Daniela Witten

Keshav Motwani, Daniela Witten

Recent work has focused on the very common practice of prediction-based inference: that is, (i) using a pre-trained machine learning model to predict an unobserved response variable, and then (ii) conducting inference on the association between that predicted response and some covariates. As pointed out by Wang et al. (2020), applying a standard inferential approach in (ii) does not accurately quantify the association between the unobserved (as opposed to the predicted) response and the covariates. In recent work, Wang et al. (2020) and Angelopoulos et al. (2023) propose corrections to step (ii) in order to enable valid inference on the association between the unobserved response and the covariates. Here, we show that the method proposed by Angelopoulos et al. (2023) successfully controls the type 1 error rate and provides confidence intervals with correct nominal coverage, regardless of the quality of the pre-trained machine learning model used to predict the unobserved response. However, the method proposed by Wang et al. (2020) provides valid inference only under very strong conditions that rarely hold in practice: for instance, if the machine learning model perfectly estimates the true regression function in the study population of interest.

Lucy L. Gao, Jacob Bien, Daniela Witten

Classical tests for a difference in means control the type I error rate when the groups are defined a priori. However, when the groups are instead defined via clustering, then applying a classical test yields an extremely inflated type I error rate. Notably, this problem persists even if two separate and independent data sets are used to define the groups and to test for a difference in their means. To address this problem, in this paper, we propose a selective inference approach to test for a difference in means between two clusters. Our procedure controls the selective type I error rate by accounting for the fact that the choice of null hypothesis was made based on the data. We describe how to efficiently compute exact p-values for clusters obtained using agglomerative hierarchical clustering with many commonly-used linkages. We apply our method to simulated data and to single-cell RNA-sequencing data.

Lucy L. Gao, Daniela Witten, Jacob Bien

In this paper, we consider data consisting of multiple networks, each comprised of a different edge set on a common set of nodes. Many models have been proposed for the analysis of such multi-view network data under the assumption that the data views are closely related. In this paper, we provide tools for evaluating this assumption. In particular, we ask: given two networks that each follow a stochastic block model, is there an association between the latent community memberships of the nodes in the two networks? To answer this question, we extend the stochastic block model for a single network view to the two-view setting, and develop a new hypothesis test for the null hypothesis that the latent community memberships in the two data views are independent. We apply our test to protein-protein interaction data from the HINT database (Das and Hint, 2012). We find evidence of a weak association between the latent community memberships of proteins defined with respect to binary interaction data and the latent community memberships of proteins defined with respect to co-complex association data. We also extend this proposal to the setting of a network with node covariates.

Lucy L. Gao, Jacob Bien, Daniela Witten

In the Pioneer 100 (P100) Wellness Project (Price and others, 2017), multiple types of data are collected on a single set of healthy participants at multiple timepoints in order to characterize and optimize wellness. One way to do this is to identify clusters, or subgroups, among the participants, and then to tailor personalized health recommendations to each subgroup. It is tempting to cluster the participants using all of the data types and timepoints, in order to fully exploit the available information. However, clustering the participants based on multiple data views implicitly assumes that a single underlying clustering of the participants is shared across all data views. If this assumption does not hold, then clustering the participants using multiple data views may lead to spurious results. In this paper, we seek to evaluate the assumption that there is some underlying relationship among the clusterings from the different data views, by asking the question: are the clusters within each data view dependent or independent? We develop a new test for answering this question, which we then apply to clinical, proteomic, and metabolomic data, across two distinct timepoints, from the P100 study. We find that while the subgroups of the participants defined with respect to any single data type seem to be dependent across time, the clustering among the participants based on one data type (e.g. proteomic data) appears not to be associated with the clustering based on another data type (e.g. clinical data).

Kean Ming Tan, Qiang Sun, Daniela Witten

We propose robust sparse reduced rank regression for analyzing large and complex high-dimensional data with heavy-tailed random noise. The proposed method is based on a convex relaxation of a rank- and sparsity-constrained non-convex optimization problem, which is then solved using the alternating direction method of multipliers algorithm. We establish non-asymptotic estimation error bounds under both Frobenius and nuclear norms in the high-dimensional setting. This is a major contribution over existing results in reduced rank regression, which mainly focus on rank selection and prediction consistency. Our theoretical results quantify the tradeoff between heavy-tailedness of the random noise and statistical bias. For random noise with bounded $(1+δ)$th moment with $δ\in (0,1)$, the rate of convergence is a function of $δ$, and is slower than the sub-Gaussian-type deviation bounds; for random noise with bounded second moment, we obtain a rate of convergence as if sub-Gaussian noise were assumed. Furthermore, the transition between the two regimes is smooth. We illustrate the performance of the proposed method via extensive numerical studies and a data application.

Sen Zhao, Daniela Witten, Ali Shojaie

A great deal of interest has recently focused on conducting inference on the parameters in a high-dimensional linear model. In this paper, we consider a simple and very naïve two-step procedure for this task, in which we (i) fit a lasso model in order to obtain a subset of the variables, and (ii) fit a least squares model on the lasso-selected set. Conventional statistical wisdom tells us that we cannot make use of the standard statistical inference tools for the resulting least squares model (such as confidence intervals and $p$-values), since we peeked at the data twice: once in running the lasso, and again in fitting the least squares model. However, in this paper, we show that under a certain set of assumptions, with high probability, the set of variables selected by the lasso is identical to the one selected by the noiseless lasso and is hence deterministic. Consequently, the naïve two-step approach can yield asymptotically valid inference. We utilize this finding to develop the \emph{naïve confidence interval}, which can be used to draw inference on the regression coefficients of the model selected by the lasso, as well as the \emph{naïve score test}, which can be used to test the hypotheses regarding the full-model regression coefficients.

Asad Haris, Daniela Witten, Noah Simon

We consider the task of fitting a regression model involving interactions among a potentially large set of covariates, in which we wish to enforce strong heredity. We propose FAMILY, a very general framework for this task. Our proposal is a generalization of several existing methods, such as VANISH [Radchenko and James, 2010], hierNet [Bien et al., 2013], the all-pairs lasso, and the lasso using only main effects. It can be formulated as the solution to a convex optimization problem, which we solve using an efficient alternating directions method of multipliers (ADMM) algorithm. This algorithm has guaranteed convergence to the global optimum, can be easily specialized to any convex penalty function of interest, and allows for a straightforward extension to the setting of generalized linear models. We derive an unbiased estimator of the degrees of freedom of FAMILY, and explore its performance in a simulation study and on an HIV sequence data set.

Ashley Petersen, Daniela Witten, Noah Simon

We consider the problem of predicting an outcome variable using $p$ covariates that are measured on $n$ independent observations, in the setting in which flexible and interpretable fits are desirable. We propose the fused lasso additive model (FLAM), in which each additive function is estimated to be piecewise constant with a small number of adaptively-chosen knots. FLAM is the solution to a convex optimization problem, for which a simple algorithm with guaranteed convergence to the global optimum is provided. FLAM is shown to be consistent in high dimensions, and an unbiased estimator of its degrees of freedom is proposed. We evaluate the performance of FLAM in a simulation study and on two data sets.

Shikai Luo, Rui Song, Daniela Witten

We propose {graphical sure screening}, or GRASS, a very simple and computationally-efficient screening procedure for recovering the structure of a Gaussian graphical model in the high-dimensional setting. The GRASS estimate of the conditional dependence graph is obtained by thresholding the elements of the sample covariance matrix. The proposed approach possesses the sure screening property: with very high probability, the GRASS estimated edge set contains the true edge set. Furthermore, with high probability, the size of the estimated edge set is controlled. We provide a choice of threshold for GRASS that can control the expected false positive rate. We illustrate the performance of GRASS in a simulation study and on a gene expression data set, and show that in practice it performs quite competitively with more complex and computationally-demanding techniques for graph estimation.

Kean Ming Tan, Noah Simon, Daniela Witten

We consider large-scale studies in which it is of interest to test a very large number of hypotheses, and then to estimate the effect sizes corresponding to the rejected hypotheses. For instance, this setting arises in the analysis of gene expression or DNA sequencing data. However, naive estimates of the effect sizes suffer from selection bias, i.e., some of the largest naive estimates are large due to chance alone. Many authors have proposed methods to reduce the effects of selection bias under the assumption that the naive estimates of the effect sizes are independent. Unfortunately, when the effect size estimates are dependent, these existing techniques can have very poor performance, and in practice there will often be dependence. We propose an estimator that adjusts for selection bias under a recently-proposed frequentist framework, without the independence assumption. We study some properties of the proposed estimator, and illustrate that it outperforms past proposals in a simulation study and on two gene expression data sets.

Kean Ming Tan, Palma London, Karthik Mohan et al.

We consider the problem of learning a high-dimensional graphical model in which certain hub nodes are highly-connected to many other nodes. Many authors have studied the use of an l1 penalty in order to learn a sparse graph in high-dimensional setting. However, the l1 penalty implicitly assumes that each edge is equally likely and independent of all other edges. We propose a general framework to accommodate more realistic networks with hub nodes, using a convex formulation that involves a row-column overlap norm penalty. We apply this general framework to three widely-used probabilistic graphical models: the Gaussian graphical model, the covariance graph model, and the binary Ising model. An alternating direction method of multipliers algorithm is used to solve the corresponding convex optimization problems. On synthetic data, we demonstrate that our proposed framework outperforms competitors that do not explicitly model hub nodes. We illustrate our proposal on a webpage data set and a gene expression data set.

Arend Voorman, Ali Shojaie, Daniela Witten

In recent years, there has been considerable theoretical development regarding variable selection consistency of penalized regression techniques, such as the lasso. However, there has been relatively little work on quantifying the uncertainty in these selection procedures. In this paper, we propose a new method for inference in high dimensions using a score test based on penalized regression. In this test, we perform penalized regression of an outcome on all but a single feature, and test for correlation of the residuals with the held-out feature. This procedure is applied to each feature in turn. Interestingly, when an $\ell_1$ penalty is used, the sparsity pattern of the lasso corresponds exactly to a decision based on the proposed test. Further, when an $\ell_2$ penalty is used, the test corresponds precisely to a score test in a mixed effects model, in which the effects of all but one feature are assumed to be random. We formulate the hypothesis being tested as a compromise between the null hypotheses tested in simple linear regression on each feature and in multiple linear regression on all features, and develop reference distributions for some well-known penalties. We also examine the behavior of the test on real and simulated data.

Kean Ming Tan, Daniela Witten, Ali Shojaie

We consider the task of estimating a Gaussian graphical model in the high-dimensional setting. The graphical lasso, which involves maximizing the Gaussian log likelihood subject to an l1 penalty, is a well-studied approach for this task. We begin by introducing a surprising connection between the graphical lasso and hierarchical clustering: the graphical lasso in effect performs a two-step procedure, in which (1) single linkage hierarchical clustering is performed on the variables in order to identify connected components, and then (2) an l1-penalized log likelihood is maximized on the subset of variables within each connected component. In other words, the graphical lasso determines the connected components of the estimated network via single linkage clustering. Unfortunately, single linkage clustering is known to perform poorly in certain settings. Therefore, we propose the cluster graphical lasso, which involves clustering the features using an alternative to single linkage clustering, and then performing the graphical lasso on the subset of variables within each cluster. We establish model selection consistency for this technique, and demonstrate its improved performance relative to the graphical lasso in a simulation study, as well as in applications to an equities data set, a university webpage data set, and a gene expression data set.

Karthik Mohan, Palma London, Maryam Fazel et al.

We consider the problem of estimating high-dimensional Gaussian graphical models corresponding to a single set of variables under several distinct conditions. This problem is motivated by the task of recovering transcriptional regulatory networks on the basis of gene expression data {containing heterogeneous samples, such as different disease states, multiple species, or different developmental stages}. We assume that most aspects of the conditional dependence networks are shared, but that there are some structured differences between them. Rather than assuming that similarities and differences between networks are driven by individual edges, we take a node-based approach, which in many cases provides a more intuitive interpretation of the network differences. We consider estimation under two distinct assumptions: (1) differences between the K networks are due to individual nodes that are perturbed across conditions, or (2) similarities among the K networks are due to the presence of common hub nodes that are shared across all K networks. Using a row-column overlap norm penalty function, we formulate two convex optimization problems that correspond to these two assumptions. We solve these problems using an alternating direction method of multipliers algorithm, and we derive a set of necessary and sufficient conditions that allows us to decompose the problem into independent subproblems so that our algorithm can be scaled to high-dimensional settings. Our proposal is illustrated on synthetic data, a webpage data set, and a brain cancer gene expression data set.