Leveraging within-host M. tuberculosis diversity data to enhance transmission inference

项目摘要 K 01职业发展奖的申请是为了支持凯瑟琳·沃尔特博士的培训， 研究结核病基因组流行病学的新方法。沃尔特博士的研究重点是 开发和应用工具，利用病原体变异来描述传染病传播的特征 和进化，以便在发病率高、资源贫乏的环境中阻断传播。沃尔特博士的研究 利用宿主内结核分枝杆菌基因组变异重建结核病 传输链基因组流行病学研究越来越多地用于结核病的特征描述 传输然而，目前的方法具有有限的分辨率，因为它们对单个M进行测序。 每个感染者的结核病基因组。尽管流行病学和临床意义， 寄主内M.结核病多样性，一致和准确地恢复这种多样性的工具， 缺乏将该信息结合到传输推断中。本研究旨在（1） 系统地评估从痰液样本中恢复宿主内多样性的方法， 在高发病率的情况下进行主动筛查，（2）测量M。结核病传播的多样性， 二次感染持续存在，（3）建立一个模型来推断使用宿主内M. 结核病多样性数据。拟议的项目将利用和扩大主要导师的国立卫生研究院- 资助的R 01研究（AI 130058，AI 149620; PI：Andrews）。在五年的培训计划中，沃尔特博士将获得 技能（1）基因组数据的统计分析和可视化，（2）进化的数学建模， 传输，以及（3）为基因组数据编写开放和可重复的生物信息学工作流程。沃尔特医生会 由斯坦福大学医学院医学副教授Jason Andrews博士指导， 在资源有限的情况下诊断、治疗和控制结核病的专家。她会在- 由耶鲁大学微生物疾病流行病学副教授西奥多科恩博士指导 他的研究开创了M.结核在 此外，沃尔特博士将与传染病医生-科学家胡利奥·克罗达博士密切合作， 巴西南马托格罗索联邦大学教授， 前瞻性队列研究、基因组流行病学研究和结核病和热带疾病的临床试验， 巴西她还将与西蒙弗雷泽大学数学教授Caroline Colijn博士合作， 他开发了几种用于传输推断的统计方法。这项研究的结果和 培训提案将为未来的R 01应用程序提供基础，该应用程序将开发自动化的 实时传播推断和结核病发病率估计的管道， 年的基因组监测数据。这项建议将为她提供研究，培训和专业 发展时间过渡到一个独立的教师职位。

Project Summary This application to the K01 Career Development Award is to support Dr. Katharine Walter in her training and research into new methods for tuberculosis genomic epidemiology. Dr. Walter’s research focuses on developing and applying tools to harness pathogen variation to characterize infectious disease transmission and evolution in order to interrupt transmission in high-incidence, resource-poor settings. Dr. Walter’s research proposal leverages within-host Mycobacterium tuberculosis genomic variation to reconstruct tuberculosis transmission chains. Genomic epidemiology studies are increasingly used to characterize tuberculosis transmission. However, current approaches have limited resolution because they sequence a single M. tuberculosis genome from each infected individual. Despite the epidemiological and clinical significance of within-host M. tuberculosis diversity, tools to consistently and accurately recover such diversity and to incorporate this information into transmission inferences are lacking. This research proposal aims to (1) systematically assess methods for recovering within-host diversity from sputum samples collected during active screening in a high-incidence setting, (2) measure the M. tuberculosis diversity that is transmitted and persists in a secondary infection, and (3) develop a model to infer transmission linkages using within-host M. tuberculosis diversity data. The proposed project will leverage and expand upon the primary mentor’s NIH- funded R01 studies (AI130058, AI149620; PI: Andrews). In a five-year training plan, Dr. Walter will acquire skills in (1) statistical analysis and visualization of genomic data, (2) mathematical modeling of evolution and transmission, and (3) writing open and reproducible bioinformatic workflows for genomic data. Dr. Walter will be mentored by Dr. Jason Andrews, Associate Professor of Medicine at Stanford School of Medicine, a global expert in the diagnosis, treatment and control of tuberculosis in resource-limited settings. She will be co- mentored by Dr. Theodore Cohen, Associate Professor of Epidemiology of Microbial Diseases at the Yale School of Public Health, whose research pioneered the study of mixed strain infections in M. tuberculosis. In addition, Dr. Walter will collaborate closely with Dr. Julio Croda, an infectious disease physician-scientist and Professor at Federal University of Mato Grosso do Sul, Brazil, who has extensive experiencing leading prospective cohorts, genomic epidemiology studies, and clinical trials on tuberculosis and tropical diseases in Brazil. She will also collaborate with Dr. Caroline Colijn, Professor of Mathematics at Simon Fraser University, who has developed several statistical approaches for transmission inference. The results of this research and training proposal will provide the foundation for a future R01 application, which will develop an automated pipeline for real-time transmission inference and TB incidence estimation harnessing population-level, multi- year genomic surveillance data. This proposal will provide her the research, training, and professional development time to transition to an independent faculty position.