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.

项目摘要 /摘要 在儿童中诊断结核病（TB）（TB）（肺和传播形式）是 由于当前的测试依赖于痰液或 胃抽吸。结核分枝杆菌的培养可能需要数周 从幼儿那里获得适当的样本很困难。即使有最好的可用 当前方法仅在20-30％的20-30％实现了儿童结核病的明确诊断 临床诊断为结核病的儿童。缺乏准确和快速的诊断测试 导致许多儿童的治疗延迟，相反对儿童进行过度治疗 谁可能没有结核病也很常见。因此，迫切需要改进 儿童结核病的诊断测试。 作为检测病因分枝杆菌的替代方法，鉴定了变化 血液蛋白或血细胞中基因激活的模式（蛋白质或基因特征） 或生物标志物）是诊断许多感染的有前途的方法。我们的成员 财团以前已经研究了特征良好的结核病儿童， 与儿童结核病相似的其他一系列其他感染。我们已经确定了 候选蛋白和基因“特征”，可能在诊断儿童期有用 TB。我们的建议是提出六个有前途的蛋白质和基因特征（三个基于三个的蛋白质和基因特征 关于蛋白质和三个基于表达基因的变化），以进一步验证井 在四个具有较高的非洲国家的儿童既有疑似结核病 儿童结核病的伯伦斯（南非，马拉维，肯尼亚和冈比亚）。 使用来自4,000多个特征良好的儿童结核病嫌疑人的可用样本 首先使用与检测到的相同技术对六个候选生物标志物进行验证 原始的生物标志物，然后使用更简单的技术来实现大量的技术 要分析的患者。为了确保只有最准确和繁殖 生物标志物是向前带来的，我们将在至少三个不同的情况下验证每个生物标志物 乡村队列。我们将使用复杂的统计方法来选择最多 可以将其前进的精确生物标志物作为临床使用的测试。 为了将承诺转换为生物标志物，即使在 资源差的设置我们将使用新技术来检测蛋白质和基因 签名将被验证为诊断测试的基础。

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