@article{adc101207f4c4189923980c9bf8becb4,
title = "Multi-objective optimization identifies a specific and interpretable COVID-19 host response signature",
abstract = "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.",
keywords = "COVID-19, cross-reactivity, epigenomics, host response signature, interpretability, optimization, plasmablasts, robustness, transcriptomics, viral infection diagnosis",
author = "Antonio Cappuccio and Chawla, {Daniel G.} and Xi Chen and Rubenstein, {Aliza B.} and Cheng, {Wan Sze} and Weiguang Mao and Burke, {Thomas W.} and Tsalik, {Ephraim L.} and Elizabeth Petzold and Ricardo Henao and McClain, {Micah T.} and Woods, {Christopher W.} and Maria Chikina and Troyanskaya, {Olga G.} and Sealfon, {Stuart C.} and Kleinstein, {Steven H.} and Elena Zaslavsky",
note = "Funding Information: This study was supported by the Defense Advanced Research Projects Agency (contract number N6600119C4022). Conceptualization: S.H.K. S.C.S. and E.Z.; data curation: A.C. D.G.C. and W.S.C; software: A.C. and D.G.C.; formal analysis: A.C. D.G.C. A.B.R. X.C. and W.M.; methodology: A.C. D.G.C. S.C.S. S.H.K. and E.Z.; writing − original draft: A.C. D.G.C. S.C.S. S.H.K. and E.Z.; writing – review and editing: all authors; visualization: A.C. D.G.C. S.C.S. S.H.K. and E.Z. Icahn School of Medicine at Mount Sinai has submitted a provisional patent related to this work. A.C. D.G.C. S.C.S. S.H.K. and E.Z. are inventors of the technology filed through ISMMS related to this manuscript. S.H.K. receives consulting fees from Peraton. C.W.W. is a founder of Predigen, Inc, and consultant and Chief Medical Officer of Biomeme. C.W.W. also consults for Arena Pharmaceuticals, Biofire, Karius, and FHI Clinical. T.W.B. is a consultant for and equity owner in Biomeme. E.L.T. is an employee and shareholder of Danaher Corp. M.T.M. E.L.T. R.H. T.W.B. and C.W.W. are co-inventors of technology filed under patent application “Methods to Detect and Treat SARS-COV2 (COVID19) Infection.” O.G.T. is on the advisory board of Cell Systems. Funding Information: This study was supported by the Defense Advanced Research Projects Agency (contract number N6600119C4022 ). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = dec,
day = "21",
doi = "10.1016/j.cels.2022.11.008",
language = "English",
volume = "13",
pages = "989--1001.e8",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "12",
}