LAUSR

Summary 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.