Validation of Biomarkers of Pediatric TB and further development for use in diagnosis of childhood TB

儿童结核病生物标志物的验证和进一步开发用于诊断儿童结核病

• 批准号: 10062471
• 负责人: Michael Levin
• 金额: $ 83.07万
• 依托单位: IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062471
• 关键词: Affect; Africa; African; Aspirate substance; Bacteria; Bioinformatics; Biological Assay; Biological Markers; Blood Cells; Blood Proteins; Blood specimen; Child; Childhood; Clinical; Clinical Research; Clinical/Radiologic; Country; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Ensure; Environment; Gambia; Gene Activation; Gene Expression Profile; Genes; Genetic Transcription; Genus Mycobacterium; HIV; HIV Infections; Health Benefit; Infection; Interferon Type II; Kenya; Lung; Lung diseases; Malawi; Mass Spectrum Analysis; Methodology; Methods; MicroRNAs; Microbiology; Miniaturization; Mycobacterium tuberculosis; Patients; Pattern; Pediatric cohort; Performance; Phenotype; Proteins; Proteomics; Public Health; RNA; Rapid diagnostics; Reproducibility; Resources; Sampling; Serum; South Africa; Sputum; Stomach; Symptoms; Technology; Test Result; Testing; Transcript; Translating; Tuberculosis; United States National Institutes of Health; Validation; Whole Blood; accurate diagnostics; base; biobank; biomarker signature; biomarker validation; candidate marker; clinical Diagnosis; clinical practice; co-infection; cohort; detection method; detection platform; genetic signature; improved; lateral flow assay; member; microRNA biomarkers; new technology; overtreatment; point of care; prototype; respiratory pathogen; surface enhanced laser desorption ionization; tuberculosis treatment; unnecessary treatment; validation studies

Project summary / abstract The diagnosis of tuberculosis (TB) (both pulmonary and disseminated forms) in children is extremely difficult as current tests rely on culture of the causative bacteria from sputum or gastric aspirates. Culture of Mycobacterium tuberculosis may take several weeks and obtaining appropriate samples from young children is difficult. Even with the best available current methods a definitive diagnosis of childhood TB is only achieved in 20-30% of children clinically diagnosed as having TB. Lack of accurate and rapid diagnostic tests results in delayed treatment for many children, and conversely over-treatment of children who may not actually have TB is also common. There is thus an urgent need for improved diagnostic tests for childhood TB. As an alternative to detecting the causative Mycobacterium, identification of changes in blood proteins or the pattern of activation of genes in blood cells (protein or gene signatures or biomarkers) is a promising method for diagnosing many infections. The members of our consortium have previously studied well-characterised large groups of children with TB, and a range of other infections with similar symptoms to childhood TB. We have identified candidate protein and gene “signatures” which may be useful in the diagnosis of childhood TB. Our proposal is to take forward six promising protein and gene signatures (three based on proteins and three based on changes in expressed genes) for further validation in well established cohorts of children with suspected TB in four African countries which have high burdens of childhood TB (South Africa, Malawi, Kenya and The Gambia). Using available samples from over 4,000 well characterised child TB suspects, each of the six candidate biomarkers will be validated first using the same technology as used to detect the original biomarker and then using simpler technology which enables large numbers of patients to be analysed. In order to ensure that only the most accurate and reproducible biomarkers are taken forward, we will validate each biomarker in at least three different country cohorts. We will use sophisticated statistical methodology to select the most accurate biomarkers which can be taken forward for development as tests for clinical use. In order to translate promising biomarkers to clinical tests which can be applied even in resource poor settings we will use novel technology to detect the protein and gene signatures which will be validated as the basis of a diagnostic test.

项目概要/摘要 儿童结核病 (TB)（肺结核和播散性结核）的诊断是 极其困难，因为目前的测试依赖于痰或痰中致病细菌的培养 胃吸出物培养结核分枝杆菌可能需要数周时间 即使有最好的样本，从幼儿身上获取适当的样本也很困难。 目前的方法仅对 20-30% 的儿童结核病做出明确诊断。 临床诊断患有结核病的儿童缺乏准确和快速的诊断测试。 导致很多儿童延误治疗，反过来又造成儿童过度治疗 实际上并未患有结核病的人也很常见，因此迫切需要进行改进。 儿童结核病的诊断测试。 作为检测致病分枝杆菌的替代方法，鉴定 血液蛋白质或血细胞中基因的激活模式（蛋白质或基因特征 或生物标志物）是诊断许多感染的一种有前途的方法。 该联盟之前曾研究过大量具有明确特征的结核病儿童群体，并且 我们已经发现了一系列与儿童结核病症状相似的其他感染。 候选蛋白质和基因“特征”可能有助于儿童诊断 我们的建议是推进六个有前途的蛋白质和基因特征（三个基于 蛋白质和三个基于表达基因的变化），以便在井中进一步验证 在四个非洲国家建立了疑似结核病儿童队列，这些国家的结核病发病率很高 儿童结核病的负担（南非、马拉维、肯尼亚和冈比亚）。 使用来自 4,000 多名特征明确的儿童结核病嫌疑人的可用样本，每一位 六种候选生物标志物将首先使用与检测相同的技术进行验证 原始的生物标志物，然后使用更简单的技术，使大量 以确保只有最准确和可重复的患者。 生物标志物取得进展后，我们将在至少三个不同的方面验证每个生物标志物 我们将使用复杂的统计方法来选择最多的国家群体。 准确的生物标志物，可以作为临床使用的测试进行开发。 为了将有前途的生物标志物转化为临床测试，甚至可以应用于 资源匮乏的环境下我们将使用新技术来检测蛋白质和基因 将作为诊断测试的基础进行验证的签名。

项目成果

Transcriptomics for child and adolescent tuberculosis.

• DOI: 10.1111/imr.13116
• 发表时间: 2022-08
• 期刊: Immunological reviews
• 影响因子: 8.7

Treatment of Multisystem Inflammatory Syndrome in Children: Understanding Differences in Results of Comparative Effectiveness Studies.

• DOI: 10.1002/acr2.11478
• 发表时间: 2022-09
• 期刊: ACR OPEN RHEUMATOLOGY
• 影响因子: 3.4
• 作者: Melgar, Michael;Seaby, Eleanor G;McArdle, Andrew J;Young, Cameron C;Campbell, Angela P;Murray, Nancy L;Patel, Manish M;Levin, Michael;Randolph, Adrienne G;Son, Mary Beth F
• 通讯作者: Son, Mary Beth F

Treatment of Multisystem Inflammatory Syndrome in Children.

• DOI: 10.1056/nejmoa2102968
• 发表时间: 2021-07-01
• 期刊: The New England journal of medicine
• 作者: McArdle AJ;Vito O;Patel H;Seaby EG;Shah P;Wilson C;Broderick C;Nijman R;Tremoulet AH;Munblit D;Ulloa-Gutierrez R;Carter MJ;De T;Hoggart C;Whittaker E;Herberg JA;Kaforou M;Cunnington AJ;Levin M;BATS Consortium
• 通讯作者: BATS Consortium