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High-confidence structural annotation of metabolites absent from spectral libraries.
Nat. Biotechnol. 40, 411–421 (2021)
Untargeted metabolomics experiments rely on spectral libraries for structure annotation, but, typically, only a small fraction of spectra can be matched. Previous in silico methods search in structure databases but cannot distinguish between correct and incorrect annotations. Here we introduce the COSMIC workflow that combines in silico structure database generation and annotation with a confidence score consisting of kernel density P value estimation and a support vector machine with enforced directionality of features. On diverse datasets, COSMIC annotates a substantial number of hits at low false discovery rates and outperforms spectral library search. To demonstrate that COSMIC can annotate structures never reported before, we annotated 12 natural bile acids. The annotation of nine structures was confirmed by manual evaluation and two structures using synthetic standards. In human samples, we annotated and manually validated 315 molecular structures currently absent from the Human Metabolome Database. Application of COSMIC to data from 17,400 metabolomics experiments led to 1,715 high-confidence structural annotations that were absent from spectral libraries.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Molecular-structure Databases; Tandem Mass-spectra; High-fat Diet; Peptide Identification; Metabolomics Data; Ms/ms Spectra; Proteomics; Acid; Discovery; Fragmentation
ISSN (print) / ISBN
1087-0156
e-ISSN
1546-1696
Journal
Nature Biotechnology
Quellenangaben
Volume: 40,
Issue: 3,
Pages: 411–421
Publisher
Nature Publishing Group
Publishing Place
New York, NY
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Metabolomics & Proteomics (CF-MPC)
Grants
NIGMS NIH HHS
NCI NIH HHS
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
Gordon and Betty Moore Foundation (Gordon E. and Betty I. Moore Foundation)
NCI NIH HHS
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
Gordon and Betty Moore Foundation (Gordon E. and Betty I. Moore Foundation)