A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.

Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

PURPOSE: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. PATIENTS AND METHODS: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. RESULTS: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. CONCLUSIONS: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

DIMPLE: An R package to quantify, visualize, and model spatial cellular interactions from multiplex imaging with distance matrices.

A major challenge in the spatial analysis of multiplex imaging (MI) data is choosing how to measure cellular spatial interactions and how to relate them to patient outcomes. Existing methods to quantify cell-cell interactions do not scale to the rapidly evolving technical landscape, where both the number of unique cell types and the number of images in a dataset may be large. We propose a scalable analytical framework and accompanying R package, DIMPLE, to quantify, visualize, and model cell-cell interactions in the TME. By applying DIMPLE to publicly available MI data, we uncover statistically significant associations between image-level measures of cell-cell interactions and patient-level covariates.

Pan-Cancer Drug Response Prediction Using Integrative Principal Component Regression.

The pursuit of precision oncology heavily relies on large-scale genomic and pharmacological data garnered from preclinical cancer model systems such as cell lines. While cell lines are instrumental in understanding the interplay between genomic programs and drug response, it well-established that they are not fully representative of patient tumors. Development of integrative methods that can systematically assess the commonalities between patient tumors and cell-lines can help bridge this gap. To this end, we introduce the Integrative Principal Component Regression (iPCR) model which uncovers both joint and model-specific structured variations in the genomic data of cell lines and patient tumors through matrix decompositions. The extracted joint variation is then used to predict patient drug responses based on the pharmacological data from preclinical models. Moreover, the interpretability of our model allows for the identification of key driver genes and pathways associated with the treatment-specific response in patients across multiple cancers. We demonstrate that the outputs of the iPCR model can assist in inferring both model-specific and shared co-expression networks between cell lines and patients. We show that iPCR performs favorably compared to competing approaches in predicting patient drug responses, in both simulation studies and real-world applications, in addition to identifying key genomic drivers of cancer drug responses.

Tumor radiogenomics in gliomas with Bayesian layered variable selection.

We propose a statistical framework to analyze 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. We provide a R package that can be used to deploy our framework to identify radiogenomic associations.

PROBABILISTIC LEARNING OF TREATMENT TREES IN CANCER.

Accurate identification of synergistic treatment combinations and their underlying biological mechanisms is critical across many disease domains, especially cancer. In translational oncology research, preclinical systems such as patient-derived xenografts (PDX) have emerged as a unique study design evaluating multiple treatments administered to samples from the same human tumor implanted into genetically identical mice. In this paper, we propose a novel Bayesian probabilistic tree-based framework for PDX data to investigate the hierarchical relationships between treatments by inferring treatment cluster trees, referred to as treatment trees (Rx-tree). The framework motivates a new metric of mechanistic similarity between two or more treatments accounting for inherent uncertainty in tree estimation; treatments with a high estimated similarity have potentially high mechanistic synergy. Building upon Dirichlet Diffusion Trees, we derive a closed-form marginal likelihood encoding the tree structure, which facilitates computationally efficient posterior inference via a new two-stage algorithm. Simulation studies demonstrate superior performance of the proposed method in recovering the tree structure and treatment similarities. Our analyses of a recently collated PDX dataset produce treatment similarity estimates that show a high degree of concordance with known biological mechanisms across treatments in five different cancers. More importantly, we uncover new and potentially effective combination therapies that confer synergistic regulation of specific downstream biological pathways for future clinical investigations. Our accompanying code, data, and shiny application for visualization of results are available at: https://github.com/bayesrx/RxTree.

DIMPLE: AN R PACKAGE TO QUANTIFY, VISUALIZE, AND MODEL SPATIAL CELLULAR INTERACTIONS FROM MULTIPLEX IMAGING WITH DISTANCE MATRICES.

The tumor microenvironment (TME) is a complex ecosystem containing tumor cells, other surrounding cells, blood vessels, and extracellular matrix. Recent advances in multiplexed imaging technologies allow researchers to map several cellular markers in the TME at the single cell level while preserving their spatial locations. Evidence is mounting that cellular interactions in the TME can promote or inhibit tumor development and contribute to drug resistance. Current statistical approaches to quantify cell-cell interactions do not readily scale to the outputs of new imaging technologies which can distinguish many unique cell phenotypes in one image. We propose a scalable analytical framework and accompanying R package, DIMPLE, to quantify, visualize, and model cell-cell interactions in the TME. In application of DIMPLE to publicly available MI data, we uncover statistically significant associations between image-level measures of cell-cell interactions and patient-level covariates.

Optimizing Precision Medicine for Breast Cancer Brain Metastases with Functional Drug Response Assessment.

The development of novel therapies for brain metastases is an unmet need. Brain metastases may have unique molecular features that could be explored as therapeutic targets. A better understanding of the drug sensitivity of live cells coupled to molecular analyses will lead to a rational prioritization of therapeutic candidates. We evaluated the molecular profiles of 12 breast cancer brain metastases (BCBM) and matched primary breast tumors to identify potential therapeutic targets. We established six novel patient-derived xenograft (PDX) from BCBM from patients undergoing clinically indicated surgical resection of BCBM and used the PDXs as a drug screening platform to interrogate potential molecular targets. Many of the alterations were conserved in brain metastases compared with the matched primary. We observed differential expressions in the immune-related and metabolism pathways. The PDXs from BCBM captured the potentially targetable molecular alterations in the source brain metastases tumor. The alterations in the PI3K pathway were the most predictive for drug efficacy in the PDXs. The PDXs were also treated with a panel of over 350 drugs and demonstrated high sensitivity to histone deacetylase and proteasome inhibitors. Our study revealed significant differences between the paired BCBM and primary breast tumors with the pathways involved in metabolisms and immune functions. While molecular targeted drug therapy based on genomic profiling of tumors is currently evaluated in clinical trials for patients with brain metastases, a functional precision medicine strategy may complement such an approach by expanding potential therapeutic options, even for BCBM without known targetable molecular alterations. Significance: Examining genomic alterations and differentially expressed pathways in brain metastases may inform future therapeutic strategies. This study supports genomically-guided therapy for BCBM and further investigation into incorporating real-time functional evaluation will increase confidence in efficacy estimations during drug development and predictive biomarker assessment for BCBM.

SPARTIN: a Bayesian method for the quantification and characterization of cell type interactions in spatial pathology data.

Introduction: The acquisition of high-resolution digital pathology imaging data has sparked the development of methods to extract context-specific features from such complex data. In the context of cancer, this has led to increased exploration of the tumor microenvironment with respect to the presence and spatial composition of immune cells. Spatial statistical modeling of the immune microenvironment may yield insights into the role played by the immune system in the natural development of cancer as well as downstream therapeutic interventions. Methods: In this paper, we present SPatial Analysis of paRtitioned Tumor-Immune imagiNg (SPARTIN), a Bayesian method for the spatial quantification of immune cell infiltration from pathology images. SPARTIN uses Bayesian point processes to characterize a novel measure of local tumor-immune cell interaction, Cell Type Interaction Probability (CTIP). CTIP allows rigorous incorporation of uncertainty and is highly interpretable, both within and across biopsies, and can be used to assess associations with genomic and clinical features. Results: Through simulations, we show SPARTIN can accurately distinguish various patterns of cellular interactions as compared to existing methods. Using SPARTIN, we characterized the local spatial immune cell infiltration within and across 335 melanoma biopsies and evaluated their association with genomic, phenotypic, and clinical outcomes. We found that CTIP was significantly (negatively) associated with deconvolved immune cell prevalence scores including CD8+ T-Cells and Natural Killer cells. Furthermore, average CTIP scores differed significantly across previously established transcriptomic classes and significantly associated with survival outcomes. Discussion: SPARTIN provides a general framework for investigating spatial cellular interactions in high-resolution digital histopathology imaging data and its associations with patient level characteristics. The results of our analysis have potential implications relevant to both treatment and prognosis in the context of Skin Cutaneous Melanoma. The R-package for SPARTIN is available at https://github.com/bayesrx/SPARTIN along with a visualization tool for the images and results at: https://nateosher.github.io/SPARTIN.

BaySyn: Bayesian Evidence Synthesis for Multi-system Multiomic Integration.

The discovery of cancer drivers and drug targets are often limited to the biological systems - from cancer model systems to patients. While multiomic patient databases have sparse drug response data, cancer model systems databases, despite covering a broad range of pharmacogenomic platforms, provide lower lineage-specific sample sizes, resulting in reduced statistical power to detect both functional driver genes and their associations with drug sensitivity profiles. Hence, integrating evidence across model systems, taking into account the pros and cons of each system, in addition to multiomic integration, can more efficiently deconvolve cellular mechanisms of cancer as well as learn therapeutic associations. To this end, we propose BaySyn - a hierarchical Bayesian evidence synthesis framework for multi-system multiomic integration. BaySyn detects functionally relevant driver genes based on their associations with upstream regulators using additive Gaussian process models and uses this evidence to calibrate Bayesian variable selection models in the (drug) outcome layer. We apply BaySyn to multiomic cancer cell line and patient datasets from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas, respectively, across pan-gynecological cancers. Our mechanistic models implicate several relevant functional genes across cancers such as PTPN6 and ERBB2 in the KEGG adherens junction gene set. Furthermore, our outcome model is able to make higher number of discoveries in drug response models than its uncalibrated counterparts under the same thresholds of Type I error control, including detection of known lineage-specific biomarker associations such as BCL11A in breast and FGFRL1 in ovarian cancers. All our results and implementation codes are freely available via an interactive R Shiny dashboard at tinyurl.com/BaySynApp. The supplementary materials are available online at tinyurl.com/BaySynSup.

Bayesian hierarchical quantile regression with application to characterizing the immune architecture of lung cancer.

The successful development and implementation of precision immuno-oncology therapies requires a deeper understanding of the immune architecture at a patient level. T-cell receptor (TCR) repertoire sequencing is a relatively new technology that enables monitoring of T-cells, a subset of immune cells that play a central role in modulating immune response. These immunologic relationships are complex and are governed by various distributional aspects of an individual patient's tumor profile. We propose Bayesian QUANTIle regression for hierarchical COvariates (QUANTICO) that allows simultaneous modeling of hierarchical relationships between multilevel covariates, conducts explicit variable selection, estimates quantile and patient-specific coefficient effects, to induce individualized inference. We show QUANTICO outperforms existing approaches in multiple simulation scenarios. We demonstrate the utility of QUANTICO to investigate the effect of TCR variables on immune response in a cohort of lung cancer patients. At population level, our analyses reveal the mechanistic role of T-cell proportion on the immune cell abundance, with tumor mutation burden as an important factor modulating this relationship. At a patient level, we find several outlier patients based on their quantile-specific coefficient functions, who have higher mutational rates and different smoking history.

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 paper, we develop selection-aware Bayesian methods, which (1) 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 ℓ1 -regularized algorithms; (2) strike an inevitable trade-off between the quality of model selection and inferential power when the same data set 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 tractable updates when gradient-based Markov chain Monte Carlo (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.

Role of multiresolution vulnerability indices in COVID-19 spread in India: a Bayesian model-based analysis.

OBJECTIVES: COVID-19 has differentially affected countries, with health infrastructure and other related vulnerability indicators playing a role in determining the extent of its spread. Vulnerability of a geographical region to COVID-19 has been a topic of interest, particularly in low-income and middle-income countries like India to assess its multifactorial impact on incidence, prevalence or mortality. This study aims to construct a statistical analysis pipeline to compute such vulnerability indices and investigate their association with metrics of the pandemic growth. DESIGN: Using publicly reported observational socioeconomic, demographic, health-based and epidemiological data from Indian national surveys, we compute contextual COVID-19 Vulnerability Indices (cVIs) across multiple thematic resolutions for different geographical and spatial administrative regions. These cVIs are then used in Bayesian regression models to assess their impact on indicators of the spread of COVID-19. SETTING: This study uses district-level indicators and case counts data for the state of Odisha, India. PRIMARY OUTCOME MEASURE: We use instantaneous R (temporal average of estimated time-varying reproduction number for COVID-19) as the primary outcome variable in our models. RESULTS: Our observational study, focussing on 30 districts of Odisha, identified housing and hygiene conditions, COVID-19 preparedness and epidemiological factors as important indicators associated with COVID-19 vulnerability. CONCLUSION: Having succeeded in containing COVID-19 to a reasonable level during the first wave, the second wave of COVID-19 made greater inroads into the hinterlands and peripheral districts of Odisha, burdening the already deficient public health system in these areas, as identified by the cVIs. Improved understanding of the factors driving COVID-19 vulnerability will help policy makers prioritise resources and regions, leading to more effective mitigation strategies for the present and future.

NetCellMatch: Multiscale Network-Based Matching of Cancer Cell Lines to Patients Using Graphical Wavelets.

Cancer cell lines serve as model in vitro systems for investigating therapeutic interventions. Recent advances in high-throughput genomic profiling have enabled the systematic comparison between cell lines and patient tumor samples. The highly interconnected nature of biological data, however, presents a challenge when mapping patient tumors to cell lines. Standard clustering methods can be particularly susceptible to the high level of noise present in these datasets and only output clusters at one unknown scale of the data. In light of these challenges, we present NetCellMatch, a robust framework for network-based matching of cell lines to patient tumors. NetCellMatch first constructs a global network across all cell line-patient samples using their genomic similarity. Then, a multi-scale community detection algorithm integrates information across topologically meaningful (clustering) scales to obtain Network-Based Matching Scores (NBMS). NBMS are measures of cluster robustness which map patient tumors to cell lines. We use NBMS to determine representative "avatar" cell lines for subgroups of patients. We apply NetCellMatch to reverse-phase protein array data obtained from The Cancer Genome Atlas for patients and the MD Anderson Cell Line Project for cell lines. Along with avatar cell line identification, we evaluate connectivity patterns for breast, lung, and colon cancer and explore the proteomic profiles of avatars and their corresponding top matching patients. Our results demonstrate our framework's ability to identify both patient-cell line matches and potential proteomic drivers of similarity. Our methods are general and can be easily adapted to other'omic datasets.

SpaceX: gene co-expression network estimation for spatial transcriptomics.

MOTIVATION: The analysis of spatially resolved transcriptome enables the understanding of the spatial interactions between the cellular environment and transcriptional regulation. In particular, the characterization of the gene-gene co-expression at distinct spatial locations or cell types in the tissue enables delineation of spatial co-regulatory patterns as opposed to standard differential single gene analyses. To enhance the ability and potential of spatial transcriptomics technologies to drive biological discovery, we develop a statistical framework to detect gene co-expression patterns in a spatially structured tissue consisting of different clusters in the form of cell classes or tissue domains. RESULTS: We develop SpaceX (spatially dependent gene co-expression network), a Bayesian methodology to identify both shared and cluster-specific co-expression network across genes. SpaceX uses an over-dispersed spatial Poisson model coupled with a high-dimensional factor model which is based on a dimension reduction technique for computational efficiency. We show via simulations, accuracy gains in co-expression network estimation and structure by accounting for (increasing) spatial correlation and appropriate noise distributions. In-depth analysis of two spatial transcriptomics datasets in mouse hypothalamus and human breast cancer using SpaceX, detected multiple hub genes which are related to cognitive abilities for the hypothalamus data and multiple cancer genes (e.g. collagen family) from the tumor region for the breast cancer data. AVAILABILITY AND IMPLEMENTATION: The SpaceX R-package is available at github.com/bayesrx/SpaceX. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bayesian graphical models for modern biological applications.

Graphical models are powerful tools that are regularly used to investigate complex dependence structures in high-throughput biomedical datasets. They allow for holistic, systems-level view of the various biological processes, for intuitive and rigorous understanding and interpretations. In the context of large networks, Bayesian approaches are particularly suitable because it encourages sparsity of the graphs, incorporate prior information, and most importantly account for uncertainty in the graph structure. These features are particularly important in applications with limited sample size, including genomics and imaging studies. In this paper, we review several recently developed techniques for the analysis of large networks under non-standard settings, including but not limited to, multiple graphs for data observed from multiple related subgroups, graphical regression approaches used for the analysis of networks that change with covariates, and other complex sampling and structural settings. We also illustrate the practical utility of some of these methods using examples in cancer genomics and neuroimaging.

Bayesian Covariate-Dependent Gaussian Graphical Models with Varying Structure.

We introduce Bayesian Gaussian graphical models with covariates (GGMx), a class of multivariate Gaussian distributions with covariate-dependent sparse precision matrix. We propose a general construction of a functional mapping from the covariate space to the cone of sparse positive definite matrices, which encompasses many existing graphical models for heterogeneous settings. Our methodology is based on a novel mixture prior for precision matrices with a non-local component that admits attractive theoretical and empirical properties. The flexible formulation of GGMx allows both the strength and the sparsity pattern of the precision matrix (hence the graph structure) change with the covariates. Posterior inference is carried out with a carefully designed Markov chain Monte Carlo algorithm, which ensures the positive definiteness of sparse precision matrices at any given covariates' values. Extensive simulations and a case study in cancer genomics demonstrate the utility of the proposed model.

A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

Bayesian Structure Learning in Multi-layered Genomic Networks.

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 layers, dictated by multiple platforms, and exhibit both undirected and directed relationships. We propose a multi-layered Gaussian graphical model (mlGGM) to investigate conditional independence structures in such multi-level genomic networks in human cancers. We implement a Bayesian node-wise selection (BANS) approach based on variable selection techniques that coherently accounts for the multiple types of dependencies in mlGGM; this flexible strategy exploits edge-specific prior knowledge and selects sparse and interpretable models. Through simulated data generated under various scenarios, we demonstrate that BANS outperforms other existing multivariate regression-based methodologies. Our integrative genomic network analysis for key signaling pathways across multiple cancer types highlights commonalities and differences of p53 integrative networks and epigenetic effects of BRCA2 on p53 and its interaction with T68 phosphorylated CHK2, that may have translational utilities of finding biomarkers and therapeutic targets.

Quantile Function on Scalar Regression Analysis for Distributional Data.

Radiomics involves the study of tumor images to identify quantitative markers explaining cancer heterogeneity. The predominant approach is to extract hundreds to thousands of image features, including histogram features comprised of summaries of the marginal distribution of pixel intensities, which leads to multiple testing problems and can miss out on insights not contained in the selected features. In this paper, we present methods to model the entire marginal distribution of pixel intensities via the quantile function as functional data, regressed on a set of demographic, clinical, and genetic predictors to investigate their effects of imaging-based cancer heterogeneity. We call this approach quantile functional regression, regressing subject-specific marginal distributions across repeated measurements on a set of covariates, allowing us to assess which covariates are associated with the distribution in a global sense, as well as to identify distributional features characterizing these differences, including mean, variance, skewness, heavy-tailedness, and various upper and lower quantiles. To account for smoothness in the quantile functions, account for intrafunctional correlation, and gain statistical power, we introduce custom basis functions we call quantlets that are sparse, regularized, near-lossless, and empirically defined, adapting to the features of a given data set and containing a Gaussian subspace so non-Gaussianness can be assessed. We fit this model using a Bayesian framework that uses nonlinear shrinkage of quantlet coefficients to regularize the functional regression coefficients and provides fully Bayesian inference after fitting a Markov chain Monte Carlo. We demonstrate the benefit of the basis space modeling through simulation studies, and apply the method to Magnetic resonance imaging (MRI) based radiomic dataset from Glioblastoma Multiforme to relate imaging-based quantile functions to various demographic, clinical, and genetic predictors, finding specific differences in tumor pixel intensity distribution between males and females and between tumors with and without DDIT3 mutations.