MOTIVATION: Cross-linking tandem mass spectrometry (XL-MS/MS) is an established analytical platform used to determine distance constraints between residues within a protein or from physically interacting proteins, thus improving our understanding of protein structure and function. To aid biological discovery with XL-MS/MS, it is essential that pairs of chemically linked peptides be accurately identified, a process that requires: (i) database search, that creates a ranked list of candidate peptide pairs for each experimental spectrum and (ii) false discovery rate (FDR) estimation, that determines the probability of a false match in a group of top-ranked peptide pairs with scores above a given threshold. Currently, the only available FDR estimation mechanism in XL-MS/MS is the target-decoy approach (TDA). However, despite its simplicity, TDA has both theoretical and practical limitations that impact the estimation accuracy and increase run time over potential decoy-free approaches (DFAs). RESULTS: We introduce a novel decoy-free framework for FDR estimation in XL-MS/MS. Our approach relies on multi-sample mixtures of skew normal distributions, where the latent components correspond to the scores of correct peptide pairs (both peptides identified correctly), partially incorrect peptide pairs (one peptide identified correctly, the other incorrectly), and incorrect peptide pairs (both peptides identified incorrectly). To learn these components, we exploit the score distributions of first- and second-ranked peptide-spectrum matches for each experimental spectrum and subsequently estimate FDR using a novel expectation-maximization algorithm with constraints. We evaluate the method on ten datasets and provide evidence that the proposed DFA is theoretically sound and a viable alternative to TDA owing to its good performance in terms of accuracy, variance of estimation, and run time. AVAILABILITY AND IMPLEMENTATION: https://github.com/shawn-peng/xlms.

MOTIVATION: Accurate estimation of false discovery rate (FDR) of spectral identification is a central problem in mass spectrometry-based proteomics. Over the past two decades, target-decoy approaches (TDAs) and decoy-free approaches (DFAs) have been widely used to estimate FDR. TDAs use a database of decoy species to faithfully model score distributions of incorrect peptide-spectrum matches (PSMs). DFAs, on the other hand, fit two-component mixture models to learn the parameters of correct and incorrect PSM score distributions. While conceptually straightforward, both approaches lead to problems in practice, particularly in experiments that push instrumentation to the limit and generate low fragmentation-efficiency and low signal-to-noise-ratio spectra. RESULTS: We introduce a new decoy-free framework for FDR estimation that generalizes present DFAs while exploiting more search data in a manner similar to TDAs. Our approach relies on multi-component mixtures, in which score distributions corresponding to the correct PSMs, best incorrect PSMs and second-best incorrect PSMs are modeled by the skew normal family. We derive EM algorithms to estimate parameters of these distributions from the scores of best and second-best PSMs associated with each experimental spectrum. We evaluate our models on multiple proteomics datasets and a HeLa cell digest case study consisting of more than a million spectra in total. We provide evidence of improved performance over existing DFAs and improved stability and speed over TDAs without any performance degradation. We propose that the new strategy has the potential to extend beyond peptide identification and reduce the need for TDA on all analytical platforms. AVAILABILITYAND IMPLEMENTATION: https://github.com/shawn-peng/FDR-estimation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mapping structural brain connectomes for living human brains typically requires expert analysis and rule-based models on diffusion-weighted magnetic resonance imaging. A data-driven approach, however, could overcome limitations in such rule-based approaches and improve precision mappings for individuals. In this work, we explore a framework that facilitates applying learning algorithms to automatically extract brain connectomes. Using a tensor encoding, we design an objective with a group-regularizer that prefers biologically plausible fascicle structure. We show that the objective is convex and has unique solutions, ensuring identifiable connectomes for an individual. We develop an efficient optimization strategy for this extremely high-dimensional sparse problem, by reducing the number of parameters using a greedy algorithm designed specifically for the problem. We show that this greedy algorithm significantly improves on a standard greedy algorithm, called Orthogonal Matching Pursuit. We conclude with an analysis of the solutions found by our method, showing we can accurately reconstruct the diffusion information while maintaining contiguous fascicles with smooth direction changes.

Motivation: Modern problems of concept annotation associate an object of interest (gene, individual, text document) with a set of interrelated textual descriptors (functions, diseases, topics), often organized in concept hierarchies or ontologies. Most ontology can be seen as directed acyclic graphs (DAGs), where nodes represent concepts and edges represent relational ties between these concepts. Given an ontology graph, each object can only be annotated by a consistent sub-graph; that is, a sub-graph such that if an object is annotated by a particular concept, it must also be annotated by all other concepts that generalize it. Ontologies therefore provide a compact representation of a large space of possible consistent sub-graphs; however, until now we have not been aware of a practical algorithm that can enumerate such annotation spaces for a given ontology. Results: We propose an algorithm for enumerating consistent sub-graphs of DAGs. The algorithm recursively partitions the graph into strictly smaller graphs until the resulting graph becomes a rooted tree (forest), for which a linear-time solution is computed. It then combines the tallies from graphs created in the recursion to obtain the final count. We prove the correctness of this algorithm, propose several practical accelerations, evaluate it on random graphs and then apply it to characterize four major biomedical ontologies. We believe this work provides valuable insights into the complexity of concept annotation spaces and its potential influence on the predictability of ontological annotation. Availability and implementation: https://github.com/shawn-peng/counting-consistent-sub-DAG. Supplementary information: Supplementary data are available at Bioinformatics online.