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

利用宿主内结核分枝杆菌多样性数据增强传播推断

• 批准号: 10570803
• 负责人: Katharine Sassandra Walter
• 金额: $ 13.21万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-08 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570803
• 关键词: Bioinformatics; Brazil; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Consensus; Consensus Sequence; Development; Diagnosis; Drug resistance; Enrollment; Epidemic; Epidemiology; Event; Evolution; Faculty; Foundations; Funding; Future; Genetic; Genetic Models; Genome; Genomics; Genotype; Hybrids; Incidence; Individual; Infection; Interruption; K-Series Research Career Programs; Link; Location; M. tuberculosis genome; Mathematics; Measures; Medicine; Mentors; Methods; Minority; Modeling; Molecular Epidemiology; Mycobacterium tuberculosis; Participant; Pattern; Phylogenetic Analysis; Physicians; Population; Population Genetics; Positioning Attribute; Prisons; Prospective cohort; Public Health Schools; Recovery; Reference Standards; Reporting; Reproducibility; Research; Research Proposals; Resolution; Resource-limited setting; Risk; Sampling; Scientist; Sputum; Statistical Data Interpretation; Time; Training; Treatment outcome; Trees; Tropical Disease; Tuberculosis; United States National Institutes of Health; Universities; Variant; Visualization; Writing; burden of illness; career; clinically significant; deep sequencing; disease transmission; diverse data; epidemiological model; epidemiology study; experience; genomic data; genomic epidemiology; genomic tools; genomic variation; information model; innovation; mathematical model; medical schools; microbial disease; mid-career faculty; novel; novel strategies; pathogen; professor; programs; prospective; reference genome; screening; secondary infection; skill acquisition; surveillance data; tool; transmission process

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.

项目概要 申请 K01 职业发展奖是为了支持 Katharine Walter 博士的培训和 沃尔特博士的研究重点是结核病基因组流行病学新方法。 开发和应用工具来利用病原体变异来表征传染病的传播 沃尔特博士的研究旨在通过进化来中断高发病率、资源匮乏的环境中的传播。 提案利用宿主内结核分枝杆菌基因组变异来重建结核病 基因组流行病学研究越来越多地用于描述结核病的特征。 然而，当前的方法分辨率有限，因为它们对单个 M 进行排序。 尽管具有流行病学和临床意义，但来自每个感染个体的结核病基因组。 宿主内结核分枝杆菌多样性，一致且准确地恢复这种多样性的工具，并 缺乏将此信息纳入传输推论中，该研究提案旨在 (1)。 彻底评估从期间收集的痰样本中恢复宿主内多样性的方法 在高发病率环境中主动筛查，（2）测量传播和传播的结核分枝杆菌多样性 持续存在继发感染，(3) 开发一个模型，利用宿主内分枝杆菌推断传播联系。 拟议的项目将利用和扩展主要导师的 NIH-数据。 资助的 R01 研究（AI130058、AI149620；PI：安德鲁斯）在五年培训计划中，沃尔特博士将获得 (1) 基因组数据的统计分析和可视化技能，(2) 进化的数学建模和 Walter 博士将：（3）为基因组数据编写开放且可重复的生物信息学工作流程。 由斯坦福大学医学院医学副教授 Jason Andrews 博士指导 她将是资源有限环境中结核病诊断、治疗和控制方面的专家。 由耶鲁大学微生物疾病流行病学副教授 Theodore Cohen 博士指导 公共卫生学院，其研究开创了结核分枝杆菌混合菌株感染的研究。 此外，Walter 博士将与传染病医师科学家 Julio Croda 博士密切合作， 巴西南马托格罗索联邦大学教授，拥有丰富的领导经验 结核病和热带病的前瞻性队列、基因组流行病学研究和临床试验 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。 培训提案将为未来的 R01 应用奠定基础，该应用将开发自动化的 利用人口水平、多因素进行实时传播推断和结核病发病率估计的管道 该提案将为她提供研究、培训和专业知识。 过渡到独立教职职位的发展时间。