Development of MR Based Biomarker Panels for NAFLD _ A NASH CRN Ancillary Study

描述（由申请人提供）：该提案是针对PAR-09-247的非酒精性脂肪性肝炎临床研究网络（NASH CRN）批准的一项辅助研究。广泛的长期目标是改善非酒精性脂肪性肝病（NAFLD）患者的健康状况。当前的目标是克服诊断和评估NAFLD的一个关键障碍：缺乏准确的非侵入性生物标志物来区分NASH（更快速进展的变体和治疗干预的目标）与孤立性脂肪变性，评估NAFLD疾病活动性和纤维化分期。健康相关性：NAFLD是美国儿童和成人中最常见的慢性肝病，与胰岛素抵抗和肥胖密切相关。这种情况可能会发展为肝硬化和肝癌，并导致糖尿病和心血管疾病的发展。目前，准确评估NAFLD需要肝活检，这一要求阻碍了临床护理和NAFLD的研究。该提案将开发急需的非侵入性MR生物标志物面板来评估NAFLD。将这些生物标志物面板整合到临床实践和临床试验终点将推进NAFLD的治疗和研究。具体目的是在患有NAFLD的儿童和成人中开发MR生物标志物小组，以诊断NASH （Aim 1）的存在，NAFLD疾病活动性等级（Aim 2），并诊断中度（Aim 3a）或晚期（Aim 3b）纤维化的存在。参考标准将集中评分肝脏组织学。设计：我们建议对NASH CRN（美国主要的NAFLD研究网络）进行一项五点、前瞻性、观察性、横断面的辅助研究。NASH CRN将提供临床和组织学特征的大量不同种族的受试者。方法:150

DESCRIPTION (provided by applicant): This proposal is for an ancillary study to and approved by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) in response to PAR-09-247. The broad, long-term objective is to improve the health of people with Non-Alcoholic Fatty Liver Disease (NAFLD). The immediate objective is to overcome a key barrier in the diagnosis and assessment of NAFLD: the lack of accurate non-invasive biomarkers to differentiate NASH - the more rapidly progressive variant and target for therapeutic intervention - from isolated steatosis, evaluate NAFLD disease activity, and stage fibrosis. Health relatedness: NAFLD is the most common chronic liver disease in children and adults in the United States, and it is intimately related to insulin resistance and obesity. The condition may progress to cirrhosis and liver cancer, and it contributes to the development of diabetes and cardiovascular disease. Currently, accurate assessment of NAFLD requires liver biopsy, a requirement that hampers clinical care and impedes NAFLD research. This proposal will develop much-needed non-invasive MR biomarker panels to evaluate NAFLD. The integration of these biomarker panels into clinical practice and clinical trial endpoints will advance NAFLD care and research. The specific aims are to develop panels of MR biomarkers in children and adults with NAFLD to diagnose the presence of NASH (Aim 1), grade NAFLD disease activity (Aim 2), and diagnose the presence of moderate (Aim 3a) or advanced (Aim 3b) fibrosis. The reference standard will be centrally scored liver histology. Design: We propose a five-site, prospective, observational, cross-sectional ancillary study to the NASH CRN, the leading NAFLD research network in the United States. The NASH CRN will provide a large, ethnically diverse population of clinically and histologically characterized subjects. Methods: 150 children and 150 adults in the NASH CRN with liver biopsy-confirmed NAFLD will be enrolled and have research MR examinations within 60 days of biopsy. MR examinations will include advanced MR imaging, MR spectroscopy, and MR elastography techniques and last 45-60 minutes without contrast agent use. Techniques will be optimized to mitigate confounding effects. Candidate MR biomarkers will be measured including fat fraction, transverse relaxation values, shear stiffness, true diffusion coefficient, perfusion fraction, and extrahepatic adipose tissue volumes. Statistical analyses: MR measurements will be compared with histology findings. Multivariate models will be built to develop pediatric- and adult-specific MR biomarker panels to diagnose the presence of NASH, grade NAFLD disease activity, and diagnose moderate and advanced fibrosis. The development of accurate, precise non-invasive MR biomarker panels to evaluate NAFLD will advance both clinical care and clinical research.