Heterogeneous Image-based Classification Using Distributional Data Analysis

Diagnostic imaging has gained prominence as potential biomarkers for early detection and diagnosis in a diverse array of disorders including cancer. However, existing methods routinely face challenges arising from various factors such as image heterogeneity. We develop a novel imaging-based distributional data analysis (DDA) approach that incorporates the probability (quantile) distribution of the pixel-level features as covariates. The proposed approach uses a smoothed quantile distribution (via a suitable basis representation) as functional predictors in a scalar-on-functional quantile regression model. Some distinctive features of the proposed approach include the ability to: (i) account for heterogeneity within the image; (ii) incorporate granular information spanning the entire distribution; and (iii) tackle variability in image sizes for unregistered images in cancer applications. Our primary goal is risk prediction in Hepatocellular carcinoma that is achieved via predicting the change in tumor grades at post-diagnostic visits using pre-diagnostic enhancement pattern mapping (EPM) images of the liver. Along the way, the proposed DDA approach is also used for case versus control diagnosis and risk stratification objectives. Our analysis reveals that when coupled with global structural radiomics features derived from the corresponding T1-MRI scans, the proposed smoothed quantile distributions derived from EPM images showed considerable improvements in sensitivity and comparable specificity in contrast to classification based on routinely used summary measures that do not account for image heterogeneity. Given that there are limited predictive modeling approaches based on heterogeneous images in cancer, the proposed method is expected to provide considerable advantages in image-based early detection and risk prediction.

Importance of Feature Extraction in the Calculation of Fréchet Distance for Medical Imaging

Fr\'echet Inception Distance is a widely used metric for evaluating synthetic image quality that utilizes an ImageNet-trained InceptionV3 network as a feature extractor. However, its application in medical imaging lacks a standard feature extractor, leading to biased and inconsistent comparisons. This study aimed to compare state-of-the-art feature extractors for computing Fr\'echet Distances (FDs) in medical imaging. A StyleGAN2 network was trained with data augmentation techniques tailored for limited data domains on datasets comprising three medical imaging modalities and four anatomical locations. Human evaluation of generative quality (via a visual Turing test) was compared to FDs calculated using ImageNet-trained InceptionV3, ResNet50, SwAV, DINO, and Swin Transformer architectures, in addition to an InceptionV3 network trained on a large medical dataset, RadImageNet. All ImageNet-based extractors were consistent with each other, but only SwAV was significantly correlated with medical expert judgment. The RadImageNet-based FD showed volatility and lacked correlation with human judgment. Caution is advised when using medical image-trained extraction networks in the FD calculation. These networks should be rigorously evaluated on the imaging modality under consideration and publicly released. ImageNet-based extractors, while imperfect, are consistent and widely understood. Training extraction networks with SwAV is a promising approach for synthetic medical image evaluation.

Bayesian longitudinal tensor response regression for modeling neuroplasticity

A major interest in longitudinal neuroimaging studies involves investigating voxel-level neuroplasticity due to treatment and other factors across visits. However, traditional voxel-wise methods are beset with several pitfalls, which can compromise the accuracy of these approaches. We propose a novel Bayesian tensor response regression approach for longitudinal imaging data, which pools information across spatially-distributed voxels to infer significant changes while adjusting for covariates. The proposed method, which is implemented using Markov chain Monte Carlo (MCMC) sampling, utilizes low-rank decomposition to reduce dimensionality and preserve spatial configurations of voxels when estimating coefficients. It also enables feature selection via joint credible regions which respect the shape of the posterior distributions for more accurate inference. In addition to group level inferences, the method is able to infer individual-level neuroplasticity, allowing for examination of personalized disease or recovery trajectories. The advantages of the proposed approach in terms of prediction and feature selection over voxel-wise regression are highlighted via extensive simulation studies. Subsequently, we apply the approach to a longitudinal Aphasia dataset consisting of task functional MRI images from a group of subjects who were administered either a control intervention or intention treatment at baseline and were followed up over subsequent visits. Our analysis revealed that while the control therapy showed long-term increases in brain activity, the intention treatment produced predominantly short-term changes, both of which were concentrated in distinct localized regions. In contrast, the voxel-wise regression failed to detect any significant neuroplasticity after multiplicity adjustments, which is biologically implausible and implies lack of power.

Accounting for Temporal Variability in Functional Magnetic Resonance Imaging Improves Prediction of Intelligence

Neuroimaging-based prediction methods for intelligence and cognitive abilities have seen a rapid development, while prediction based on functional connectivity (FC) has shown great promise. The overwhelming majority of literature has focused on static FC with extremely limited results available on dynamic FC or region level fMRI time series. Unlike static FC, the latter features include the temporal variability in the fMRI data. In this project, we propose a novel bi-LSTM approach that incorporates an $L_0$ regularization for feature selection. The proposed pipeline is applied to prediction based on region level fMRI time series as well as dynamic FC and implemented via an efficient algorithm. We undertake a detailed comparison of prediction performance for different intelligence measures based on fMRI features acquired from the Adolescent Brain Cognitive Development (ABCD) study. Our analysis illustrates that static FC consistently has inferior performance compared to region level fMRI time series or dynamic FC for unimodal rest and task fMRI experiments, as well as in almost all cases for multi-task analysis. The proposed pipeline based on region level time-series identifies several important brain regions that drive fluctuations in intelligence measures. Strong test-retest reliability of the selected features is reported, pointing to reproducible findings. Given the large sample size from ABCD study, our results provide conclusive evidence that superior intelligence prediction can be achieved by considering temporal variations in the fMRI data, either at the region level, or based on dynamic FC, which is one of the first such findings in literature. These results are particularly noteworthy, given the low dimensionality of the region level time series, easier interpretability, and extremely quick computation times, compared to network-based analysis.

High-dimensional Measurement Error Models for Lipschitz Loss

Recently emerging large-scale biomedical data pose exciting opportunities for scientific discoveries. However, the ultrahigh dimensionality and non-negligible measurement errors in the data may create difficulties in estimation. There are limited methods for high-dimensional covariates with measurement error, that usually require knowledge of the noise distribution and focus on linear or generalized linear models. In this work, we develop high-dimensional measurement error models for a class of Lipschitz loss functions that encompasses logistic regression, hinge loss and quantile regression, among others. Our estimator is designed to minimize the $L_1$ norm among all estimators belonging to suitable feasible sets, without requiring any knowledge of the noise distribution. Subsequently, we generalize these estimators to a Lasso analog version that is computationally scalable to higher dimensions. We derive theoretical guarantees in terms of finite sample statistical error bounds and sign consistency, even when the dimensionality increases exponentially with the sample size. Extensive simulation studies demonstrate superior performance compared to existing methods in classification and quantile regression problems. An application to a gender classification task based on brain functional connectivity in the Human Connectome Project data illustrates improved accuracy under our approach, and the ability to reliably identify significant brain connections that drive gender differences.

Evaluating the Performance of StyleGAN2-ADA on Medical Images

Although generative adversarial networks (GANs) have shown promise in medical imaging, they have four main limitations that impeded their utility: computational cost, data requirements, reliable evaluation measures, and training complexity. Our work investigates each of these obstacles in a novel application of StyleGAN2-ADA to high-resolution medical imaging datasets. Our dataset is comprised of liver-containing axial slices from non-contrast and contrast-enhanced computed tomography (CT) scans. Additionally, we utilized four public datasets composed of various imaging modalities. We trained a StyleGAN2 network with transfer learning (from the Flickr-Faces-HQ dataset) and data augmentation (horizontal flipping and adaptive discriminator augmentation). The network's generative quality was measured quantitatively with the Fr\'echet Inception Distance (FID) and qualitatively with a visual Turing test given to seven radiologists and radiation oncologists. The StyleGAN2-ADA network achieved a FID of 5.22 ($\pm$ 0.17) on our liver CT dataset. It also set new record FIDs of 10.78, 3.52, 21.17, and 5.39 on the publicly available SLIVER07, ChestX-ray14, ACDC, and Medical Segmentation Decathlon (brain tumors) datasets. In the visual Turing test, the clinicians rated generated images as real 42% of the time, approaching random guessing. Our computational ablation study revealed that transfer learning and data augmentation stabilize training and improve the perceptual quality of the generated images. We observed the FID to be consistent with human perceptual evaluation of medical images. Finally, our work found that StyleGAN2-ADA consistently produces high-quality results without hyperparameter searches or retraining.

Elastic Shape Analysis of Brain Structures for Predictive Modeling of PTSD

There is increasing evidence on the importance of brain morphology in predicting and classifying mental disorders. However, the vast majority of current shape approaches rely heavily on vertex-wise analysis that may not successfully capture complexities of subcortical structures. Additionally, the past works do not include interactions between these structures and exposure factors. Predictive modeling with such interactions is of paramount interest in heterogeneous mental disorders such as PTSD, where trauma exposure interacts with brain shape changes to influence behavior. We propose a comprehensive framework that overcomes these limitations by representing brain substructures as continuous parameterized surfaces and quantifying their shape differences using elastic shape metrics. Using the elastic shape metric, we compute shape summaries of subcortical data and represent individual shapes by their principal scores. These representations allow visualization tools that help localize changes when these PCs are varied. Subsequently, these PCs, the auxiliary exposure variables, and their interactions are used for regression modeling. We apply our method to data from the Grady Trauma Project, where the goal is to predict clinical measures of PTSD using shapes of brain substructures. Our analysis revealed considerably greater predictive power under the elastic shape analysis than widely used approaches such as vertex-wise shape analysis and even volumetric analysis. It helped identify local deformations in brain shapes related to change in PTSD severity. To our knowledge, this is one of the first brain shape analysis approaches that can seamlessly integrate the pre-processing steps under one umbrella for improved accuracy and are naturally able to account for interactions between brain shape and additional covariates to yield superior predictive performance when modeling clinical outcomes.