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 integrative probabilistic frameworks for high-dimensional multiple-domain cancer data that coherently incorporate dependence within and between domains to accurately detect tumor subtypes, thus providing a catalogue of genomic aberrations associated with cancer taxonomy. We propose an innovative, flexible and scalable Bayesian nonparametric framework for simultaneous clustering of both tumor samples and genomic probes. We describe an efficient variable selection procedure to identify relevant genomic aberrations that can potentially reveal underlying drivers of a disease. Although the work is motivated by several investigations related to lung cancer, the proposed methods are broadly applicable in a variety of contexts involving high-dimensional data. The success of the methodology is demonstrated using artificial data and lung cancer omics profiles publicly available from The Cancer Genome Atlas.
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…
Personalized treatment of patients based on tissue-specific cancer subtypes has strongly increased the efficacy of the chosen therapies. Even though the amount of data measured for cancer patients has increased over the last years, most cancer subtypes are still diagnosed based on individual data sources (e.g. gene expression data). We propose an unsupervised data integration method based on kernel principal component analysis. Principal component analysis is one of the most widely used techniques in data analysis. Unfortunately, the straight-forward multiple-kernel extension of this method le…
The increased availability of the multi-view data (data on the same samples from multiple sources) has led to strong interest in models based on low-rank matrix factorizations. These models represent each data view via shared and individual components, and have been successfully applied for exploratory dimension reduction, association analysis between the views, and further learning tasks such as consensus clustering. Despite these advances, there remain significant challenges in modeling partially-shared components, and identifying the number of components of each type (shared/partially-share…
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 …
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…
We present a method for individual and integrative analysis of high dimension, low sample size data that capitalizes on the recurring theme in multivariate analysis of projecting higher dimensional data onto a few meaningful directions that are solutions to a generalized eigenvalue problem. We propose a general framework, called SELP (Sparse Estimation with Linear Programming), with which one can obtain a sparse estimate for a solution vector of a generalized eigenvalue problem. We demonstrate the utility of SELP on canonical correlation analysis for an integrative analysis of methylation and …
Data integration is the problem of combining multiple data groups (studies, cohorts) and/or multiple data views (variables, features). This task is becoming increasingly important in many disciplines due to the prevalence of large and heterogeneous data sets. Data integration commonly aims to identify structure that is consistent across multiple cohorts and feature sets. While such joint analyses can boost information from single data sets, it is also possible that a globally restrictive integration of heterogeneous data may obscure signal of interest. Here, we therefore propose a data adaptiv…
We consider the task of meta-analysis in high-dimensional settings in which the data sources are similar but non-identical. To borrow strength across such heterogeneous datasets, we introduce a global parameter that emphasizes interpretability and statistical efficiency in the presence of heterogeneity. We also propose a one-shot estimator of the global parameter that preserves the anonymity of the data sources and converges at a rate that depends on the size of the combined dataset. For high-dimensional linear model settings, we demonstrate the superiority of our identification restrictions i…
For data with high-dimensional covariates but small to moderate sample sizes, the analysis of single datasets often generates unsatisfactory results. The integrative analysis of multiple independent datasets provides an effective way of pooling information and outperforms single-dataset analysis and some alternative multi-datasets approaches including meta-analysis. Under certain scenarios, multiple datasets are expected to share common important covariates, that is, the multiple models have similarity in sparsity structures. However, the existing methods do not have a mechanism to {\it promot…
Comparison of the LASSO and Integrative LASSO with Penalty Factors (IPF-LASSO) methods for multi-omics data: Variable selection with Type I error control
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…
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…
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…
In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is a heterogeneous disease. Examining similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to better understanding of their connections and distinctions. Classic meta-analysis approaches analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis approaches, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta-analysis. In this study, progn…
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 integrativ…
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…
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 many biomedical problems, data are often heterogeneous, with samples spanning multiple patient subgroups, where different subgroups may have different disease subtypes, stages, or other medical contexts. These subgroups may be related, but they are also expected to have differences with respect to the underlying biology. The heterogeneous data presents a precious opportunity to explore the heterogeneities and commonalities between related subgroups. Unfortunately, effective statistical analysis methods are still lacking. Recently, several novel methods based on integrative analysis have bee…
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…
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…
MRC Biostatistics Unit（MRC生物统计学单元）；Cambridge Institute of Therapeutic Immunology & Infectious Disease（剑桥治疗免疫学与传染病研究所）；University of Cambridge（剑桥大学）
Diverse applications - particularly in tumour subtyping - have demonstrated the importance of integrative clustering techniques for combining information from multiple data sources. Cluster-Of-Clusters Analysis (COCA) is one such approach that has been widely applied in the context of tumour subtyping. However, the properties of COCA have never been systematically explored, and its robustness to the inclusion of noisy datasets, or datasets that define conflicting clustering structures, is unclear. We rigorously benchmark COCA, and present Kernel Learning Integrative Clustering (KLIC) as an alt…
Analysis of multi-source dataset, where data on the same objects are collected from multiple sources, is of rising importance in many fields, most notably in multi-omics biology. A novel framework and algorithms for integrative decomposition of such multi-source data are proposed to identify and sort out common factor scores in terms of whether the scores are relevant to all data sources (fully joint), to some data sources (partially joint), or to a single data source. The key difference between the proposed method and existing approaches is that raw source-wise factor score subspaces are util…
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…
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…
Scientific studies increasingly collect multiple modalities of data to investigate a phenomenon from several perspectives. In integrative data analysis it is important to understand how information is heterogeneously spread across these different data sources. To this end, we consider a parametric clustering model for the subjects in a multi-view data set (i.e. multiple sources of data from the same set of subjects) where each view marginally follows a mixture model. In the case of two views, the dependence between them is captured by a cluster membership matrix parameter and we aim to learn t…
VICatMix: variational Bayesian clustering and variable selection for discrete biomedical data
MRC Biostatistics Unit University of Cambridge East Forvie Building（医学研究理事会生物统计学单位剑桥大学东部大楼）；MRC Biostatistics Unit and CRUK Cambridge Centre Ovarian Programme and Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) University of Cambridge（医学研究理事会生物统计学单位和癌症研究英国委员会剑桥中心卵巢计划及剑桥治疗免疫学和传染病研究所（CITIID）剑桥大学）
