Multidimensional phenotype classification in grade 3 BPD

项目摘要/摘要 支气管肺发育不良(BPD)是一种严重的慢性肺部疾病，在发病的头几个月发病。 超过一半的婴儿出生时孕周不到30wk。每天发育3级的婴儿，最多 严重的疾病形式(定义为经后36周的有创呼吸机)，终生风险高 健康和认知方面的缺陷以及生活质量差。不幸的是，3级石油日产量正在上升，而且 目前还没有任何疗法被证明可以治疗这种毁灭性的疾病。造成这些护理差距的一个关键因素是 几乎完全依赖规定的呼吸支持来定义BPD的存在和严重程度，选择 治疗干预，并评估预后。我们的数据和其他人的数据表明，这种主观诊断 治疗方法掩盖了临床表现、治疗反应和结果的显著异质性。在……里面 其他异质性慢性呼吸道疾病，如COPD、囊性纤维化和哮喘，证据- 基于表型(基于共同特征的患者亚组识别)已成为新的 黄金标准，客观地对不同的疾病亚型进行分类，改进患者咨询，识别新的 疾病机制，并发现和实施更有效的治疗方法。我们的中心假设是 3级BPD的多维表型是可行的，将准确地表征疾病的异质性， 并将改善结果预测。这一假设的确认将推动一种框架向 目的：在BPD中采用系统诊断方法，并首次在新生儿学中进行表型特异性试验。 重要的是，我们鼓舞人心的初步数据支持了这一假设。使用以下项目的回顾结果 胸部CT、心脏回声和支气管镜检查，我们显示3级BPD的早产儿可以 根据是否有严重的肺部实质性疾病分为表型、异常 大气道和肺动脉高压。这种诊断方法与预放电相关。 结果，并建议可能的表型特异性治疗。然而，它依赖于选定的调查员 表型而不是经验派生的亚群，只使用了3次诊断测试的定性结果， 并且没有评估纵向表型稳定性或出院后结果。我们最近的数据表明 对BPD已证实的机械性因素的连续定量心肺成像和评估可能 改进疾病表型和预后预测。我们的建议建立在这些初步数据的基础上，并将 利用强大的集群分析和纵向多维成像、生物和临床数据 大量预期的极早产儿队列，以实现以下具体目标：(1)确定 客观的、基于证据的表型在3年级BPD中，和(2)定义之间的关联强度 3级BPD表型和经过2年校正年龄的神经发育和肺结果 使用标准化的开发测试和经过验证的结果度量。

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease that develops over the first months of life in more than half of infants born less than 30wk of gestation. Infants who develop grade 3 BPD, the most severe disease form (defined as invasive ventilation at 36wk postmenstrual age), are at high risk for life-long deficits in health and cognition and poor quality of life. Unfortunately, rates of grade 3 BPD are increasing, and no therapies have been proven to treat this devastating disease. A key contributor to these care gaps is the nearly singular reliance on the prescribed respiratory support to define BPD presence and severity, select therapeutic interventions, and assess prognosis. Our data and others’ show that this subjective diagnostic approach masks significant heterogeneity in clinical presentation, treatment responsiveness, and outcomes. In other heterogenous chronic respiratory conditions such as COPD, cystic fibrosis, and asthma, evidence- based phenotyping (identification of patient subgroups based on shared characteristics) has become the new gold-standard to objectively classify distinct disease sub-types, improve patient counseling, identify novel disease mechanisms, and discover and implement more effective treatments. Our central hypothesis is that multidimensional phenotyping in grade 3 BPD is feasible, will accurately characterize disease heterogeneity, and will improve outcome prediction. Confirmation of this hypothesis will promote a frameshift towards an objective, systematic diagnostic approach in BPD and first-ever phenotype-specific trials in neonatology. Importantly, our motivating preliminary data support this hypothesis. Using retrospective results from chest CT, cardiac echo, and bronchoscopy, we showed that preterm infants with grade 3 BPD can be classified into phenotypes based on the presence or absence of severe parenchymal lung disease, abnormal large airways, and pulmonary arterial hypertension. This diagnostic approach correlated with pre-discharge outcomes and suggested possible phenotype-specific therapies. However, it relied on investigator chosen phenotypes rather than empirically derived subgroups, used qualitative results from only 3 diagnostic tests, and did not assess longitudinal phenotype stability or post-discharge outcomes. Our recent data indicate that serial quantitative cardiopulmonary imaging and evaluation of proven mechanistic contributors to BPD may improve disease phenotyping and outcome prediction. Our proposal builds on these preliminary data and will employ robust cluster analyses and longitudinal multidimensional imaging, biological, and clinical data in a large, prospective cohort of very preterm infants to accomplish the following Specific Aims: (1) define objective, evidence-based phenotypes in grade 3 BPD, and (2) define the strength of association between grade 3 BPD phenotypes and neurodevelopmental and pulmonary outcomes through 2 years’ corrected age using standardized development testing and validated outcome measures.