Combining blood transcriptomic signatures improves the prediction of progression to tuberculosis among household contacts in Brazil

ABSTRACT Tuberculosis remains a major health threat, infecting nearly a third of the world’s population. Of those infected, 5-10% progress from latent infection to active tuberculosis (TB) disease and biomarkers to identify which individuals will progress are needed to allow targeted prophylactic treatment. Several risk biomarkers have been developed to predict progression but have not been tested head-to-head on the same platform. Here, we used the NanoString platform and compared the performance of 15 published gene signatures in predicting progression at baseline in a household contact cohort. Expression of gene signatures was profiled in RNA extracted from whole blood and scored using GSVA and PLAGE. We found that specificity is enhanced by combining signatures and report that the performance of a combined signature that includes a newly derived parsimonious signature through machine learning and a published signature met WHO TPP levels for a triage test. The combined signature had a 90.9% sensitivity and 88% specificity with a PPV of 0.24 and NPV of 1. This combined signature has potential clinical utility in identifying high-risk individuals for targeted prophylaxis to prevent TB morbidity and mortality. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was funded by the National Institute of Allergy and Infectious Diseases, National NJ ACTS Fellowship program Institutes of Health grants U19AI111276 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Comite de Ética em Pesquisa do Hospital Universitário Cassiano Antonio de Morais, Brazil, and the Institutional Review Boards of Rutgers Biomedical Health Sciences, gave ethical approval of work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors