| Summary: | 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. Fund: Funds for the Central Universities, the National Natural Science Foundation of China. Keywords: Exosomal miRNA, Electronic health record, Tuberculosis differential diagnosis, Machine learning
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