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结核病（tuberculosis，TB）已经超过艾滋病成为最致命的单一因素传染病，这主要是由于早期且明确的诊断和及时治疗的难度很大。在活动性结核病例中，肺结核（PTB）占所有结核病的80％，结核性脑膜炎（TBM）占所有结核病例的1.6％。然而，TBM是最严重的结核病形式，占结核病相关死亡率的50％。目前可用于结核病诊断的方法有其固有局限性，例如孵育时间长（使用基于培养的方法）、经济成本高、医疗条件差（例如GenXpert检测）、灵敏度低等，往往不符合临床要求，并且电子健康档案（electronic health records，EHR）通常不足以做出准确的诊断。因此，当前迫切需要新的生物标志物或临床方法来改善结核病诊断，特别是针对PTB和TBM。 近日，来自四川大学华西医院和加拿大多伦多大学的研究人员建立外泌体miRNA信息联合电子健康档案数据，利用其改善肺结核、结核性脑膜炎等结核病的临床诊断效果。相关研究结果发表于EBioMedicine杂志上。在该研究的Exploratory Step中，研究人员通过使用微阵列平台鉴定了11种在结核病例（包括PTB和TBM）和健康对照之间显著差异表达的外泌体miRNA。在Selection Step中，通过将PTB/TBM与其各自的对照进行比较并使用qRT-PCR方法，进一步筛选至6个miRNA。在Training Step中，通过结合支持向量机机器学习（SVM）模型、外泌体miRNA数据与EHR数据，来区分PTB/TBM患者与其疾病对照或健康对照。最后，在Testing Step中，研究人员评估了新的PTB/TBM模型的性能。结果发现，六种外泌体miRNA（miR-20a，miR-20b，miR-26a，miR-106a，miR-191和miR-486）在TB患者中差异表达。进一步比较三种SVM模型，“EHR + miRNA”、“仅miRNA”和“仅EHR”，发现联合“EHR + miRNA”模型比单独使用EHR数据或miRNA数据表现更好，其对TBM的诊断灵敏度为0.94，特异性为0.95。 这项研究结果表明，联合外泌体miRNA和EHR可能有助于改善TBM和PTB的临床诊断准确度，同时首次证明外泌体miRNA是TBM疾病的有效生物标志物。 推荐阅读原文： Integrating exosomal microRNAs and electronic health data improved tuberculosis diagnosis. BACKGROUND: Tuberculosis (TB) is difficult to diagnose under complex clinical conditions as electronic health records (EHRs) are often inadequate in making an affirmative diagnosis. As exosomal miRNAs emerged as promising biomarkers, we investigated the potential of using exosomal miRNAs and EHRs in TB diagnosis. METHODS: A total of 370 individuals, including pulmonary tuberculosis (PTB), tuberculous meningitis (TBM), non-TB disease controls and healthy state controls, were enrolled. Exosomal miRNAs were profiled in the exploratory cohort using microarray and miRNA candidates were selected in the selection cohort using qRT-PCR. EHRs and follow-up information of the patients were collected accordingly. miRNAs and EHRs were used to develop diagnostic models for PTB and TBM in the selection cohort with the Support Vector Machine (SVM) algorithm. These models were further evaluated in an independent testing cohort. FINDINGS: Six exosomal miRNAs (miR-20a, miR-20b, miR-26a, miR-106a, miR-191, miR-486) were differentially expressed in the TB patients. Three SVM models, 'EHR+miRNA', 'miRNA only' and 'EHR only' were compared, and 'EHR + miRNA' model achieved the highest diagnostic efficacy, with an AUC up to 0.97 (95% CI 0.80-0.99) in TBM and 0.97 (0.87-0.99) in PTB, respectively. However, 'EHR only' model only showed an AUC of 0.67 (0.46-0.83) in TBM. After 2-month anti-tuberculosis therapy, overexpressed miRNAs presented a decreased expression trend (p= 4.80 × 10-5). INTERPRETATION: Our results showed that the combination of exosomal miRNAs and EHRs could potentially improve clinical diagnosis of TBM and PTB. |
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