The effect of host factors on discriminatory performance of a transcriptomic signature of tuberculosis risk.

Background: We aimed to understand host factors that affect discriminatory performance of a transcriptomic signature of tuberculosis risk (RISK11).
Methods: HIV-negative adults aged 18-60 years were evaluated in a prospective study of RISK11 and surveilled for tuberculosis through 15 months. Generalised linear models and receiver-operating characteristic (ROC) regression were used to estimate effect of host factors on RISK11 score (%marginal effect) and on discriminatory performance for tuberculosis disease (area under the curve, AUC), respectively.
Findings: Among 2923 participants including 74 prevalent and 56 incident tuberculosis cases, percentage marginal effects on RISK11 score were increased among those with prevalent tuberculosis (+18·90%, 95%CI 12·66-25·13), night sweats (+14·65%, 95%CI 5·39-23·91), incident tuberculosis (+7·29%, 95%CI 1·46-13·11), flu-like symptoms (+5·13%, 95%CI 1·58-8·68), and smoking history (+2·41%, 95%CI 0·89-3·93) than those without; and reduced in males (-6·68%, 95%CI -8·31- -5·04) and with every unit increase in BMI (-0·13%, 95%CI -0·25- -0·01). Adjustment for host factors affecting controls did not change RISK11 discriminatory performance. Cough was associated with 72·55% higher RISK11 score in prevalent tuberculosis cases. Stratification by cough improved diagnostic performance from AUC = 0·74 (95%CI 0·67-0·82) overall, to 0·97 (95%CI 0·90-1·00, p < 0·001) in cough-positive participants. Combining host factors with RISK11 improved prognostic performance, compared to RISK11 alone, (AUC = 0·76, 95%CI 0·69-0·83 versus 0·56, 95%CI 0·46-0·68, p < 0·001) over a 15-month predictive horizon.
Interpretation: Several host factors affected RISK11 score, but only adjustment for cough affected diagnostic performance. Combining host factors with RISK11 should be considered to improve prognostic performance.
Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.
Competing Interests: Declaration of interests 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 patents of the RISK11 and RISK6 signatures pending; 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.
(Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)