Challenging targets or describing mismatches? A comment on Common Decoy Distribution by Madej et al

TL;DR

This paper comments on the Common Decoy Distribution method for FDR control in peptide-spectrum-match validation, discussing its conceptual basis, relation to existing approaches, and implications for proteomics and biostatistics.

Contribution

It provides a critical analysis of the CDD approach, clarifying its theoretical position and suggesting potential improvements for FDR control methods in proteomics.

Findings

CDD combines strengths of decoy-based and decoy-free methods

It highlights the importance of theoretical distinctions in FDR control

Practical insights for improving proteomics FDR methods

Abstract

In their recent article, Madej et al. 1 proposed an original way to solve the recurrent issue of controlling for the false discovery rate (FDR) in peptide-spectrum-match (PSM) validation. Briefly, they proposed to derive a single precise distribution of decoy matches termed the Common Decoy Distribution (CDD) and to use it to control for FDR during a target-only search. Conceptually, this approach is appealing as it takes the best of two worlds, i.e., decoy-based approaches (which leverage a large-scale collection of empirical mismatches) and decoy-free approaches (which are not subject to the randomness of decoy generation while sparing an additional database search). Interestingly, CDD also corresponds to a middle-of-the-road approach in statistics with respect to the two main families of FDR control procedures: Although historically based on estimating the falsepositive distribution, FDR control has recently been demonstrated to be possible thanks to competition between the original variables (in proteomics, target sequences) and their fictional counterparts (in proteomics, decoys). Discriminating between these two theoretical trends is of prime importance for computational proteomics. In addition to highlighting why proteomics was a source of inspiration for theoretical biostatistics, it provides practical insights into the improvements that can be made to FDR control methods used in proteomics, including CDD.