{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:52:38Z","timestamp":1790689958874,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Regulatory\u2010accepted efficacy endpoints for nonalcoholic steatohepatitis (NASH; recently updated to metabolic\u2010dysfunction associated steatohepatitis, MASH) clinical trials include fibrosis improvement with no worsening of NASH or NASH resolution with no worsening of fibrosis determined by liver biopsy using the NASH Clinical Research Network criteria. These endpoints involve the scoring of four liver histology parameters, all of which are associated with significant inter\u2212\/intra\u2010reader variability. Since few trials have shown positive results with these endpoints, we evaluated the effects of imprecision in histologic scoring on trial results from a statistical perspective.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Estimating the probability (sensitivity) of accurately scoring histology is based on the relationship between measures of agreement and sensitivity. We simulated kappa values for a range of sensitivities. Then, using published kappa values from NASH trials, we selected corresponding sensitivities for histology parameters. Finally, simulations assuming a range of \u201coverscore\u201d and \u201cunderscore\u201d probabilities were conducted to estimate the dilution of the true effect size.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Simulations for 2\u2010arm trials with sample sizes of 400 (mix of stage 2\/3 fibrosis) subjects showed ~50% dilution of the true effect size for both approvable endpoints due to scoring imprecision. Such dilution remains constant regardless of sample size.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Imprecise histologic scoring disproportionately impacts the \u2018superior\u2019 arm as the error is proportional to the true response rate. This dilution of effect size should be considered when weighing the clinical benefit and the overall risk\u2013benefit profile in the review of NASH studies. This argues for the adoption of non\u2010invasive biomarkers rather than histologic endpoints.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.70023","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T14:00:04Z","timestamp":1739455204000},"page":"1489-1499","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Challenges in Histological Endpoints for <scp>MASH<\/scp> Therapies: An Exercise in Statistical Modelling"],"prefix":"10.1111","volume":"61","author":[{"given":"Amrik","family":"Shah","sequence":"first","affiliation":[{"name":"Karma Statistics LLC  Skillman New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"MacConell","sequence":"additional","affiliation":[{"name":"Hightide Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Liberman","sequence":"additional","affiliation":[{"name":"Hightide Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6075-9305","authenticated-orcid":false,"given":"Adrian M.","family":"Di Bisceglie","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Saint Louis University  Saint Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Integrated Quality Resources  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000323"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000520"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17930"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24127"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.01.043"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17752"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17958"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2024.101011"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468\u20101253(23)00141\u20103"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0266859"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17564"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22742"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2022.2032640"},{"key":"e_1_2_7_15_1","unstructured":"Research CfDEa \u201cNoncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment \u201d2023 https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/noncirrhotic\u2010nonalcoholic\u2010steatohepatitis\u2010liver\u2010fibrosis\u2010developing\u2010drugs\u2010treatment."},{"key":"e_1_2_7_16_1","unstructured":"Agency EM. Committee for Medicinal Products for Human Use \u201cGuideline on Bioanalytical Method Validation \u201d2011."},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.06.025"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.12565"},{"key":"e_1_2_7_21_1","unstructured":"FDA \u201cRezdiffra Prescribing Information \u201d2024 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/217785s000lbl.pdf."},{"key":"e_1_2_7_22_1","unstructured":"S.Harrison V.Ratziu P.Bedossa et\u00a0al. \u201cRESOLVE\u2010IT Phase 3 Trial of Elafibranor in NASH: Final Results of the Week 72 Interim Surrogate Efficacy Analysis \u201d2020."},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.08.004"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.02.027"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31622"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(19)33041\u20107"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309000"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/00029238.1971.11080840"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14301"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.024"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/HC9.0000000000000244"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14593"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14625"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2023.107352"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001652\u20108"}],"container-title":["Alimentary Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apt.70023","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T18:32:01Z","timestamp":1744223521000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apt.70023"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":34,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1111\/apt.70023"],"URL":"https:\/\/doi.org\/10.1111\/apt.70023","archive":["Portico"],"relation":{},"ISSN":["0269-2813","1365-2036"],"issn-type":[{"value":"0269-2813","type":"print"},{"value":"1365-2036","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,13]]},"assertion":[{"value":"2024-10-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}