Integrative metabolomic characterization of ADHD and asthma comorbidity

项目摘要/摘要 苏海珠，博士，硕士，生物统计学家和分子流行病学家，有强烈的和实质性的承诺 呼吸系统和神经发育疾病的综合组学研究。她的职业目标是成为 在开发和应用新的统计方法和多元统计方面具有专业知识的独立调查员 促进呼吸系统和呼吸系统交叉点的机械理解的网络方法 神经发育疾病。这一建议结合了朱博士在整合组学方法方面的广泛培训 发展，以及她在遗传和新陈代谢研究方面的经验，以检查 哮喘的代谢病因学和注意缺陷/多动障碍重叠(AAO)。一大笔钱 流行病学文献以惊人的一致性揭示出哮喘患者的风险更大。 对于ADHD，反之亦然，许多关于儿童哮喘的纵向研究表明，儿童患哮喘的风险过高 青春期和成年期的ADHD。然而，还没有研究直接询问生物机制。 这些情况可能与此相关。这一建议的中心假设是儿童哮喘和 ADHD既有共同的也有不同的代谢失调过程，其中一些可能有驱动因素 都是遗传的。这将使用儿童时期现有的遗传和代谢数据进行探索。 哮喘管理计划(CAMP)、维生素D产前哮喘缓解试验(VDAART)和 2010年哥本哈根儿童哮喘前瞻性研究(COPSAC)，三大前瞻性队列 患有广泛的纵向表型和多种基因组数据类型的儿童，通过识别代谢物和 与AAO相关的代谢谱(AIM 1)，构建多组学模型和特征 AAO异常代谢过程及其上游驱动因素(AIM 2)，以及验证和复制 所有调查结果(目标3)。随着朱博士完成这些目标，她的职业发展计划将促进 实现她的主要培训目标：1)增加对ADHD和哮喘诊断的临床理解 和治疗；2)对生物治疗的最佳方法和实践经验有细致入微的理解 和遗传和代谢数据的统计整合；3)发展机器学习和整合的技能 多组学分析的网络方法；4)加强当前的经验领域，以保持在 新的分析和研究设计技术；以及5)提高指导、教学和责任人的技能 研究的开展和交流。由世界专家组成的多元化指导团队的支持 在哮喘和精神病学遗传学、代谢组学、综合组学和统计学领域，与她一起 强大的量化培训和充满活力的哈佛医学院和布里格姆大学的知识界 和妇女医院，确保这项提议的成功。最后，这项研究将使用最先进的 多组学技术为理解哮喘和ADHD的病理生物学奠定初步基础 合并症，这是一个重要的和公认的公共卫生问题，新的研究计划将由此产生。

PROJECT SUMMARY/ABSTRACT Su H. Chu, PhD, MS is a biostatistician and molecular epidemiologist with strong and substantial commitments to integrative omic research in respiratory and neurodevelopmental disease. Her career objective is to become an independent investigator with expertise in developing and applying novel statistical methods and multiomic network approaches that facilitate mechanistic understanding of the intersection of respiratory and neurodevelopmental disease. This proposal combines Dr. Chu’s extensive training in integrative omic methods development, along with her experience in genetic and metabolomic research, to examine the integrative metabolomic etiology of asthma and attention-deficit/hyperactivity disorder overlap (AAO). A wealth of epidemiological literature has revealed with remarkable consistency that asthmatic patients are at greater risk for ADHD, and vice versa, with a number of longitudinal studies of childhood asthma indicating excess risk of ADHD in adolescence and adulthood. However, no studies have directly interrogated the biological mechanisms by which these conditions may be related. The central hypothesis of this proposal is that childhood asthma and ADHD share both common and distinct dysregulated metabolic processes, some of which may have drivers that are genetic in origin. This will be explored using existing genetic and metabolomic data from the Childhood Asthma Management Program (CAMP), the Vitamin D Antenatal Asthma Reduction Trial (VDAART), and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC), three large prospective cohorts of children with extensive longitudinal phenotyping and multiple omic data types, by identifying metabolites and metabolic profiles associated with AAO (aim 1), constructing multiomic models and features that characterize dysregulated metabolic processes and their upstream drivers in AAO (aim 2), and validation and replication of all findings (aim 3). As Dr. Chu completes these aims, her career development program will facilitate the achievement of her primary training goals: 1) increase clinical understanding of ADHD and asthma diagnosis and treatment; 2) gain a nuanced understanding of best methods for, and practical experience in, the biological and statistical integration of genetic and metabolomic data; 3) develop skills in machine learning and integrative network methods for multiomic analysis; 4) strengthen current areas of experience to stay on the cutting edge of new analytic and study design techniques; and 5) enhance skills in mentorship, teaching, and the responsible conduct and communication of research. The support of a diverse mentoring team comprised of world experts in the fields of asthma and psychiatric genetics, metabolomics, integrative omics, and statistics, along with her strong quantitative training and the vibrant intellectual community of Harvard Medical School and the Brigham and Women’s Hospital, ensure the success of this proposal. Finally, this research will use state-of-the-art multiomic techniques to lay the initial groundwork for understanding the pathobiology of asthma and ADHD comorbidity, a major and well-established public health concern, from which new research programs will emerge.