Blood RNA alternative splicing events as diagnostic biomarkers for infectious disease

Zijun Zhang, Natalie Sauerwald, Antonio Cappuccio, Irene Ramos, Venugopalan D. Nair, German Nudelman, Elena Zaslavsky, Yongchao Ge, Angelo Gaitas, Hui Ren, Joel Brockman, Jennifer Geis, Naveen Ramalingam, David King, Micah T. McClain, Christopher W. Woods, Ricardo Henao, Thomas W. Burke, Ephraim L. Tsalik, Carl W. GoforthRhonda A. Lizewski, Stephen E. Lizewski, Dawn L. Weir, Andrew G. Letizia, Stuart C. Sealfon, Olga G. Troyanskaya

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Article number100395
JournalCell Reports Methods
Issue number2
StatePublished - Feb 27 2023

All Science Journal Classification (ASJC) codes

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Biochemistry
  • Radiology Nuclear Medicine and imaging
  • Biotechnology
  • Computer Science Applications


  • RNA splicing
  • SARS-CoV-2
  • diagnostic biomarker
  • host response assays
  • infectious disease
  • viral infection


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