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.

项目概要 尽管采取了新的公共卫生措施，包括采取更有效的治疗措施，但结核病 (TB) 发病率仍呈下降趋势。 仅逐步减少，这是由于无法遏制社区结核病传播而产生的影响。早期的 感染者的识别和治疗对于打破传播链至关重要，但作用有限 高达 40% 的结核病病例仍未确诊。相关的持续时间延长 传染性和治疗开始的延迟极大地促进了结核病的持续传播。 未确诊病例包括被医疗保健系统遗漏的患病个体以及那些 无症状（亚临床结核病），其传播结核病的能力未知。在我们的初步数据中，使用 通过积极的病例发现和全血 RNA 生物标志物，我们发现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。这些案例与存在可行的 痰中含有杆菌，表明存在大量潜在的传染性个体。在高传输设置下， 诸如家庭接触者调查等高度针对性的方法只能捕获一小部分结核病病例， 然而，针对一般人群的方法效率太低，不切实际。需要新的病例发现方法 通过对高患病率和高传播亚人群进行有针对性的筛查来提高诊断率。 在低发病率环境中，已使用标准制图工具来确定目标人群，以加强 案件查找。类似的方法在流行环境中是否足够尚不清楚，但对于推进新方法至关重要 案例查找方法。为了制定适当的策略，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。空间和基因组方面的进展 统计模型与敏感诊断相结合现在可以评估空间靶向结核病筛查 在高负担社区。我们假设传播热点地区藏有大量患有此病的人 未确诊和亚临床结核病如果有针对性的话可以提高结核病病例发现的效率。在目标 1 中，我们 确定空间组织热点内发生的结核病传播比例。在目标 2 中，我们测试 空间针对性的病例查找是否会比更广泛的识别方法更加有效和高效？ 活动性和亚临床流行结核病。为了实现我们的目标，我们结合了创新的空间统计 使用贝叶斯系统动力学方法进行建模，利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 结合胸部放射线检查来检测社区中流行的结核病。 如果未被发现的流行结核病，包括亚临床形式，实际上集中在传播地点，那么 将对有针对性的社区结核病筛查策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。