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Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.

Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu .

We present a penalized matrix decomposition (PMD), a new framework for computing a rank-K approximation for a matrix. We approximate the matrix X as circumflexX = sigma(k=1)(K) d(k)u(k)v(k)(T), where d(k), u(k), and v(k) minimize the squared Frobenius norm of X - circumflexX, subject to penalties on u(k) and v(k). This results in a regularized version of the singular value decomposition. Of particular interest is the use of L(1)-penalties on u(k) and v(k), which yields a decomposition of X using sparse vectors. We show that when the PMD is applied using an L(1)-penalty on v(k) but not on u(k), a method for sparse principal components results. In fact, this yields an efficient algorithm for the "SCoTLASS" proposal (Jolliffe and others 2003) for obtaining sparse principal components. This method is demonstrated on a publicly available gene expression data set. We also establish connections between the SCoTLASS method for sparse principal component analysis and the method of Zou and others (2006). In addition, we show that when the PMD is applied to a cross-products matrix, it results in a method for penalized canonical correlation analysis (CCA). We apply this penalized CCA method to simulated data and to a genomic data set consisting of gene expression and DNA copy number measurements on the same set of samples.

Summary We consider the problem of estimating multiple related Gaussian graphical models from a high-dimensional data set with observations belonging to distinct classes. We propose the joint graphical lasso, which borrows strength across the classes in order to estimate multiple graphical models that share certain characteristics, such as the locations or weights of nonzero edges. Our approach is based upon maximizing a penalized log likelihood. We employ generalized fused lasso or group lasso penalties, and implement a fast ADMM algorithm to solve the corresponding convex optimization problems. The performance of the proposed method is illustrated through simulated and real data examples.

We consider the problem of clustering observations using a potentially large set of features. One might expect that the true underlying clusters present in the data differ only with respect to a small fraction of the features, and will be missed if one clusters the observations using the full set of features. We propose a novel framework for sparse clustering, in which one clusters the observations using an adaptively chosen subset of the features. The method uses a lasso-type penalty to select the features. We use this framework to develop simple methods for sparse K-means and sparse hierarchical clustering. A single criterion governs both the selection of the features and the resulting clusters. These approaches are demonstrated on simulated data and on genomic data sets.

Statistical learning refers to a set of tools for making sense of complex datasets. In recent years, we have seen a staggering increase in the scale and scope of data collection across virtually all areas of science and industry. As a result, statistical learning has become a critical toolkit for anyone who wishes to understand data -and as more and more of today's jobs involve data, this means that statistical learning is fast becoming a critical toolkit for everyone.One of the first books on statistical learning -The Elements of Statistical Learning (ESL, by Hastie, Tibshirani, and Friedman) -was published in 2001, with a second edition in 2009. ESL has become a popular text not only in statistics but also in related fields. One of the reasons for ESL's popularity is its relatively accessible style. But ESL is best-suited for individuals with advanced training in the mathematical sciences.An Introduction to Statistical Learning (ISL) arose from the clear need for a broader and less technical treatment of the key topics in statistical learning. The intention behind ISL is to concentrate more on the applications of the methods and less on the mathematical details. Beginning with Chapter 2, each chapter in ISL contains a lab illustrating how to implement the statistical learning methods seen in that chapter using the popular statistical software package R. These labs provide the reader with valuable hands-on experience.ISL is appropriate for advanced undergraduates or master's students in Statistics or related quantitative fields, or for individuals in other disciplines who wish to use statistical learning tools to analyze their data. It can be used as a textbook for a course spanning two semesters.

In recent work, several authors have introduced methods for sparse canonical correlation analysis (sparse CCA). Suppose that two sets of measurements are available on the same set of observations. Sparse CCA is a method for identifying sparse linear combinations of the two sets of variables that are highly correlated with each other. It has been shown to be useful in the analysis of high-dimensional genomic data, when two sets of assays are available on the same set of samples. In this paper, we propose two extensions to the sparse CCA methodology. (1) Sparse CCA is an unsupervised method; that is, it does not make use of outcome measurements that may be available for each observation (e.g., survival time or cancer subtype). We propose an extension to sparse CCA, which we call sparse supervised CCA, which results in the identification of linear combinations of the two sets of variables that are correlated with each other and associated with the outcome. (2) It is becoming increasingly common for researchers to collect data on more than two assays on the same set of samples; for instance, SNP, gene expression, and DNA copy number measurements may all be available. We develop sparse multiple CCA in order to extend the sparse CCA methodology to the case of more than two data sets. We demonstrate these new methods on simulated data and on a recently published and publicly available diffuse large B-cell lymphoma data set.