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

镰状细胞病（SCD）影响美国超过10万人，主要来自 少数民族的疾病，导致发病率高，生活质量差，往往是由于反复和慢性 痛苦SCD患者反复发作急性疼痛向慢性疼痛转变的时间过程及机制 代表着该领域的关键知识差距。更好地了解风险因素和机制， 过渡到慢性疼痛可以促进有针对性的和有效的干预措施的发展。候选 和她的导师已经开发并建立了基于网络的电子疼痛日记的内容有效性， 在病人的自然环境中捕捉瞬间的疼痛。这些方法也使研究 疼痛强度的波动或个体内变异性，与疼痛强度不同，作为疼痛的一个重要方面， SCD的疼痛体验。这些方法现在可以应用于确定导致 慢性疼痛的发展是SCD患者，以及找出导致慢性疼痛持续的因素。 尽管通过造血细胞移植（HCT）治愈了SCD，但仍然存在疼痛。HCT提供了一个独特的模型， 研究慢性疼痛，其中通过HCT消除了潜在的镰状化和血管闭塞。目标1 根据提案，候选人将使用两个大型NIH赞助的HCT多中心临床试验的框架， SCD旨在解决疼痛变异性与患者报告的身体、社会和 情绪功能，以及识别疼痛的表型。在目标2中，她将使用先进的统计模型 和定量感觉测试，以确定尽管SCD已治愈但仍导致疼痛持续的因素 HCT，疼痛和PRO的轨迹，并将确定最有可能从疼痛中受益的患者 HCT。在目标3中，她将首次确定对 SCD中慢性疼痛的发展。通过这个职业发展奖，候选人还将获得 高级统计方法的专业知识，获得管理疼痛和PRO终点收集的经验 在大型多中心试验中，以及在前瞻性、纵向观察性研究的设计和执行中， SCD中的慢性疼痛。候选人是一个独特的资格和有前途的早期职业临床研究员在SCD 疼痛研究她的顾问委员会由SCD的专家组成（Lakshmanan Krishnamurti博士，Wally博士 Smith和Clinton Joiner博士），SCD的HCT（Lakshmanan Krishnamurti博士和Edmund Waller博士），以及 纵向日记数据建模的生物统计学方法（考特尼·麦克拉肯博士）。Aflac癌症和 血液疾病中心和埃默里大学提供了一个优秀的研究环境， 对候选人的支持和支持。研究和培训计划将允许候选人建立 她本人作为一名独立的临床研究者，处于SCD、疼痛和PRO研究的独特十字路口， 使用创新方法推进SCD慢性疼痛领域的发展。

PROJECT SUMMARY 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 time course and mechanisms of transition from recurrent acute pain episodes to chronic pain in SCD represent critical knowledge gaps in the field. A better understanding of the risk factors and mechanisms of transition to chronic pain can facilitate the development of targeted and effective interventions. 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. These methods also allow the study of fluctuations or intra-individual variability in pain intensity, distinct from pain intensity, as an important facet of the pain experience in SCD. These approaches can now be applied to identify the factors that contribute to the development of chronic pain is SCD patients, as well as to identify the factors that lead to persistence of chronic pain despite cure of SCD by hematopoietic cell transplantation (HCT). HCT provides a unique model for the study of chronic pain where the underlying sickling and vaso-occlusion are removed by HCT. In Aim 1 of this proposal, the candidate will use the framework of two large NIH-sponsored multi-center clinical trials of HCT for SCD to address the relevance of pain variability on patient-reported outcomes (PROs) of physical social and emotional functioning, and in identifying phenotypes of pain. In Aim 2, she will use advanced statistical models and quantitative sensory testing to identify the factors that contribute to pain persistence despite cure of SCD by HCT, the trajectories of pain and PROs, and will identify the patients whose pain is most likely to benefit from HCT. In Aim 3, she will, for the first time, determine the feasibility of a prospective, longitudinal study of the development of chronic pain in SCD. Through this career development award, the candidate will also acquire expertise in advanced statistical methods, gain experience in managing the collection of pain and PRO endpoints in large multicenter trials, and in the design and execution of prospective, longitudinal observational studies of chronic pain in SCD. The candidate is a uniquely qualified and promising early-career clinical investigator in SCD pain research. 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 longitudinal diary data (Dr. Courtney McCracken). The Aflac Cancer and Blood Disorders Center, and Emory University provide an outstanding research environment with requisite resources and support for the candidate. The research and training plan will allow the candidate to establish herself as an independent clinical investigator at the unique crossroads of SCD, pain and PRO research, and the use of innovative approaches to advance the field of chronic pain in SCD.