High-confidence structural annotation of metabolites absent from spectral libraries
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Abstract
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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Recent studies demonstrated that bacteria have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified.
“Recent studies demonstrated that bacteria, in addition to the host, have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified1–4,6,17.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [4]
The Results section (‘Searching for novel bile acid conjugates’; page not provided) reports amino-acid-conjugated bile acids, including 12 leading novel annotations, and a matching spectrum in a bacterial culture. It says microbial involvement in producing the 12 is suggested, not demonstrated; it does not establish bacterial bile acid amine N-acyltransferase activity or the identification of dozens of bacterially conjugated amidates. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes.
“Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1–6; however, the bacterial gene(s) responsible for their production remain unknown.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [4]
In Results, ‘Searching for novel bile acid conjugates’ (page unavailable), the paper describes amino-acid bile acid conjugates produced by microbes and suggests microbial involvement in producing additional conjugates. It says bile acids act as signaling molecules, but does not establish that the amino-acid conjugates affect host-mediated metabolic processes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe bacterial enzymes responsible for producing amino acid bile acid amidates are unknown.
“The enzymes responsible for these conjugation reactions are unknown.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [4]
The Results section, “Searching for novel bile acid conjugates” (page unavailable), describes amino acid–bile acid conjugates and suggests microbial involvement in their production. It does not address whether the enzymes responsible for the conjugation reactions are known; searches for the enzyme claim and related terms found no such statement. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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- Authors
- Hoffmann, M. A., Nothias, L.-F., Ludwig, M., Fleischauer, M., Gentry, E. C., Witting, M., Dorrestein, P. C., Dührkop, K., & Böcker, S.
- Affiliations
- Max Planck Institute for Chemical Ecology (DE)
- Friedrich Schiller University Jena (DE)
- University of California San Diego (US)
- Helmholtz Munich (DE)
- Corresponding author
- Dührkop, Kai
- Böcker, Sebastian
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2021-10-14
- Volume
- 40
- Issue
- 3
- Pages
- 411-421
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC8926923
- OpenAlex
- W3206878019
- Cited by
- 388
- References
- 99
- Citations by year
- 2026: 91 · 2025: 97 · 2024: 75 · 2023: 74 · 2022: 46 · 2021: 5
- FWCI
- 15.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Biotechnology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (R01 GM107550, P41 GM103484, R03 CA211211, U19 AG063744 01)
- Gordon and Betty Moore Foundation (GBMF 7622)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- spectral library, untargeted metabolomics, support vector machine, confidence scores, bile acids, HMDB, false discovery rate
- MeSH terms
- Humans, Molecular Structure, Databases, Factual, Tandem Mass Spectrometry, Metabolomics, Metabolome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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