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. 2022 Apr 21:47:101396.
doi: 10.1016/j.eclinm.2022.101396. eCollection 2022 May.

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

Humphrey Mulenga  1 , Andrew Fiore-Gartland  2 , Simon C Mendelsohn  1 , Adam Penn-Nicholson  1 , Stanley Kimbung Mbandi  1 , Elisa Nemes  1 , Bhavesh Borate  2 , Munyaradzi Musvosvi  1 , Michèle Tameris  1 , Gerhard Walzl  3 , Kogieleum Naidoo  4   5 , Gavin Churchyard  6   7   8 , Thomas J Scriba  1 , Mark Hatherill  1 ; CORTIS Study Team
Affiliations

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

Humphrey Mulenga et al. EClinicalMedicine. .

Abstract

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.

Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.

Keywords: Combination; Mycobacterium tuberculosis; Performance; QuantiFERON; Signature; Transcriptomic.

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Conflict of interest statement

AP-N, GW, GC, TJS, and MH report grants from the Bill & Melinda Gates Foundation, during the conduct of the study; AP-N and GW report grants from the South African Medical Research Council, during the conduct of the study; GW and TJS report grants from the South African National Research Foundation, during the conduct of the study. In addition, AP-N and TJS have a patent of the RISK11 and RISK6 signatures issued; GW has a patent “TB diagnostic markers” (PCT/IB2013/054377) issued and a patent “Method for diagnosing TB” (PCT/IB2017/052142) pending. All other authors had nothing to disclose.

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