Browsing by Author "Doo, Edward"

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    Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-assigned Steatosis Grades of Liver Biopsies from Adults with Nonalcoholic Steatohepatitis
    (Elsevier, 2017) Middleton, Michael S.; Heba, Elhamy R.; Hooker, Catherine A.; Bashir, Mustafa R.; Fowler, Kathryn J.; Sandrasegaran, Kumar; Brunt, Elizabeth M.; Kleiner, David E.; Doo, Edward; Van Natta, Mark L.; Tonascia, James; Lavine, Joel E.; Neuschwander-Tetri, Brent A.; Sanyal, Arun; Loomba, Rohit; Sirlin, Claude B.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Background & Aims We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Methods We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. Results At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0–1 vs 2–3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91–0.98), and grade 0–2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93–0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2–3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71–0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63–0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Conclusions Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.
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    Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels
    (Wolters Kluwer, 2019-10-01) Gawrieh, Samer; Wilson, Laura A.; Cummings, Oscar W.; Clark, Jeanne M.; Loomba, Rohit; Hameed, Bilal; Abdelmalek, Manal F.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Kowdley, Kris; Kleiner, David; Doo, Edward; Tonascia, James; Sanyal, Arun; Chalasani, Naga; Network and the NASH Clinical Research; Medicine, School of Medicine
    Background and aims: Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels. Methods: We evaluated 534 adults with biopsy-proven NAFLD and ALT and AST < 40 U/L within 3 months of their liver biopsy. Histological phenotypes of primary interest were NASH with stage 2-3 fibrosis (NASH F2-3) and cirrhosis. Using multiple logistic regression models with Akaike’s Information Criteria (AIC), we identified variables associated with these histological phenotypes. We developed and internally validated their clinical prediction models. Results: The prevalence of NASH F2-F3 and cirrhosis were 19% and 7%, respectively. The best multiple regression AIC model for NASH F2-3 consisted of type 2 diabetes, White race, lower LDL, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The best AIC model for cirrhosis consisted of lower platelet count, lower AST/ALT ratio, higher BMI, and female sex. The area under the receiver operator curves of the prediction models were 0.70 (95% CI: 0.65-0.76) for detecting NASH-F2-3 and 0.85 (95% CI: 0.77-0.92) for detecting cirrhosis. When models were fixed at maximum Youden’s index, their positive and negative predictive values were 35% and 88% for NASH F2-F3 and 30% and 98% for cirrhosis, respectively. Conclusion: Clinically significant histological phenotypes are observed in patients with NAFLD and normal aminotransferase levels. Our models can assist the clinicians in excluding advanced liver histology in NAFLD patients with normal aminotransferase levels.
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    Performance Characteristics of Vibration-Controlled Transient Elastography for Evaluation of Non-Alcoholic Fatty Liver Disease
    (Wiley, 2017) Vuppalanchi, Raj; Siddiqui, Mohammad S.; Van Natta, Mark L.; Hallinan, Erin; Brandman, Danielle; Kowdley, Kris; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Dasarathy, Srinivas; Abdelmalek, Manal; Doo, Edward; Tonascia, James A.; Kleiner, David E.; Sanyal, Arun J.; Chalasani, Naga; Department of Medicine, School of Medicine
    Background: Vibration-controlled transient elastography (VCTE) estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) which are noninvasive assessments of hepatic fibrosis and steatosis respectively. However, prior VCTE studies reported high failure rate in patients with non-alcoholic fatty liver disease (NAFLD). Aim: To examine the performance characteristics of Fibroscan 502 Touch with two probes, medium (M+) and extra-large (XL+), in patients with NAFLD in a multicenter setting. Methods: A total of 1696 exams were attempted in 992 patients (BMI: 33.6 ± 6.5 kg/m2) with histologically confirmed NAFLD. Simultaneous assessment of LSM and CAP was performed using Fibroscan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (88%) or two operators (12%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM IQR/median was >30%. Significant disagreement between two readings was defined as greater than >95% limits of agreement between two readings. Results: A total of 1641 examinations yielded valid results with a failure rate of 3.2% (55/1696). The proportion of unreliable scans for LSM was 2.4%. The proportion of unreliable scans with operator experience in the top quartile (≥ 59 procedures) was significantly lower than lower three quarters combined (1.6% vs.4.7%, p=0.01 by Fisher's Exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11% respectively. Conclusion: VCTE for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility.
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    Vibration-controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease
    (Elsevier, 2018) Siddiqui, Mohammad S.; Vuppalanchi, Raj; Van Natta, Mark L.; Hallinan, Erin; Kowdley, Kris V.; Abdelmalek, Manal; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Dasarathy, Srinivasan; Brandman, Danielle; Doo, Edward; Tonascia, James A.; Kleiner, David E.; Chalasani, Naga; Sanyal, Arun J.; Medicine, School of Medicine
    Background & Aims Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients. Methods We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 days; interquartile range, 25–78 days), from July 1, 2014 through July 31, 2017. Liver stiffness measurement (LSM) cutoffs for pairwise fibrosis stage and controlled attenuation parameter (CAP) cutoffs for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at sensitivity fixed at 90% and specificity fixed at 90%. Results LSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79– 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90–0.97). At fixed sensitivity, a cutoff LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91; a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive 0.71 and patients with cirrhosis with a positive predictive value of 0.41. CAP analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64–0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or presence of NASH. Conclusion In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.