Recent technological advances have made it possible to collect high-dimensional genomic data along with clinical data on a large number of subjects. In the studies of chronic diseases such as cancer, it is of great interest to integrate clinical and genomic data to build a comprehensive understanding of the disease mechanisms. Despite extensive studies on integrative analysis, it remains an ongoing challenge to model the interaction effects between clinical and genomic variables, due to high-dimensionality of the data and heterogeneity across data types. In this paper, we propose an integrative approach that models interaction effects using a single-index varying-coefficient model, where the effects of genomic features can be modified by clinical variables. We propose a penalized approach for separate selection of main and interaction effects. We demonstrate the advantages of the proposed methods through extensive simulation studies and provide applications to a motivating cancer genomic study.
Integrating the summary statistics from genome-wide association study (\textsc{gwas}) and expression quantitative trait loci (e\textsc{qtl}) data provides a powerful way of identifying the genes whose expression levels are potentially associated with complex diseases. A parameter called $T$-score that quantifies the genetic overlap between a gene and the disease phenotype based on the summary statistics is introduced based on the mean values of two Gaussian sequences. Specifically, given two independent samples $\mathbf{x}_n\sim N(θ, Σ_1)$ and $\mathbf{y}_n\sim N(μ, Σ_2)$, the $T$-score is def…
In this paper, we propose a new method remMap -- REgularized Multivariate regression for identifying MAster Predictors -- for fitting multivariate response regression models under the high-dimension-low-sample-size setting. remMap is motivated by investigating the regulatory relationships among different biological molecules based on multiple types of high dimensional genomic data. Particularly, we are interested in studying the influence of DNA copy number alterations on RNA transcript levels. For this purpose, we model the dependence of the RNA expression levels on DNA copy numbers through m…
A variety of genome-wide profiling techniques are available to probe complementary aspects of genome structure and function. Integrative analysis of heterogeneous data sources can reveal higher-level interactions that cannot be detected based on individual observations. A standard integration task in cancer studies is to identify altered genomic regions that induce changes in the expression of the associated genes based on joint analysis of genome-wide gene expression and copy number profiling measurements. In this review, we provide a comparison among various modeling procedures for integrati…
For survival data with high-dimensional covariates, results generated in the analysis of a single dataset are often unsatisfactory because of the small sample size. Integrative analysis pools raw data from multiple independent studies with comparable designs, effectively increases sample size, and has better performance than meta-analysis and single-dataset analysis. In this study, we conduct integrative analysis of survival data under the accelerated failure time (AFT) model. The sparsity structures of multiple datasets are described using the homogeneity and heterogeneity models. For variabl…
Significant advances in biotechnology have allowed for simultaneous measurement of molecular data points across multiple genomic and transcriptomic levels from a single tumor/cancer sample. This has motivated systematic approaches to integrate multi-dimensional structured datasets since cancer development and progression is driven by numerous co-ordinated molecular alterations and the interactions between them. We propose a novel two-step Bayesian approach that combines a variable selection framework with integrative structure learning between multiple sources of data. The structure learning i…
Integrative network modeling of data arising from multiple genomic platforms provides insight into the holistic picture of the interactive system, as well as the flow of information across many disease domains including cancer. The basic data structure consists of a sequence of hierarchically ordered datasets for each individual subject, which facilitates integration of diverse inputs, such as genomic, transcriptomic, and proteomic data. A primary analytical task in such contexts is to model the layered architecture of networks where the vertices can be naturally partitioned into ordered layer…
In cancer research, high-throughput profiling has been extensively conducted. In recent studies, the integrative analysis of data on multiple cancer patient groups/subgroups has been conducted. Such analysis has the potential to reveal the genomic commonality as well as difference across groups/subgroups. However, in the existing literature, methods with a special attention to the genomic commonality and difference are very limited. In this study, a novel estimation and marker selection method based on the sparse boosting technique is developed to address the commonality/difference problem. In…
Rapid technological advances have allowed for molecular profiling across multiple omics domains from a single sample for clinical decision making in many diseases, especially cancer. As tumor development and progression are dynamic biological processes involving composite genomic aberrations, key challenges are to effectively assimilate information from these domains to identify genomic signatures and biological entities that are druggable, develop accurate risk prediction profiles for future patients, and identify novel patient subgroups for tailored therapy and monitoring. We propose integra…
It is more and more common to explore the genome at diverse levels and not only at a single omic level. Through integrative statistical methods, omics data have the power to reveal new biological processes, potential biomarkers, and subgroups of a cohort. The matrix factorization (MF) is a unsupervised statistical method that allows giving a clustering of individuals, but also revealing relevant omic variables from the various blocks. Here, we present PIntMF (Penalized Integrative Matrix Factorization), a model of MF with sparsity, positivity and equality constraints.To induce sparsity in the …
Rapid advancements in collection and dissemination of multi-platform molecular and genomics data has resulted in enormous opportunities to aggregate such data in order to understand, prevent, and treat human diseases. While significant improvements have been made in multi-omic data integration methods to discover biological markers and mechanisms underlying both prognosis and treatment, the precise cellular functions governing these complex mechanisms still need detailed and data-driven de-novo evaluations. We propose a framework called Functional Integrative Bayesian Analysis of High-dimensio…
University of Cambridge（剑桥大学）；Newcastle University（纽卡斯尔大学）
High-dimensional biomarkers such as genomics are increasingly being measured in randomized clinical trials. Consequently, there is a growing interest in developing methods that improve the power to detect biomarker-treatment interactions. We adapt recently proposed two-stage interaction detecting procedures in the setting of randomized clinical trials. We also propose a new stage 1 multivariate screening strategy using ridge regression to account for correlations among biomarkers. For this multivariate screening, we prove the asymptotic between-stage independence, required for family-wise erro…
Dynamic gene-regulatory networks are complex since the number of potential components involved in the system is very large. Estimating dynamic networks is an important task because they compromise valuable information about interactions among genes. Graphical models are a powerful class of models to estimate conditional independence among random variables, e.g. interactions in dynamic systems. Indeed, these interactions tend to vary over time. However, the literature has been focused on static networks, which can only reveal overall structures. Time-course experiments are performed in order to…
The identification of predictive biomarkers from a large scale of covariates for subgroup analysis has attracted fundamental attention in medical research. In this article, we propose a generalized penalized regression method with a novel penalty function, for enforcing the hierarchy structure between the prognostic and predictive effects, such that a nonzero predictive effect must induce its ancestor prognostic effects being nonzero in the model. Our method is able to select useful predictive biomarkers by yielding a sparse, interpretable, and predictable model for subgroup analysis, and can …
Lunenfeld-Tanenbaum Research Institute（卢嫩菲尔德-坦南鲍姆研究所）；York University（约克大学）
Recent advances in biological research have seen the emergence of high-throughput technologies with numerous applications that allow the study of biological mechanisms at an unprecedented depth and scale. A large amount of genomic data is now distributed through consortia like The Cancer Genome Atlas (TCGA), where specific types of biological information on specific type of tissue or cell are available. In cancer research, the challenge is now to perform integrative analyses of high-dimensional multi-omic data with the goal to better understand genomic processes that correlate with cancer outc…
Integrative analysis of disparate data blocks measured on a common set of experimental subjects is one major challenge in modern data analysis. This data structure naturally motivates the simultaneous exploration of the joint and individual variation within each data block resulting in new insights. For instance, there is a strong desire to integrate the multiple genomic data sets in The Cancer Genome Atlas (TCGA) to characterize the common and also the unique aspects of cancer genetics and cell biology for each source. In this paper we introduce Non-iterative Joint and Individual Variation Ex…
Integrative learning of multiple datasets has the potential to mitigate the challenge of small $n$ and large $p$ that is often encountered in analysis of big biomedical data such as genomics data. Detection of weak yet important signals can be enhanced by jointly selecting features for all datasets. However, the set of important features may not always be the same across all datasets. Although some existing integrative learning methods allow heterogeneous sparsity structure where a subset of datasets can have zero coefficients for some selected features, they tend to yield reduced efficiency, …
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 …
Integrative analysis of multi-level pharmacogenomic data for modeling dependencies across various biological domains is crucial for developing genomic-testing based treatments. Chain graphs characterize conditional dependence structures of such multi-level data where variables are naturally partitioned into multiple ordered layers, consisting of both directed and undirected edges. Existing literature mostly focus on Gaussian chain graphs, which are ill-suited for non-normal distributions with heavy-tailed marginals, potentially leading to inaccurate inferences. We propose a Bayesian robust cha…
Genomic instability, the propensity of aberrations in chromosomes, plays a critical role in the development of many diseases. High throughput genotyping experiments have been performed to study genomic instability in diseases. The output of such experiments can be summarized as high dimensional binary vectors, where each binary variable records aberration status at one marker locus. It is of keen interest to understand how these aberrations interact with each other. In this paper, we propose a novel method, \texttt{LogitNet}, to infer the interactions among aberration events. The method is bas…
In many biomedical research, multiple views of data (e.g., genomics, proteomics) are available, and a particular interest might be the detection of sample subgroups characterized by specific groups of variables. Biclustering methods are well-suited for this problem as they assume that specific groups of variables might be relevant only to specific groups of samples. Many biclustering methods exist for identifying row-column clusters in a view but few methods exist for data from multiple views. The few existing algorithms are heavily dependent on regularization parameters for getting row-column…
The integrative analysis of multiple datasets is an important strategy in data analysis. It is increasingly popular in genomics, which enjoys a wealth of publicly available datasets that can be compared, contrasted, and combined in order to extract novel scientific insights. This paper studies a stylized example of data integration for a classical statistical problem: leveraging side information to estimate a vector of normal means. This task is formulated as a compound decision problem, an oracle integrative decision rule is derived, and a data-driven estimate of this rule based on minimizing…
Computational efficient evaluation of penalized estimators of multivariate exponential family distributions is sought. These distributions encompass among others Markov random fields with variates of mixed type (e.g. binary and continuous) as special case of interest. The model parameter is estimated by maximization of the pseudo-likelihood augmented with a convex penalty. The estimator is shown to be consistent. With a world of multi-core computers in mind, a computationally efficient parallel Newton-Raphson algorithm is presented for numerical evaluation of the estimator alongside conditions…
When measuring a range of different genomic, epigenomic, transcriptomic and other variables, an integrative approach to analysis can strengthen inference and give new insights. This is also the case when clustering patient samples, and several integrative cluster procedures have been proposed. Common for these methodologies is the restriction of a joint cluster structure, which is equal for all data layers. We instead present Joint and Individual Clustering (JIC), which estimates both joint and data type-specific clusters simultaneously, as an extension of the JIVE algorithm (Lock et. al, 2013…
Large-scale {\it in vitro} drug sensitivity screens are an important tool in personalized oncology to predict the effectiveness of potential cancer drugs. The prediction of the sensitivity of cancer cell lines to a panel of drugs is a multivariate regression problem with high-dimensional heterogeneous multi-omics data as input data and with potentially strong correlations between the outcome variables which represent the sensitivity to the different drugs. We propose a joint penalized regression approach with structured penalty terms which allow us to utilize the correlation structure between …
In mixed multi-view data, multiple sets of diverse features are measured on the same set of samples. By integrating all available data sources, we seek to discover common group structure among the samples that may be hidden in individualistic cluster analyses of a single data-view. While several techniques for such integrative clustering have been explored, we propose and develop a convex formalization that will inherit the strong statistical, mathematical and empirical properties of increasingly popular convex clustering methods. Specifically, our Integrative Generalized Convex Clustering Opt…
Environmental health studies are increasingly measuring multiple pollutants to characterize the joint health effects attributable to exposure mixtures. However, the underlying dose-response relationship between toxicants and health outcomes of interest may be highly nonlinear, with possible nonlinear interaction effects. Existing penalized regression methods that account for exposure interactions either cannot accommodate nonlinear interactions while maintaining strong heredity or are computationally unstable in applications with limited sample size. In this paper, we propose a general shrinka…
In the genomic analysis, it is significant while challenging to identify markers associated with cancer outcomes or phenotypes. Based on the biological mechanisms of cancers and the characteristics of datasets as well, this paper proposes a novel integrative interaction approach under the semiparametric model, in which the genetic factors and environmental factors are included as the parametric and nonparametric components, respectively. The goal of this approach is to identify the genetic factors and gene-gene interactions associated with cancer outcomes, and meanwhile, estimate the nonlinear…
University of Minnesota School of Public Health（明尼苏达大学公共卫生学院）；Division of Biostatistics（生物统计学系）
Advances in molecular "omics'" technologies have motivated new methodology for the integration of multiple sources of high-content biomedical data. However, most statistical methods for integrating multiple data matrices only consider data shared vertically (one cohort on multiple platforms) or horizontally (different cohorts on a single platform). This is limiting for data that take the form of bidimensionally linked matrices (e.g., multiple cohorts measured on multiple platforms), which are increasingly common in large-scale biomedical studies. In this paper, we propose BIDIFAC (Bidimensiona…
With fast advancements in technologies, the collection of multiple types of measurements on a common set of subjects is becoming routine in science. Some notable examples include multimodal neuroimaging studies for the simultaneous investigation of brain structure and function, and multi-omics studies for combining genetic and genomic information. Integrative analysis of multimodal data allows scientists to interrogate new mechanistic questions. However, the data collection and generation of integrative hypotheses is outpacing available methodology for joint analysis of multimodal measurements…
This paper introduces sparse dynamic chain graph models for network inference in high dimensional non-Gaussian time series data. The proposed method parametrized by a precision matrix that encodes the intra time-slice conditional independence among variables at a fixed time point, and an autoregressive coefficient that contains dynamic conditional independences interactions among time series components across consecutive time steps. The proposed model is a Gaussian copula vector autoregressive model, which is used to model sparse interactions in a high-dimensional setting. Estimation is achiev…
Multi-view data have been routinely collected in various fields of science and engineering. A general problem is to study the predictive association between multivariate responses and multi-view predictor sets, all of which can be of high dimensionality. It is likely that only a few views are relevant to prediction, and the predictors within each relevant view contribute to the prediction collectively rather than sparsely. We cast this new problem under the familiar multivariate regression framework and propose an integrative reduced-rank regression (iRRR), where each view has its own low-rank…
Integrative analysis of disparate data blocks measured on a common set of experimental subjects is a major challenge in modern data analysis. This data structure naturally motivates the simultaneous exploration of the joint and individual variation within each data block resulting in new insights. For instance, there is a strong desire to integrate the multiple genomic data sets in The Cancer Genome Atlas to characterize the common and also the unique aspects of cancer genetics and cell biology for each source. In this paper we introduce Angle-Based Joint and Individual Variation Explained cap…
Gaussian graphical models are often used to infer gene networks based on microarray expression data. Many scientists, however, have begun using high-throughput sequencing technologies to measure gene expression. As the resulting high-dimensional count data consists of counts of sequencing reads for each gene, Gaussian graphical models are not optimal for modeling gene networks based on this discrete data. We develop a novel method for estimating high-dimensional Poisson graphical models, the Log-Linear Graphical Model, allowing us to infer networks based on high-throughput sequencing data. Our…
Motivation: Genome-wide association studies (GWASs), which assay more than a million single nucleotide polymorphisms (SNPs) in thousands of individuals, have been widely used to identify genetic risk variants for complex diseases. However, most of the variants that have been identified contribute relatively small increments of risk and only explain a small portion of the genetic variation in complex diseases. This is the so-called missing heritability problem. Evidence has indicated that many complex diseases are genetically related, meaning these diseases share common genetic risk variants. T…
Comparison of the LASSO and Integrative LASSO with Penalty Factors (IPF-LASSO) methods for multi-omics data: Variable selection with Type I error control
It is well known that the integration among different data-sources is reliable because of its potential of unveiling new functionalities of the genomic expressions which might be dormant in a single source analysis. Moreover, different studies have justified the more powerful analyses of multi-platform data. Toward this, in this study, we consider the circadian genes' omics profile such as copy number changes and RNA sequence data along with their survival response. We develop a Bayesian structural equation modeling coupled with linear regressions and log normal accelerated failure time regres…
Mediation analysis draws increasing attention in many scientific areas such as genomics, epidemiology and finance. In this paper, we propose new statistical inference procedures for high dimensional mediation models, in which both the outcome model and the mediator model are linear with high dimensional mediators. Traditional procedures for mediation analysis cannot be used to make statistical inference for high dimensional linear mediation models due to high-dimensionality of the mediators. We propose an estimation procedure for the indirect effects of the models via a partial penalized least…
Rooted in genetics, human complex diseases are largely influenced by environmental factors. Existing literature has shown the power of integrative gene-environment interaction analysis by considering the joint effect of environmental mixtures on a disease risk. In this work, we propose a functional varying index coefficient model for longitudinal measurements of a phenotypic trait together with multiple environmental variables, and assess how the genetic effects on a longitudinal disease trait are nonlinearly modified by a mixture of environmental influences. We derive an estimation procedure …
Recent advances in genomics have underscored the surprising ubiquity of DNA copy number variation (CNV). Fortunately, modern genotyping platforms also detect CNVs with fairly high reliability. Hidden Markov models and algorithms have played a dominant role in the interpretation of CNV data. Here we explore CNV reconstruction via estimation with a fused-lasso penalty as suggested by Tibshirani and Wang [Biostatistics 9 (2008) 18--29]. We mount a fresh attack on this difficult optimization problem by the following: (a) changing the penalty terms slightly by substituting a smooth approximation to…
In the genomic era, the identification of gene signatures associated with disease is of significant interest. Such signatures are often used to predict clinical outcomes in new patients and aid clinical decision-making. However, recent studies have shown that gene signatures are often not replicable. This occurrence has practical implications regarding the generalizability and clinical applicability of such signatures. To improve replicability, we introduce a novel approach to select gene signatures from multiple datasets whose effects are consistently non-zero and account for between-study he…
There has been an intense development of Bayes graphical model estimation approaches over the past decade - however, most of the existing methods are restricted to moderate dimensions. We propose a novel approach suitable for high dimensional settings, by decoupling model fitting and covariance selection. First, a full model based on a complete graph is fit under novel class of continuous shrinkage priors on the precision matrix elements, which induces shrinkage under an equivalence with Cholesky-based regularization while enabling conjugate updates of entire precision matrices. Subsequently, …
We consider the problem of jointly estimating multiple inverse covariance matrices from high-dimensional data consisting of distinct classes. An $\ell_2$-penalized maximum likelihood approach is employed. The suggested approach is flexible and generic, incorporating several other $\ell_2$-penalized estimators as special cases. In addition, the approach allows specification of target matrices through which prior knowledge may be incorporated and which can stabilize the estimation procedure in high-dimensional settings. The result is a targeted fused ridge estimator that is of use when the preci…
High-dimensional sparse modeling with censored survival data is of great practical importance, as exemplified by modern applications in high-throughput genomic data analysis and credit risk analysis. In this article, we propose a class of regularization methods for simultaneous variable selection and estimation in the additive hazards model, by combining the nonconcave penalized likelihood approach and the pseudoscore method. In a high-dimensional setting where the dimensionality can grow fast, polynomially or nonpolynomially, with the sample size, we establish the weak oracle property and ora…
The rapid development of high-throughput technologies has enabled the generation of data from biological or disease processes that span multiple layers, like genomic, proteomic or metabolomic data, and further pertain to multiple sources, like disease subtypes or experimental conditions. In this work, we propose a general statistical framework based on Gaussian graphical models for horizontal (i.e. across conditions or subtypes) and vertical (i.e. across different layers containing data on molecular compartments) integration of information in such datasets. We start with decomposing the multi-…
