AI-based histologic scoring enables automated and reproducible assessment of enrollment criteria and endpoints in NASH clinical trials

Clinical trials in nonalcoholic steatohepatitis (NASH) require histologic scoring for assessment of inclusion criteria and endpoints. However, guidelines for scoring key features have led to variability in interpretation, impacting clinical trial outcomes. We developed an artificial intelligence (AI)-based measurement (AIM) tool for scoring NASH histology (AIM-NASH). AIM-NASH predictions for NASH Clinical Research Network (CRN) grades of necroinflammation and stages of fibrosis aligned with expert consensus scores and were reproducible. Continuous scores produced by AIM-NASH for key histological features of NASH correlated with mean pathologist scores and with noninvasive biomarkers and strongly predicted patient outcomes. In a retrospective analysis of the ATLAS trial, previously unmet pathological endpoints were met when scored by the AIM-NASH algorithm alone. Overall, these results suggest that AIM-NASH may assist pathologists in histologic review of NASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient therapeutic response. ### Competing Interest Statement A.N.B. is an employee of and holds stock in Gilead Sciences, Inc. He received study materials from PathAI, Inc. in support of this manuscript. A.D.B. serves as a consultant to 23andMe, Alimentiv, Allergan, Dialectica, PathAI, Inc., Source Bioscience, and Verily. He is on Scientific Advisory Boards with 3Helix, Avacta, and GSK. His institution has received funding for educational programs from Eli Lilly. A.H.B. is an employee of and holds stock in PathAI, Inc. He has received financial support for the manuscript from Gilead Sciences, Inc. and PathAI, Inc. A.P. has received financial support for the manuscript from PathAI, Inc., owns patents with PathAI, Inc., and received option grants while employed with PathAI, Inc. A.T-W is an employee of PathAI, Inc. C.B-S. is a former employee of and holds stock in PathAI, Inc. C.C. is an employee of Inipharm and owns stock in Gilead Sciences, Inc. and Inipharm. D.J. is an employee of and holds stock in PathAI, Inc., and owns patents with PathAI, Inc. H.E. is a former employee of and holds stock in PathAI, Inc., and is named on a patent (US 11527319) held by PathAI, Inc. H.P. is an employee of and owns stock in PathAI, Inc., and owns patents with PathAI, Inc. I.W. is an employee of and owns stock in PathAI, Inc., and owns a patent (US 10650520). J.G. is an employee of and owns stock in PathAI, Inc., and receives support for meeting attendance from PathAI, Inc. J.S.I. is an employee of and owns stock in PathAI, Inc., and owns a patent. K.L. owns stock in PathAI, Inc. and received an ISO grant while employed at PathAI, Inc. K.W. is an employee of PathAI, Inc. and receives support for meeting attendance from PathAI, Inc. M.L. is an employee of and owns stock in PathAI, Inc., and received funding for the manuscript as well as support for meeting attendance from PathAI, Inc. M.C.M. is an employee of and holds stock in PathAI, Inc., receives financial support from PathAI, Inc. to attend meetings, holds stock in Bristol Myers Squibb, and holds a leadership position with the Digital Pathology Association. M.R. receives consulting fees from PathAI, Inc., and received financial support for the manuscript. M.P. is an employee of AstraZeneca. O.C-Z. was employed by PathAI, Inc. at the time of the study, received stock options while employed at PathAI, Inc., and has a patent pending (US 20220245802A1). Q.L. is an employee of and owns stock in PathAI, Inc., and owns a patent. R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead Sciences, Inc., Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead Sciences, Inc., Intercept, Hanmi, Inventiva, Ionis, Janssen Inc., Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc. R.P.M. is an employee of Orsobio, Inc., and owns stock in OrsoBio, Inc. and Gilead Sciences, Inc. S.H. is an employee of and owns stock in PathAI, Inc., and receives support for meeting attendance from PathAI, Inc. T.R.W. is an employee of and holds stock in Gilead Sciences, Inc. Z.S. is an employee of and holds stock in PathAI, Inc., and owns a patent with PathAI, Inc. ### Funding Statement This study was funded by PathAI, Inc. and Gilead Sciences, Inc. Rohit Loomba receives funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), and NIAAA (U01AA029019). Medical writing support and editorial assistance were provided by Sandra J Page, PhD, and Agata Shodeke, PhD, of Spark Medica Inc, according to Good Publication Practice guidelines, funded by PathAI. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written informed consent was obtained from each patient prior to the initiation of study activities. The study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki and were approved by all participating institutional review boards or ethics committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Codes for cell- and tissue-type model training, inference, and feature extractions are not disclosed. Access requests for such a code will not be considered to safeguard PathAI intellectual property. Access to histopathology features will be granted upon reasonable request from academic investigators without relevant conflicts of interest for non-commercial use who agree not to distribute the data. Access requests can be made to: ilan.wapinski@pathai.com.