Multi-objective optimization identifies a specific and interpretable COVID-19 host response signature

Applying a multi-objective optimization framework to both massive public and new multi-omics data, we identified a COVID-19 signature regulated at both transcriptional and epigenetic levels. We validated the signature’s robustness in multiple independent COVID-19 cohorts.

Using public data from 8630 subjects and 53 conditions, we demonstrated no cross-reactivity with other viral and bacterial infections, COVID-19 comorbidities, and confounders. In contrast, all previously reported COVID-19 signatures were associated with significant cross-reactivity. The signature’s interpretation, based on cell-type deconvolution and single cell data analysis, revealed prominent yet complementary roles for plasmablasts and memory T cells.