Genomic Data Analysis using a Two Stage Expectation Propagation Algorithm for Analysis of Sparse Bayesian High-Dimensional Instrumental Variables Regression
Simultaneous analysis of gene expression data and genetic variants is highly of interest, especially when the number of gene expressions and genetic variants are both greater than the sample size. Association of both causal genes and effective SNPs makes the use of sparse modeling of such genetic data sets, highly important. The high-dimensional sparse instrumental variables models are one of such useful association models, which models the simultaneous relation of the gene expressions and genetic variants with complex traits. From a Bayesian viewpoint, the sparsity can be favored using sparsity-enforcing priors such as spike-and-slab priors. A two-stage modification of the expectation propagation (EP) algorithm is proposed and examined for approximate inference in high-dimensional sparse instrumental variables models with spike-and-slab priors. This method is an adoption of the classical two-stage least squares method, to be used with the Bayes context. A simulation study is performed to examine the performance of the methods. The proposed method is applied to analysis of the mouse obesity data.
In genetical genomics studies, it is important to jointly analyze gene expression data and genetic variants in exploring their associations with complex traits, where the dimensionality of gene expressions and genetic variants can both be much larger than the sample size. Motivated by such modern applications, we consider the problem of variable selection and estimation in high-dimensional sparse instrumental variables models. To overcome the difficulty of high dimensionality and unknown optimal instruments, we propose a two-stage regularization framework for identifying and estimating importa…
Causal gene networks model the flow of information within a cell, but reconstructing them from omics data is challenging because correlation does not imply causation. Combining genomics and transcriptomics data from a segregating population allows to orient the direction of causality between gene expression traits using genomic variants. Instrumental-variable methods (IV) use a local expression quantitative trait locus (eQTL) as a randomized instrument for a gene's expression level, and assign target genes based on distal eQTL associations. Mediation-based methods (ME) additionally require tha…
The method of instrumental variables provides a fundamental and practical tool for causal inference in many empirical studies where unmeasured confounding between the treatments and the outcome is present. Modern data such as the genetical genomics data from these studies are often high-dimensional. The high-dimensional linear instrumental-variables regression has been considered in the literature due to its simplicity albeit a true nonlinear relationship may exist. We propose a more data-driven approach by considering the nonparametric additive models between the instruments and the treatment…
Gene expression and phenotype association can be affected by potential unmeasured confounders from multiple sources, leading to biased estimates of the associations. Since genetic variants largely explain gene expression variations, they can be used as instruments in studying the association between gene expressions and phenotype in the framework of high dimensional instrumental variable (IV) regression. However, because the dimensions of both genetic variants and gene expressions are often larger than the sample size, statistical inferences such as hypothesis testing for such high dimensional…
Cornell University（康奈尔大学）；Tsinghua University（清华大学）；Massachusetts Institute of Technology（麻省理工学院）；Stanford University（斯坦福大学）
In this paper, we study nonparametric estimation of instrumental variable (IV) regressions. Recently, many flexible machine learning methods have been developed for instrumental variable estimation. However, these methods have at least one of the following limitations: (1) restricting the IV regression to be uniquely identified; (2) only obtaining estimation error rates in terms of pseudometrics (\emph{e.g.,} projected norm) rather than valid metrics (\emph{e.g.,} $L_2$ norm); or (3) imposing the so-called closedness condition that requires a certain conditional expectation operator to be suff…
We propose a two-stage penalized least squares method to build large systems of structural equations based on the instrumental variables view of the classical two-stage least squares method. We show that, with large numbers of endogenous and exogenous variables, the system can be constructed via consistent estimation of a set of conditional expectations at the first stage, and consistent selection of regulatory effects at the second stage. While the consistent estimation at the first stage can be obtained via the ridge regression, the adaptive lasso is employed at the second stage to achieve t…
Hematopoiesis is the process of blood cell formation, through which progenitor stem cells differentiate into mature forms, such as white and red blood cells or mature platelets. While the precursors of the mature forms share many regulatory pathways involving common cellular nuclear factors, specific networks of regulation shape their fate towards one lineage or another. In this study, we aim to analyse the complex regulatory network that drives the formation of mature red blood cells and platelets from their common precursor. To this aim, we develop a dedicated graphical model which we infer …
The results from Genome-Wide Association Studies (GWAS) on thousands of phenotypes provide an unprecedented opportunity to infer the causal effect of one phenotype (exposure) on another (outcome). Mendelian randomization (MR), an instrumental variable (IV) method, has been introduced for causal inference using GWAS data. Due to the polygenic architecture of complex traits/diseases and the ubiquity of pleiotropy, however, MR has many unique challenges compared to conventional IV methods. We propose a Bayesian weighted Mendelian randomization (BWMR) for causal inference to address these challeng…
Variable selection for structured covariates lying on an underlying known graph is a problem motivated by practical applications, and has been a topic of increasing interest. However, most of the existing methods may not be scalable to high dimensional settings involving tens of thousands of variables lying on known pathways such as the case in genomics studies. We propose an adaptive Bayesian shrinkage approach which incorporates prior network information by smoothing the shrinkage parameters for connected variables in the graph, so that the corresponding coefficients have a similar degree of…
In this article, we propose a covariance based method for combining partial data sets in the genotype to phenotype spectrum. In particular, an expectation-maximization algorithm that can be used to combine partially overlapping relationship/covariance matrices is introduced. Combining data this way, based on relationship matrices, can be contrasted with a feature imputation based approach. We used several public genomic data sets to explore the accuracy of combining genomic relationship matrices. We have also used the heterogeneous genotype/phenotype data sets in the https://triticeaetoolbox.o…
We develop results for the use of Lasso and Post-Lasso methods to form first-stage predictions and estimate optimal instruments in linear instrumental variables (IV) models with many instruments, $p$. Our results apply even when $p$ is much larger than the sample size, $n$. We show that the IV estimator based on using Lasso or Post-Lasso in the first stage is root-n consistent and asymptotically normal when the first-stage is approximately sparse; i.e. when the conditional expectation of the endogenous variables given the instruments can be well-approximated by a relatively small set of variab…
In this article, we consider the problem of reconstructing networks for continuous, binary, count and discrete ordinal variables by estimating sparse precision matrix in Gaussian copula graphical models. We propose two approaches: $\ell_1$ penalized extended rank likelihood with Monte Carlo Expectation-Maximization algorithm (copula EM glasso) and copula skeptic with pair-wise copula estimation for copula Gaussian graphical models. The proposed approaches help to infer networks arising from nonnormal and mixed variables. We demonstrate the performance of our methods through simulation studies …
We propose a statistical framework to integrate radiological magnetic resonance imaging (MRI) and genomic data to identify the underlying radiogenomic associations in lower grade gliomas (LGG). We devise a novel imaging phenotype by dividing the tumor region into concentric spherical layers that mimics the tumor evolution process. MRI data within each layer is represented by voxel--intensity-based probability density functions which capture the complete information about tumor heterogeneity. Under a Riemannian-geometric framework these densities are mapped to a vector of principal component sc…
This paper aims at developing a quasi-Bayesian analysis of the nonparametric instrumental variables model, with a focus on the asymptotic properties of quasi-posterior distributions. In this paper, instead of assuming a distributional assumption on the data generating process, we consider a quasi-likelihood induced from the conditional moment restriction, and put priors on the function-valued parameter. We call the resulting posterior quasi-posterior, which corresponds to ``Gibbs posterior'' in the literature. Here we focus on priors constructed on slowly growing finite-dimensional sieves. We …
Purdue University（普渡大学）；Indiana University（印第安纳大学）；Indiana University School of Medicine（印第安纳大学医学院）
Parameter estimation of mixture regression model using the expectation maximization (EM) algorithm is highly sensitive to outliers. Here we propose a fast and efficient robust mixture regression algorithm, called Component-wise Adaptive Trimming (CAT) method. We consider simultaneous outlier detection and robust parameter estimation to minimize the effect of outlier contamination. Robust mixture regression has many important applications including in human cancer genomics data, where the population often displays strong heterogeneity added by unwanted technological perturbations. Existing robu…
In recent years, a large number of genomic and epigenomic studies have been focusing on the integrative analysis of multiple experimental datasets measured over a large number of observational units. The objectives of such studies include not only inferring a hidden state of activity for each unit over individual experiments, but also detecting highly associated clusters of units based on their inferred states. In this paper, we develop the MBASIC (Matrix Based Analysis for State-space Inference and Clustering) framework. MBASIC consists of two parts: state-space mapping and state-space cluste…
High-throughput scientific studies involving no clear a'priori hypothesis are common. For example, a large-scale genomic study of a disease may examine thousands of genes without hypothesizing that any specific gene is responsible for the disease. In these studies, the objective is to explore a large number of possible factors (e.g. genes) in order to identify a small number that will be considered in follow-up studies that tend to be more thorough and on smaller scales. For large-scale studies, we propose a nonparametric Bayesian approach based on random partition models. Our model thus divid…
Latent factor models are the canonical statistical tool for exploratory analyses of low-dimensional linear structure for an observation matrix with p features across n samples. We develop a structured Bayesian group factor analysis model that extends the factor model to multiple coupled observation matrices; in the case of two observations, this reduces to a Bayesian model of canonical correlation analysis. The main contribution of this work is to carefully define a structured Bayesian prior that encourages both element-wise and column-wise shrinkage and leads to desirable behavior on high-dim…
