Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease
Abstract
Thousands of pathogens are known to infect humans, but only a fraction are readily identifiable using current diagnostic methods. Microbial cell-free DNA sequencing offers the potential to non-invasively identify a wide range of infections throughout the body, but the challenges of clinical-grade metagenomic testing must be addressed. Here we describe the analytical and clinical validation of a next-generation sequencing test that identifies and quantifies microbial cell-free DNA in plasma from 1,250 clinically relevant bacteria, DNA viruses, fungi and eukaryotic parasites. Test accuracy, precision, bias and robustness to a number of metagenomics-specific challenges were determined using a panel of 13 microorganisms that model key determinants of performance in 358 contrived plasma samples, as well as 2,625 infections simulated in silico and 580 clinical study samples. The test showed 93.7% agreement with blood culture in a cohort of 350 patients with a sepsis alert and identified an independently adjudicated cause of the sepsis alert more often than all of the microbiological testing combined (169 aetiological determinations versus 132). Among the 166 samples adjudicated to have no sepsis aetiology identified by any of the tested methods, sequencing identified microbial cell-free DNA in 62, likely derived from commensal organisms and incidental findings unrelated to the sepsis alert. Analysis of the first 2,000 patient samples tested in the CLIA laboratory showed that more than 85% of results were delivered the day after sample receipt, with 53.7% of reports identifying one or more microorganisms.
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Blood-based microbial DNA can be clinically informative in cancer, including cancers with blood-barrier or lymphatic disruptions.
“There is mounting evidence that blood-based microbial DNA (hereafter “mbDNA”) can be clinically informative in cancer39–44, including those featuring blood-barrier or lymphatic disruptions (e.g. COAD)39”
From RETRACTED ARTICLE: Microbiome analyses of blood and tissues suggest cancer diagnostic approach (2020) · cites this paper as [40]
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- Authors
- Blauwkamp, T. A., Thair, S., Rosen, M. J., Blair, L., Lindner, M. S., Vilfan, I. D., Kawli, T., Christians, F. C., Venkatasubrahmanyam, S., Wall, G. D., Cheung, A., Rogers, Z. N., Meshulam-Simon, G., Huijse, L., Balakrishnan, S., Quinn, J. V., Hollemon, D., Hong, D. K., Vaughn, M. L., Kertesz, M., Bercovici, S., Wilber, J. C., & Yang, S.
- Affiliations
- Karius, Inc. (United States) (US)
- Stanford University (US)
- Corresponding author
- Blauwkamp, Timothy A.
- ORCID
- Venue
- Nature Microbiology
- Published
- 2019-02-11
- Volume
- 4
- Issue
- 4
- Pages
- 663-674
- ISSN
- 2058-5276 (ISSN-L)
- OpenAlex
- W2911798461
- Cited by
- 962
- References
- 53
- Citations by year
- 2026: 118 · 2025: 168 · 2024: 164 · 2023: 139 · 2022: 108 · 2021: 117 · 2020: 96 · 2019: 51 · 2018: 1
- FWCI
- 66.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. National Library of Medicine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Bacterial Identification and Susceptibility Testing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- microbial cell-free DNA, metagenomic sequencing, infectious disease diagnosis, sepsis, non-invasive diagnosis, test validation, blood culture comparison, commensal organisms, incidental finding, DNA viruses, fungi, eukaryotic parasites
- MeSH terms
- Cell-Free Nucleic Acids, Communicable Diseases, DNA, Bacterial, DNA, Fungal, DNA, Viral, Humans, Cohort Studies, Sepsis, High-Throughput Nucleotide Sequencing
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