James B. Brown

Omid S. Solari, James B. Brown, Peter J. Bickel

A new approach to the sparse Canonical Correlation Analysis (sCCA)is proposed with the aim of discovering interpretable associations in very high-dimensional multi-view, i.e.observations of multiple sets of variables on the same subjects, problems. Inspired by the sparse PCA approach of Journee et al. (2010), we also show that the sparse CCA formulation, while non-convex, is equivalent to a maximization program of a convex objective over a compact set for which we propose a first-order gradient method. This result helps us reduce the search space drastically to the boundaries of the set. Consequently, we propose a two-step algorithm, where we first infer the sparsity pattern of the canonical directions using our fast algorithm, then we shrink each view, i.e. observations of a set of covariates, to contain observations on the sets of covariates selected in the previous step, and compute their canonical directions via any CCA algorithm. We also introduceDirected Sparse CCA, which is able to find associations which are aligned with a specified experiment design, andMulti-View sCCA which is used to discover associations between multiple sets of covariates. Our simulations establish the superior convergence properties and computational efficiency of our algorithm as well as accuracy in terms of the canonical correlation and its ability to recover the supports of the canonical directions. We study the associations between metabolomics, trasncriptomics and microbiomics in a multi-omic study usingMuLe, which is an R-package that implements our approach, in order to form hypotheses on mechanisms of adaptations of Drosophila Melanogaster to high doses of environmental toxicants, specifically Atrazine, which is a commonly used chemical fertilizer.

Omid Shams Solari, Rojin Safavi, James B. Brown

We introduce Block Sparse Canonical Correlation Analysis which estimates multiple pairs of canonical directions (together a "block") at once, resulting in significantly improved orthogonality of the sparse directions which, we demonstrate, translates to more interpretable solutions. Our approach builds on the sparse CCA method of (Solari, Brown, and Bickel 2019) in that we also express the bi-convex objective of our block formulation as a concave minimization problem over an orthogonal k-frame in a unit Euclidean ball, which in turn, due to concavity of the objective, is shrunk to a Stiefel manifold, which is optimized via gradient descent algorithm. Our simulations show that our method outperforms existing sCCA algorithms and implementations in terms of computational cost and stability, mainly due to the drastic shrinkage of our search space, and the correlation within and orthogonality between pairs of estimated canonical covariates. Finally, we apply our method, available as an R-package called BLOCCS, to multi-omic data on Lung Squamous Cell Carcinoma(LUSC) obtained via The Cancer Genome Atlas, and demonstrate its capability in capturing meaningful biological associations relevant to the hypothesis under study rather than spurious dominant variations.

Karl Kumbier, Sumanta Basu, Erwin Frise et al.

Standard ChIP-seq peak calling pipelines seek to differentiate biochemically reproducible signals of individual genomic elements from background noise. However, reproducibility alone does not imply functional regulation (e.g., enhancer activation, alternative splicing). Here we present a general-purpose, interpretable machine learning method: signed iterative random forests (siRF), which we use to infer regulatory interactions among transcription factors and functional binding signatures surrounding enhancer elements in Drosophila melanogaster.

Sumanta Basu, Karl Kumbier, James B. Brown et al.

Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interact in vivo as components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on Random Forests (RF), Random Intersection Trees (RITs), and through extensive, biologically inspired simulations, we developed the iterative Random Forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with same order of computational cost as RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the early Drosophila embryo and alternative splicing of primary transcripts in human derived cell lines. In Drosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, novel third-order interactions, e.g. between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated splicing regulation, and identified novel 5th and 6th order interactions, indicative of multi-valent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens new avenues of inquiry into the molecular mechanisms underlying genome biology.