Advanced Quantitative Magnetic Resonance Imaging Phantoms for Nonalcoholic Fatty Liver Disease

项目总结 这个第一阶段提案的总体目标是设计和测试新型磁共振的可行性 成像(MRI)参考标准(Pantom)是全面和标准化急需的 非酒精性脂肪性肝病(NAFLD)定量MRI生物标志物的质量保证我们建议 开发1)定量磁共振弹性成像(MRE)刚体模型，以及2)组合定量MRE 以及质子密度脂肪分数(PDFF)模体，模拟肝纤维化和脂肪的同时存在。 在过去的十年中，定量MRI方法，包括MRE，作为肝脏的生物标记物来测量硬度 纤维化和化学位移编码的磁共振成像(CSE-MRI)作为肝脏脂肪的生物标志物，测量PDFF已经出现 作为评估NAFLD的无创性护理标准。快速采用MRE和PDFF方法 在世界各地的数千个地点产生了对定量MRE和PDFF幻影的迫切需求， 实现可靠的定量质量保证，以确保无偏见和可重复性的测量。缺乏临床质量保证可以 导致误诊，临床试验中的QA不足可能导致初级诊断的错误和不一致 试验终点(肝脏僵硬和PDFF)会导致宝贵的患者数据丢失，并可能导致试验失败。 目前可用的单刚度MRE模体不足以进行定量质量保证，因为它们仅模拟 随时间漂移的单个刚度值。这些幻影还需要特定于幻影的MRE协议 这与临床MRE方案有很大不同，导致技术故障和繁琐的质量保证过程。 重要的是，大多数评估NAFLD的临床MRI方案同时测量了MRE-Stiffness和PDFF在 同样的考试。通过市场研究，Calimetrix确定了对两个新的量化幻影的需求：1) 多刚度磁流变液体模；和2)组合磁流变液/偏心距体模。两个幻影都必须稳定在 时间和设计旨在简化QA设置，最大限度地减少用户和技术错误。 在这项提案中，我们组建了一个由PDFF和MRE的主要发明者组成的团队 包括来自威斯康星大学、Calimetrix、梅奥诊所和Resoundant的专家。我们建议 设计、开发和验证不同硬度凝胶的化学配方，这些凝胶跨越临床相关 肝脏硬度范围(目标1)和同时变化硬度和PDFF值的乳剂 肝脏硬度和脂肪的临床相关范围(目标2)。我们还建议设计和验证一个体模 便于准确定量测量的外壳，具有独立的高效率和易用性 在单个紧凑型单元中包含多个刚度和/或PDFF值的隔室(目标3)，最后是 演示MRE和MRE/PDFF模型原型的可行性，包括易用性、高图像 临床MRE和CSE-MRI方案的质量和有效性(目标4)。如果成功，我们将开发出 并论证了真正定量的MRE和MRE/PDFF模体的可行性 为保证NAFLD定量MRI生物标志物的质量。

PROJECT SUMMARY The overall goal of this Phase I proposal is to design and test the feasibility of novel magnetic resonance imaging (MRI) reference standards (“phantoms”) that are urgently needed for comprehensive and standardized quality assurance (QA) of quantitative MRI biomarkers of non-alcoholic fatty liver disease (NAFLD). We propose to develop 1) a quantitative MR elastography (MRE) stiffness phantom, and 2) a combined quantitative MRE and proton density fat fraction (PDFF) phantom that mimics the simultaneous presence of liver fibrosis and fat. Over the past decade, quantitative MRI methods, including MRE to measure stiffness as a biomarker of liver fibrosis and chemical shift encoded MRI (CSE-MRI) to measure PDFF as a biomarker of liver fat, have emerged as the noninvasive standard of care for assessment of NAFLD. The rapid adoption of MRE and PDFF methods at thousands of sites worldwide has created an urgent need for quantitative MRE and PDFF phantoms that enable robust quantitative QA to ensure unbiased and reproducible measurements. Lack of clinical QA can result in misdiagnosis, and inadequate QA in clinical trials can result in errors and inconsistency in the primary trial endpoints (liver stiffness and PDFF) leading to loss of valuable patient data and potentially a failed trial. Currently available single-stiffness MRE phantoms are insufficient for quantitative QA because they mimic only a single stiffness value which drifts over time. These phantoms also require phantom-specific MRE protocols that differ significantly from clinical MRE protocols, leading to technical failures and a cumbersome QA process. Importantly, most clinical MRI protocols evaluating NAFLD measure both MRE-stiffness and PDFF in the same exam. Through market research, Calimetrix has identified the need for two new quantitative phantoms: 1) a multi-stiffness MRE phantom; and 2) a combined MRE/PDFF phantom. Both phantoms must be stable over time and be designed to simplify QA setup, minimizing user and technical errors. In this proposal, we have assembled a team consisting of the primary inventors of both PDFF and MRE including experts from the University of Wisconsin, Calimetrix, the Mayo Clinic, and Resoundant. We propose to design, develop, and validate chemical formulations for gels of varying stiffnesses that span the clinically relevant range of liver stiffness (Aim 1) and emulsions with simultaneously varying stiffness and PDFF values that span the clinically relevant range of liver stiffness and fat (Aim 2). We also propose to design and validate a phantom housing that facilitates accurate quantitative measurements and is efficient and easy-to-use with separate compartments to contain multiple stiffness and/or PDFF values in a single compact unit (Aim 3), and finally, to demonstrate the feasibility of the MRE and MRE/PDFF phantom prototypes, including ease-of-use, high image quality, and utility for QA of clinical MRE and CSE-MRI protocols (Aim 4). If successful, we will have developed and demonstrated the feasibility of truly quantitative MRE and MRE/PDFF phantoms that are urgently needed for quality assurance of quantitative MRI biomarkers of NAFLD.