Newborn Screening, Malnutrition and Lung Disease in Children with Cystic Fibrosis

描述（由申请人提供）：囊性纤维化（CF）是美国最常见的缩短寿命的遗传性疾病之一，其活产率为1:4000。CF以胃肠道和肺部表现为特征。营养不良和生长迟缓很普遍，甚至发生在通过新生儿筛查（NBS）确诊的婴儿身上。阻塞性肺病伴反复呼吸道感染是不可避免的。虽然中位生存年龄稳步提高，2008年达到37岁，但20%的CF死亡仍然发生在20岁之前。本研究的总体目标是通过流行病学和临床研究量化CF患儿NBS、营养不良和肺部疾病之间的关系，最终目标是制定循证指南，以提高CF的诊断质量、医疗服务和健康结果。1)通过使用自1985年以来收集的三个正在进行的免费数据库，即CF基金会患者登记处、CF NBS项目的威斯康星州随机临床试验（RCT）和威斯康星州常规CF NBS项目，验证CF中营养不良和肺部疾病由“基线风险”（例如人口统计学、诊断、基因型、表型）和“纵向风险”（例如前几年的变化）决定的假设。2)通过比较威斯康星常规CF NBS队列（出生在1994-2003年）和威斯康星RCT CF NBS队列（出生在1985-1994年）的营养和肺部结果，检验在常规和研究环境中实施的CF NBS同样有效的假设；3)检验纯母乳喂养与生命最初两年生长迟缓风险较高但呼吸道感染风险较低相关的假设。通过开展一项前瞻性观察性研究，纳入2011-2015年出生后不久通过NBS诊断的CF婴儿，这些婴儿来自三个州（WI， in和UT）的四个CF中心，系统地获取母乳喂养（完全/部分，持续时间）和配方（类型，热量密度，数量）的详细数据，以检查母乳喂养对营养和肺部结局的潜在益处和风险。没有其他调查有可比的研究人员和工具来进行拟议的工作。首席研究员是全国公认的CF流行病学家，以其利用大型复杂纵向数据库进行结果研究的专业知识而闻名。自2002年以来，在NIDDK的支持下，首席研究员与特定目标1相关的工作产生了新的、基于证据的知识，改善了CF的临床实践。鉴于2010年开始在全国范围内实施CF NBS，完成特定目标2和3的临床和公共卫生影响也可以预见在不久的将来。完成这项拨款将促进对CF中营养不良和肺部疾病进展的关键决定因素的理解，改善CF的临床实践，提高CF患儿的健康结果，并解决关于CF中母乳喂养的潜在益处和风险的争议，从而建立最佳的喂养指南。

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders with an incidence of 1:4000 live births in the US. CF is characterized by gastrointestinal and pulmonary manifestations. Malnutrition and growth faltering are prevalent, and occur even in infants diagnosed through newborn screening (NBS). Obstructive lung disease with recurrent respiratory infections is inevitable. Although median age of survival has improved steadily and reached 37 years in 2008, 20% of CF deaths still occur before 20 years of age. The overall objective of this research is to quantify the associations among NBS, malnutrition and lung disease in children with CF through epidemiological and clinical studies, with the ultimate goal of developing evidence-based guidelines for improving the quality of diagnosis, medical care and health outcomes of CF. Specific Aims are: 1) to test the hypothesis that malnutrition and lung disease in CF are determined by "baseline risk" (e.g., demographics, diagnosis, genotype, phenotype), and "longitudinal risk" (e.g., changes in the preceding years) by using three ongoing, complimentary databases collected since 1985, namely, the CF Foundation Patient Registry, the Wisconsin Randomized Clinical Trial (RCT) of CF NBS Project and the Wisconsin Routine CF NBS Program, 2) to test the hypothesis that CF NBS implemented in the routine and research settings are similarly effective, by comparing nutritional and pulmonary outcomes of the Wisconsin Routine CF NBS cohort (born 1994-2003) to the Wisconsin RCT CF NBS cohort (born 1985-1994), and 3) to test the hypothesis that exclusive breastfeeding is associated with higher risk of growth faltering but lower risk of respiratory infections in the first two years of life, by conducting a prospective observational study that enrolls CF infants diagnosed through NBS in 2011-2015 soon after birth from four CF Centers in three states (WI, IN and UT) to systematically obtain detailed data on breastfeeding (exclusive/partial, duration) and formula (type, caloric density, amount) at frequent intervals in order to examine the potential benefits and risks of breastfeeding on nutritional and pulmonary outcomes. No other investigation has comparable researchers and tools to conduct the proposed work. The Principal Investigator is a nationally recognized CF epidemiologist known for her expertise in utilizing large complex longitudinal databases for outcome studies. With NIDDK's support since 2002, the Principal Investigator's work related to Specific Aim 1 has generated new, evidence-based knowledge that improved the clinical practices of CF. In view of the nationwide implementation of CF NBS beginning 2010, the clinical and public health impacts as a result of completing Specific Aims 2 and 3 are also foreseeable in the near future. Accomplishing this grant will advance the understanding of critical determinants of malnutrition and lung disease progression in CF, improve clinical practices of CF, enhance health outcomes of children with CF, and resolve the controversy on the potential benefits and risks of breastfeeding associated with CF in order to establish optimal feeding guidelines.