Tree-guided group lasso for multi-response regression with structured sparsity, with an application to eQTL mapping

We consider the problem of estimating a sparse multi-response regression function, with an application to expression quantitative trait locus (eQTL) mapping, where the goal is to discover genetic variations that influence gene-expression levels. In particular, we investigate a shrinkage technique capable of capturing a given hierarchical structure over the responses, such as a hierarchical clustering tree with leaf nodes for responses and internal nodes for clusters of related responses at multiple granularity, and we seek to leverage this structure to recover covariates relevant to each hierarchically-defined cluster of responses. We propose a tree-guided group lasso, or tree lasso, for estimating such structured sparsity under multi-response regression by employing a novel penalty function constructed from the tree. We describe a systematic weighting scheme for the overlapping groups in the tree-penalty such that each regression coefficient is penalized in a balanced manner despite the inhomogeneous multiplicity of group memberships of the regression coefficients due to overlaps among groups. For efficient optimization, we employ a smoothing proximal gradient method that was originally developed for a general class of structured-sparsity-inducing penalties. Using simulated and yeast data sets, we demonstrate that our method shows a superior performance in terms of both prediction errors and recovery of true sparsity patterns, compared to other methods for learning a multivariate-response regression.Comment: Published in at http://dx.doi.org/10.1214/12-AOAS549 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Structured penalized regression for drug sensitivity prediction

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 drugs with group-lasso-type penalties and at the same time address the heterogeneity between omics data sources by introducing data-source-specific penalty factors to penalize different data sources differently. By combining integrative penalty factors (IPF) with tree-guided group lasso, we create the IPF-tree-lasso method. We present a unified framework to transform more general IPF-type methods to the original penalized method. Because the structured penalty terms have multiple parameters, we demonstrate how the interval-search Efficient Parameter Selection via Global Optimization (EPSGO) algorithm can be used to optimize multiple penalty parameters efficiently. Simulation studies show that IPF-tree-lasso can improve the prediction performance compared to other lasso-type methods, in particular for heterogenous data sources. Finally, we employ the new methods to analyse data from the Genomics of Drug Sensitivity in Cancer project.Comment: Zhao Z, Zucknick M (2020). Structured penalized regression for drug sensitivity prediction. Journal of the Royal Statistical Society, Series C. 19 pages, 6 figures and 2 table

Variable Selection for Model-Based High-Dimensional Clustering and Its Application to Microarray Data

Variable selection in high-dimensional clustering analysis is an important yet challenging problem. In this article, we propose two methods that simultaneously separate data points into similar clusters and select informative variables that contribute to the clustering. Our methods are in the framework of penalized model-based clustering. Unlike the classical L 1 -norm penalization, the penalty terms that we propose make use of the fact that parameters belonging to one variable should be treated as a natural “group.” Numerical results indicate that the two new methods tend to remove noninformative variables more effectively and provide better clustering results than the L 1 -norm approach.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66311/1/j.1541-0420.2007.00922.x.pd

Structured Learning in Time-dependent Cox Models

Cox models with time-dependent coefficients and covariates are widely used in survival analysis. In high-dimensional settings, sparse regularization techniques are employed for variable selection, but existing methods for time-dependent Cox models lack flexibility in enforcing specific sparsity patterns (i.e., covariate structures). We propose a flexible framework for variable selection in time-dependent Cox models, accommodating complex selection rules. Our method can adapt to arbitrary grouping structures, including interaction selection, temporal, spatial, tree, and directed acyclic graph structures. It achieves accurate estimation with low false alarm rates. We develop the sox package, implementing a network flow algorithm for efficiently solving models with complex covariate structures. Sox offers a user-friendly interface for specifying grouping structures and delivers fast computation. Through examples, including a case study on identifying predictors of time to all-cause death in atrial fibrillation patients, we demonstrate the practical application of our method with specific selection rules.Comment: 49 pages (with 19 pages of appendix),9 tables, 3 figure

Incorporating Pathway Information into Feature Selection Towards Better Performed Gene Signatures

To analyze gene expression data with sophisticated grouping structures and to extract hidden patterns from such data, feature selection is of critical importance. It is well known that genes do not function in isolation but rather work together within various metabolic, regulatory, and signaling pathways. If the biological knowledge contained within these pathways is taken into account, the resulting method is a pathway-based algorithm. Studies have demonstrated that a pathway-based method usually outperforms its gene-based counterpart in which no biological knowledge is considered. In this article, a pathway-based feature selection is firstly divided into three major categories, namely, pathway-level selection, bilevel selection, and pathway-guided gene selection. With bilevel selection methods being regarded as a special case of pathway-guided gene selection process, we discuss pathway-guided gene selection methods in detail and the importance of penalization in such methods. Last, we point out the potential utilizations of pathway-guided gene selection in one active research avenue, namely, to analyze longitudinal gene expression data. We believe this article provides valuable insights for computational biologists and biostatisticians so that they can make biology more computable

Data Fusion and Systems Engineering Approaches for Quality and Performance Improvement of Health Care Systems: From Diagnosis to Care to System-level Decision-making

abstract: Technology advancements in diagnostic imaging, smart sensing, and health information systems have resulted in a data-rich environment in health care, which offers a great opportunity for Precision Medicine. The objective of my research is to develop data fusion and system informatics approaches for quality and performance improvement of health care. In my dissertation, I focus on three emerging problems in health care and develop novel statistical models and machine learning algorithms to tackle these problems from diagnosis to care to system-level decision-making. The first topic is diagnosis/subtyping of migraine to customize effective treatment to different subtypes of patients. Existing clinical definitions of subtypes use somewhat arbitrary boundaries primarily based on patient self-reported symptoms, which are subjective and error-prone. My research develops a novel Multimodality Factor Mixture Model that discovers subtypes of migraine from multimodality imaging MRI data, which provides complementary accurate measurements of the disease. Patients in the different subtypes show significantly different clinical characteristics of the disease. Treatment tailored and optimized for patients of the same subtype paves the road toward Precision Medicine. The second topic focuses on coordinated patient care. Care coordination between nurses and with other health care team members is important for providing high-quality and efficient care to patients. The recently developed Nurse Care Coordination Instrument (NCCI) is the first of its kind that enables large-scale quantitative data to be collected. My research develops a novel Multi-response Multi-level Model (M3) that enables transfer learning in NCCI data fusion. M3 identifies key factors that contribute to improving care coordination, and facilitates the design and optimization of nurses’ training, workload assignment, and practice environment, which leads to improved patient outcomes. The last topic is about system-level decision-making for Alzheimer’s disease early detection at the early stage of Mild Cognitive Impairment (MCI), by predicting each MCI patient’s risk of converting to AD using imaging and proteomic biomarkers. My research proposes a systems engineering approach that integrates the multi-perspectives, including prediction accuracy, biomarker cost/availability, patient heterogeneity and diagnostic efficiency, and allows for system-wide optimized decision regarding the biomarker testing process for prediction of MCI conversion.Dissertation/ThesisDoctoral Dissertation Industrial Engineering 201