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 to estimate multiple graphical models that share certain characteristics, such as the locations or weights of non‐zero edges. Our approach is based on maximizing a penalized log‐likelihood. We employ generalized fused lasso or group lasso penalties and implement a fast alternating directions method of multipliers algorithm to solve the corresponding convex optimization problems. The performance of the method proposed is illustrated through simulated and real data examples.
Abstract
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 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 and genomic data.
We consider the supervised classification setting, in which the data consist of p features measured on n observations, each of which belongs to one of K classes. Linear discriminant analysis (LDA) is ...a classical method for this problem. However, in the high dimensional setting where p≫n, LDA is not appropriate for two reasons. First, the standard estimate for the within‐class covariance matrix is singular, and so the usual discriminant rule cannot be applied. Second, when p is large, it is difficult to interpret the classification rule that is obtained from LDA, since it involves all p features. We propose penalized LDA, which is a general approach for penalizing the discriminant vectors in Fisher's discriminant problem in a way that leads to greater interpretability. The discriminant problem is not convex, so we use a minorization–maximization approach to optimize it efficiently when convex penalties are applied to the discriminant vectors. In particular, we consider the use of L1 and fused lasso penalties. Our proposal is equivalent to recasting Fisher's discriminant problem as a biconvex problem. We evaluate the performances of the resulting methods on a simulation study, and on three gene expression data sets. We also survey past methods for extending LDA to the high dimensional setting and explore their relationships with our proposal.
We consider the task of learning a dynamical system from high-dimensional time-course data. For instance, we might wish to estimate a gene regulatory network from gene expression data measured at ...discrete time points. We model the dynamical system nonparametrically as a system of additive ordinary differential equations. Most existing methods for parameter estimation in ordinary differential equations estimate the derivatives from noisy observations. This is known to be challenging and inefficient. We propose a novel approach that does not involve derivative estimation. We show that the proposed method can consistently recover the true network structure even in high dimensions, and we demonstrate empirical improvement over competing approaches. Supplementary materials for this article are available online.
Testing for a change in mean after changepoint detection Jewell, Sean; Fearnhead, Paul; Witten, Daniela
Journal of the Royal Statistical Society. Series B, Statistical methodology,
September 2022, Volume:
84, Issue:
4
Journal Article
Peer reviewed
Open access
While many methods are available to detect structural changes in a time series, few procedures are available to quantify the uncertainty of these estimates post‐detection. In this work, we fill this ...gap by proposing a new framework to test the null hypothesis that there is no change in mean around an estimated changepoint. We further show that it is possible to efficiently carry out this framework in the case of changepoints estimated by binary segmentation and its variants, ℓ0 segmentation, or the fused lasso. Our setup allows us to condition on much less information than existing approaches, which yields higher powered tests. We apply our proposals in a simulation study and on a dataset of chromosomal guanine‐cytosine content. These approaches are freely available in the R package ChangepointInference at
https://jewellsean.github.io/changepoint‐inference/.
Current methods for annotating and interpreting human genetic variation tend to exploit a single information type (for example, conservation) and/or are restricted in scope (for example, to missense ...changes). Here we describe Combined Annotation-Dependent Depletion (CADD), a method for objectively integrating many diverse annotations into a single measure (C score) for each variant. 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 precompute 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 they 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 single-annotation method.
Candidate enhancers can be identified on the basis of chromatin modifications, the binding of chromatin modifiers and transcription factors and cofactors, or chromatin accessibility. However, ...validating such candidates as bona fide enhancers requires functional characterization, typically achieved through reporter assays that test whether a sequence can increase expression of a transcriptional reporter via a minimal promoter. A longstanding concern is that reporter assays are mainly implemented on episomes, which are thought to lack physiological chromatin. However, the magnitude and determinants of differences in cis-regulation for regulatory sequences residing in episomes versus chromosomes remain almost completely unknown. To address this systematically, we developed and applied a novel lentivirus-based massively parallel reporter assay (lentiMPRA) to directly compare the functional activities of 2236 candidate liver enhancers in an episomal versus a chromosomally integrated context. We find that the activities of chromosomally integrated sequences are substantially different from the activities of the identical sequences assayed on episomes, and furthermore are correlated with different subsets of ENCODE annotations. The results of chromosomally based reporter assays are also more reproducible and more strongly predictable by both ENCODE annotations and sequence-based models. With a linear model that combines chromatin annotations and sequence information, we achieve a Pearson's R
of 0.362 for predicting the results of chromosomally integrated reporter assays. This level of prediction is better than with either chromatin annotations or sequence information alone and also outperforms predictive models of episomal assays. Our results have broad implications for how cis-regulatory elements are identified, prioritized and functionally validated.
In recent years, advances in high throughput sequencing technology have led to a need for specialized methods for the analysis of digital gene expression data. While gene expression data measured on ...a microarray take on continuous values and can be modeled using the normal distribution, RNA sequencing data involve nonnegative counts and are more appropriately modeled using a discrete count distribution, such as the Poisson or the negative binomial. Consequently, analytic tools that assume a Gaussian distribution (such as classification methods based on linear discriminant analysis and clustering methods that use Euclidean distance) may not perform as well for sequencing data as methods that are based upon a more appropriate distribution. Here, we propose new approaches for performing classification and clustering of observations on the basis of sequencing data. Using a Poisson log linear model, we develop an analog of diagonal linear discriminant analysis that is appropriate for sequencing data. We also propose an approach for clustering sequencing data using a new dissimilarity measure that is based upon the Poisson model. We demonstrate the performances of these approaches in a simulation study, on three publicly available RNA sequencing data sets, and on a publicly available chromatin immunoprecipitation sequencing data set.
Calcium imaging data promises to transform the field of neuroscience by making it possible to record from large populations of neurons simultaneously. However, determining the exact moment in time at ...which a neuron spikes, from a calcium imaging data set, amounts to a non-trivial deconvolution problem which is of critical importance for downstream analyses. While a number of formulations have been proposed for this task in the recent literature, in this article, we focus on a formulation recently proposed in Jewell and Witten (2018. Exact spike train inference via $\ell_{0} $ optimization. The Annals of Applied Statistics12(4), 2457-2482) that can accurately estimate not just the spike rate, but also the specific times at which the neuron spikes. We develop a much faster algorithm that can be used to deconvolve a fluorescence trace of 100 000 timesteps in less than a second. Furthermore, we present a modification to this algorithm that precludes the possibility of a "negative spike". We demonstrate the performance of this algorithm for spike deconvolution on calcium imaging datasets that were recently released as part of the $\texttt{spikefinder}$ challenge (http://spikefinder.codeneuro.org/). The algorithm presented in this article was used in the Allen Institute for Brain Science's "platform paper" to decode neural activity from the Allen Brain Observatory; this is the main scientific paper in which their data resource is presented. Our $\texttt{C++}$ implementation, along with $\texttt{R}$ and $\texttt{python}$ wrappers, is publicly available. $\texttt{R}$ code is available on $\texttt{CRAN}$ and $\texttt{Github}$, and $\texttt{python}$ wrappers are available on $\texttt{Github}$; see https://github.com/jewellsean/FastLZeroSpikeInference.
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