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

• Published in: Cell systems Vol. 13; no. 12; pp. 989 - 1001.e8
• Main Authors: Cappuccio, Antonio, Chawla, Daniel G., Chen, Xi, Rubenstein, Aliza B., Cheng, Wan Sze, Mao, Weiguang, Burke, Thomas W., Tsalik, Ephraim L., Petzold, Elizabeth, Henao, Ricardo, McClain, Micah T., Woods, Christopher W., Chikina, Maria, Troyanskaya, Olga G., Sealfon, Stuart C., Kleinstein, Steven H., Zaslavsky, Elena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.12.2022
• Subjects: COVID-19; cross-reactivity; epigenomics; host response signature; Humans; interpretability; optimization; plasmablasts; robustness; SARS-CoV-2; transcriptomics; viral infection diagnosis; Virus Diseases; COVID-19; plasmablasts; host response signature; optimization; transcriptomics; robustness; epigenomics; interpretability; cross-reactivity; viral infection diagnosis
• ISSN: 2405-4712; 2405-4720; 2639-5460; 2405-4720
• DOI: 10.1016/j.cels.2022.11.008

The identification of a COVID-19 host response signature in blood can increase the understanding of SARS-CoV-2 pathogenesis and improve diagnostic tools. 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 8,630 subjects and 53 conditions, we demonstrated no cross-reactivity with other viral and bacterial infections, COVID-19 comorbidities, or confounders. In contrast, 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. Although the signal from plasmablasts mediated COVID-19 detection, the signal from memory T cells controlled against cross-reactivity with other viral infections. This framework identified a robust, interpretable COVID-19 signature and is broadly applicable in other disease contexts. A record of this paper’s transparent peer review process is included in the supplemental information. [Display omitted] •Multi-objective optimization identifies a host response COVID-19 signature•The transcriptional- and epigenetic-based signature is validated in multiple cohorts•COVID-19 is detected specifically, without cross-reactivity to other infections•The host response is attributed to plasmablasts and memory T cells Host response signatures to infection have emerged as a new paradigm for infection diagnosis. Using multi-objective optimization, we identify a transcriptional- and epigenetic-based COVID-19 signature. The signature, validated in multiple cohorts, detects COVID-19 specifically, without cross-reactivity to other infections. The host response is attributed to plasmablasts and memory T cells.