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How to Train a Postprocessor for Tandem Mass Spectrometry Proteomics Database Search While Maintaining Control of the False Discovery Rate
Univ Sydney, Sch Math & Stat F07, Sydney, NSW 2006, Australia.
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.ORCID iD: 0000-0001-5689-9797
Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA; Univ Washington, Paul G Allen Sch Comp Sci & Engn, Seattle, WA 98195 USA.ORCID iD: 0000-0001-7283-4715
Univ Sydney, Sch Math & Stat F07, Sydney, NSW 2006, Australia.
2025 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 24, no 5, p. 2266-2279Article in journal (Refereed) Published
Abstract [en]

Decoy-based methods are a popular choice for the statistical validation of peptide detection in tandem mass spectrometry and proteomics data. Such methods can achieve a substantial boost in statistical power when coupled with postprocessors such as Percolator that use auxiliary features to learn a better-discriminating scoring function. However, we recently showed that Percolator can struggle to control the false discovery rate (FDR) when reporting the list of discovered peptides. To address this problem, we introduce Percolator-RESET, which is an adaptation of our recently developed RESET meta-procedure to the peptide detection problem. Specifically, Percolator-RESET fuses Percolator's iterative SVM training procedure with RESET's general framework to provide valid false discovery rate control. Percolator-RESET operates in both a standard single-decoy mode and a two-decoy mode, with the latter requiring the generation of two decoys per target. We demonstrate that Percolator-RESET controls the FDR in both modes, both theoretically and empirically, while typically reporting only a marginally smaller number of discoveries than Percolator in the single-decoy mode. The two-decoy mode is marginally more powerful than both Percolator and the single-decoy mode and exhibits less variability than the latter.

Place, publisher, year, edition, pages
American Chemical Society (ACS) , 2025. Vol. 24, no 5, p. 2266-2279
Keywords [en]
proteomics, false discovery rate control, tandemmass spectrometry
National Category
Bioinformatics and Computational Biology
Identifiers
URN: urn:nbn:se:kth:diva-362990DOI: 10.1021/acs.jproteome.4c00742ISI: 001456007300001PubMedID: 40163043Scopus ID: 2-s2.0-105001488019OAI: oai:DiVA.org:kth-362990DiVA, id: diva2:1956408
Note

QC 20250506

Available from: 2025-05-06 Created: 2025-05-06 Last updated: 2025-05-06Bibliographically approved

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Käll, Lukas

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