Technical Validation of MR Biomarkers of Obesity-Associated NAFLD

! 项目概要： 该应用程序的广泛，长期目标是改善数百万患有肥胖症或有肥胖风险的美国人的健康， 非酒精性脂肪肝（NAFLD）是美国最常见的慢性肝病。后 首次成功验证了肝脏脂肪变性（NAFLD最早的组织学特征）的MR成像生物标志物， 本周期的补助金，这种竞争性更新的重点是肝纤维化和炎症，非酒精性的特点， 脂肪性肝炎（NASH），NAFLD的侵袭性亚型，其可进展为肝硬化、肝癌和肝脏相关性肝炎。 死亡磁共振弹性成像（MRE）是一种非侵入性的方法来量化组织硬度，是领先的成像技术 用于评估NAFLD中的肝纤维化，但MRE用于检测纤维化和NASH的真正诊断性能 横截面上，并监测其变化纵向，是不完全理解。通过优化 并为此目的严格评估地雷风险教育，我们将解决主要的知识和技术差距， 模糊了该技术在临床护理和研究中的适当利用。目标1：优化MRE波场 在严重肥胖症中，适用于传统的2D和先进的3D-MRE。目标2：描述 传统2D和高级3D-MRE在重度肥胖症中的精确度特征（同一天的可重复性，场强 再现性、读取器再现性、日间再现性）。目的3：确定传统2D-2D的准确性。 和先进的3D-MRE在严重肥胖症，以a）诊断纤维化和NASH的横截面和B）监测变化， 纤维化和NASH纵向消退。重要性：通过确定 用于检测和监测肥胖患者纤维化和NASH的常规2D和高级3D-MRE， 拟议的研究将为MRE在临床护理、临床试验和其他研究中的适当利用提供信息， 肥胖相关的NAFLD。此外，如果研究证实了先进的3D-MRE检测早期阶段的承诺， NASH，这将代表一种改变游戏规则的新技术能力。创新：该应用程序带来了创新， 三个主题领域：（1）研究设计：肥胖患者的前瞻性横断面和纵向研究， 技术上具有挑战性的人群，疾病严重程度分布均衡，是实现科学目标的理想选择。（二） 波场生成：测试用于生成高质量波场的新型灵活驱动器。(3)MRE分析： 先进的3D-MRE重建和分析方法的严格测试， 显示出诊断早期NASH的前景。研究设计和方法：这项2个地点研究的第1阶段将优化 通过识别最大化MRE精度的驾驶员类型和位置，在严重肥胖症中生成MRE波场。 使用最佳驾驶员类型/位置，第2阶段将招募100名接受减肥的严重肥胖成年人（50名/研究中心） 在多个时间点进行2D和3D-MRE的前瞻性纵向研究中进行手术。的参比标准品 纤维化和NASH的存在及其变化，将包括专家共识评分和定量图像分析， 手术时和6个月时获得的配对同期活检。补充人体测量，实验室， 将获得MRI测量结果，以确定影响MRE性能的因素，并为未来的研究提出假设。!

! PROJECT SUMMARY: This application's broad, long-term objective is to improve the health of millions of Americans with or at risk for obesity- associated non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the United States. After successfully validating MR imaging biomarkers for hepatic steatosis, the earliest histologic feature of NAFLD, in the first cycle of this grant, this competitive renewal focuses on hepatic fibrosis and inflammation, features of non-alcoholic steatohepatitis (NASH), the aggressive subtype of NAFLD that can progress to cirrhosis, liver cancer, and liver-related death. MR elastography (MRE), a noninvasive method to quantify tissue stiffness, is the leading imaging-based technique for assessing liver fibrosis in NAFLD, but the true diagnostic performance of MRE for detecting fibrosis and NASH cross-sectionally, and for monitoring their change longitudinally, is incompletely understood. By optimizing and rigorously evaluating MRE for these purposes, we will address major knowledge and technical gaps that have obscured the appropriate utilization of this technology in clinical care and research. Aim 1: Optimize MRE wavefield generation in severe obesity, applicable to both conventional 2D- and advanced 3D-MRE. Aim 2: Characterize the precision profile of conventional 2D- and advanced 3D-MRE in severe obesity (same-day repeatability, field-strength reproducibility, reader reproducibility, between-day reproducibility). Aim 3: Determine the accuracy of conventional 2D- and advanced 3D-MRE in severe obesity to a) diagnose fibrosis and NASH cross-sectionally and b) monitor change in fibrosis and resolution of NASH longitudinally. Significance: By determining the true diagnostic performance of conventional 2D- and advanced 3D-MRE for detecting and monitoring fibrosis and NASH in bariatric patients, the proposed research will inform the appropriate utilization of MRE for clinical care, clinical trials, and other research in obesity-associated NAFLD. Additionally, if the research confirms the promise of advanced 3D-MRE to detect early-stage NASH, this will represent a game-changing new technical capability. Innovation: This application brings innovation in three thematic areas: (1) Study design: prospective cross-sectional and longitudinal study in bariatric patients, a technically challenging population with balanced disease severity distribution ideal for addressing the scientific aims. (2) Wavefield generation: testing of new flexible drivers designed to generate high-quality wavefields. (3) MRE analysis: rigorous testing of advanced 3D-MRE reconstruction and analysis methods that in preliminary animal and human studies show promise for diagnosing early-stage NASH. Research design & methods: Phase 1 of this 2-site study will optimize MRE wavefield generation in severe obesity by identifying the driver type and position that maximize MRE precision. Using that optimal driver type/position, Phase 2 will enroll 100 severely obese adults (50/site) undergoing weight-loss surgery in a prospective longitudinal study with 2D- and 3D-MRE at multiple time points. Reference standards for the presence of fibrosis and NASH, and their change, will include expert consensus scoring and quantitative image analysis of paired contemporaneous biopsies obtained at surgery and at 6 months. Complementary anthropometric, laboratory, and MRI measures will be acquired to identify factors that affect MRE performance and develop hypotheses for future studies. !