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）是最常见的缩短寿命的遗传性疾病之一，在美国的发病率为1：4000活产。CF以胃肠道和肺部表现为特征。营养不良和生长迟缓是普遍存在的，甚至发生在通过新生儿筛查（NBS）诊断的婴儿中。阻塞性肺病合并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，但仍有20%的CF死亡发生在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儿童NBS、营养不良和肺部疾病之间的关联，最终目标是制定循证指南，以提高CF的诊断、医疗护理和健康结局的质量。 具体目的是：1）检验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），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计划，2）检验在常规和研究环境中实施的CF NBS具有相似有效性的假设，通过比较威斯康星州常规CF NBS队列的营养和肺部结局，（出生于1994-2003年）至威斯康星州RCT CF NBS队列（1985-1994年出生），以及3）为了检验纯母乳喂养与生命头两年中生长迟缓的风险较高但呼吸道感染的风险较低相关的假设，通过进行一项前瞻性观察研究，招募了2011-2015年在三个州的四个CF中心出生后不久通过NBS诊断的CF婴儿，（威斯康星州、印第安纳州和犹他州）系统地获得关于母乳喂养的详细数据（完全/部分、持续时间）和配方奶粉（类型、热量密度、数量），以检查母乳喂养对营养和肺部结果的潜在益处和风险。 没有其他调查有类似的研究人员和工具来进行拟议的工作。主要研究者是一位全国公认的CF流行病学家，以其利用大型复杂纵向数据库进行结局研究的专业知识而闻名。自2002年以来，在NIDDK的支持下，主要研究者与特定目标1相关的工作产生了新的循证知识，改善了CF的临床实践。鉴于从2010年开始在全国范围内实施CF NBS，在不久的将来也可以预见完成具体目标2和3所带来的临床和公共卫生影响。完成这项赠款将促进对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儿童的健康结果，并解决与CF相关的母乳喂养的潜在益处和风险的争议，以建立最佳喂养指南。 囊性纤维化是一种遗传性疾病，影响超过30，000名美国人。营养不良和肺部疾病降低了囊性纤维化患者的生存率; 20%的死亡发生在20岁之前，一半在30多岁之前死亡。该研究项目包括流行病学和临床研究，这些研究将产生制定循证指南所需的新知识，以提高囊性纤维化儿童的诊断，医疗护理和临床结局的质量。

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. PUBLIC HEALTH RELEVANCE: Cystic fibrosis is a genetic disease that affects more than 30,000 Americans. Malnutrition and lung disease reduce survival of cystic fibrosis patients; 20% of deaths occur before 20 years of age and half die before mid 30's. This research project includes epidemiological and clinical studies that will generate new knowledge needed to develop evidence-based guidelines for improving the quality of diagnosis, medical care and clinical outcomes of children with cystic fibrosis.