Access to Liver Transplantation for Patients with Primary Sclerosing Cholangitis

描述(申请人提供)：原发性硬化性胆管炎(PSC)是一种慢性肝病，没有治疗方法，在没有肝移植的情况下是一种致命的疾病。与其他终末期肝病患者相比，PSC患者面临着独特的并发症，包括胆管癌(CCA)、胆管狭窄导致的胆管炎以及伴随的炎症性肠病导致的结肠癌等并发症。目前的肝脏分配模型建立于2002年2月27日，依赖于患者的终末期肝病模型(MELD)评分，该评分考虑了患者的血清INR、肌酐和胆红素。MELD评分更重视INR和肌酐，尽管在PSC患者中胆红素不成比例地升高。这一事实，以及诸如CCA等并发症没有被MELD数据元素捕获的事实，使我们相信MELD评分可能会使PSC患者处于生存劣势。如果这是真的，那么这可能会成为改变肝脏分配方式的政策基础。对于等待名单上的PSC患者，他们的死亡风险可能会更高，原因有两个。对于PSC患者，给定MELD评分的死亡风险更高，或者在PSC患者中，MELD评分上升更慢，从而降低患者接受移植的可能性，从而更长时间地暴露于临床恶化和从等待名单中移除的风险。我们的第一个目标将通过三种方式解决这个主要的研究问题。我们将开发两个COX比例风险模型，一个考虑患者在等待名单上的所有MELD评分，另一个仅在上市时调整MELD。我们还将进行Logistic回归来评估死亡与移植在临床上的重要结果。我们的第二个目标将用于确定因临床恶化而将潜在的肝移植接受者从等待名单中移出的频率，这些人的退出原因未在联合国操作系统数据中具体说明。通过从各个移植中心收集患者水平数据，我们将能够计算结果错误分类的程度，从而指导AIM I中我们的主要模型的定量敏感性分析。最后，我们将评估引入MELD系统进行肝脏分配是否与PSC患者的活体供肝移植比率相对于非PSC患者的相应比率的变化有关。这一分析是必要的，因为患有和不患有PSC的患者活体供体移植转诊率的差异可能会影响AIM I的诊断可能影响结果的程度。拟议的研究项目将在申请人努力攻读临床流行病学理学硕士学位的背景下进行，因此课堂上的教学学习，重点是流行病学基础知识、研究设计以及研究的统计和分析方法，将加强和指导申请人的研究过程。申请者对这个项目的长期目标是收集和分析数据，准备出版手稿，并以数据为基础，作为未来申请K奖的一部分。 公共卫生相关性：肝脏移植器官的分配具有重大的公共卫生影响，因为我们必须就如何分配稀缺的资源做出决定。至关重要的是，我们在一个公平的系统内执业，而不是因为一组患者的疾病状况而使他们处于不利地位。如果发现原发性硬化性胆管炎患者在目前的肝脏分配制度下处于不利地位，那么这将为考虑进行大规模的政策变化以带来更公平的器官移植制度奠定基础。

DESCRIPTION (provided by applicant): Primary sclerosing cholangitis (PSC) is a chronic liver disease that has no treatment and is an otherwise fatal disease without liver transplantation. Patients with PSC face unique complications as compared to other patients with end-stage liver disease, including cholangiocarcinoma (CCA), cholangitis from biliary strictures, and complications such as colon cancer from concomitant inflammatory bowel disease. The current model for allocation of livers, instituted on February 27th, 2002, relies on a patient's Model for End Stage Liver Disease (MELD) score, which accounts for a patient's serum INR, creatinine, and bilirubin. The MELD score places more weight on the INR and creatinine, although in patients with PSC the bilirubin is disproportionately elevated. This fact, along with the fact that complications such as CCA are not captured by the MELD data elements, leads us to believe that the MELD score may place patients with PSC at a survival disadvantage. If this is true, then this may serve as a basis for a policy change in how livers are allocated. For patients with PSC on the waitlist, their risk of death may be higher for two reasons. Either the risk of death for a given MELD score is higher for patients with PSC, or in patients with PSC, the MELD score rises more slowly, making patients less likely to receive a transplant and thereby exposed for a longer duration to the risks of clinical deterioration and removal from the waitlist. Our first aim will address this primary research question in three ways. We will develop two Cox proportional hazard models, one accounting for all of a patient's MELD scores while on the waitlist, and another adjusting only for MELD at listing. We will also perform logistic regression to evaluate the clinically important outcome of death vs. transplant. Our second aim will serve to determine the frequencies with which potential liver transplant recipients are removed from the waitlist due to clinical deterioration among those in whom the reasons for withdrawal are unspecified in UNOS data. By collecting patient level data from individual transplant centers, we will be able to calculate the extent of this outcome misclassification and thereby guide quantitative sensitivity analyses of our primary models in Aim I. Lastly, we will evaluate whether introduction of the MELD system for liver allocation was associated with changes in rates of living donor liver transplantation among patients with PSC relative to corresponding rates among patients without PSC. This analysis is needed as differential rates of referral for living donor transplant among patients with and without PSC could affect the extent to which diagnosis may influence the outcomes in Aim I. The proposed research project will be in the context of the applicant working towards a Masters of Science in Clinical Epidemiology, whereby didactic learning in the classroom, focusing on fundamentals of epidemiology, study design, and statistical and analytic methods of research will enhance and guide the research process of the applicant. The long-term objectives of the applicant for this project are to collect and analyze the data, prepare manuscripts for publication, and build upon the data as part of a future application for a K award. PUBLIC HEALTH RELEVANCE: The allocation of organs for liver transplantation has major public health implications in that decisions must be made as to how we allocate a scarce resource. It is critical that we practice within a system that is equitable, and does not disadvantage one group of patients as a result of their disease status. If it is found that patients with primary sclerosing cholangitis are disadvantaged by the current liver allocation system, then this will form a foundation for which large-scale policy changes are considered to bring about a fairer system of organ transplantation.