MOTIVATION: Correctly identifying epitope-binding T-cell receptors (TCRs) is important to both understand their underlying biological mechanism in association to some phenotype and accordingly develop T-cell mediated immunotherapy treatments. Although the importance of the CDR3 region in TCRs for epitope recognition is well recognized, methods for profiling their interactions in association to a certain disease or phenotype remains less studied. We developed EpicPred to identify phenotype-specific TCR-epitope interactions. EpicPred first predicts and removes unlikely TCR-epitope interactions to reduce false positives using the Open-set Recognition (OSR). Subsequently, multiple instance learning was used to identify TCR-epitope interactions specific to a cancer type or severity levels of COVID-19 infected patients. RESULTS: From six public TCR databases, 244 552 TCR sequences and 105 unique epitopes were used to predict epitope-binding TCRs and to filter out non-epitope-binding TCRs using the OSR method. The predicted interactions were used to further predict the phenotype groups in two cancer and four COVID-19 TCR-seq datasets of both bulk and single-cell resolution. EpicPred outperformed the competing methods in predicting the phenotypes, achieving an average AUROC of 0.80 ± 0.07. AVAILABILITY AND IMPLEMENTATION: The EpicPred Software is available at https://github.com/jaeminjj/EpicPred.

In gene expression analysis, understanding a biological event that is observed at some time instance often requires capturing genes whose expression levels modulate before and after the event. Such genes are expected to be the responders to the event and will exhibit similar expression patterns during the event. However, after the effect of the event fades, their expression levels may loose their correlation. Hence, it is a non-trivial task to identify genes that share highly similar local expression patterns nearby the event and also allowing some level of divergent expression patterns further away from the event’s time point. Here, we propose LOCOS (LOcal COSine), a novel time-course clustering algorithm tailored to cluster genes exhibiting similar expression patterns within a specified time interval. LOCOS is an extension of the traditional Non-negative Matrix Factorization (NMF), which incorporates the cosine similarity and Euclidean distances in its update procedure. LOCOS maximizes the cosine similarity within an interval of interest, while allowing a relaxed minimization of Euclidean distance outside it. Using synthetic and non-biological time-course data, we showed that LOCOS was able to correctly detect the known local patterns within a specified interval. Furthermore, we used longitudinal single-cell RNA-seq samples from four patients showing deteriorating and recovering health conditions to identify genes related to each of the phenotype. As a result, LOCOS was able to capture gene clusters with distinct expression patterns that aligned with the intervals embedding the clinical deterioration and recovery events.

BACKGROUND: Selecting informative genes or eliminating uninformative ones before any downstream gene expression analysis is a standard task with great impact on the results. A carefully curated gene set significantly enhances the likelihood of identifying meaningful biomarkers. METHOD: In contrast to the conventional forward gene search methods that focus on selecting highly informative genes, we propose a backward search method, DenoiseIt, that aims to remove potential outlier genes yielding a robust gene set with reduced noise. The gene set constructed by DenoiseIt is expected to capture biologically significant genes while pruning irrelevant ones to the greatest extent possible. Therefore, it also enhances the quality of downstream comparative gene expression analysis. DenoiseIt utilizes non-negative matrix factorization in conjunction with isolation forests to identify outlier rank features and remove their associated genes. RESULTS: DenoiseIt was applied to both bulk and single-cell RNA-seq data collected from TCGA and a COVID-19 cohort to show that it proficiently identified and removed genes exhibiting expression anomalies confined to specific samples rather than a known group. DenoiseIt also showed to reduce the level of technical noise while preserving a higher proportion of biologically relevant genes compared to existing methods. The DenoiseIt Software is publicly available on GitHub at https://github.com/cobi-git/DenoiseIt.