Targeting TB transmission hotspots to find undiagnosed TB in South Africa: a genomic, geospatial and modeling study (TARGET- TB)

针对南非的结核病传播热点寻找未确诊的结核病：一项基因组、地理空间和建模研究 (TARGET-TB)

• 批准号: 10211889
• 负责人: Barun Mathema
• 金额: $ 77.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-11 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211889
• 关键词: Area; Automobile Driving; Bacillus; Biological Markers; COVID-19 pandemic; Caring; Clinic; Communities; Coupled; Data; Data Element; Detection; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early identification; Early treatment; Epidemic; Evaluation; Exhibits; Failure; General Population; Genetic Transcription; Genomics; Geography; HIV/TB; Health system; Healthcare Systems; Heterogeneity; High Prevalence; Household; Incidence; Individual; Infection; Interruption; Intervention; Investigation; Link; Locales; Location; Methods; Modeling; National Institute of Allergy and Infectious Disease; Natural History; Patients; Pattern; Population; Preventive therapy; Public Health; RNA; Research Priority; South Africa; Southern Africa; Sputum; Statistical Data Interpretation; Statistical Models; Study models; Symptoms; Target Populations; Testing; Thoracic Radiography; Trees; Tuberculosis; Visit; Vulnerable Populations; Whole Blood; Work; base; case finding; community burden; data integration; design; effective therapy; fight against; genome sequencing; improved; innovation; molecular diagnostics; novel; novel diagnostics; novel strategies; pathogen; peri-urban; programs; screening; success; tool; transmission process; tuberculosis treatment; whole genome

Project Summary Despite renewed public health efforts, including more effective treatment, tuberculosis (TB) incidence has reduced only incrementally, an effect driven by the inability to contain community TB transmission. Early identification and treatment of infectious individuals is central to breaking the chain of transmission and is limited by the fact that up to 40% of incident TB cases remain undiagnosed. The associated prolonged duration of infectiousness and delays in treatment initiation contributes significantly to ongoing TB transmission. Undiagnosed cases comprise diseased individuals who have been missed by the healthcare system and those without symptoms (subclinical TB) where the ability to transmit TB is unknown. In our preliminary data, using active case finding and whole blood RNA biomarker, we identified subclinical TB disease at proportions that approach or exceed that of symptomatic active TB. These cases were associated with the presence of viable bacilli in the sputum, pointing to a large potentially infectious pool of individuals. In high-transmission settings, highly targeted approaches like household contact investigation will capture only a small proportion of TB cases, yet general-population approaches are too inefficient to be practical. New case finding methods are needed that increase diagnostic yield through targeted screening in high-prevalence and high-transmission subpopulations. In low-incidence settings, standard mapping tools have been used to identify target populations for enhanced case-finding. Whether similar methods are sufficient in endemic settings is unknown and critical to advance new case-finding approaches. To develop appropriate strategies, we must first understand the mechanisms and spatial patterns of community-level TB transmission that include subclinical TB. Advances in spatial and genomic statistical modeling coupled with sensitive diagnostics now enable evaluation of spatially targeted TB screening in high-burden communities. We hypothesize that transmission hotspots harbor large number of individuals with undiagnosed and subclinical TB that when targeted can improve efficiency of TB case finding. In Aim 1, we determine the proportion of TB transmission that occur within spatially organized hotspots. In Aim 2, we test whether spatially targeted case-finding will be more effective and efficient than broader approaches for identifying active and subclinical prevalent TB. To accomplish our aims, we incorporate innovative spatial statistical modeling with Bayesian phylodynamic methods to infer TB transmission using whole genome sequencing data, and use novel RNA biomarker and Xpert Ultra with chest radiography to detect prevalent TB in the community. If undetected prevalent TB, including subclinical forms are, in fact, concentrated in locales of transmission, this would have important and practical implications for targeted community TB screening strategies as a means to identify infectious individuals early and interrupt transmission by early initiation of TB treatment.

项目摘要 尽管新的公共卫生努力，包括更有效的治疗，结核病(TB)的发病率 仅以递增方式减少，这是由于无法控制社区结核病传播造成的影响。早些时候 对感染者的识别和治疗是打破传播链的核心，而且是有限的 高达40%的结核病病例仍未得到诊断。相关延长的持续时间 传染性和治疗开始的延迟是结核病持续传播的重要原因。 未诊断的病例包括被医疗系统遗漏的疾病患者和 没有症状(亚临床结核病)，传播结核病的能力未知。在我们的初步数据中，使用 活动性病例发现和全血RNA生物标记物，我们确定了亚临床结核病的比例 接近或超过有症状的活动性结核病。这些病例与活体病毒的存在有关。 痰中有杆菌，表明有大量潜在的感染性个体。在高传输设置中， 像家庭接触调查这样的高度针对性的方法只会捕获一小部分结核病病例， 然而，普通人群的方法效率太低，不切实际。需要新的病例发现方法 通过在高流行率和高传播亚群中进行有针对性的筛查，提高诊断产量。 在低发病率环境中，已使用标准测绘工具来识别目标人群，以加强 查案。类似的方法在流行环境中是否足够还是个未知数，对于推动新的 病例查找方法。要制定适当的战略，我们必须首先了解机制和 社区一级结核病传播的空间模式，包括亚临床结核病。空间和基因组研究进展 与敏感诊断相结合的统计建模现在能够评估空间定向的结核病筛查 在高负担社区。我们假设传播热点地区有大量的人患有 未确诊和亚临床结核病，如果有针对性，可以提高结核病病例发现的效率。在目标1中，我们 确定在空间组织的热点地区内发生的结核病传播的比例。在目标2中，我们测试 空间定向病例发现是否会比更广泛的识别方法更有效和更有效率 活动性和亚临床流行的结核病。为了实现我们的目标，我们结合了创新的空间统计 用贝叶斯系统动力学方法建模以使用全基因组测序数据推断结核病传播， 并使用新型RNA生物标志物和Xpert Ultra胸片检测社区流行的结核病。 如果未发现的流行结核病，包括亚临床形式，实际上集中在传播地点，这 将对有针对性的社区结核病筛查战略产生重要和实际的影响，作为一种手段 及早识别感染者，并通过及早开始结核病治疗来阻断传播。