NAFLD: Time to apply quantitation in liver biopsies as endpoints in clinical trials

Forlano, Roberta; Mullish, Benjamin H.; Maurice, James; Thursz, Mark; Goldin, Robert; Manousou, Pinelopi

doi:10.1016/j.jhep.2020.08.025

Cited by 7 publications

(8 citation statements)

References 6 publications

(10 reference statements)

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“…These results, irrespective of the modeling approach, offer further confirmation regarding the generalizability of the NASH CRN scale in that significantly high reliability was not achievable, either between or within pathologists. These findings are consistent with a crop of new studies which have disputed the generalizability of the original NASH scale establishment [9][10][11][12][13][14][15][16] .…”

Section: Discussionsupporting

confidence: 89%

“…For example, numerous studies have highlighted the high inter-and intra-rater reliability of the NASH CRN staging scale (e.g. carefully chosen representative tissue samples and scoring performed by experts with decades of experience as opposed to variable tissue quality interpreted by a generalist) [9][10][11][12][13][14][15][16] . It is feasible that the described qualitative scoring system, which was designed for clinical prognostication, is not reproducible or reliable enough to rigorously gauge fibrosis regression in a drug trial.…”

Section: Introductionmentioning

confidence: 99%

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Estimating the Inter- and Intra-Rater Reliability for NASH Fibrosis Staging in the Presence of Bridge Ordinal Ratings with Hierarchical Bridge Category Models

Levy

Bobak

Azizgolshani

et al. 2021

Preprint

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The public health burden of non-alcoholic steatohepatitis (NASH), a liver condition characterized by excessive lipid accumulation and subsequent tissue inflammation and fibrosis, has burgeoned with the spread of western lifestyle habits. Progression of fibrosis into cirrhosis is assessed using histological staging scales (e.g., NASH Clinical Research Network (NASH CRN)). These scales are used to monitor disease progression as well as to evaluate the effectiveness of therapies. However, clinical drug trials for NASH are typically underpowered due to lower than expected inter-/intra-rater reliability, which impacts measurements at screening, baseline, and endpoint. Bridge ratings represent a phenomenon where pathologists assign two adjacent stages simultaneously during assessment and may further complicate these analyses when ad hoc procedures are applied. Statistical techniques, dubbed Bridge Category Models, have been developed to account for bridge ratings, but not for the scenario where multiple pathologists assess biopsies across time points. Here, we develop hierarchical Bayesian extensions for these statistical methods to account for repeat observations and use these methods to assess the impact of bridge ratings on the inter-/intra-rater reliability of the NASH CRN staging scale. We also report on how pathologists may differ in their assignment of bridge ratings to highlight different staging practices. Our findings suggest that Bridge Category Models can capture additional fibrosis staging heterogeneity with greater precision, which translates to potentially higher reliability estimates in contrast to the information lost through ad hoc approaches.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Estimating the Inter- and Intra-Rater Reliability for NASH Fibrosis Staging in the Presence of Bridge Ordinal Ratings with Hierarchical Bridge Category Models

Levy

Bobak

Azizgolshani

et al. 2021

Preprint

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“…While this new analysis further supports that virtual trichrome staining is a viable intermediate diagnostic decision aid, there is clearly further room for improvement. Regardless, the application of the Bridge Category Model to the assessment of Virtual Staining technologies may serve as a guide for other biomedical researchers seeking to validate their technologies using best statistical practices 2,9 . For instance, the Bridge Category Model presents pathologist specific estimates of the tendency to up/downstage bridge categories, which provide useful information for finetuning staging / prognostication / drug effect technologies and understanding clinical decision making (as well as suggesting a potential new avenue for training and maintenance of certification).…”

Section: Discussionmentioning

confidence: 99%

Improving the Virtual Trichrome Assessment through Bridge Category Models

Levy

Bobak

Azizgolshani

et al. 2021

Preprint

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Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by excessive lipid accumulation and disease progression is typically assessed through inspection of a Trichrome stain for Fibrosis staging. As the public health burden of NASH worsens due to evolving lifestyle habits, pathology laboratory resources will become increasingly strained due to rising demand for specialized stains. Virtual staining processes, computational methods which can synthesize the application of chemical staining reagents, can potentially provide resource savings by obviating the need to acquire specialized stains. Virtual staining technologies are assessed by comparing virtual and real tissue stains for their realism and ability to stage. However, these assessment methods are rife with statistical mistreatment of observed phenomena that are difficult to account for. Bridge category ratings represent a phenomenon where a pathologist may assign two adjacent stages simultaneously, which may bias and/or reduce the power of research findings. Such stage assignments were frequently reported in a large-scale assessment of Virtual Trichrome technologies yet were unaccounted for since no statistical adjustment procedures existed. In this work, we provide an updated assessment of Virtual Trichrome technologies using Bridge Category Models, which account for these bridge ratings. We report that two of four pathologists tended to assign lower Fibrosis stages to virtually stained tissue while the other two pathologists assigned similar stages. These research findings differ when bridge ratings are not accounted for. While promising, these results indicate further room for algorithmic finetuning of Virtual Trichrome technologies.

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“…For instance, collagen proportionate area (CPA) as assessed by digital image analysis may offer a more granular assessment of fibrosis than routine histological analysis. Small changes detected by CPA might be missed when comparing fibrosis stages [ 114 , 115 ]. Furthermore, ML-based histological assessment is worth evaluation as a surrogate endpoint in clinical trials.…”

Section: Dynamic Monitoring and Prognosis Risk Assessmentmentioning

confidence: 99%

Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis

Shi¹,

Fan²

2023

Clin Mol Hepatol

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Nonalcoholic steatohepatitis (NASH) is the aggressive form of nonalcoholic fatty liver disease (NAFLD), characterized as steatosis-associated inflammation and liver injury.Without effective treatment or management, NASH would develop life-threatening outcomes. In this situation, evaluation and identification of those at-risk for adverse outcomes are important. The key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and their dynamic changes during follow-up. Currently, the staging for NASH and evaluation of effectiveness for drugs still rely on pathological diagnosis, while liver biopsy brings sample error issues and subjectivity. To address this problem, optimizing the pathological assessment and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation is of significance. Although noninvasive methods including elastography, serum soluble biomarkers and combined models have been widely studied in the last decade, the application of noninvasive diagnostic measurements in clinical practice is still insufficient. Much work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH and identify the changes of disease severity. In this review, we summarized the current state of the noninvasive methods for detecting steatosis, steatohepatitis and fibrosis of NASH, introduced the noninvasive assessment for screening at-risk patients, and focused on the characteristics should be monitored in the follow-up.

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NAFLD: Time to apply quantitation in liver biopsies as endpoints in clinical trials

Cited by 7 publications

References 6 publications

Estimating the Inter- and Intra-Rater Reliability for NASH Fibrosis Staging in the Presence of Bridge Ordinal Ratings with Hierarchical Bridge Category Models

Estimating the Inter- and Intra-Rater Reliability for NASH Fibrosis Staging in the Presence of Bridge Ordinal Ratings with Hierarchical Bridge Category Models

Improving the Virtual Trichrome Assessment through Bridge Category Models

Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis

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