Background and Aims: Management of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH., Methods: We studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI)., Results: The NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively)., Conclusion: We validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH., Competing Interests: 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 Dr. Cynthia Behling: Dr. Behling is a consultant for ICON, COVANCE, Eli Lilly, Hologic, and Leica outside the submitted work. Dr. Naga Chalasani: There are none for this paper. For full disclosure, Dr. Chalasani has ongoing consulting activities (or had in preceding 12 months) with Abbvie, Madrigal, Zydus, Galectin, Boehringer-Ingelheim, Altimmune, and Foresite. These consulting activities are generally in the areas of nonalcoholic fatty liver disease and drug hepatotoxicity. Dr. Chalasani has equity in RestUp, a home health care provider agency. Dr. Chalasani receives research grant support from DSM and Exact Sciences where his institution receives the funding. Dr. Anna Mae Diehl: Dr. Diehl has consulted for Allergan, Alderya Therapeutics, Boehringer-Ingelheim, Celgene, Filcitrine, IBM Watson Health, Lumena, Merk, Novartis, Pfizer, Pliant, Roche, Quest Diagnostics, and twoXAR. She has research collaborations with Allergan, Boehringer-Ingelheim, Bristol Myers Squibb, Conatus, Exalenze, Galactin, Galmed, Genfit, Gilead, Hanmi, Hi La, Immuron, Intercept, Madrigal Metabolomics, NGM Pharmaceuticals, Prometheus, and Shire. Dr. Samer Gawrieh: Dr. Gawrieh has consulted for TransMedics and Pfizer and received research grant support from Cirius, Galmed, Viking, Zydus and Sonic Incytes. Dr. Kris Kowdley: Dr. Kowdley has consulted for Akero, Calliditas, Corcept, CymaBay, Enanta, Genfit, Gilead, HighTide, Inipharm and Intercept. His institution has received grant and research support from Allergan, Enanta, Galectin, Gilead, Immuron, Intercept, Novartis, Prometheus, and Zydus. Dr. Kowdley is on the Advisory Board for Conatus and Gilead, and is on the Speaker Bureau for Abbvie, Gilead and Intercept. 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 This does not alter our adherence to PLOS ONE policies on sharing data and materials.