@article{de5fb383192e4cd195a3ef10220e3ce5,
title = "Blood RNA alternative splicing events as diagnostic biomarkers for infectious disease",
abstract = "Assays detecting blood transcriptome changes are studied for infectious disease diagnosis. Blood-based RNA alternative splicing (AS) events, which have not been well characterized in pathogen infection, have potential normalization and assay platform stability advantages over gene expression for diagnosis. Here, we present a computational framework for developing AS diagnostic biomarkers. Leveraging a large prospective cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and whole-blood RNA sequencing (RNA-seq) data, we identify a major functional AS program switch upon viral infection. Using an independent cohort, we demonstrate the improved accuracy of AS biomarkers for SARS-CoV-2 diagnosis compared with six reported transcriptome signatures. We then optimize a subset of AS-based biomarkers to develop microfluidic PCR diagnostic assays. This assay achieves nearly perfect test accuracy (61/62 = 98.4%) using a naive principal component classifier, significantly more accurate than a gene expression PCR assay in the same cohort. Therefore, our RNA splicing computational framework enables a promising avenue for host-response diagnosis of infection.",
keywords = "RNA splicing, SARS-CoV-2, diagnostic biomarker, host response assays, infectious disease, viral infection",
author = "Zijun Zhang and Natalie Sauerwald and Antonio Cappuccio and Irene Ramos and Nair, {Venugopalan D.} and German Nudelman and Elena Zaslavsky and Yongchao Ge and Angelo Gaitas and Hui Ren and Joel Brockman and Jennifer Geis and Naveen Ramalingam and David King and McClain, {Micah T.} and Woods, {Christopher W.} and Ricardo Henao and Burke, {Thomas W.} and Tsalik, {Ephraim L.} and Goforth, {Carl W.} and Lizewski, {Rhonda A.} and Lizewski, {Stephen E.} and Weir, {Dawn L.} and Letizia, {Andrew G.} and Sealfon, {Stuart C.} and Troyanskaya, {Olga G.}",
note = "Funding Information: We thank the many US Navy corpsmen who assisted in the logistics and sample acquisition and the devoted Marine recruits who volunteered for this study. This study was approved by the Naval Medical Research Center (NMRC) institutional review board (IRB), protocol number NMRC.2020.0006, in compliance with all applicable US federal regulations governing the protection of human subjects. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the US government. A.G.L. C.W.G. R.A.L. S.E.L. and D.L.W. are military service members. This work was prepared as part of their official duties. This work was supported/funded by work unit numbers Defense Advanced Research Projects Agency contract number N6600119C4022 (S.C.S.), Defense Health Agency grant 9700130 through the Naval Medical Research Center (A.G.L.), National Institutes of Health grant R01GM071966 (O.G.T.), and Simons Foundation grant 395506 (O.G.T.). Conceptualization, Z.Z. O.G.T. and S.C.S.; methodology and software, Z.Z.; formal analysis, Z.Z. N.S. and A.C.; investigation, I.R. V.D.N. G.N. E.Z. C.W.G. R.A.L. S.E.L. D.L.W. and A.G.L.; validation, H.R. J.B. J.G. N.R. D.K. M.T.M. C.W.W. R.H. T.W.B. and E.L.T.; resources, S.C.S. and O.G.T.; data curation, Y.G.; funding acquisition, A.G.L. S.C.S. and O.G.T.; project administration, A.G.L. S.C.S. and O.G.T.; supervision, S.C.S. and O.G.T.; writing – original draft, Z.Z. N.S. O.G.T. and S.C.S.; writing – review & editing, Z.Z. N.S. A.C. O.G.T. and S.C.S. A provisional patent application on this work has been submitted, and the Icahn School of Medicine at Mount Sinai and Princeton University are in discussions about licensing the technology. Z.Z. O.G.T. and S.C.S. are co-inventors of this technology and may benefit from any licensing. Funding Information: We thank the many US Navy corpsmen who assisted in the logistics and sample acquisition and the devoted Marine recruits who volunteered for this study. This study was approved by the Naval Medical Research Center ( NMRC ) institutional review board (IRB), protocol number NMRC.2020.0006 , in compliance with all applicable US federal regulations governing the protection of human subjects. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the US government. A.G.L., C.W.G., R.A.L., S.E.L., and D.L.W. are military service members. This work was prepared as part of their official duties. This work was supported/funded by work unit numbers Defense Advanced Research Projects Agency contract number N6600119C4022 (S.C.S.), Defense Health Agency grant 9700130 through the Naval Medical Research Center (A.G.L.), National Institutes of Health grant R01GM071966 (O.G.T.), and Simons Foundation grant 395506 (O.G.T.). Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = feb,
day = "27",
doi = "10.1016/j.crmeth.2023.100395",
language = "English",
volume = "3",
journal = "Cell Reports Methods",
issn = "2667-2375",
publisher = "Cell Press",
number = "2",
}