| Summary: | Summary: There is a need to identify biomarkers predictive of severe dengue. Single-cohort transcriptomics has not yielded generalizable results or parsimonious, predictive gene sets. We analyzed blood samples of dengue patients from seven gene expression datasets (446 samples, five countries) using an integrated multi-cohort analysis framework and identified a 20-gene set that predicts progression to severe dengue. We validated the predictive power of this 20-gene set in three retrospective dengue datasets (84 samples, three countries) and a prospective Colombia cohort (34 patients), with an area under the receiver operating characteristic curve of 0.89, 100% sensitivity, and 76% specificity. The 20-gene dengue severity scores declined during the disease course, suggesting an infection-triggered host response. This 20-gene set is strongly associated with the progression to severe dengue and represents a predictive signature, generalizable across ages, host genetic factors, and virus strains, with potential implications for the development of a host response-based dengue prognostic assay. : Biomarkers predictive of severe dengue are needed. Robinson et al. revealed a 20-gene set that predicts progression to severe dengue in existing and prospective cohorts via a multi-cohort analysis framework. This 20-gene set is generalizable across ages and host genetic factors and has potential implications for prognostic assay development. Keywords: transcriptomics, multi-coherent analysis, prognostics, biomarkers, severe dengue
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