref 15 Newsome et al) also included an external US NAFLD population in which the FAST score was validated, my main question is why the authors expected that the diagnostic performance of the FAST would be different in this specific NAFLD cohort? Were there large differences in baseline characteristics between the cohort in this study and the original validation study? In case the cohorts were similar, what is the added value of this study (larger population? Subgroups)? Please specifiy.

I also have some minor questions.

- Was the fibroscan performed standard in this cohort or by indication?

- How did the Pathology committee deal with discrepancies between histologic scores between observers?

- The authors mention that there was no difference found by Fibroscan probe type (XL vs M) when probe type was selected by the machine, was there a difference when the operator chose the probe type?

- The diagnostic accuracy of the CAP seems low when looking at tabel 5, what is the added value of this parameter when added tot he FAST-score?

- There were only 20 patients with unreliable LSM, what were the characteristics? Were they all morbid obese? Were these results also included in the analyses, and did the authors perform a sensitivity analysis without these unreliable results to check whether there is still a significiant difference between BMI groups?

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Reviewer #1: No

Reviewer #2: No

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Validation of the accuracy of the FASTTM score for detecting patients with at-risk nonalcoholic steatohepatitis (NASH) in a North American cohort and comparison to other non-invasive algorithms

PONE-D-22-00397R1

Dear Dr. Woreta,

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,

Pavel Strnad

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

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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

**********

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

Reviewer #1: 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: 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

**********

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 adequately addressed my comments.

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Reviewer #1: No