STUDYING INTRA-INDIVIDUAL PAIN VARIABILITY IN SICKLE CELL DISEASE AND RESOLUTION OF PAIN AFTER HEMATOPOIETIC CELL TRANSPLANT: A NOVEL MODEL SYSTEM TO ELUCIDATE MECHANISMS OF TRANSITION TO CHRONIC PAIN

项目摘要(来自父K23应用程序) 镰状细胞病(SCD)在美国影响超过10万人，主要来自少数族裔，主要是 严重的发病率和较差的生活质量，通常是由于复发性和慢性疼痛。它的作用机制 从复发性急性疼痛发作到慢性疼痛的转变知之甚少。尽管痛苦一直是 用替代标记物测量，例如医疗保健对疼痛的利用和作为疾病严重程度的标记物， 这些严重低估了疼痛对功能和患者报告结果的真实负担和影响 (PRO)在SCD患者中。候选人和她的导师已经开发并建立了 一种基于Web的电子疼痛日记，在患者的自然状态下捕捉瞬间的疼痛 环境。疼痛强度的个体内变异性，与疼痛强度不同，正在被公认为 这是疼痛体验的一个独立而重要的方面。造血细胞移植(HCT)提供了 一种研究慢性疼痛的独特模型，其中潜在的镰状和血管闭塞通过 HCT。初步数据表明，并不是每个人都能在治愈后体验到疼痛的缓解。候选人将会 使用NIH赞助的两个大型HCT治疗SCD多中心临床试验的框架来解决关键问题 关于SCD疼痛的知识差距和疼痛变异性与PRO的相关性，以及在确定SCD疼痛的表型方面 痛苦(目标1)。在目标2(A)中，她将研究HCT前疼痛属性和HCT后并发症对疼痛的作用 SCD治愈后消退。使用高级统计模型，她将定义疼痛解决的轨迹 在HCT之后，目标是确定治愈后持续性疼痛的预测因素，并确定其 疼痛最有可能从HCT中受益。在本提案的目标2b中，使用定量感觉测试(QST) 方法，她将调查中枢敏感化指标是否在那些持续疼痛的患者中持续存在 SCD的治愈，为SCD的慢性疼痛提供了新的见解。在目标3中，她将第一次确定 SCD慢性疼痛发展的前瞻性纵向研究的可行性。候选人有独一无二的 处于SCD、疼痛和健康结果研究的十字路口的研究利基，并正在寻求使用创新的 推进慢性疼痛领域的方法。她也是唯一有资格成为SCD痛苦的少数人之一 精通QST方法学的研究人员。这项提议设想候选人将在以下方面获得专业知识 通过教学课程和应用于指导研究的先进统计方法，获得经验 在大型多中心试验和前瞻性试验中管理疼痛和Promis终点的获取， 纵向观测研究。她的咨询委员会由SCD专家组成(Lakshmanan博士 Krishnamurti博士、Wally Smith博士和Clinton Joiner博士)、SCD的HCT(Lakshmanan Krishnamurti博士和Dr. Edmund Waller)和纵向日记数据建模的生物统计学方法(Dr.Courtney McCracken)， 有着长期的指导关系，并致力于她的研究成功。埃默里大学提供 优秀的研究环境，并承诺为候选人提供必要的资源和支持。

PROJECT SUMMARY (FROM PARENT K23 APPLICATION) Sickle Cell Disease (SCD) affects over 100,000 individuals in the U.S, mostly from minority ethnicities, leading to significant morbidity and poorer quality of life, often due to recurrent and chronic pain. The mechanisms of transition from recurrent acute pain episodes to chronic pain are poorly understood. Although pain has been measured with surrogate markers such as healthcare utilization for pain and as markers of disease severity, these grossly underestimate the true burden and impact of pain on functioning and patient-reported outcomes (PROs) in patients with SCD. The candidate and her mentor have developed and established content validity of a web-based electronic pain diary which captures pain on a momentary level, in the patient’s natural environment. Intra-individual variability in pain intensity, distinct from pain intensity, is becoming recognized as an independent and important facet of the pain experience. Hematopoietic Cell Transplantation (HCT) provides a unique model for the study of chronic pain where the underlying sickling and vasocclusion are removed by HCT. Preliminary data suggest that not everyone experiences resolution of pain after cure. The candidate will use the framework of two large NIH-sponsored multi-center clinical trials of HCT for SCD to address critical knowledge gaps in SCD pain and the relevance of pain variability on PROs, and on identifying phenotypes of pain (Aim 1). In Aim 2(a), she will study the role of pre- HCT pain attributes and post-HCT complications on pain resolution after cure of SCD. Using advanced statistical models, she will define trajectories of pain resolution following HCT with the goal to identify predictors of persistent pain after cure, and identify the patients whose pain is most likely to benefit from HCT. In Aim 2b of this proposal, using Quantitative Sensory Testing (QST) methods, she will investigate whether indicators of central sensitization persist in those with persistent pain after cure of SCD, providing novel insights into chronic pain in SCD. In Aim 3, she will, for the first time, determine the feasibility of a prospective, longitudinal study of development of chronic pain in SCD. The candidate has a unique research niche at the crossroads of SCD, pain and health outcomes research and is seeking to use an innovative approaches to advance the field of chronic pain. She is also uniquely qualified as one of the few SCD pain researchers skilled in QST methodology. This proposal envisages that the candidate will acquire expertise in advanced statistical methods through didactic courses and application in mentored research, gain experience managing the acquisition of pain and PROMIS endpoints in large multicenter trials, and in prospective, longitudinal observational studies. Her advisory committee consists of experts in SCD (Dr. Lakshmanan Krishnamurti, Dr. Wally Smith, and Dr. Clinton Joiner), HCT for SCD (Dr. Lakshmanan Krishnamurti, and Dr. Edmund Waller), and biostatistical methods for modeling of longitudinal diary data (Dr. Courtney McCracken), with a long-standing mentoring relationship and commitment to her research success. Emory University provides an outstanding research environment and has committed requisite resources and support to the candidate.