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We outline emerging opportunities and challenges to enhance the utility of AI for scientific discovery. The distinct goals of AI for industry versus the goals of AI for science create tension between identifying patterns in data versus discovering patterns in the world from data. If we address the fundamental challenges associated with "bridging the gap" between domain-driven scientific models and data-driven AI learning machines, then we expect that these AI models can transform hypothesis generation, scientific discovery, and the scientific process itself.

We developed Distilled Graph Attention Policy Network (DGAPN), a reinforcement learning model to generate novel graph-structured chemical representations that optimize user-defined objectives by efficiently navigating a physically constrained domain. The framework is examined on the task of generating molecules that are designed to bind, noncovalently, to functional sites of SARS-CoV-2 proteins. We present a spatial Graph Attention (sGAT) mechanism that leverages self-attention over both node and edge attributes as well as encoding the spatial structure -- this capability is of considerable interest in synthetic biology and drug discovery. An attentional policy network is introduced to learn the decision rules for a dynamic, fragment-based chemical environment, and state-of-the-art policy gradient techniques are employed to train the network with stability. Exploration is driven by the stochasticity of the action space design and the innovation reward bonuses learned and proposed by random network distillation. In experiments, our framework achieved outstanding results compared to state-of-the-art algorithms, while reducing the complexity of paths to chemical synthesis.

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., Comment: 45 Pages

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., Comment: 8 pages

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.

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.

Gene co-expression network differential analysis is designed to help biologists understand gene expression patterns under different condition. By comparing different gene co-expression networks we may find conserved part as well as condition specific set of genes. Taking the network as a collection as modules, we use a sample-saving method to construct condition-specific gene co-expression network, and identify differentially expressed subnetworks as conserved or condition specific modules which may be associated with biological processes. We have implemented the method as an R package which establishes a pipeline from expression profile to biological explanations. The usefulness of the method is also demonstrated by synthetic data as well as Daphnia magna gene expression data under different environmental stresses.

Reproducibility is essential to reliable scientific discovery in high-throughput experiments. In this work we propose a unified approach to measure the reproducibility of findings identified from replicate experiments and identify putative discoveries using reproducibility. Unlike the usual scalar measures of reproducibility, our approach creates a curve, which quantitatively assesses when the findings are no longer consistent across replicates. Our curve is fitted by a copula mixture model, from which we derive a quantitative reproducibility score, which we call the "irreproducible discovery rate" (IDR) analogous to the FDR. This score can be computed at each set of paired replicate ranks and permits the principled setting of thresholds both for assessing reproducibility and combining replicates. Since our approach permits an arbitrary scale for each replicate, it provides useful descriptive measures in a wide variety of situations to be explored. We study the performance of the algorithm using simulations and give a heuristic analysis of its theoretical properties. We demonstrate the effectiveness of our method in a ChIP-seq experiment., Comment: Published in at http://dx.doi.org/10.1214/11-AOAS466 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Large-scale statistical analysis of data sets associated with genome sequences plays an important role in modern biology. A key component of such statistical analyses is the computation of $p$-values and confidence bounds for statistics defined on the genome. Currently such computation is commonly achieved through ad hoc simulation measures. The method of randomization, which is at the heart of these simulation procedures, can significantly affect the resulting statistical conclusions. Most simulation schemes introduce a variety of hidden assumptions regarding the nature of the randomness in the data, resulting in a failure to capture biologically meaningful relationships. To address the need for a method of assessing the significance of observations within large scale genomic studies, where there often exists a complex dependency structure between observations, we propose a unified solution built upon a data subsampling approach. We propose a piecewise stationary model for genome sequences and show that the subsampling approach gives correct answers under this model. We illustrate the method on three simulation studies and two real data examples., Comment: Published in at http://dx.doi.org/10.1214/10-AOAS363 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)