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Cited by 448Liver Disease Diagnosis and TreatmentReliability and Agreement in MeasurementStatistical Methods in Clinical Trials

Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials

Davison, Beth A., Harrison, Stephen A., Cotter, Gad, Alkhouri, Naim, Sanyal, Arun, Edwards, Christopher, Colca, Jerry R., Iwashita, Julie +2 more·2020·Journal of Hepatology
DOI 10.1016/j.jhep.2020.06.025
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Abstract

Background & aims Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Methods Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study - examining a novel insulin sensitizer (MSDC-0602K) in NASH - were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Results Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power - from >90% in a well-powered study to as low as 40%. Conclusions The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Lay summary Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials.

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  • A phase 2 RCT investigating reversible FASN inhibitor TVB-2640 in people with MASLD showed moderate reduction in steatosis and increase in circulating adiponectin, without effects on body weight and unchanged circulating triglyceride levels.

    “A phase 2 RCT investigating the reversible FASN inhibitor TVB-2640 in people with MASLD showed a moderate reduction in steatosis and an increase in circulating adiponectin, notably without effects on body weight as well as unchanged circulating triglyceride levels [227].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [227]

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Authors
Davison, B. A., Harrison, S. A., Cotter, G., Alkhouri, N., Sanyal, A., Edwards, C., Colca, J. R., Iwashita, J., Koch, G. G., & Dittrich, H. C.
Affiliations
  • Momentum Research (US)
  • University of Oxford (GB)
  • Texas Liver Institute (US)
  • Virginia Commonwealth University (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Davison, Beth A.
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2020-12
Volume
73
Issue
6
Pages
1322-1332
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2020.06.025
OpenAlex
W3038092240
Cited by
448
References
10
Citations by year
2026: 70 · 2025: 58 · 2024: 81 · 2023: 83 · 2022: 78 · 2021: 62 · 2020: 16
FWCI
42.85
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Cirius Therapeutics
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Reliability and Agreement in Measurement
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords
liver biopsy, nonalcoholic steatohepatitis, inter-reader reliability, histological scoring, fibrosis assessment, steatosis, lobular inflammation, ballooning, study power, insulin sensitizers, paired biopsies
MeSH terms
Acetophenones, Biopsy, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Insulin Resistance, Liver, Liver Cirrhosis, Male, Middle Aged, Prognosis, Research Design, Reproducibility of Results, Disease Progression, Risk Assessment, Thiazolidinediones, Non-alcoholic Fatty Liver Disease

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