MOTIVATION: It is more and more common to perform multi-omics analyses to explore the genome at diverse levels and not only at a single level. Through integrative statistical methods, multi-omics data have the power to reveal new biological processes, potential biomarkers and subgroups in a cohort. Matrix factorization (MF) is an unsupervised statistical method that allows a clustering of individuals, but also reveals relevant omics variables from the various blocks. RESULTS: Here, we present PIntMF (Penalized Integrative Matrix Factorization), an MF model with sparsity, positivity and equality constraints. To induce sparsity in the model, we used a classical Lasso penalization on variable and individual matrices. For the matrix of samples, sparsity helps in the clustering, while normalization (matching an equality constraint) of inferred coefficients is added to improve interpretation. Moreover, we added an automatic tuning of the sparsity parameters using the famous glmnet package. We also proposed three criteria to help the user to choose the number of latent variables. PIntMF was compared with other state-of-the-art integrative methods including feature selection techniques in both synthetic and real data. PIntMF succeeds in finding relevant clusters as well as variables in two types of simulated data (correlated and uncorrelated). Next, PIntMF was applied to two real datasets (Diet and cancer), and it revealed interpretable clusters linked to available clinical data. Our method outperforms the existing ones on two criteria (clustering and variable selection). We show that PIntMF is an easy, fast and powerful tool to extract patterns and cluster samples from multi-omics data. AVAILABILITY AND IMPLEMENTATION: An R package is available at https://github.com/mpierrejean/pintmf. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Recent advances in NGS sequencing, microarrays and mass spectrometry for omics data production have enabled the generation and collection of different modalities of high-dimensional molecular data. The integration of multiple omics datasets is a statistical challenge, due to the limited number of individuals, the high number of variables and the heterogeneity of the datasets to integrate. Recently, a lot of tools have been developed to solve the problem of integrating omics data including canonical correlation analysis, matrix factorization and SM. These commonly used techniques aim to analyze simultaneously two or more types of omics. In this article, we compare a panel of 13 unsupervised methods based on these different approaches to integrate various types of multi-omics datasets: iClusterPlus, regularized generalized canonical correlation analysis, sparse generalized canonical correlation analysis, multiple co-inertia analysis (MCIA), integrative-NMF (intNMF), SNF, MoCluster, mixKernel, CIMLR, LRAcluster, ConsensusClustering, PINSPlus and multi-omics factor analysis (MOFA). We evaluate the ability of the methods to recover the subgroups and the variables that drive the clustering on eight benchmarks of simulation. MOFA does not provide any results on these benchmarks. For clustering, SNF, MoCluster, CIMLR, LRAcluster, ConsensusClustering and intNMF provide the best results. For variable selection, MoCluster outperforms the others. However, the performance of the methods seems to depend on the heterogeneity of the datasets (especially for MCIA, intNMF and iClusterPlus). Finally, we apply the methods on three real studies with heterogeneous data and various phenotypes. We conclude that MoCluster is the best method to analyze these omics data. Availability: An R package named CrIMMix is available on GitHub at https://github.com/CNRGH/crimmix to reproduce all the results of this article.

Motivation: In cancer, clonal evolution is assessed based on information coming from single nucleotide variants and copy number alterations. Nonetheless, existing methods often fail to accurately combine information from both sources to truthfully reconstruct clonal populations in a given tumor sample or in a set of tumor samples coming from the same patient. Moreover, previously published methods detect clones from a single set of variants. As a result, compromises have to be done between stringent variant filtering [reducing dispersion in variant allele frequency estimates (VAFs)] and using all biologically relevant variants. Results: We present a framework for defining cancer clones using most reliable variants of high depth of coverage and assigning functional mutations to the detected clones. The key element of our framework is QuantumClone, a method for variant clustering into clones based on VAFs, genotypes of corresponding regions and information about tumor purity. We validated QuantumClone and our framework on simulated data. We then applied our framework to whole genome sequencing data for 19 neuroblastoma trios each including constitutional, diagnosis and relapse samples. We confirmed an enrichment of damaging variants within such pathways as MAPK (mitogen-activated protein kinases), neuritogenesis, epithelial-mesenchymal transition, cell survival and DNA repair. Most pathways had more damaging variants in the expanding clones compared to shrinking ones, which can be explained by the increased total number of variants between these two populations. Functional mutational rate varied for ancestral clones and clones shrinking or expanding upon treatment, suggesting changes in clone selection mechanisms at different time points of tumor evolution. Availability and implementation: Source code and binaries of the QuantumClone R package are freely available for download at https://CRAN.R-project.org/package=QuantumClone. Contact: [email protected] or [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Summary: Predicted deleteriousness of coding variants is a frequently used criterion to filter out variants detected in next-generation sequencing projects and to select candidates impacting on the risk of human diseases. Most available dedicated tools implement a base-to-base annotation approach that could be biased in presence of several variants in the same genetic codon. We here proposed the MACARON program that, from a standard VCF file, identifies, re-annotates and predicts the amino acid change resulting from multiple single nucleotide variants (SNVs) within the same genetic codon. Applied to the whole exome dataset of 573 individuals, MACARON identifies 114 situations where multiple SNVs within a genetic codon induce an amino acid change that is different from those predicted by standard single SNV annotation tool. Such events are not uncommon and deserve to be studied in sequencing projects with inconclusive findings. Availability and implementation: MACARON is written in python with codes available on the GENMED website (www.genmed.fr). Supplementary information: Supplementary data are available at Bioinformatics online.