Integration of deep learning-based histopathology and transcriptomics reveals key genes associated with fibrogenesis in patients with advanced NASH.

Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for liver transplantation in the US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features and transcriptomics, to identify genes that are associated with disease progression and clinical events. A histopathology-driven 5-gene expression signature predicted disease progression and clinical events in patients with NASH with F3 (pre-cirrhotic) and F4 (cirrhotic) fibrosis. Notably, the Notch signaling pathway and genes implicated in liver-related diseases were enriched in this expression signature. In a validation cohort where pharmacologic intervention improved disease histology, multiple Notch signaling components were suppressed.
Competing Interests: Declaration of interests J.C. is an employee and shareholder of PathAI, Inc. M.P. is a shareholder of PathAI, Inc. Y.G. is a shareholder of Gilead Sciences, Inc. D.Z.P. is an employee of and shareholder of Gilead Sciences, Inc. O.M.C.-Z. is a shareholder of PathAI, Inc. V.M. is an employee and shareholder of PathAI, Inc. G.M.S. is an employee and shareholder of OrsoBio, Inc., and a shareholder of Gilead Sciences, Inc. M.C.M. is an employee and shareholder of PathAI, Inc. M.R. is an employee and shareholder of PathAI, Inc. A.H.B. is a co-founder, employee, and shareholder of PathAI, Inc. R.S.H. is an employee and shareholder of OrsoBio, Inc., and a shareholder of Gilead Sciences, Inc. R.P.M. is an employee and shareholder of OrsoBio, Inc., and a shareholder of Gilead Sciences, Inc. A.T.-W. is an employee and shareholder of PathAI, Inc. I.W. is an employee and shareholder of PathAI, Inc. C.C. is an employee and shareholder of Inipharm, Inc., and shareholder of Gilead Sciences, Inc.
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