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Abstract Details
Utility of pathologist panels for achieving consensus in NASH histologic scoring in clinical trials: Data from a phase 3 study
Hepatol Commun. 2023 Dec 22;8(1):e0325.doi: 10.1097/HC9.0000000000000325. eCollection 2024 Jan 1.
1Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA.
2Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
3Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
4Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié Salpêtriére University Hospital, Paris, France.
5Liver Institute Northwest, Seattle, Washington, USA.
6Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
7Pinnacle Clinical Research, San Antonio, Texas, USA.
8Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA.
9Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA.
10Inova Medicine, Inova Healthy System, Falls Church, Virginia, USA.
Abstract
Background: Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials.
Methods: Two panels, each comprising 3 liver fellowship-trained pathologists who underwent NASH histology training, independently evaluated scanned whole slide images, scoring fibrosis, inflammation, hepatocyte ballooning, and steatosis from baseline and month 18 biopsies for 100 patients from the precirrhotic NASH study REGENERATE. The consensus score for each parameter was defined as agreement by ≥2 pathologists. If consensus was not reached, all 3 pathologists read the slide jointly to achieve a consensus score.
Results: Between the 2 panels, the consensus was 97%-99% for steatosis, 91%-93% for fibrosis, 88%-92% for hepatocyte ballooning, and 84%-91% for inflammation. Linear weighted kappa scores between panels were similar to published NASH CRN values.
Conclusions: A panel of 3 trained pathologists independently scoring 4 NASH CRN histology parameters produced high consensus rates. Interpanel kappa values were comparable to NASH CRN metrics, supporting the accuracy and reproducibility of this method. The high concordance for fibrosis scoring was reassuring, as fibrosis is predictive of liver-specific outcomes and all-cause mortality.