Novel transcriptional signatures for sputum-independent diagnostics of tuberculosis in children

Abstract

Pediatric tuberculosis (TB) is challenging to diagnose, confirmed by growth of Mycobacterium tuberculosis at best in 40% of cases. The WHO has assigned high priority to the development of non-sputum diagnostic tools. We therefore sought to identify transcriptional signatures in whole blood of Indian children, capable of discriminating intra-thoracic TB disease from other symptomatic illnesses. We investigated the expression of 198 genes in a training set, comprising 47 TB cases (19 definite/28 probable) and 36 asymptomatic household controls, and identified a 7- and a 10-transcript signature, both including NOD2, GBP5, IFITM1/3, KIF1B and TNIP1. The discriminatory abilities of the signatures were evaluated in a test set comprising 24 TB cases (17 definite/7 probable) and 26 symptomatic non-TB cases. In separating TB-cases from symptomatic non-TB cases, both signatures provided an AUC of 0.94 (95%CI, 0.88–1.00), a sensitivity of 91.7% (95%CI, 71.5–98.5) regardless of culture status, and 100% sensitivity for definite TB. The 7-transcript signature provided a specificity of 80.8% (95%CI, 60.0–92.7), and the 10-transcript signature a specificity of 88.5% (95%CI, 68.7–96.9%). Although warranting exploration and validation in other populations, our findings are promising and potentially relevant for future non-sputum based POC diagnostic tools for pediatric TB.

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

“…Baseline characteristics of the study participants are shown in Supplementary Table 1 Of the 17 identified signatures ( Table 2), two were discovered from paediatric populations 28,29 . Four signature discovery datasets included HIV-infected and -uninfected participants 11,13,29,30 , one was discovered in an exclusively HIV-infected population for the purpose of active case finding 31 , while the remainder were discovered in HIV-negative populations.…”

“…Four signatures were discovered with the intention of diagnosis of incipient TB [16][17][18] , with the remaining 13 discovered for diagnosis of active TB disease. Of these, five 11,14,28,32,33 targeted discrimination of TB from other diseases in addition to discriminating people who were healthy or with LTBI. Of the 17 included signatures, only three were not discovered through a genome-wide approach 15,28,33 .…”

“…Of these, five 11,14,28,32,33 targeted discrimination of TB from other diseases in addition to discriminating people who were healthy or with LTBI. Of the 17 included signatures, only three were not discovered through a genome-wide approach 15,28,33 . Four signatures required reconstruction of support vector machine (SVM) models 16,18,32,34 , and one required reconstruction of a random forest model 15 .…”

“…In contrast, the nine signatures with inferior performance included two discovered from children 28,29 , one study that prioritised discrimination of active TB from other bacterial and viral infections 14 , and one study that conducted active case-finding for TB among people living with HIV 31 . The differences in primary intended applications, which are reflected in the study populations used for biomarker discovery, may account for their inferior performance when evaluated solely for identification of incipient TB in a predominantly healthy, HIVnegative adult population.…”

Adolescents and young adults: a neglected population group for tuberculosis surveillance

“…In countries where the private sector plays an important role in health delivery, the likelihood of missed notifications despite correct diagnosis is potentially higher [14]. Although paediatric TB has been historically neglected, there has been a renewed interest and awareness of this public health problem in recent years, which has led to efforts to improve its surveillance and reporting, as well as to develop new therapeutic formulations and, to a lesser extent, new diagnostic tests [5,[15][16][17].…”