The Optimal Timing of Transplantation in Pediatric Acute Liver Failure

描述（由申请人提供）：小儿急性肝衰竭（PALF）是一种复杂的疾病，有多种原因，并与高死亡风险相关。对于患有PALF的儿童来说，肝移植是一项挽救生命的手术。然而，对于患儿的临床医生和家庭成员来说，决定进行移植有两个主要原因。首先，如果孩子能够在没有移植的情况下存活足够长的时间，那么孩子的肝脏很有可能会自行恢复。其次，在近50%的PALF病例中，病因不明，这使得在没有移植的情况下很难预测这些患者的预后。临床医生面临着一个两难的选择：是将一个孩子列入接受已故捐赠者肝脏移植的名单，还是等待孩子康复。儿童的家庭成员必须决定是否成为活体供体，超过14%的患者因急性肝衰竭接受移植。有人担心，移植可能“太早”进行，因为等待可能会让受损的肝脏在不做手术的情况下恢复。为了解决这个问题，该研究将使用来自PALF注册表的数据，这是世界上最大和最详细的PALF患者纵向数据库。这项研究将是两个研究小组的合作成果，这两个研究小组特别适合评估影响何时进行移植的因素。首席研究员的建模小组在肝脏疾病进展的数学建模，将模拟模型应用于器官分配政策和表示复杂的医疗决策方面具有丰富的经验。该研究的总体目标是通过(1)建立预后和疾病进展的定量模型以及(2)使用这些模型校准移植决策的优化模型来改善PALF病例的临床决策。这些目标将通过两个具体目标来实现。目的1是对PALF患儿的短期自然病史进行定性和定量描述。这将需要估计移植前和移植后生存的统计模型，以及开发疾病进展的定量模型。目的2是构建一个概念验证模型，评估PALF患儿肝移植的最佳时机，包括活体供体器官移植的可能性。我们将修改现有的美国器官分配系统模拟模型，使其包括PALF，并将验证该模型以确保它代表PALF的时间过程，并将使用该模型来检查PALF儿童的移植时间实践。公共卫生相关性：儿童急性肝功能衰竭是一种毁灭性的，往往是致命的疾病，其中一个潜在的治疗方法是肝移植。然而，选择用移植来治疗孩子的决定是困难的，因为即使孩子病得很重，孩子的肝脏也有可能自己恢复，而不需要手术，因此移植是不必要的。决定何时再等一段时间或何时进行移植的最佳策略尚不确定。我们在这里描述的研究将使用统计和数学模型来更好地预测儿童肝病的发展速度。该研究的目的是改善年轻急性肝病患者使用肝移植的决策。

DESCRIPTION (provided by applicant): Pediatric acute liver failure (PALF) is a complex disease that has multiple causes and is associated with a high risk of death. For a child with PALF, liver transplantation can be a lifesaving procedure. However, there are two primary reasons that the decision to pursue transplantation is difficult for the child's clinicians and family members. First, there is a very real chance that the child's liver will recover on its own if the child is able to survive for enough time without a transplant. Second, in nearly 50% of cases of PALF, the cause of the disease is unknown, and this makes it very difficult to predict the outcomes for these patients in the absence of transplantation. Clinicians are faced with the dilemma of whether to place a child on the list to receive a liver from a deceased donor or whether to wait for the child to recover. A child's family member must decide whether to become a living donor, as occurs in over 14% of cases in which patients receive transplants for acute liver failure. There is some concern that transplantation may be pursued "too early," when waiting may allow the damaged liver to recover without surgery. To address this problem, the proposed study will use data from the PALF registry, which is the largest and most clinically detailed longitudinal database of PALF patients in the world. The study will be a collaborative effort of two research groups that are uniquely suited to evaluate factors influencing when to pursue transplantation. The Principal Investigator's modeling group has extensive experience in mathematically modeling the progression of liver disease, applying simulation models to organ allocation policies, and representing complex medical decisions. The overall goals of the study are to improve clinical decision making in cases of PALF by (1) developing quantitative models of prognosis and disease progression and (2) using these models to calibrate optimization models of the transplant decision. These goals will be accomplished through two specific aims. Aim 1 is to characterize and quantitatively describe the short-term natural history of children with PALF. This will require estimating statistical models of pretransplant and post transplant survival, as well as developing quantitative models of disease progression. Aim 2 is to construct a proof-of-concept model evaluating the optimal timing of liver transplantation for children with PALF, including the possibility of transplanting an organ from a living donor. We will modify our existing simulation model of the US organ allocation system to include PALF, will validate the model to ensure that it represents the time course of PALF, and will use the model to examine transplant timing practices in children with PALF. PUBLIC HEALTH RELEVANCE: Acute liver failure in children is a devastating, often fatal condition for which one of the potential treatments is liver transplantation. However, the decision to choose to treat a child with a transplant is difficult, because even if a child is very ill, there is a chance that the child's liver would recover on its own, without surgery, and that the transplant would therefore be unnecessary. The best strategy for deciding when to wait a little longer or when to undertake transplantation is not known with certainty. The research we describe here will use statistics and mathematical models to better predict how fast liver disease will progress in children. The goal of the research is to improve decisions regarding the use of liver transplantation for young patients with acute liver disease.