arXiv subjects

Veerabhadran Baladandayuthapani

Publications and source records attributed to Veerabhadran Baladandayuthapani.

At least 19 recordsLinked to original sources

arXiv2026

Structure Learning on Clustered Data

Recent algorithmic advances have made directed acyclic graph (DAG) structure learning scalable for causal discovery. Yet, the currently available techniques assume a completely homogeneous population, precluding their application to clustered data where cluster-specific variations (e.g., patient-specific effects) are common. We address this issue by introducing a new approach that estimates a global structure while accounting for local cluster-level effects. The key idea is to extend the fixed- and random-effects framework of classical mixed models to the structure learning setting. Towards this end, we present a differentiable graph coupling mechanism that guarantees the union of the fixed- and random-effects graphs remains acyclic. Computationally, we provide a provably convergent first-order method and leverage efficient batched updates across clusters. Statistically, we establish identifiability of the model and show that our approach recovers the true structure asymptotically. In experiments on real and synthetic data, our proposal detects dependencies missed by alternative estimators, underscoring its value for structure learning in clustered settings.

cs.LG↗

arXiv2026

MoSAIC: Multi-Resolution Spatial Regression Analysis of Cellular Colocalizations in Cancer Imaging

Hierarchical multiplex imaging approaches generate spatially resolved single-cell measurements across multiple, spatially organized fields of view (FOVs) within patient tumor specimens, thereby enabling systematic investigation of how the organization of the tumor microenvironment varies along biologically meaningful intratumoral gradients. Existing approaches fail to jointly address this multi-resolution data structure needed to recover true biological signals. We propose MoSAIC: multi-resolution spatial regression analysis of cell colocalizations, a hierarchical Bayesian spatial regression model designed for multi-resolution spatial data. MoSAIC decomposes the joint variation into three model components: (i) global tumor-gradient effects, (ii) patient-specific effects to capture inter-patient variability, and (iii) Gaussian process models to account for spatial dependence between FOVs within each patient tumor tissue. Simulations demonstrate MoSAIC has improved prediction and model fit compared to existing spatial and non-spatial model alternatives. Our method is motivated by and applied to a renal cell carcinoma multiplex imaging cohort to investigate immune-tumor colocalization patterns across the epithelial-to-mesenchymal transition (EMT) gradient. MoSAIC identifies increased macrophage-tumor colocalization and decreased cytotoxic T-tumor colocalization progressing across the increasing EMT gradient, consistent with EMT-associated immune suppression and spatially varying immune engagement. Overall, MoSAIC provides an interpretable, multi-resolution framework for quantifying spatial tumor-gradient effects in cancer imaging studies. Software is available on GitHub at jcaldous/MoSAIC.

stat.ME↗

arXiv2026

Multi-resolution Spatial Graphical Regression Models for Hierarchical Spatial Transcriptomics Data

Advances in spatial transcriptomics (ST) technologies enable systematic molecular characterization of tumor microenvironment, tumor gradients and gene regulatory networks. Cancer progression is known to vary along pathological gradients, yet existing network approaches for gene network inference typically ignore hierarchical spatial organization across the tumor. We develop a Bayesian multi-resolution spatial graphical regression (mSGR) framework to infer spatially varying gene networks from multi-resolution ST data. The proposed model allows precision matrices to vary across hierarchically structured spatial domains, capturing both local and global organization within the tumor. To identify spatially varying regulatory relationships, we introduce a spatially structured edge selection strategy that borrows strength across regions according to spatial proximity and pathological gradients, while Gaussian-process priors flexibly model spatial variation in edge strengths. Scalable inference is achieved through an augmented mean-field variational Bayes algorithm with node-wise parallel regressions, enabling efficient estimation in high-dimensional settings. Simulation studies demonstrate improved recovery of network structures compared with competing approaches. Applying mSGR to multi-resolution ST data from kidney cancer reveals stronger regulatory connectivity in transitional regions of epithelial-mesenchymal transition pathway and identifies hub genes along the tumor gradient, illustrating how spatially resolved network analysis can provide key insights into tumor microenvironment organization.

stat.AP↗

arXiv2026

A Time-Varying and Covariate-Dependent Correlation Model for Multivariate Longitudinal Studies

In multivariate longitudinal studies, associations between outcomes often exhibit time-varying and individual level heterogeneity, motivating the modeling of correlations as an explicit function of time and covariates. However, most existing methods for correlation analysis fail to simultaneously capture the time-varying and covariate-dependent effects. We propose a Time-Varying and Covariate-Dependent (TiVAC) correlation model that jointly allows covariate effects on correlation to change flexibly and smoothly across time. TiVAC employs a bivariate Gaussian model where the covariate-dependent correlations are modeled semiparametrically using penalized splines. We develop a penalized maximum likelihood-based Newton-Raphson algorithm, and inference on time-varying effects is provided through simultaneous confidence bands. Simulation studies show that TiVAC consistently outperforms existing methods in accurately estimating correlations across a wide range of settings, including binary and continuous covariates, sparse to dense observation schedules, and across diverse correlation trajectory patterns. We apply TiVAC to a psychiatric case study of 291 bipolar I patients, modeling the time-varying correlation between depression and anxiety scores as a function of their clinical variables. Our analyses reveal significant heterogeneity associated with gender and nervous-system medication use, which varies with age, revealing the complex dynamic relationship between depression and anxiety in bipolar disorders.

stat.ME↗

arXiv2025

TopSpace: spatial topic modeling for unsupervised discovery of multicellular spatial tissue structures in multiplex imaging

Motivation: Understanding the spatial architecture of tissues is essential for decoding the complex interactions within cellular ecosystems and their implications for disease pathology and clinical outcomes. Recent advances in multiplex imaging technologies have enabled high-resolution profiling of cellular phenotypes and their spatial distributions, revealing critical roles of tissue structures such as tertiary lymphoid structures (TLSs) in shaping immune responses and influencing disease progression. However, existing methods for analyzing spatial tissue structures often rely on hard clustering or adjacency-based spatial models, which are limited in capturing the nuanced and overlapping nature of cellular communities. To address these challenges, we develop a novel spatial topic modeling framework for the unsupervised discovery of spatial tissue structures in multiplex imaging data. Results: We propose TopSpace, a novel Bayesian spatial topic model that integrates Gaussian processes into latent Dirichlet allocation to flexibly model spatial dependencies in tissue microenvironments. By leveraging the Bayesian framework, TopSpace supports multicellular mixed-membership clustering and offers key inferential advantages, including robust uncertainty quantification and data-driven determination of the number of multicellular microenvironments. We demonstrate the utility of TopSpace through simulations and a case study on non-small cell lung cancer (NSCLC) data. Simulations show that TopSpace accurately recovers latent tissue microenvironments and spatial clustering patterns, outperforming existing methods in scenarios with varying spatial dependencies. Applied to NSCLC data, TopSpace successfully identifies TLS and captures their spatial probability distribution, which strongly correlates with patient survival outcomes.

q-bio.QM↗

arXiv2025

Geometry-driven Bayesian Inference for Ultrametric Covariance Matrices

Ultrametric matrices are a class of covariance matrices that arise in latent tree models. As a parameter space in a statistical model, the set of ultrametric matrices is neither convex nor a smooth manifold. Focus in the literature has hitherto been restricted to estimation through projections and relaxation-based techniques, and inferential methods are lacking. Motivated by this, we establish a bijection between the set of positive definite ultrametric matrices and the set of rooted, leaf-labeled trees equipped with the stratified geometry of the well-known phylogenetic treespace. Using the pullback geometry under the bijection and by adapting sampling algorithms in Bayesian phylogenetics, we develop algorithms to sample from the posterior distribution on the set of ultrametric matrices in a Bayesian latent tree model where the tree may be binary or multifurcating. We demonstrate the utility of the algorithms in simulation studies, and illustrate them on a pre-clinical cancer application to quantify uncertainty about treatment trees that identify treatments with high mechanism similarity that target correlated pathways.

stat.ME↗

arXiv2024

Statistical Analysis of Quantitative Cancer Imaging Data

Recent advances in types and extent of medical imaging technologies has led to proliferation of multimodal quantitative imaging data in cancer. Quantitative medical imaging data refer to numerical representations derived from medical imaging technologies, such as radiology and pathology imaging, that can be used to assess and quantify characteristics of diseases, especially cancer. The use of such data in both clinical and research setting enables precise quantifications and analyses of tumor characteristics that can facilitate objective evaluation of disease progression, response to therapy, and prognosis. The scale and size of these imaging biomarkers is vast and presents several analytical and computational challenges that range from high-dimensionality to complex structural correlation patterns. In this review article, we summarize some state-of-the-art statistical methods developed for quantitative medical imaging data ranging from topological, functional and shape data analyses to spatial process models. We delve into common imaging biomarkers with a focus on radiology and pathology imaging in cancer, address the analytical questions and challenges they present, and highlight the innovative statistical and machine learning models that have been developed to answer relevant scientific and clinical questions. We also outline some emerging and open problems in this area for future explorations.

stat.AP↗

arXiv2024

Spatially Structured Regression for Non-conformable Spaces: Integrating Pathology Imaging and Genomics Data in Cancer

The spatial composition and cellular heterogeneity of the tumor microenvironment plays a critical role in cancer development and progression. High-definition pathology imaging of tumor biopsies provide a high-resolution view of the spatial organization of different types of cells. This allows for systematic assessment of intra- and inter-patient spatial cellular interactions and heterogeneity by integrating accompanying patient-level genomics data. However, joint modeling across tumor biopsies presents unique challenges due to non-conformability (lack of a common spatial domain across biopsies) as well as high-dimensionality. To address this problem, we propose the Dual random effect and main effect selection model for Spatially structured regression model (DreameSpase). DreameSpase employs a Bayesian variable selection framework that facilitates the assessment of spatial heterogeneity with respect to covariates both within (through fixed effects) and between spaces (through spatial random effects) for non-conformable spatial domains. We demonstrate the efficacy of DreameSpase via simulations and integrative analyses of pathology imaging and gene expression data obtained from $335$ melanoma biopsies. Our findings confirm several existing relationships, e.g. neutrophil genes being associated with both inter- and intra-patient spatial heterogeneity, as well as discovering novel associations. We also provide freely available and computationally efficient software for implementing DreameSpase.

stat.AP↗

arXiv2023

Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe)

We propose a new method for the simultaneous selection and estimation of multivariate sparse additive models with correlated errors. Our method called Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe) simultaneously selects among null, linear, and smooth non-linear effects for each predictor while incorporating joint estimation of the sparse residual structure among responses, with the motivation that accounting for inter-response correlation structure can lead to improved accuracy in variable selection and estimation efficiency. CoMPAdRe is constructed in a computationally efficient way that allows the selection and estimation of linear and non-linear covariates to be conducted in parallel across responses. Compared to single-response approaches that marginally select linear and non-linear covariate effects, we demonstrate in simulation studies that the joint multivariate modeling leads to gains in both estimation efficiency and selection accuracy, of greater magnitude in settings where signal is moderate relative to the level of noise. We apply our approach to protein-mRNA expression levels from multiple breast cancer pathways obtained from The Cancer Proteome Atlas and characterize both mRNA-protein associations and protein-protein subnetworks for each pathway. We find non-linear mRNA-protein associations for the Core Reactive, EMT, PIK-AKT, and RTK pathways.

stat.ME↗

arXiv2023

Robust Bayesian Graphical Regression Models for Assessing Tumor Heterogeneity in Proteomic Networks

Graphical models are powerful tools to investigate complex dependency structures in high-throughput datasets. However, most existing graphical models make one of the two canonical assumptions: (i) a homogeneous graph with a common network for all subjects; or (ii) an assumption of normality especially in the context of Gaussian graphical models. Both assumptions are restrictive and can fail to hold in certain applications such as proteomic networks in cancer. To this end, we propose an approach termed robust Bayesian graphical regression (rBGR) to estimate heterogeneous graphs for non-normally distributed data. rBGR is a flexible framework that accommodates non-normality through random marginal transformations and constructs covariate-dependent graphs to accommodate heterogeneity through graphical regression techniques. We formulate a new characterization of edge dependencies in such models called conditional sign independence with covariates along with an efficient posterior sampling algorithm. In simulation studies, we demonstrate that rBGR outperforms existing graphical regression models for data generated under various levels of non-normality in both edge and covariate selection. We use rBGR to assess proteomic networks across two cancers: lung and ovarian, to systematically investigate the effects of immunogenic heterogeneity within tumors. Our analyses reveal several important protein-protein interactions that are differentially impacted by the immune cell abundance; some corroborate existing biological knowledge whereas others are novel findings.

stat.ME↗

arXiv2023

Bayesian Covariate-Dependent Quantile Directed Acyclic Graphical Models for Individualized Inference

We propose an approach termed ``qDAGx'' for Bayesian covariate-dependent quantile directed acyclic graphs (DAGs) where these DAGs are individualized, in the sense that they depend on individual-specific covariates. The individualized DAG structure of the proposed approach can be uniquely identified at any given quantile, based on purely observational data without strong assumptions such as a known topological ordering. To scale the proposed method to a large number of variables and covariates, we propose for the model parameters a novel parameter expanded horseshoe prior that affords a number of attractive theoretical and computational benefits to our approach. By modeling the conditional quantiles, qDAGx overcomes the common limitations of mean regression for DAGs, which can be sensitive to the choice of likelihood, e.g., an assumption of multivariate normality, as well as to the choice of priors. We demonstrate the performance of qDAGx through extensive numerical simulations and via an application in precision medicine, which infers patient-specific protein--protein interaction networks in lung cancer.

stat.ME↗

arXiv2023

Nonparametric Bayes Differential Analysis of Multigroup DNA Methylation Data

DNA methylation datasets in cancer studies are comprised of measurements on a large number of genomic locations called cytosine-phosphate-guanine (CpG) sites with complex correlation structures. A fundamental goal of these studies is the development of statistical techniques that can identify disease genomic signatures across multiple patient groups defined by different experimental or biological conditions. We propose BayesDiff, a nonparametric Bayesian approach for differential analysis relying on a novel class of first order mixture models called the Sticky Pitman-Yor process or two-restaurant two-cuisine franchise (2R2CF). The BayesDiff methodology flexibly utilizes information from all CpG sites or probes, adaptively accommodates any serial dependence due to the widely varying inter-probe distances and performs simultaneous inferences about the differential genomic signature of the patient groups. Using simulation studies, we demonstrate the effectiveness of the BayesDiff procedure relative to existing statistical techniques for differential DNA methylation. The methodology is applied to analyze a gastrointestinal (GI) cancer dataset that displays both serial correlations and interaction patterns. The results support and complement known aspects of DNA methylation and gene association in upper GI cancers.

stat.ME↗

arXiv2022

Functional Integrative Bayesian Analysis of High-dimensional Multiplatform Genomic Data

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-dimensional Multiplatform Genomic Data (fiBAG), that allows simultaneous identification of upstream functional evidence of proteogenomic biomarkers and the incorporation of such knowledge in Bayesian variable selection models to improve signal detection. fiBAG employs a conflation of Gaussian process models to quantify (possibly non-linear) functional evidence via Bayes factors, which are then mapped to a novel calibrated spike-and-slab prior, thus guiding selection and providing functional relevance to the associations with patient outcomes. Using simulations, we illustrate how integrative methods with functional calibration have higher power to detect disease related markers than non-integrative approaches. We demonstrate the profitability of fiBAG via a pan-cancer analysis of 14 cancer types to identify and assess the cellular mechanisms of proteogenomic markers associated with cancer stemness and patient survival.

stat.ME↗

arXiv2022

Integrative Bayesian models using Post-selective Inference: a case study in Radiogenomics

Integrative analyses based on statistically relevant associations between genomics and a wealth of intermediary phenotypes (such as imaging) provide vital insights into their clinical relevance in terms of the disease mechanisms. Estimates for uncertainty in the resulting integrative models are however unreliable unless inference accounts for the selection of these associations with accuracy. In this article, we develop selection-aware Bayesian methods which: (i) counteract the impact of model selection bias through a "selection-aware posterior" in a flexible class of integrative Bayesian models post a selection of promising variables via $\ell_1$-regularized algorithms; (ii) strike an inevitable tradeoff between the quality of model selection and inferential power when the same dataset is used for both selection and uncertainty estimation. Central to our methodological development, a carefully constructed conditional likelihood function deployed with a reparameterization mapping provides notably tractable updates when gradient-based MCMC sampling is used for estimating uncertainties from the selection-aware posterior. Applying our methods to a radiogenomic analysis, we successfully recover several important gene pathways and estimate uncertainties for their associations with patient survival times.

stat.AP↗

arXiv2022

Nonparametric Bayes Differential Analysis for Dependent Multigroup Data with Application to DNA Methylation Analyses in Cancer

Modern cancer genomics datasets involve widely varying sizes and scales, measurement variables, and correlation structures. A fundamental analytical goal in these high-throughput studies is the development of general statistical techniques that can cleanly sift the signal from noise in identifying disease-specific genomic signatures across a set of experimental or biological conditions. We propose BayesDiff, a nonparametric Bayesian approach based on a novel class of first order mixture models, called the Sticky Poisson-Dirichlet process or multicuisine restaurant franchise. The BayesDiff methodology flexibly utilizes information from all the measurements and adaptively accommodates any serial dependence in the data, accounting for the inter-probe distances, to perform simultaneous inferences on the variables. The technique is applied to analyze a DNA methylation gastrointestinal (GI) cancer dataset, which displays both serial correlations and complex interaction patterns. Our analyses and results both support and complement known aspects of DNA methylation and gene association in upper GI cancers. In simulation studies, we demonstrate the effectiveness of the BayesDiff procedure relative to existing techniques for differential DNA methylation.

stat.ME↗

arXiv2021

Bayesian Robust Learning in Chain Graph Models for Integrative Pharmacogenomics

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 chain graph model (RCGM) based on random transformations of marginals using Gaussian scale mixtures to account for node-level non-normality in continuous multivariate data. This flexible modeling strategy facilitates identification of conditional sign dependencies among non-normal nodes while still being able to infer conditional dependencies among normal nodes. In simulations, we demonstrate that RCGM outperforms existing Gaussian chain graph inference methods in data generated from various non-normal mechanisms. We apply our method to genomic, transcriptomic and proteomic data to understand underlying biological processes holistically for drug response and resistance in lung cancer cell lines. Our analysis reveals inter- and intra- platform dependencies of key signaling pathways to monotherapies of icotinib, erlotinib and osimertinib among other drugs, along with shared patterns of molecular mechanisms behind drug actions.

stat.AP↗

arXiv2021

Bayesian Variable Selection in Multivariate Nonlinear Regression with Graph Structures

Gaussian graphical models (GGMs) are well-established tools for probabilistic exploration of dependence structures using precision matrices. We develop a Bayesian method to incorporate covariate information in this GGMs setup in a nonlinear seemingly unrelated regression framework. We propose a joint predictor and graph selection model and develop an efficient collapsed Gibbs sampler algorithm to search the joint model space. Furthermore, we investigate its theoretical variable selection properties. We demonstrate our method on a variety of simulated data, concluding with a real data set from the TCPA project.

stat.ME↗

arXiv2021

Tumor Radiogenomics with Bayesian Layered Variable Selection

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 scores which act as imaging phenotypes. Subsequently, we build Bayesian variable selection models for each layer with the imaging phenotypes as the response and the genomic markers as predictors. Our novel hierarchical prior formulation incorporates the interior-to-exterior structure of the layers, and the correlation between the genomic markers. We employ a computationally-efficient Expectation--Maximization-based strategy for estimation. Simulation studies demonstrate the superior performance of our approach compared to other approaches. With a focus on the cancer driver genes in LGG, we discuss some biologically relevant findings. Genes implicated with survival and oncogenesis are identified as being associated with the spherical layers, which could potentially serve as early-stage diagnostic markers for disease monitoring, prior to routine invasive approaches.

stat.ME↗