Development and evaluation of a risk-based approach to target vitamin A therapy to prevent bronchopulmonary dysplasia among very low birth weight infants

项目总结/摘要 支气管肺发育不良（BPD）是早产后的一种慢性肺部疾病， 每年有超过10，000名美国婴儿死亡，导致长期呼吸功能障碍，生长衰竭和 神经发育障碍，以及大量的医疗费用。尽管付出了巨大的努力， 研究BPD的预防，在过去十年中BPD的发病率几乎没有改善， 超过三分之一的极低出生体重婴儿受到影响。维生素A疗法是为数不多的 在大型随机临床试验中证明可降低BPD发生率的疗法;最新的科克伦 对维生素A治疗试验的回顾（2016）显示，对10项试验的荟萃分析支持其疗效。 然而，这种疗法的临床应用是可变的。最近的研究估计， 的符合试验条件的婴儿在美国接受维生素A治疗，由于担心其成本和持续 相关性主要临床试验20年后，由尤妮斯肯尼迪施莱佛NICHD新生儿 研究网络，已出版。新生儿学家每天都面临着是否使用维生素C的问题。 但缺乏证据支持他们的决策。拟议的工作将评估成本- 利用针对风险的方法对最有可能发生以下情况的婴儿进行维生素A治疗的有效性 我们将使用先前详细阐述的基于多变量风险的临床试验解释方法， NICHD新生儿研究网络维生素A治疗效果异质性评价预测 试验，最大的维生素A治疗的临床试验。使用来自同一网络的最新数据，我们将评估 自试验进行以来，BPD谱和发生率的变化如何影响对 试验结果。我们将比较替代风险目标应用的增量成本和收益， 维生素A治疗在最近的队列。这项研究的总体目标是建立客观的证据- 指导维生素A治疗的最佳应用，以减少临床和公共卫生负担 关于BPD本工作中探索的方法也适用于与其他相关的临床试验解释。 临床问题，目的是改善围绕临床和公共卫生的决策 实施临床试验结果对生殖医学的影响。重要的是，研究和培训计划 在这里详细阐述，重点是合作的跨学科科学和翻译的方法，从其他领域 将为申请人提供一个坚实的基础，发展成为一个富有成效的，独立的 临床医生-科学家，具有在临床实践中改善科学证据解释的技能。

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD), a form of chronic lung disease following premature birth, affects more than 10,000 U.S. infants annually and leads to death, long-term respiratory dysfunction, growth failure and neurodevelopmental impairment, as well as substantial healthcare costs. Despite enormous efforts devoted to researching the prevention of BPD, there has been little improvement in BPD incidence during the last decade, with greater than one-third of very low birth weight infants affected. Vitamin A therapy is among the few therapies proven in large randomized clinical trials to reduce the incidence of BPD; the most recent Cochrane review of trials of vitamin A therapy (2016) showed that a meta-analysis of 10 trials supported its efficacy. However, clinical uptake of this therapy has been variable. Recent studies estimate that less than one-quarter of trial-eligible infants in the U.S. receive vitamin A therapy due to concerns about its cost and continued relevance two decades after the principal clinical trial, by the Eunice Kennedy Shriver NICHD Neonatal Research Network, was published. Neonatologists are faced with the daily question of whether to use vitamin A therapy yet lack evidence to support their decision-making. The proposed work will evaluate the cost- effectiveness of utilizing risk-targeted approaches to administer vitamin A therapy to infants most likely to benefit from it. We will use previously elaborated clinical trial interpretation methods based on multivariable risk prediction to evaluate for treatment effect heterogeneity in the NICHD Neonatal Research Network Vitamin A Trial, the largest clinical trial of vitamin A therapy. Using recent data from the same Network, we will evaluate how changes in the spectrum and incidence of BPD since the trial was performed affect interpretation of the trial results. We will compare the incremental costs and benefits of alternative risk-targeted applications of vitamin A therapy within the recent cohort. The overall goal of this research is to develop objective, evidence- based methods to guide optimal application of vitamin A therapy to reduce the clinical and public health burden of BPD. Methods explored in this work will also be applicable to clinical trial interpretation related to other clinical questions, with the objective to improve decision-making surrounding the clinical and public health impact of implementing clinical trial results in neonatology. Importantly, the research and training plan elaborated here, focused on collaborative interdisciplinary science and translation of methods from other fields to neonatology, will provide the applicant with a solid foundation to develop as a productive, independent clinician-scientist with skills to improve the interpretation of scientific evidence in clinical practice.