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

项目摘要 申请K01职业发展奖是为了支持凯瑟琳·沃尔特博士的培训和 结核病基因组流行病学新方法研究。沃尔特博士的研究重点是 开发和应用工具来利用病原体变异来表征传染病传播 和进化，以便在高发病率、资源匮乏的环境中中断传输。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的方案 传动链。基因组流行病学研究越来越多地被用来描述结核病 变速箱。然而，目前的方法分辨率有限，因为它们对单个M进行测序。 每个感染者的结核病基因组。尽管流行性感冒具有流行病学和临床意义 宿主内结核分枝杆菌的多样性，一致和准确地恢复这种多样性和 将这些信息合并到传输中缺乏推论。本研究建议旨在(1) 系统地评估从收集的痰样本中恢复宿主内多样性的方法 在高发病率环境中进行主动筛查，(2)测量传播的结核分枝杆菌的多样性，并 持续存在二次感染，以及(3)开发一个模型，利用宿主内的M。 结核病多样性数据。拟议的项目将利用并扩大主要导师的NIH- 资助的R01研究(AI130058，AI149620；PI：Andrews)。在一项五年培训计划中，沃尔特博士将获得 具备以下技能：(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现的生物信息学工作流程。沃尔特医生会 由斯坦福医学院医学副教授Jason Andrews博士指导，全球 在资源有限的情况下诊断、治疗和控制结核病的专家。她将成为-- 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 他的研究开创了结核分枝杆菌混合菌株感染研究的先河。在……里面 此外，沃尔特博士将与传染病内科医生兼科学家胡里奥·克罗达博士密切合作 巴西南马托格罗索州联邦大学教授，具有丰富的领导经验 年结核病和热带疾病的前瞻性队列、基因组流行病学研究和临床试验 巴西。她还将与西蒙·弗雷泽大学数学教授卡罗琳·科利恩博士合作， 世卫组织开发了几种用于传播推断的统计方法。这项研究的结果和 培训计划将为未来的R01应用程序提供基础，该应用程序将开发自动化的 用于实时传播推断和结核病发病率估计的流水线，利用人群水平，多 年基因组监测数据。这项建议将为她提供研究、培训和专业知识 过渡到独立教员职位的发展时间。

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.