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Ani Eloyan

Publications and source records attributed to Ani Eloyan.

15 recordsLinked to original sources
arXiv2026

Causal Inference for Unobservable Multivariate Outcomes, with Applications to Brain Effective Connectivity

Evaluating the causal effect of an intervention on multivariate outcomes is challenging when the outcomes are interdependent and derived rather than directly observed. Effective connectivity, which summarizes the directional neural communication between brain regions, is one such derived relational outcome. Estimating how external interventions affect effective connectivity introduces two layers of causal inference problems: identifying directional relationships among brain regions from high-dimensional neuroimaging time series and estimating the causal effect of the intervention on these derived relationships. Each layer introduces distinct biases. The first arises from within-outcome dependencies unrelated to the intervention; to address this, we propose a sample-splitting method for estimating meaningful, and potentially causally informative, effective connectivity measures. The second arises from confounding between the intervention and the derived outcomes; to address this, we apply inverse probability weighting methods and incorporate multiple testing when causal effects on multiple components of the outcomes are of interest. We demonstrate, through theoretical results and simulations, that the proposed methods are asymptotically valid under certain conditions with effective type-I and familywise error control. Finally, we apply the proposed methods to examine the causal effect of amyloid on effective connectivity using the resting-state fMRI data from the Alzheimer's Disease Neuroimaging Initiative database.

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arXiv2025

TRAECR: A Tool for Preprocessing Positron Emission Tomography Imaging for Statistical Modeling

Positron emission tomography (PET) imaging is widely used in a number of clinical applications, including cancer and Alzheimer's disease (AD) diagnosis, monitoring of disease development, and treatment effect evaluation. Statistical modeling of PET imaging is essential to address continually emerging scientific questions in these research fields, including hypotheses related to evaluation of effects of disease modifying treatments on amyloid reduction in AD and associations between amyloid reduction and cognitive function, among many others. In this paper, we provide background information and tools for statisticians interested in developing statistical models for PET imaging to pre-process and prepare data for analysis. We introduce our novel pre-processing and visualization tool TRAECR (Template registration, MRI-PET co-Registration, Anatomical brain Extraction and COMBAT/RAVEL harmonization) to facilitate data preparation for statistical analysis.

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arXiv2025

Geometric Modeling of Hippocampal Tau Deposition: A Surface-Based Framework for Covariate Analysis and Off-Target Contamination Detection

We introduce a framework combining geometric modeling with disease progression analysis to investigate tau deposition in Alzheimer's disease (AD) using positron emission tomography (PET) data. Focusing on the hippocampus, we construct a principal surface that captures the spatial distribution and morphological changes of tau pathology. By projecting voxels onto this surface, we quantify tau coverage, intensity, and thickness through bidirectional projection distances and interpolated standardized uptake value ratios (SUVR). This low-dimensional embedding preserves spatial specificity while mitigating multiple comparison issues. Covariate effects are analyzed using a two-stage regression model with inverse probability weighting to adjust for signal sparsity and selection bias. Using the SuStaIn model, we identify subtypes and stages of AD, revealing distinct tau dynamics: the limbic-predominant subtype shows age-related nonlinear accumulation in coverage and thickness, whereas the posterior subtype exhibits uniform SUVR increases across disease progression. Model-based predictions show that hippocampal tau deposition follows a structured spatial trajectory expanding bidirectionally with increasing thickness, while subtype differences highlight posterior hippocampal involvement consistent with whole-brain patterns. Finally, directional signal patterns on the principal surface reveal contamination from the choroid plexus, demonstrating the broader applicability of the proposed framework across modalities including amyloid PET.

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arXiv2024

Longitudinal Principal Manifold Estimation

Longitudinal magnetic resonance imaging data is used to model trajectories of change in brain regions of interest to identify areas susceptible to atrophy in those with neurodegenerative conditions like Alzheimer's disease. Most methods for extracting brain regions are applied to scans from study participants independently, resulting in wide variability in shape and volume estimates of these regions over time in longitudinal studies. To address this problem, we propose a longitudinal principal manifold estimation method, which seeks to recover smooth, longitudinally meaningful manifold estimates of shapes over time. The proposed approach uses a smoothing spline to smooth over the coefficients of principal manifold embedding functions estimated at each time point. This mitigates the effects of random disturbances to the manifold between time points. Additionally, we propose a novel data augmentation approach to enable principal manifold estimation on self-intersecting manifolds. Simulation studies demonstrate performance improvements over naive applications of principal manifold estimation and principal curve/surface methods. The proposed method improves the estimation of surfaces of hippocampuses and thalamuses using data from participants of the Alzheimer's Disease Neuroimaging Initiative. An analysis of magnetic resonance imaging data from 236 individuals shows the advantages of our proposed methods that leverage regional longitudinal trends for segmentation.

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arXiv2024

Randomness of Shapes and Statistical Inference on Shapes via the Smooth Euler Characteristic Transform

In this article, we establish the mathematical foundations for modeling the randomness of shapes and conducting statistical inference on shapes using the smooth Euler characteristic transform. Based on these foundations, we propose two chi-squared statistic-based algorithms for testing hypotheses on random shapes. Simulation studies are presented to validate our mathematical derivations and to compare our algorithms with state-of-the-art methods to demonstrate the utility of our proposed framework. As real applications, we analyze a data set of mandibular molars from four genera of primates and show that our algorithms have the power to detect significant shape differences that recapitulate known morphological variation across suborders. Altogether, our discussions bridge the following fields: algebraic and computational topology, probability theory and stochastic processes, Sobolev spaces and functional analysis, analysis of variance for functional data, and geometric morphometrics.

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arXiv2024

Population-level Task-evoked Functional Connectivity via Fourier Analysis

Functional magnetic resonance imaging (fMRI) is a non-invasive and in-vivo imaging technique essential for measuring brain activity. Functional connectivity is used to study associations between brain regions, either while study subjects perform tasks or during periods of rest. In this paper, we propose a rigorous definition of task-evoked functional connectivity at the population level (ptFC). Importantly, our proposed ptFC is interpretable in the context of task-fMRI studies. An algorithm for estimating the ptFC is provided. We present the performance of the proposed algorithm compared to existing functional connectivity frameworks using simulations. Lastly, we apply the proposed algorithm to estimate the ptFC in a motor-task study from the Human Connectome Project.

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arXiv2024

Distributed model building and recursive integration for big spatial data modeling

Motivated by the need for computationally tractable spatial methods in neuroimaging studies, we develop a distributed and integrated framework for estimation and inference of Gaussian process model parameters with ultra-high-dimensional likelihoods. We propose a shift in viewpoint from whole to local data perspectives that is rooted in distributed model building and integrated estimation and inference. The framework's backbone is a computationally and statistically efficient integration procedure that simultaneously incorporates dependence within and between spatial resolutions in a recursively partitioned spatial domain. Statistical and computational properties of our distributed approach are investigated theoretically and in simulations. The proposed approach is used to extract new insights on autism spectrum disorder from the Autism Brain Imaging Data Exchange.

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arXiv2023

Leveraging population information in brain connectivity via Bayesian ICA with a novel informative prior for correlation matrices

Brain functional connectivity (FC), the temporal synchrony between brain networks, is essential to understand the functional organization of the brain and to identify changes due to neurological disorders, development, treatment, and other phenomena. Independent component analysis (ICA) is a matrix decomposition method used extensively for simultaneous estimation of functional brain topography and connectivity. However, estimation of FC via ICA is often sub-optimal due to the use of ad-hoc estimation methods or temporal dimension reduction prior to ICA. Bayesian ICA can avoid dimension reduction, estimate latent variables and model parameters more accurately, and facilitate posterior inference. In this paper, we develop a novel, computationally feasible Bayesian ICA method with population-derived priors on both the spatial ICs and their temporal correlation, i.e. FC. For the latter we consider two priors: the inverse-Wishart, which is conjugate but is not ideally suited for modeling correlation matrices; and a novel informative prior for correlation matrices. For each prior, we derive a variational Bayes algorithm to estimate the model variables and facilitate posterior inference. Through extensive simulation studies, we evaluate the performance of the proposed methods and benchmark against existing approaches. We also analyze fMRI data from over 400 healthy adults in the Human Connectome Project. We find that our Bayesian ICA model and algorithms result in more accurate measures of functional connectivity and spatial brain features. Our novel prior for correlation matrices is more computationally intensive than the inverse-Wishart but provides improved accuracy and inference. The proposed framework is applicable to single-subject analysis, making it potentially clinically viable.

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arXiv2023

Statistical Inference on Grayscale Images via the Euler-Radon Transform

Tools from topological data analysis have been widely used to represent binary images in many scientific applications. Methods that aim to represent grayscale images (i.e., where pixel intensities instead take on continuous values) have been relatively underdeveloped. In this paper, we introduce the Euler-Radon transform, which generalizes the Euler characteristic transform to grayscale images by using o-minimal structures and Euler integration over definable functions. Coupling the Karhunen-Loeve expansion with our proposed topological representation, we offer hypothesis-testing algorithms based on the chi-squared distribution for detecting significant differences between two groups of grayscale images. We illustrate our framework via extensive numerical experiments and simulations.

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arXiv2023

Brain Functional Connectivity Estimation Utilizing Diffusion Kernels on a Structural Connectivity Graph

Functional connectivity (FC) refers to the investigation of interactions between brain regions to understand integration of neural activity in several regions. FC is often estimated using functional magnetic resonance images (fMRI). There has been increasing interest in the potential of multi-modal imaging to obtain robust estimates of FC in high-dimensional settings. We develop novel algorithms adapting graphical methods incorporating diffusion tensor imaging (DTI) to estimate FC with computational efficiency and scalability. We propose leveraging a graphical random walk on DTI to define a new measure of structural connectivity highlighting spurious connected components. Our proposed approach is based on finding appropriate subnetwork topology using permutation testing before selection of subnetwork components comprising FC. Extensive simulations demonstrate that the performance of our methods is comparable to or better than currently used approaches in estimation accuracy, with the advantage of greater speed and simpler implementation. We analyze task-based fMRI data obtained from the Human Connectome Project database using our proposed methods and reveal novel insights into brain interactions during performance of a motor task. We expect that the transparency and flexibility of our approach will prove valuable as further understanding of the structure-function relationship informs future network estimation.

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arXiv2021

Principal manifold estimation via model complexity selection

We propose a framework of principal manifolds to model high-dimensional data. This framework is based on Sobolev spaces and designed to model data of any intrinsic dimension. It includes principal component analysis and principal curve algorithm as special cases. We propose a novel method for model complexity selection to avoid overfitting, eliminate the effects of outliers, and improve the computation speed. Additionally, we propose a method for identifying the interiors of circle-like curves and cylinder/ball-like surfaces. The proposed approach is compared to existing methods by simulations and applied to estimate tumor surfaces and interiors in a lung cancer study.

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arXiv2016

PCA leverage: outlier detection for high-dimensional functional magnetic resonance imaging data

Outlier detection for high-dimensional (HD) data is a popular topic in modern statistical research. However, one source of HD data that has received relatively little attention is functional magnetic resonance images (fMRI), which consists of hundreds of thousands of measurements sampled at hundreds of time points. At a time when the availability of fMRI data is rapidly growing---primarily through large, publicly available grassroots datasets---automated quality control and outlier detection methods are greatly needed. We propose PCA leverage and demonstrate how it can be used to identify outlying time points in an fMRI run. Furthermore, PCA leverage is a measure of the influence of each observation on the estimation of principal components, which are often of interest in fMRI data. We also propose an alternative measure, PCA robust distance, which is less sensitive to outliers and has controllable statistical properties. The proposed methods are validated through simulation studies and are shown to be highly accurate. We also conduct a reliability study using resting-state fMRI data from the Autism Brain Imaging Data Exchange and find that removal of outliers using the proposed methods results in more reliable estimation of subject-level resting-state networks using ICA.

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arXiv2015

Relating multi-sequence longitudinal intensity profiles and clinical covariates in new multiple sclerosis lesions

Structural magnetic resonance imaging (MRI) can be used to detect lesions in the brains of multiple sclerosis (MS) patients. The formation of these lesions is a complex process involving inflammation, tissue damage, and tissue repair, all of which are visible on MRI. Here we characterize the lesion formation process on longitudinal, multi-sequence structural MRI from 34 MS patients and relate the longitudinal changes we observe within lesions to therapeutic interventions. In this article, we first outline a pipeline to extract voxel level, multi-sequence longitudinal profiles from four MRI sequences within lesion tissue. We then propose two models to relate clinical covariates to the longitudinal profiles. The first model is a principal component analysis (PCA) regression model, which collapses the information from all four profiles into a scalar value. We find that the score on the first PC identifies areas of slow, long-term intensity changes within the lesion at a voxel level, as validated by two experienced clinicians, a neuroradiologist and a neurologist. On a quality scale of 1 to 4 (4 being the highest) the neuroradiologist gave the score on the first PC a median rating of 4 (95% CI: [4,4]), and the neurologist gave it a median rating of 3 (95% CI: [3,3]). In the PCA regression model, we find that treatment with disease modifying therapies (p-value < 0.01), steroids (p-value < 0.01), and being closer to the boundary of abnormal signal intensity (p-value < 0.01) are associated with a return of a voxel to intensity values closer to that of normal-appearing tissue. The second model is a function-on-scalar regression, which allows for assessment of the individual time points at which the covariates are associated with the profiles. In the function-on-scalar regression both age and distance to the boundary were found to have a statistically significant association with the profiles.

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arXiv2013

Homotopic Group ICA for Multi-Subject Brain Imaging Data

Independent Component Analysis (ICA) is a computational technique for revealing latent factors that underlie sets of measurements or signals. It has become a standard technique in functional neuroimaging. In functional neuroimaging, so called group ICA (gICA) seeks to identify and quantify networks of correlated regions across subjects. This paper reports on the development of a new group ICA approach, Homotopic Group ICA (H-gICA), for blind source separation of resting state functional magnetic resonance imaging (fMRI) data. Resting state brain functional homotopy is the similarity of spontaneous fluctuations between bilaterally symmetrically opposing regions (i.e. those symmetric with respect to the mid-sagittal plane) (Zuo et al., 2010). The approach we proposed improves network estimates by leveraging this known brain functional homotopy. H-gICA increases the potential for network discovery, effectively by averaging information across hemispheres. It is theoretically proven to be identical to standard group ICA when the true sources are both perfectly homotopic and noise-free, while simulation studies and data explorations demonstrate its benefits in the presence of noise. Moreover, compared to commonly applied group ICA algorithms, the structure of the H-gICA input data leads to significant improvement in computational efficiency. A simulation study comfirms its effectiveness in homotopic, non-homotopic and mixed settings, as well as on the landmark ADHD-200 dataset. From a relatively small subset of data, several brain networks were found including: the visual, the default mode and auditory networks, as well as others. These were shown to be more contiguous and clearly delineated than the corresponding ordinary group ICA. Finally, in addition to improving network estimation, H-gICA facilitates the investigation of functional homotopy via ICA-based networks.

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