DeepLINK: Deep learning inference using knockoffs with applications to genomics.

We propose a deep learning-based knockoffs inference framework, DeepLINK, that guarantees the false discovery rate (FDR) control in high-dimensional settings. DeepLINK is applicable to a broad class of covariate distributions described by the possibly nonlinear latent factor models. It consists of two major parts: an autoencoder network for the knockoff variable construction and a multilayer perceptron network for feature selection with the FDR control. The empirical performance of DeepLINK is investigated through extensive simulation studies, where it is shown to achieve FDR control in feature selection with both high selection power and high prediction accuracy. We also apply DeepLINK to three real data applications to demonstrate its practical utility.

ASYMPTOTIC DISTRIBUTIONS OF HIGH-DIMENSIONAL DISTANCE CORRELATION INFERENCE.

Distance correlation has become an increasingly popular tool for detecting the nonlinear dependence between a pair of potentially high-dimensional random vectors. Most existing works have explored its asymptotic distributions under the null hypothesis of independence between the two random vectors when only the sample size or the dimensionality diverges. Yet its asymptotic null distribution for the more realistic setting when both sample size and dimensionality diverge in the full range remains largely underdeveloped. In this paper, we fill such a gap and develop central limit theorems and associated rates of convergence for a rescaled test statistic based on the bias-corrected distance correlation in high dimensions under some mild regularity conditions and the null hypothesis. Our new theoretical results reveal an interesting phenomenon of blessing of dimensionality for high-dimensional distance correlation inference in the sense that the accuracy of normal approximation can increase with dimensionality. Moreover, we provide a general theory on the power analysis under the alternative hypothesis of dependence, and further justify the capability of the rescaled distance correlation in capturing the pure nonlinear dependency under moderately high dimensionality for a certain type of alternative hypothesis. The theoretical results and finite-sample performance of the rescaled statistic are illustrated with several simulation examples and a blockchain application.

Towards enhanced and interpretable clustering/classification in integrative genomics.

High-throughput technologies have led to large collections of different types of biological data that provide unprecedented opportunities to unravel molecular heterogeneity of biological processes. Nevertheless, how to jointly explore data from multiple sources into a holistic, biologically meaningful interpretation remains challenging. In this work, we propose a scalable and tuning-free preprocessing framework, Heterogeneity Rescaling Pursuit (Hetero-RP), which weighs important features more highly than less important ones in accord with implicitly existing auxiliary knowledge. Finally, we demonstrate effectiveness of Hetero-RP in diverse clustering and classification applications. More importantly, Hetero-RP offers an interpretation of feature importance, shedding light on the driving forces of the underlying biology. In metagenomic contig binning, Hetero-RP automatically weighs abundance and composition profiles according to the varying number of samples, resulting in markedly improved performance of contig binning. In RNA-binding protein (RBP) binding site prediction, Hetero-RP not only improves the prediction performance measured by the area under the receiver operating characteristic curves (AUC), but also uncovers the evidence supported by independent studies, including the distribution of the binding sites of IGF2BP and PUM2, the binding competition between hnRNPC and U2AF2, and the intron-exon boundary of U2AF2 [availability: https://github.com/younglululu/Hetero-RP].

SOFAR: Large-Scale Association Network Learning.

Many modern big data applications feature large scale in both numbers of responses and predictors. Better statistical efficiency and scientific insights can be enabled by understanding the large-scale response-predictor association network structures via layers of sparse latent factors ranked by importance. Yet sparsity and orthogonality have been two largely incompatible goals. To accommodate both features, in this paper we suggest the method of sparse orthogonal factor regression (SOFAR) via the sparse singular value decomposition with orthogonality constrained optimization to learn the underlying association networks, with broad applications to both unsupervised and supervised learning tasks such as biclustering with sparse singular value decomposition, sparse principal component analysis, sparse factor analysis, and spare vector autoregression analysis. Exploiting the framework of convexity-assisted nonconvex optimization, we derive nonasymptotic error bounds for the suggested procedure characterizing the theoretical advantages. The statistical guarantees are powered by an efficient SOFAR algorithm with convergence property. Both computational and theoretical advantages of our procedure are demonstrated with several simulations and real data examples.

Neural Substrates Related to Motor Memory with Multiple Timescales in Sensorimotor Adaptation.

Recent computational and behavioral studies suggest that motor adaptation results from the update of multiple memories with different timescales. Here, we designed a model-based functional magnetic resonance imaging (fMRI) experiment in which subjects adapted to two opposing visuomotor rotations. A computational model of motor adaptation with multiple memories was fitted to the behavioral data to generate time-varying regressors of brain activity. We identified regional specificity to timescales: in particular, the activity in the inferior parietal region and in the anterior-medial cerebellum was associated with memories for intermediate and long timescales, respectively. A sparse singular value decomposition analysis of variability in specificities to timescales over the brain identified four components, two fast, one middle, and one slow, each associated with different brain networks. Finally, a multivariate decoding analysis showed that activity patterns in the anterior-medial cerebellum progressively represented the two rotations. Our results support the existence of brain regions associated with multiple timescales in adaptation and a role of the cerebellum in storing multiple internal models.

Estimating and testing high-dimensional mediation effects in epigenetic studies.

MOTIVATION: High-dimensional DNA methylation markers may mediate pathways linking environmental exposures with health outcomes. However, there is a lack of analytical methods to identify significant mediators for high-dimensional mediation analysis. RESULTS: Based on sure independent screening and minimax concave penalty techniques, we use a joint significance test for mediation effect. We demonstrate its practical performance using Monte Carlo simulation studies and apply this method to investigate the extent to which DNA methylation markers mediate the causal pathway from smoking to reduced lung function in the Normative Aging Study. We identify 2 CpGs with significant mediation effects. AVAILABILITY AND IMPLEMENTATION: R package, source code, and simulation study are available at https://github.com/YinanZheng/HIMA CONTACT: lei.liu@northwestern.edu.

Optimal Nonparametric Inference with Two-Scale Distributional Nearest Neighbors.

The weighted nearest neighbors (WNN) estimator has been popularly used as a flexible and easy-to-implement nonparametric tool for mean regression estimation. The bagging technique is an elegant way to form WNN estimators with weights automatically generated to the nearest neighbors (Steele, 2009; Biau et al., 2010); we name the resulting estimator as the distributional nearest neighbors (DNN) for easy reference. Yet, there is a lack of distributional results for such estimator, limiting its application to statistical inference. Moreover, when the mean regression function has higher-order smoothness, DNN does not achieve the optimal nonparametric convergence rate, mainly because of the bias issue. In this work, we provide an in-depth technical analysis of the DNN, based on which we suggest a bias reduction approach for the DNN estimator by linearly combining two DNN estimators with different subsampling scales, resulting in the novel two-scale DNN (TDNN) estimator. The two-scale DNN estimator has an equivalent representation of WNN with weights admitting explicit forms and some being negative. We prove that, thanks to the use of negative weights, the two-scale DNN estimator enjoys the optimal nonparametric rate of convergence in estimating the regression function under the fourth-order smoothness condition. We further go beyond estimation and establish that the DNN and two-scale DNN are both asymptotically normal as the subsampling scales and sample size diverge to infinity. For the practical implementation, we also provide variance estimators and a distribution estimator using the jackknife and bootstrap techniques for the two-scale DNN. These estimators can be exploited for constructing valid confidence intervals for nonparametric inference of the regression function. The theoretical results and appealing finite-sample performance of the suggested two-scale DNN method are illustrated with several simulation examples and a real data application.

Asymptotic Theory of Eigenvectors for Random Matrices with Diverging Spikes.

Characterizing the asymptotic distributions of eigenvectors for large random matrices poses important challenges yet can provide useful insights into a range of statistical applications. To this end, in this paper we introduce a general framework of asymptotic theory of eigenvectors (ATE) for large spiked random matrices with diverging spikes and heterogeneous variances, and establish the asymptotic properties of the spiked eigenvectors and eigenvalues for the scenario of the generalized Wigner matrix noise. Under some mild regularity conditions, we provide the asymptotic expansions for the spiked eigenvalues and show that they are asymptotically normal after some normalization. For the spiked eigenvectors, we establish asymptotic expansions for the general linear combination and further show that it is asymptotically normal after some normalization, where the weight vector can be arbitrary. We also provide a more general asymptotic theory for the spiked eigenvectors using the bilinear form. Simulation studies verify the validity of our new theoretical results. Our family of models encompasses many popularly used ones such as the stochastic block models with or without overlapping communities for network analysis and the topic models for text analysis, and our general theory can be exploited for statistical inference in these large-scale applications.

Non-Concave Penalized Likelihood with NP-Dimensionality.

Penalized likelihood methods are fundamental to ultra-high dimensional variable selection. How high dimensionality such methods can handle remains largely unknown. In this paper, we show that in the context of generalized linear models, such methods possess model selection consistency with oracle properties even for dimensionality of Non-Polynomial (NP) order of sample size, for a class of penalized likelihood approaches using folded-concave penalty functions, which were introduced to ameliorate the bias problems of convex penalty functions. This fills a long-standing gap in the literature where the dimensionality is allowed to grow slowly with the sample size. Our results are also applicable to penalized likelihood with the L(1)-penalty, which is a convex function at the boundary of the class of folded-concave penalty functions under consideration. The coordinate optimization is implemented for finding the solution paths, whose performance is evaluated by a few simulation examples and the real data analysis.

A Selective Overview of Variable Selection in High Dimensional Feature Space.

High dimensional statistical problems arise from diverse fields of scientific research and technological development. Variable selection plays a pivotal role in contemporary statistical learning and scientific discoveries. The traditional idea of best subset selection methods, which can be regarded as a specific form of penalized likelihood, is computationally too expensive for many modern statistical applications. Other forms of penalized likelihood methods have been successfully developed over the last decade to cope with high dimensionality. They have been widely applied for simultaneously selecting important variables and estimating their effects in high dimensional statistical inference. In this article, we present a brief account of the recent developments of theory, methods, and implementations for high dimensional variable selection. What limits of the dimensionality such methods can handle, what the role of penalty functions is, and what the statistical properties are rapidly drive the advances of the field. The properties of non-concave penalized likelihood and its roles in high dimensional statistical modeling are emphasized. We also review some recent advances in ultra-high dimensional variable selection, with emphasis on independence screening and two-scale methods.

RANK: Large-Scale Inference with Graphical Nonlinear Knockoffs.

Power and reproducibility are key to enabling refined scientific discoveries in contemporary big data applications with general high-dimensional nonlinear models. In this paper, we provide theoretical foundations on the power and robustness for the model-X knockoffs procedure introduced recently in Candès, Fan, Janson and Lv (2018) in high-dimensional setting when the covariate distribution is characterized by Gaussian graphical model. We establish that under mild regularity conditions, the power of the oracle knockoffs procedure with known covariate distribution in high-dimensional linear models is asymptotically one as sample size goes to infinity. When moving away from the ideal case, we suggest the modified model-X knockoffs method called graphical nonlin-ear knockoffs (RANK) to accommodate the unknown covariate distribution. We provide theoretical justifications on the robustness of our modified procedure by showing that the false discovery rate (FDR) is asymptotically controlled at the target level and the power is asymptotically one with the estimated covariate distribution. To the best of our knowledge, this is the first formal theoretical result on the power for the knockoffs procedure. Simulation results demonstrate that compared to existing approaches, our method performs competitively in both FDR control and power. A real data set is analyzed to further assess the performance of the suggested knockoffs procedure.

IPAD: Stable Interpretable Forecasting with Knockoffs Inference.

Interpretability and stability are two important features that are desired in many contemporary big data applications arising in statistics, economics, and finance. While the former is enjoyed to some extent by many existing forecasting approaches, the latter in the sense of controlling the fraction of wrongly discovered features which can enhance greatly the interpretability is still largely underdeveloped. To this end, in this paper we exploit the general framework of model-X knockoffs introduced recently in Candès, Fan, Janson and Lv (2018), which is nonconventional for reproducible large-scale inference in that the framework is completely free of the use of p-values for significance testing, and suggest a new method of intertwined probabilistic factors decoupling (IPAD) for stable interpretable forecasting with knockoffs inference in high-dimensional models. The recipe of the method is constructing the knockoff variables by assuming a latent factor model that is exploited widely in economics and finance for the association structure of covariates. Our method and work are distinct from the existing literature in that we estimate the covariate distribution from data instead of assuming that it is known when constructing the knockoff variables, our procedure does not require any sample splitting, we provide theoretical justifications on the asymptotic false discovery rate control, and the theory for the power analysis is also established. Several simulation examples and the real data analysis further demonstrate that the newly suggested method has appealing finite-sample performance with desired interpretability and stability compared to some popularly used forecasting methods.

Nonuniformity of P-values Can Occur Early in Diverging Dimensions.

Evaluating the joint significance of covariates is of fundamental importance in a wide range of applications. To this end, p-values are frequently employed and produced by algorithms that are powered by classical large-sample asymptotic theory. It is well known that the conventional p-values in Gaussian linear model are valid even when the dimensionality is a non-vanishing fraction of the sample size, but can break down when the design matrix becomes singular in higher dimensions or when the error distribution deviates from Gaussianity. A natural question is when the conventional p-values in generalized linear models become invalid in diverging dimensions. We establish that such a breakdown can occur early in nonlinear models. Our theoretical characterizations are confirmed by simulation studies.

Sparse High Dimensional Models in Economics.

This paper reviews the literature on sparse high dimensional models and discusses some applications in economics and finance. Recent developments of theory, methods, and implementations in penalized least squares and penalized likelihood methods are highlighted. These variable selection methods are proved to be effective in high dimensional sparse modeling. The limits of dimensionality that regularization methods can handle, the role of penalty functions, and their statistical properties are detailed. Some recent advances in ultra-high dimensional sparse modeling are also briefly discussed.