Parametric Response Mapping (PRM) for the detection of chronic lung injury in hematopoietic cell transplant recipients

摘要 慢性肺功能障碍（CLD）是骨髓移植（BMT）的一种潜在严重并发症， 在BMT后发生慢性移植物抗宿主病（GVHD）的患者中尤其普遍。的 CLD的发展与20%-40%的长期存活率相关，大多数患者 只有在他们已经发展出显著的（并且可能是不可逆的）肺部病理学之后才被诊断为CLD。 有一个关键的需要，以确定CLD早期在其临床过程中，在一个阶段，治疗可能证明是有益的 给病人。参数响应映射（PRM）是一种基于计算机断层扫描（CT）的新方法， 当应用于标准CT扫描时，能够识别和量化各种肺部疾病亚型 在病人身上。这项技术最初是在10年前由密歇根医学公司开发的，用于患有以下疾病的患者： 慢性阻塞性肺疾病（COPD）。在单中心和多中心试验中，PRM 证实了在成人BMT患者中识别CLD的有效性。我们的中心假设是，PRM可以 识别慢性GVHD患者，他们是CLD发展的高风险人群。我们提出了一个 在患有慢性GVHD的成人和儿童受试者（≥ 3岁）中检查PRM的观察性研究 BMT。为了验证我们的假设，我们建立了三个具体目标。在前两个部分中，我们将检查PRM值 在两个主要时间点：慢性GVHD发作（目的1）和CLD发作（目的2），CLD定义为 根据NIH标准。在目标3中，我们将开发一个机器学习模型，将血清学和 肺功能测试（PFT）生物标志物与PRM值，以开发复合生物标志物策略。后 完成我们目前的提案，我们将建立PRM作为成人BMT患者CLD的预测因子。此外，本发明还提供了一种方法， 从儿童BMT患者中获得的PRM、PFT和血清学数据将为未来的研究提供数据库。 在这个人群中进行研究。从历史上看，在儿科患者中识别CLD的能力一直依赖于PFT， PFT在技术上很难在幼儿中进行。使用PRM作为CLD的诊断指标 在儿科骨髓移植患者中的应用将是这一提议的一个重大进展。最后，我们的建议将PRM 方法学在成人中向前发展，使我们能够研究成人BMT接受者肺部疾病的轨迹， 慢性GVHD和CLD发作后。

ABSTRACT Chronic lung dysfunction (CLD) is a potentially severe complication of bone marrow transplantation (BMT), particularly prevalent in patients who develop chronic graft versus host disease (GVHD) post-BMT. The development of CLD is associated with a 20%-40% long term survival rate, with the majority of patients diagnosed with CLD only after they have developed significant (and potentially irreversible) lung pathology. There is a critical need to identify CLD earlier in its clinical course, at a stage when treatment may prove beneficial to patients. Parametric response mapping (PRM) is a novel computed tomography (CT) based methodology that when applied to standard CT scans is capable of identifying and quantifying a variety of lung disease subtypes in patients. This technology was initially developed at Michigan Medicine over 10 years ago for patients with chronic obstructive pulmonary disease (COPD). In both single center and multicenter trials, PRM has demonstrated efficacy for the identification of CLD in adult BMT patients. Our central hypothesis is that PRM can identify patients with chronic GVHD who are at high risk for the development of CLD. We propose an observational study to examine PRM in adult and pediatric subjects (≥ 3 years in age) with chronic GVHD post- BMT. To test our hypothesis, we have established 3 specific aims. In the first two, we will examine PRM values at two main time points: at the onset of chronic GVHD (Aim 1) and at the onset of CLD (Aim 2), with CLD defined by standard NIH criteria. In Aim 3, we will develop a machine learning model that will incorporate serologic and pulmonary function test (PFT) biomarkers with PRM values to develop a composite biomarker strategy. Upon completion of our current proposal, we will establish PRM as a predictor of CLD in adult BMT patients. In addition, the PRM, PFT, and serologic data obtained from pediatric BMT patients will provide a data bank for future research in this population. Historically, the ability to identify CLD in pediatric patients has been PFT-dependent, with PFTs technically challenging to conduct in young children. The use of PRM as a diagnostic indicator of CLD in pediatric BMT patients will be a major advance of this proposal. Finally, our proposal takes our PRM methodology forward in adults, allowing us to study the trajectory of lung disease in adult BMT recipients with chronic GVHD, and following the onset of CLD.