Transmission of drug-resistant tuberculosis in a South African city with a high prevalence of HIV infection

项目总结 此申请表是为波士顿大学理工学院讲师丽贝卡·伯哈努医学博士颁发的K08奖。 公共卫生学院的全球卫生，正在培训成为该领域的独立调查员 分子流行病学和结核病(TB)传播研究。结核病是人类感染的主要原因。 全球范围内的死亡，是艾滋病毒携带者的头号死因。新近确诊的结核病 全基因组测序(WGS)方法的传播簇提供了对传播的独特见解 通过传统的接触者追踪无法获得的图案。 总体研究目标是利用WGS与分子时钟、系统发育和传递簇相结合 南部约翰内斯堡地区利福平和多药耐药(RR/MDR)结核病传播特征分析 非洲。研究的目的是：1)使用WGS数据计算RR/MDR-TB的分子时钟；2)使用 基于单核苷酸多态性的聚类分析和贝叶斯传递分析 最近的结核病传播集群或RR/MDR-TB，并评估艾滋病毒状况、CD4计数和 抗逆转录病毒治疗(ART)对传播结核病的可能性和3)确定WGS传播集群 利用人口统计和社交网络数据增强的身份识别可以识别 最近的RR/耐多药结核病传播。 Berhanu博士将接受结核病流行病学、生物信息学等跨学科专家团队的指导 和结核病基因组学。她的主要导师霍斯伯格博士是波士顿大学的医学和流行病学教授 他在结核病临床和翻译研究方面拥有30多年的经验。她的联合小学导师， 凯伦·雅各布森博士，波士顿大学医学助理教授，结核病流行病学专家 在高负担环境中，并利用结核病分子数据在南非广泛开展工作。伯哈努医生的 咨询委员会包括生物医学信息学助理教授玛哈·法哈特博士 在… 哈佛大学， 世卫组织发表了大量关于耐药性突变特征和最近传播的标记的文章 结核病基因组数据；约翰内斯堡NICD结核病中心主任纳齐尔·伊斯梅尔博士是一位专家 和埃文·约翰逊博士，医学和生物统计学副教授 波士顿大学，拥有生物信息学方法论方面的专业知识。Berhanu博士的培训计划与建议的 研究目标：在流行病学方面建立坚实的基础；在生物信息学方面发展新的技能， 利用WGS数据进行系统发育和传播分析。培训将通过组合的方式完成 在南非和波士顿开设了教学课程、研讨会和实践课程。这些培训和研究 这些活动将使Berhanu博士成长为一名独立的研究员，并为R01使用 分子和社会网络数据，以确定传播热点和有针对性的病例发现区域。

PROJECT SUMMARY This application is for a K08 award for Rebecca Berhanu MD, an Instructor at Boston University’s Department of Global Health in the School of Public Health, who is training to become an independent investigator in the field of molecular epidemiology and tuberculosis (TB) transmission research. TB is the leading infectious cause of death globally and the number one cause of death amongst people with HIV. The identification of recent TB transmission clusters by whole genome sequencing (WGS) methods offers unique insight into transmission patterns which cannot be obtained through traditional contact tracing. The overall research objective is to use WGS coupled with molecular clock, phylogenic and transmission cluster analysis to characterize transmission of rifampin and multi-drug resistant (RR/MDR) TB in Johannesburg, South Africa. The aims of the study are to: 1) Use WGS data to calculate the molecular clock of RR/MDR-TB, 2) Use single-nucleotide polymorphism (SNP)-based cluster analysis and Bayesian transmission analysis to identify recent TB transmission clusters or RR/MDR-TB, and evaluate the impact of HIV status, CD4 count and antiretroviral therapy (ART) on the likelihood of transmitting TB and 3) Determine if WGS transmission cluster identification augmented with demographic and social-network data can identify non-household locations of recent RR/MDR-TB transmission. Dr. Berhanu will receive mentorship from a team of inter-disciplinary experts in TB epidemiology, bioinformatics and TB genomics. Her primary mentor, Dr Horsburgh, is a Professor of Medicine and Epidemiology at Boston University and has over 30 years’ experience in TB clinical and translational research. Her co-primary mentor, Dr. Karen Jacobson, an Assistant Professor of Medicine at Boston University, is an expert in TB epidemiology in high-burden settings and has worked extensively in South Africa using TB molecular data. Dr. Berhanu’s Advisory Board includes Dr. Maha Farhat, Assistant Professor of Biomedical Information at Harvard University, who has published extensively on resistance mutation characterization and markers of recent transmission using TB genomic data; Dr. Nazir Ismail, head of the Centre for Tuberculosis of the NICD in Johannesburg, is an expert in TB molecular epidemiology, and Dr. Evan Johnson, Associate Professor of Medicine and Biostatistics at Boston University, with expertise in bioinformatics methodology. Dr. Berhanu’s training plan links to the proposed research aims: establish a solid foundation in epidemiology; and develop new skills in bioinformatics, phylogenetics and transmission analysis using WGS data. Training will be accomplished through a combination of didactic courses, workshops, and practicums in South Africa and Boston. These training and research activities will allow Dr. Berhanu to mature into an independent investigator and provide a basis for an R01 using molecular and social network data to identify transmission hotspots and areas for targeted case-finding.