Evaluation of a transcriptomic signature of tuberculosis risk in combination with an interferon gamma release assay: A diagnostic test accuracy study

Background We evaluated the diagnostic and prognostic performance of a transcriptomic signature of tuberculosis (TB) risk (RISK11) and QuantiFERON-TB Gold-plus (QFTPlus) as combination biomarkers of TB risk. Methods Healthy South Africans who were HIV-negative aged 18- 60 years with baseline RISK11 and QFTPlus results were evaluated in a prospective cohort study conducted between Sept 20, 2016 and Dec 20, 2019. Prevalence and incidence-rate ratios were used to evaluate risk of TB. Positive (LR+) and negative (LR-) likelihood ratios were used to compare individual tests versus Both-Positive (RISK11+/QFTPlus+) and Either-Positive (RISK11+ or QFTPlus+) combinations. Findings Among 2912 participants, prevalent TB in RISK11+/QFTPlus+ participants was 13.3-fold (95% CI 4.2 -42.7) higher than RISK11-/QFTPlus-; 2.4-fold (95% CI 1.2-4.8) higher than RISK11+/QFTPlus-; and 4.5-fold (95% CI 2.5-8.0) higher than RISK11-/QFTPlus+ participants. Risk of incident TB in RISK11+/QFTPlus+ participants was 8. 3-fold (95% CI 2.5-27. 0) higher than RISK11-/QFTPlus-; 2. 5-fold (95% CI 1.0-6. 6) higher than RISK11+/QFTPlus-; and 2. 1-fold (95% CI 1.2-3. 4) higher than RISK11-/QFTPlus+ participants, respectively. Compared to QFTPlus, the Both-Positive test combination increased diagnostic LR+ from 1.3 (95% CI 1.2-1.5) to 4.7 (95% CI 3.2-7.0), and prognostic LR+ from 1.4 (95% CI 1.2-1.5) to 2.8 (95% CI 1.5-5.1), but did not improve upon RISK11 alone. Compared with RISK11, the Either-Positive test combination decreased diagnostic LR- from 0.7 (95% CI 0.6-0.9) to 0.3 (95% CI 0.2-0.6), and prognostic LR- from 0.9 (95% CI 0.8-1.0) to 0.3 ( 0 . 1-0.7), but did not improve upon QFTPlus alone. Interpretation Combining two tests such as RISK11 and QFTPlus, with discordant individual performance characteristics does not improve overall discriminatory performance, relative to the individual tests. Copyright (C) 2022 The Authors. Published by Elsevier Ltd.

Automated summary

The study evaluated the diagnostic and prognostic performance of two biomarkers, RISK11 and QFTPlus, in predicting TB risk. The combination of the two markers did not improve overall discriminatory performance compared to the individual tests.