Analytical and Clinical Validation of AIM-NASH: A Digital Pathology Tool for Artificial Intelligence-based Measurement of Nonalcoholic Steatohepatitis Histology (2024)

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View ORCID ProfileHanna Pulaski, Stephen A. Harrison, Shraddha S. Mehta, Arun J Sanyal, Marlena C. Vitali, Laryssa C. Manigat, Hypatia Hou, Susan P. Madasu Christudoss, Sara M. Hoffman, Adam Stanford-Moore, Robert Egger, Jonathan Glickman, Murray Resnick, Neel Patel, Cristin E. Taylor, Robert P. Myers, Chuhan Chung, Scott D. Patterson, Anne-Sophie Sejling, Anne Minnich, Vipul Baxi, G. Mani Subramaniam, Quentin M. Anstee, Rohit Loomba, Vlad Ratziu, Michael C Montalto, Andrew H Beck, Katy Wack

doi: https://doi.org/10.1101/2024.05.29.24308109

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Abstract

Metabolic-dysfunction associated steatohepatitis (MASH) is a major cause of liver-related morbidity and mortality, yet treatment options are limited. Manual scoring of liver biopsies, currently the gold standard for clinical trial enrollment and endpoint assessment, suffers from high reader variability. This study represents the most comprehensive multi-site analytical and clinical validation of an AI-based pathology system, Artificial Intelligence-based Measurement of Nonalcoholic Steatohepatitis (AIM-NASH), to assist pathologists in MASH trial histology scoring. AIM-NASH demonstrated high repeatability and reproducibility compared to manual scoring. AIM-NASH-assisted reads by expert MASH pathologists were superior to unassisted reads in accurately assessing inflammation, ballooning, NAS >= 4 with >=1 in each score category, and MASH resolution, while maintaining non-inferiority in steatosis and fibrosis assessment. These findings suggest AIM-NASH could mitigate reader variability, providing a more reliable assessment of therapeutics in MASH clinical trials.

Competing Interest Statement

HP, HH, ASM, RE, NP, AHP and KEW are full-time, salaried employees of PathAI, Inc. SAH is a paid consultant for Akero Therapeutics, Aligos Therppeutics, Altimmune Inc, Boehringer Ingelheim, Bluejay Therapeutics, Echosens North America Inc, Galecto Inc, Gilead Sciences Inc, Glaxo Smith Kline (GSK), Hepion Pharmaceuticals Inc, Hepta Bio Inc, Histoindex PTE LTD, Kriya Therapeutics, Madrigal Pharmaceuticals Inc, Medpace Inc, MGGM Therapeutics LLC, Neurobo Pharmaceuticals Inc, Northsea Therapeutics B.V., Novo Nordisk, Pfizer, Sagimet Biosciences, Terns Inc, and Viking Therapeutics and shareholder of Akero, Cirius Therapeutics, Galectin Therapeutics, Histoindex PTE. LTD, and Northsea Therapeutics. SSM, MCV, LCM, SPMC, SHM, CET and MCC were PathAI Inc. employees at the time of the study conduct. JG and MR are paid contractors of PathAI, Inc. RPM and GMS are full-time, salaried employees of OrsoBio Inc. CC is a full-time, salaried employee of Inipharm, Inc. SDP is a full-time salaried employee of Gilead Sciences Inc. ASS is a full-time, salaried employee of Novo Nordisk. AM was a paid consultant for Bristol Myers Squibb. VB is a full-time, salaried employee of Bristol Myers Squibb. ASJ has stock options in Genfit, Akarna, Tiziana, Indalo, Durect Inversago and Galmed; is a consultant to Astra Zeneca, Nimbus, Takeda, Jannsen, Gilead, Terns, Merck, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Novartis, Novo Nordisk, Pfizer, and Genfit; has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Affimune Prosciento. His institution has received grant support from Gilead, Bristol Myers Squibb, Intercept, Merck, Astra Zeneca and Novartis. He receives royalties from Elsevier and UptoDate. QMA is a coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multi-stakeholder consortium includes industry partners. He has research grant funding from AstraZeneca, Boehringer Ingelheim and Intercept. He is a consultant on behalf of Newcastle University to Alimentiv, Akero, AstraZeneca, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, HistoIndex, Intercept, Inventiva, QVIA, Janssen, Madrigal, Merck, NGMBio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Roche and Terns. He is a speaker for Novo Nordisk, Madrigal, Springer Healthcare and receives royalties from Elsevier Ltd. RL is a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bluejay Therapeutics, Bristol Myers Squibb, Eli Lilly, Galmed, Gilead, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. He is a co-founder of LipoNexus Inc. VR is a paid consultant for Novo-Nordisk, Northsea Madrigal, Enyo, Poxel, Bristol Myers-Squibb, Intercept, NGM Bio and Sagimet.

Funding Statement

This study was 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:

Ethics committee/IRB of WCG gave ethical approval for this work

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

Footnotes

  • * Co-first authors

  • # Employee of PathAI at the time of the study

Data Availability

The glass slides and WSIs used in these validation studies are from existing clinical trials and the authors had access to these during the study in accordance with the relevant license agreements. Due to the nature of the source data, it is not currently publicly available.

Copyright

The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

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PostedMay 29, 2024.

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Analytical and Clinical Validation of AIM-NASH: A Digital Pathology Tool for Artificial Intelligence-based Measurement of Nonalcoholic Steatohepatitis Histology (2024)

FAQs

What is histologic evidence of NASH? ›

The histologic features of NASH include macrovesicular steatosis, ballooning degeneration of hepatocytes, scattered (mainly lobular) inflammation and apoptotic bodies, and Mallory-Denk bodies (MDBs) (Figure 1A). Notably, while some degree of fibrosis is often present, it is not necessary for the diagnosis.

What is the histology of hepatic steatosis? ›

Hepatic steatosis (HS) is defined by the abnormal accumulation of fat in liver hepatocytes and is an integral histological feature often evaluated in liver histological assessment. It can present in a variety of liver disease or injury with clinical implications dictated by degree of HS1.

How accurate is the NASH test? ›

It is the most reliable biomarker test available, applies to the largest number of patients (98%),4 and outperforms other testing at all stages of fibrosis.

Can you diagnose NASH without a biopsy? ›

determining prognosis based on the severity of liver injury and fibrosis. Liver biopsy is the only investigation that can reliably distinguish between simple steatosis and NASH, as well as stage the extent of fibrosis.

Should I be worried about hepatic steatosis? ›

“Many people, and even some doctors, think fatty liver is just something you have to live with.” says Dr. Halegoua-DeMarzio, “But it's not. If ignored, it can lead to serious complications including cancer or liver transplant.”

What is the life expectancy of someone with hepatic steatosis? ›

If NASH cirrhosis is diagnosed early, the life expectancy is about 10 to 15 years. However, if you develop complications such as swelling or fluid in the abdomen, confusion, or bleeding from the gastrointestinal tract, life expectancy decreases dramatically to three to five years without a liver transplant.

Can mild hepatic steatosis cause pain? ›

Fatty Liver Disease Symptoms

With ALD and MASLD, there are usually no symptoms. Some people may have signs such as tiredness or pain in the upper right side of the belly where your liver is. If you have MASH or get cirrhosis, you may have symptoms such as: Swollen belly.

WHat is the histological classification of NASH? ›

The diagnosis and severity classification of NASH depends on histopathological examination. The main pathological features of NASH are hepatocyte balloon degeneration, inflammatory infiltration, Mallory-Den K corpuscle, and zone 3 fibrosis [2, 8].

WHat is histologic scoring of the liver? ›

(I) Liver pathology was categorized based on the severity of inflammation and necrosis using the following scoring system: 0: no inflammation/ necrosis; 1: scattered immune cells/mild necrosis (<10%); 2: immune cell foci/marked necrosis (10-50%); 3: diffuse immune cell infiltrates/severe necrosis (>50%), according to [ ...

WHat is histological analysis of the liver biopsy? ›

Liver biopsy provides more morphological information than non-invasive tests. First, only histological examination can detect lobular inflammation and ballooning, which cannot be determined by current non-invasive diagnostic methods.

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