Shireen Elhabian

K M Arefeen Sultan, Md Hasibul Husain Hisham, Benjamin Orkild et al.

The accurate evaluation of left atrial fibrosis via high-quality 3D Late Gadolinium Enhancement (LGE) MRI is crucial for atrial fibrillation management but is hindered by factors like patient movement and imaging variability. The pursuit of automated LGE MRI quality assessment is critical for enhancing diagnostic accuracy, standardizing evaluations, and improving patient outcomes. The deep learning models aimed at automating this process face significant challenges due to the scarcity of expert annotations, high computational costs, and the need to capture subtle diagnostic details in highly variable images. This study introduces HAMIL-QA, a multiple instance learning (MIL) framework, designed to overcome these obstacles. HAMIL-QA employs a hierarchical bag and sub-bag structure that allows for targeted analysis within sub-bags and aggregates insights at the volume level. This hierarchical MIL approach reduces reliance on extensive annotations, lessens computational load, and ensures clinically relevant quality predictions by focusing on diagnostically critical image features. Our experiments show that HAMIL-QA surpasses existing MIL methods and traditional supervised approaches in accuracy, AUROC, and F1-Score on an LGE MRI scan dataset, demonstrating its potential as a scalable solution for LGE MRI quality assessment automation. The code is available at: $\href{https://github.com/arf111/HAMIL-QA}{\text{this https URL}}$

Shikha Dubey, Tushar Kataria, Beatrice Knudsen et al.

With the advent of digital scanners and deep learning, diagnostic operations may move from a microscope to a desktop. Hematoxylin and Eosin (H&E) staining is one of the most frequently used stains for disease analysis, diagnosis, and grading, but pathologists do need different immunohistochemical (IHC) stains to analyze specific structures or cells. Obtaining all of these stains (H&E and different IHCs) on a single specimen is a tedious and time-consuming task. Consequently, virtual staining has emerged as an essential research direction. Here, we propose a novel generative model, Structural Cycle-GAN (SC-GAN), for synthesizing IHC stains from H&E images, and vice versa. Our method expressly incorporates structural information in the form of edges (in addition to color data) and employs attention modules exclusively in the decoder of the proposed generator model. This integration enhances feature localization and preserves contextual information during the generation process. In addition, a structural loss is incorporated to ensure accurate structure alignment between the generated and input markers. To demonstrate the efficacy of the proposed model, experiments are conducted with two IHC markers emphasizing distinct structures of glands in the colon: the nucleus of epithelial cells (CDX2) and the cytoplasm (CK818). Quantitative metrics such as FID and SSIM are frequently used for the analysis of generative models, but they do not correlate explicitly with higher-quality virtual staining results. Therefore, we propose two new quantitative metrics that correlate directly with the virtual staining specificity of IHC markers.

Tushar Kataria, Beatrice Knudsen, Shireen Elhabian

Annotating medical imaging datasets is costly, so fine-tuning (or transfer learning) is the most effective method for digital pathology vision applications such as disease classification and semantic segmentation. However, due to texture bias in models trained on real-world images, transfer learning for histopathology applications might result in underperforming models, which necessitates the need for using unlabeled histopathology data and self-supervised methods to discover domain-specific characteristics. Here, we tested the premise that histopathology-specific pretrained models provide better initializations for pathology vision tasks, i.e., gland and cell segmentation. In this study, we compare the performance of gland and cell segmentation tasks with histopathology domain-specific and non-domain-specific (real-world images) pretrained weights. Moreover, we investigate the dataset size at which domain-specific pretraining produces significant gains in performance. In addition, we investigated whether domain-specific initialization improves the effectiveness of out-of-distribution testing on distinct datasets but the same task. The results indicate that performance gain using domain-specific pretrained weights depends on both the task and the size of the training dataset. In instances with limited dataset sizes, a significant improvement in gland segmentation performance was also observed, whereas models trained on cell segmentation datasets exhibit no improvement.

Jadie Adams, Nawazish Khan, Alan Morris et al.

Clinical investigations of anatomy's structural changes over time could greatly benefit from population-level quantification of shape, or spatiotemporal statistic shape modeling (SSM). Such a tool enables characterizing patient organ cycles or disease progression in relation to a cohort of interest. Constructing shape models requires establishing a quantitative shape representation (e.g., corresponding landmarks). Particle-based shape modeling (PSM) is a data-driven SSM approach that captures population-level shape variations by optimizing landmark placement. However, it assumes cross-sectional study designs and hence has limited statistical power in representing shape changes over time. Existing methods for modeling spatiotemporal or longitudinal shape changes require predefined shape atlases and pre-built shape models that are typically constructed cross-sectionally. This paper proposes a data-driven approach inspired by the PSM method to learn population-level spatiotemporal shape changes directly from shape data. We introduce a novel SSM optimization scheme that produces landmarks that are in correspondence both across the population (inter-subject) and across time-series (intra-subject). We apply the proposed method to 4D cardiac data from atrial-fibrillation patients and demonstrate its efficacy in representing the dynamic change of the left atrium. Furthermore, we show that our method outperforms an image-based approach for spatiotemporal SSM with respect to a generative time-series model, the Linear Dynamical System (LDS). LDS fit using a spatiotemporal shape model optimized via our approach provides better generalization and specificity, indicating it accurately captures the underlying time-dependency.

Syed Fahim Ahmed, Gnanesh Rasineni, Florian Koehler et al.

Whole-slide image (WSI) classification in computational pathology is commonly formulated as slide-level Multiple Instance Learning (MIL) with a single global bag representation. However, slide-level MIL is fundamentally underconstrained: optimizing only global labels encourages models to aggregate features without learning anatomically meaningful localization. This creates a mismatch between the scale of supervision and the scale of clinical reasoning. Clinicians assess tumor burden, focal lesions, and architectural patterns within millimeter-scale regions, whereas standard MIL is trained only to predict whether "somewhere in the slide there is cancer." As a result, the model's inductive bias effectively erases anatomical structure. We propose Progressive-Context MIL (PC-MIL), a framework that treats the spatial extent of supervision as a first-class design dimension. Rather than altering magnification, patch size, or introducing pixel-level segmentation, we decouple feature resolution from supervision scale. Using fixed 20x features, we vary MIL bag extent in millimeter units and anchor supervision at a clinically motivated 2mm scale to preserve comparable tumor burden and avoid confounding scale with lesion density. PC-MIL progressively mixes slide- and region-level supervision in controlled proportions, enabling explicit train-context x test-context analysis. On 1,476 prostate WSIs from five public datasets for binary cancer detection, we show that anatomical context is an independent axis of generalization in MIL, orthogonal to feature resolution: modest regional supervision improves cross-context performance, and balanced multi-context training stabilizes accuracy across slide and regional evaluation without sacrificing global performance. These results demonstrate that supervision extent shapes MIL inductive bias and support anatomically grounded WSI generalization.

K M Arefeen Sultan, Benjamin Orkild, Alan Morris et al.

Accurate assessment of left atrial fibrosis in patients with atrial fibrillation relies on high-quality 3D late gadolinium enhancement (LGE) MRI images. However, obtaining such images is challenging due to patient motion, changing breathing patterns, or sub-optimal choice of pulse sequence parameters. Automated assessment of LGE-MRI image diagnostic quality is clinically significant as it would enhance diagnostic accuracy, improve efficiency, ensure standardization, and contributes to better patient outcomes by providing reliable and high-quality LGE-MRI scans for fibrosis quantification and treatment planning. To address this, we propose a two-stage deep-learning approach for automated LGE-MRI image diagnostic quality assessment. The method includes a left atrium detector to focus on relevant regions and a deep network to evaluate diagnostic quality. We explore two training strategies, multi-task learning, and pretraining using contrastive learning, to overcome limited annotated data in medical imaging. Contrastive Learning result shows about $4\%$, and $9\%$ improvement in F1-Score and Specificity compared to Multi-Task learning when there's limited data.

Jadie Adams, Shireen Elhabian

Statistical shape modeling (SSM) directly from 3D medical images is an underutilized tool for detecting pathology, diagnosing disease, and conducting population-level morphology analysis. Deep learning frameworks have increased the feasibility of adopting SSM in medical practice by reducing the expert-driven manual and computational overhead in traditional SSM workflows. However, translating such frameworks to clinical practice requires calibrated uncertainty measures as neural networks can produce over-confident predictions that cannot be trusted in sensitive clinical decision-making. Existing techniques for predicting shape with aleatoric (data-dependent) uncertainty utilize a principal component analysis (PCA) based shape representation computed in isolation from the model training. This constraint restricts the learning task to solely estimating pre-defined shape descriptors from 3D images and imposes a linear relationship between this shape representation and the output (i.e., shape) space. In this paper, we propose a principled framework based on the variational information bottleneck theory to relax these assumptions while predicting probabilistic shapes of anatomy directly from images without supervised encoding of shape descriptors. Here, the latent representation is learned in the context of the learning task, resulting in a more scalable, flexible model that better captures data non-linearity. Additionally, this model is self-regularized and generalizes better given limited training data. Our experiments demonstrate that the proposed method provides improved accuracy and better calibrated aleatoric uncertainty estimates than state-of-the-art methods.

Md Hasibul Husain Hisham, Shireen Elhabian, Ganesh Adluru et al.

Accelerated 3D late gadolinium enhancement (LGE) MRI requires robust reconstruction methods to recover thin atrial structures from undersampled k-space data. While unrolled model-based networks effectively integrate physics-driven data consistency with learned priors, they operate at the acquired resolution and may fail to fully recover high-frequency detail. We propose a hybrid unrolled reconstruction framework in which an Enhanced Deep Super-Resolution (EDSR) network replaces the proximal operator within each iteration of the optimization loop, enabling joint super-resolution enhancement and data consistency enforcement. The model is trained end-to-end on retrospectively undersampled preclinical 3D LGE datasets and compared against compressed sensing, Model-Based Deep Learning (MoDL), and self-guided Deep Image Prior (DIP) baselines. Across acceleration factors, the proposed method consistently improves PSNR and SSIM over standard unrolled reconstruction and better preserves fine cardiac structures, leading to improved LA (left atrium) segmentation performance. These results demonstrate that integrating super-resolution priors directly within model-based reconstruction provides measurable gains in accelerated 3D LGE MRI.

Shikha Dubey, Yosep Chong, Beatrice Knudsen et al.

This paper introduces a Virtual Immunohistochemistry Multiplex staining (VIMs) model designed to generate multiple immunohistochemistry (IHC) stains from a single hematoxylin and eosin (H&E) stained tissue section. IHC stains are crucial in pathology practice for resolving complex diagnostic questions and guiding patient treatment decisions. While commercial laboratories offer a wide array of up to 400 different antibody-based IHC stains, small biopsies often lack sufficient tissue for multiple stains while preserving material for subsequent molecular testing. This highlights the need for virtual IHC staining. Notably, VIMs is the first model to address this need, leveraging a large vision-language single-step diffusion model for virtual IHC multiplexing through text prompts for each IHC marker. VIMs is trained on uniplex paired H&E and IHC images, employing an adversarial training module. Testing of VIMs includes both paired and unpaired image sets. To enhance computational efficiency, VIMs utilizes a pre-trained large latent diffusion model fine-tuned with small, trainable weights through the Low-Rank Adapter (LoRA) approach. Experiments on nuclear and cytoplasmic IHC markers demonstrate that VIMs outperforms the base diffusion model and achieves performance comparable to Pix2Pix, a standard generative model for paired image translation. Multiple evaluation methods, including assessments by two pathologists, are used to determine the performance of VIMs. Additionally, experiments with different prompts highlight the impact of text conditioning. This paper represents the first attempt to accelerate histopathology research by demonstrating the generation of multiple IHC stains from a single H&E input using a single model trained solely on uniplex data.

Jadie Adams, Shireen Y. Elhabian

Deep learning based methods for automatic organ segmentation have shown promise in aiding diagnosis and treatment planning. However, quantifying and understanding the uncertainty associated with model predictions is crucial in critical clinical applications. While many techniques have been proposed for epistemic or model-based uncertainty estimation, it is unclear which method is preferred in the medical image analysis setting. This paper presents a comprehensive benchmarking study that evaluates epistemic uncertainty quantification methods in organ segmentation in terms of accuracy, uncertainty calibration, and scalability. We provide a comprehensive discussion of the strengths, weaknesses, and out-of-distribution detection capabilities of each method as well as recommendations for future improvements. These findings contribute to the development of reliable and robust models that yield accurate segmentations while effectively quantifying epistemic uncertainty.

Abu Zahid Bin Aziz, Jadie Adams, Shireen Elhabian

Statistical shape modeling (SSM) is an enabling quantitative tool to study anatomical shapes in various medical applications. However, directly using 3D images in these applications still has a long way to go. Recent deep learning methods have paved the way for reducing the substantial preprocessing steps to construct SSMs directly from unsegmented images. Nevertheless, the performance of these models is not up to the mark. Inspired by multiscale/multiresolution learning, we propose a new training strategy, progressive DeepSSM, to train image-to-shape deep learning models. The training is performed in multiple scales, and each scale utilizes the output from the previous scale. This strategy enables the model to learn coarse shape features in the first scales and gradually learn detailed fine shape features in the later scales. We leverage shape priors via segmentation-guided multi-task learning and employ deep supervision loss to ensure learning at each scale. Experiments show the superiority of models trained by the proposed strategy from both quantitative and qualitative perspectives. This training methodology can be employed to improve the stability and accuracy of any deep learning method for inferring statistical representations of anatomies from medical images and can be adopted by existing deep learning methods to improve model accuracy and training stability.

Krithika Iyer, Alan Morris, Brian Zenger et al.

Statistical shape modeling (SSM) is a valuable and powerful tool to generate a detailed representation of complex anatomy that enables quantitative analysis and the comparison of shapes and their variations. SSM applies mathematics, statistics, and computing to parse the shape into a quantitative representation (such as correspondence points or landmarks) that will help answer various questions about the anatomical variations across the population. Complex anatomical structures have many diverse parts with varying interactions or intricate architecture. For example, the heart is four-chambered anatomy with several shared boundaries between chambers. Coordinated and efficient contraction of the chambers of the heart is necessary to adequately perfuse end organs throughout the body. Subtle shape changes within these shared boundaries of the heart can indicate potential pathological changes that lead to uncoordinated contraction and poor end-organ perfusion. Early detection and robust quantification could provide insight into ideal treatment techniques and intervention timing. However, existing SSM approaches fall short of explicitly modeling the statistics of shared boundaries. This paper presents a general and flexible data-driven approach for building statistical shape models of multi-organ anatomies with shared boundaries that capture morphological and alignment changes of individual anatomies and their shared boundary surfaces throughout the population. We demonstrate the effectiveness of the proposed methods using a biventricular heart dataset by developing shape models that consistently parameterize the cardiac biventricular structure and the interventricular septum (shared boundary surface) across the population data.

Krithika Iyer, Riddhish Bhalodia, Shireen Elhabian

The manifold assumption for high-dimensional data assumes that the data is generated by varying a set of parameters obtained from a low-dimensional latent space. Deep generative models (DGMs) are widely used to learn data representations in an unsupervised way. DGMs parameterize the underlying low-dimensional manifold in the data space using bottleneck architectures such as variational autoencoders (VAEs). The bottleneck dimension for VAEs is treated as a hyperparameter that depends on the dataset and is fixed at design time after extensive tuning. As the intrinsic dimensionality of most real-world datasets is unknown, often, there is a mismatch between the intrinsic dimensionality and the latent dimensionality chosen as a hyperparameter. This mismatch can negatively contribute to the model performance for representation learning and sample generation tasks. This paper proposes relevance encoding networks (RENs): a novel probabilistic VAE-based framework that uses the automatic relevance determination (ARD) prior in the latent space to learn the data-specific bottleneck dimensionality. The relevance of each latent dimension is directly learned from the data along with the other model parameters using stochastic gradient descent and a reparameterization trick adapted to non-Gaussian priors. We leverage the concept of DeepSets to capture permutation invariant statistical properties in both data and latent spaces for relevance determination. The proposed framework is general and flexible and can be used for the state-of-the-art VAE models that leverage regularizers to impose specific characteristics in the latent space (e.g., disentanglement). With extensive experimentation on synthetic and public image datasets, we show that the proposed model learns the relevant latent bottleneck dimensionality without compromising the representation and generation quality of the samples.

Tushar Kataria, Shikha Dubey, Mary Bronner et al.

Deep learning models can generate virtual immunohistochemistry (IHC) stains from hematoxylin and eosin (H&E) images, offering a scalable and low-cost alternative to laboratory IHC. However, reliable evaluation of image quality remains a challenge as current texture- and distribution-based metrics quantify image fidelity rather than the accuracy of IHC staining. Here, we introduce an automated and accuracy grounded framework to determine image quality across sixteen paired or unpaired image translation models. Using color deconvolution, we generate masks of pixels stained brown (i.e., IHC-positive) as predicted by each virtual IHC model. We use the segmented masks of real and virtual IHC to compute stain accuracy metrics (Dice, IoU, Hausdorff distance) that directly quantify correct pixel - level labeling without needing expert manual annotations. Our results demonstrate that conventional image fidelity metrics, including Frechet Inception Distance (FID), peak signal-to-noise ratio (PSNR), and structural similarity (SSIM), correlate poorly with stain accuracy and pathologist assessment. Paired models such as PyramidPix2Pix and AdaptiveNCE achieve the highest stain accuracy, whereas unpaired diffusion- and GAN-based models are less reliable in providing accurate IHC positive pixel labels. Moreover, whole-slide images (WSI) reveal performance declines that are invisible in patch-based evaluations, emphasizing the need for WSI-level benchmarks. Together, this framework defines a reproducible approach for assessing the quality of virtual IHC models, a critical step to accelerate translation towards routine use by pathologists.

Asma Khan, Tushar Kataria, Janmesh Ukey et al.

Statistical Shape Models (SSMs) excel at identifying population level anatomical variations, which is at the core of various clinical and biomedical applications, including morphology-based diagnostics and surgical planning. However, the effectiveness of SSM is often constrained by the necessity for expert-driven manual segmentation, a process that is both time-intensive and expensive, thereby restricting their broader application and utility. Recent deep learning approaches enable the direct estimation of Statistical Shape Models (SSMs) from unsegmented images. While these models can predict SSMs without segmentation during deployment, they do not address the challenge of acquiring the manual annotations needed for training, particularly in resource-limited settings. Semi-supervised models for anatomy segmentation can mitigate the annotation burden. Yet, despite the abundance of available approaches, there are no established guidelines to inform end-users on their effectiveness for the downstream task of constructing SSMs. In this study, we systematically evaluate the potential of semi-supervised methods as viable alternatives to manual segmentations for building SSMs. We establish a new performance benchmark by employing various semi-supervised methods for anatomy segmentation under low annotation settings, utilizing the predicted segmentations for the task of SSM. Our results indicate that some methods produce noisy segmentation, which is very unfavorable for SSM tasks, while others can capture the correct modes of variations in the population cohort with 60-80% reduction in required manual annotation

Krithika Iyer, Shireen Y. Elhabian

The study of physiology demonstrates that the form (shape)of anatomical structures dictates their functions, and analyzing the form of anatomies plays a crucial role in clinical research. Statistical shape modeling (SSM) is a widely used tool for quantitative analysis of forms of anatomies, aiding in characterizing and identifying differences within a population of subjects. Despite its utility, the conventional SSM construction pipeline is often complex and time-consuming. Additionally, reliance on linearity assumptions further limits the model from capturing clinically relevant variations. Recent advancements in deep learning solutions enable the direct inference of SSM from unsegmented medical images, streamlining the process and improving accessibility. However, the new methods of SSM from images do not adequately account for situations where the imaging data quality is poor or where only sparse information is available. Moreover, quantifying aleatoric uncertainty, which represents inherent data variability, is crucial in deploying deep learning for clinical tasks to ensure reliable model predictions and robust decision-making, especially in challenging imaging conditions. Therefore, we propose SPI-CorrNet, a unified model that predicts 3D correspondences from sparse imaging data. It leverages a teacher network to regularize feature learning and quantifies data-dependent aleatoric uncertainty by adapting the network to predict intrinsic input variances. Experiments on the LGE MRI left atrium dataset and Abdomen CT-1K liver datasets demonstrate that our technique enhances the accuracy and robustness of sparse image-driven SSM.

Abu Zahid Bin Aziz, Mokshagna Sai Teja Karanam, Tushar Kataria et al.

Transformers have emerged as the state-of-the-art architecture in medical image registration, outperforming convolutional neural networks (CNNs) by addressing their limited receptive fields and overcoming gradient instability in deeper models. Despite their success, transformer-based models require substantial resources for training, including data, memory, and computational power, which may restrict their applicability for end users with limited resources. In particular, existing transformer-based 3D image registration architectures face two critical gaps that challenge their efficiency and effectiveness. Firstly, although window-based attention mechanisms reduce the quadratic complexity of full attention by focusing on local regions, they often struggle to effectively integrate both local and global information. Secondly, the granularity of tokenization, a crucial factor in registration accuracy, presents a performance trade-off: smaller voxel-size tokens enhance detail capture but come with increased computational complexity, higher memory usage, and a greater risk of overfitting. We present \name, a transformer-based architecture for unsupervised 3D image registration that balances local and global attention in 3D volumes through a plane-based attention mechanism and employs a Hi-Res tokenization strategy with merging operations, thus capturing finer details without compromising computational efficiency. Notably, \name sets a new benchmark for performance on the OASIS dataset with 16-27x fewer parameters. https://github.com/MedVIC-Lab/Efficient_Morph_Registration

Mokshagna Sai Teja Karanam, Krithika Iyer, Sarang Joshi et al.

Spatial transformations that capture population-level morphological statistics are critical for medical image analysis. Commonly used smoothness regularizers for image registration fail to integrate population statistics, leading to anatomically inconsistent transformations. Inverse consistency regularizers promote geometric consistency but lack population morphometrics integration. Regularizers that constrain deformation to low-dimensional manifold methods address this. However, they prioritize reconstruction over interpretability and neglect diffeomorphic properties, such as group composition and inverse consistency. We introduce MORPH-LER, a Log-Euclidean regularization framework for population-aware unsupervised image registration. MORPH-LER learns population morphometrics from spatial transformations to guide and regularize registration networks, ensuring anatomically plausible deformations. It features a bottleneck autoencoder that computes the principal logarithm of deformation fields via iterative square-root predictions. It creates a linearized latent space that respects diffeomorphic properties and enforces inverse consistency. By integrating a registration network with a diffeomorphic autoencoder, MORPH-LER produces smooth, meaningful deformation fields. The framework offers two main contributions: (1) a data-driven regularization strategy that incorporates population-level anatomical statistics to enhance transformation validity and (2) a linearized latent space that enables compact and interpretable deformation fields for efficient population morphometrics analysis. We validate MORPH-LER across two families of deep learning-based registration networks, demonstrating its ability to produce anatomically accurate, computationally efficient, and statistically meaningful transformations on the OASIS-1 brain imaging dataset. https://github.com/iyerkrithika21/MORPH_LER

Anupama Goparaju, Alexandre Bone, Nan Hu et al.

Statistical shape modeling (SSM) is widely used in biology and medicine as a new generation of morphometric approaches for the quantitative analysis of anatomical shapes. Technological advancements of in vivo imaging have led to the development of open-source computational tools that automate the modeling of anatomical shapes and their population-level variability. However, little work has been done on the evaluation and validation of such tools in clinical applications that rely on morphometric quantifications (e.g., implant design and lesion screening). Here, we systematically assess the outcome of widely used, state-of-the-art SSM tools, namely ShapeWorks, Deformetrica, and SPHARM-PDM. We use both quantitative and qualitative metrics to evaluate shape models from different tools. We propose validation frameworks for anatomical landmark/measurement inference and lesion screening. We also present a lesion screening method to objectively characterize subtle abnormal shape changes with respect to learned population-level statistics of controls. Results demonstrate that SSM tools display different levels of consistencies, where ShapeWorks and Deformetrica models are more consistent compared to models from SPHARM-PDM due to the groupwise approach of estimating surface correspondences. Furthermore, ShapeWorks and Deformetrica shape models are found to capture clinically relevant population-level variability compared to SPHARM-PDM models.

Riddhish Bhalodia, Shireen Elhabian, Ladislav Kavan et al.

Deep networks are an integral part of the current machine learning paradigm. Their inherent ability to learn complex functional mappings between data and various target variables, while discovering hidden, task-driven features, makes them a powerful technology in a wide variety of applications. Nonetheless, the success of these networks typically relies on the availability of sufficient training data to optimize a large number of free parameters while avoiding overfitting, especially for networks with large capacity. In scenarios with limited training budgets, e.g., supervised tasks with limited labeled samples, several generic and/or task-specific regularization techniques, including data augmentation, have been applied to improve the generalization of deep networks.Typically such regularizations are introduced independently of that data or training scenario, and must therefore be tuned, tested, and modified to meet the needs of a particular network. In this paper, we propose a novel regularization framework that is driven by the population-level statistics of the feature space to be learned. The regularization is in the form of a \textbf{cooperating subnetwork}, which is an auto-encoder architecture attached to the feature space and trained in conjunction with the primary network. We introduce the architecture and training methodology and demonstrate the effectiveness of the proposed cooperative network-based regularization in a variety of tasks and architectures from the literature. Our code is freely available at \url{https://github.com/riddhishb/CoopSubNet

Anupama Goparaju, Ibolya Csecs, Alan Morris et al.

Statistical shape modeling (SSM) has proven useful in many areas of biology and medicine as a new generation of morphometric approaches for the quantitative analysis of anatomical shapes. Recently, the increased availability of high-resolution in vivo images of anatomy has led to the development and distribution of open-source computational tools to model anatomical shapes and their variability within populations with unprecedented detail and statistical power. Nonetheless, there is little work on the evaluation and validation of such tools as related to clinical applications that rely on morphometric quantifications for treatment planning. To address this lack of validation, we systematically assess the outcome of widely used off-the-shelf SSM tools, namely ShapeWorks, SPHARM-PDM, and Deformetrica, in the context of designing closure devices for left atrium appendage (LAA) in atrial fibrillation (AF) patients to prevent stroke, where an incomplete LAA closure may be worse than no closure. This study is motivated by the potential role of SSM in the geometric design of closure devices, which could be informed by population-level statistics, and patient-specific device selection, which is driven by anatomical measurements that could be automated by relating patient-level anatomy to population-level morphometrics. Hence, understanding the consequences of different SSM tools for the final analysis is critical for the careful choice of the tool to be deployed in real clinical scenarios. Results demonstrate that estimated measurements from ShapeWorks model are more consistent compared to models from Deformetrica and SPHARM-PDM. Furthermore, ShapeWorks and Deformetrica shape models capture clinically relevant population-level variability compared to SPHARM-PDM models.

Tushar Kataria, Beatrice Knudsen, Shireen Y. Elhabian

Hematoxylin and Eosin (H&E) staining is widely regarded as the standard in pathology for diagnosing diseases and tracking tumor recurrence. While H&E staining shows tissue structures, it lacks the ability to reveal specific proteins that are associated with disease severity and treatment response. Immunohistochemical (IHC) stains use antibodies to highlight the expression of these proteins on their respective cell types, improving diagnostic accuracy, and assisting with drug selection for treatment. Despite their value, IHC stains require additional time and resources, limiting their utilization in some clinical settings. Recent advances in deep learning have positioned Image-to-Image (I2I) translation as a computational, cost-effective alternative for IHC. I2I generates high fidelity stain transformations digitally, potentially replacing manual staining in IHC. Diffusion models, the current state of the art in image generation and conditional tasks, are particularly well suited for virtual IHC due to their ability to produce high quality images and resilience to mode collapse. However, these models require extensive and diverse datasets (often millions of samples) to achieve a robust performance, a challenge in virtual staining applications where only thousands of samples are typically available. Inspired by the success of multitask deep learning models in scenarios with limited data, we introduce STAINDIFFUSER, a novel multitask diffusion architecture tailored to virtual staining that achieves convergence with smaller datasets. STAINDIFFUSER simultaneously trains two diffusion processes: (a) generating cell specific IHC stains from H&E images and (b) performing H&E based cell segmentation, utilizing coarse segmentation labels exclusively during training. STAINDIFFUSER generates high-quality virtual stains for two markers, outperforming over twenty I2I baselines.

Krithika Iyer, Jadie Adams, Shireen Y. Elhabian

Statistical shape modeling (SSM) is a powerful computational framework for quantifying and analyzing the geometric variability of anatomical structures, facilitating advancements in medical research, diagnostics, and treatment planning. Traditional methods for shape modeling from imaging data demand significant manual and computational resources. Additionally, these methods necessitate repeating the entire modeling pipeline to derive shape descriptors (e.g., surface-based point correspondences) for new data. While deep learning approaches have shown promise in streamlining the construction of SSMs on new data, they still rely on traditional techniques to supervise the training of the deep networks. Moreover, the predominant linearity assumption of traditional approaches restricts their efficacy, a limitation also inherited by deep learning models trained using optimized/established correspondences. Consequently, representing complex anatomies becomes challenging. To address these limitations, we introduce SCorP, a novel framework capable of predicting surface-based correspondences directly from unsegmented images. By leveraging the shape prior learned directly from surface meshes in an unsupervised manner, the proposed model eliminates the need for an optimized shape model for training supervision. The strong shape prior acts as a teacher and regularizes the feature learning of the student network to guide it in learning image-based features that are predictive of surface correspondences. The proposed model streamlines the training and inference phases by removing the supervision for the correspondence prediction task while alleviating the linearity assumption.

Jadie Adams, Krithika Iyer, Shireen Elhabian

Anatomical shape analysis plays a pivotal role in clinical research and hypothesis testing, where the relationship between form and function is paramount. Correspondence-based statistical shape modeling (SSM) facilitates population-level morphometrics but requires a cumbersome, potentially bias-inducing construction pipeline. Recent advancements in deep learning have streamlined this process in inference by providing SSM prediction directly from unsegmented medical images. However, the proposed approaches are fully supervised and require utilizing a traditional SSM construction pipeline to create training data, thus inheriting the associated burdens and limitations. To address these challenges, we introduce a weakly supervised deep learning approach to predict SSM from images using point cloud supervision. Specifically, we propose reducing the supervision associated with the state-of-the-art fully Bayesian variational information bottleneck DeepSSM (BVIB-DeepSSM) model. BVIB-DeepSSM is an effective, principled framework for predicting probabilistic anatomical shapes from images with quantification of both aleatoric and epistemic uncertainties. Whereas the original BVIB-DeepSSM method requires strong supervision in the form of ground truth correspondence points, the proposed approach utilizes weak supervision via point cloud surface representations, which are more readily obtainable. Furthermore, the proposed approach learns correspondence in a completely data-driven manner without prior assumptions about the expected variability in shape cohort. Our experiments demonstrate that this approach yields similar accuracy and uncertainty estimation to the fully supervised scenario while substantially enhancing the feasibility of model training for SSM construction.

Jadie Adams, Shireen Elhabian

Correspondence-based statistical shape modeling (SSM) stands as a powerful technology for morphometric analysis in clinical research. SSM facilitates population-level characterization and quantification of anatomical shapes such as bones and organs, aiding in pathology and disease diagnostics and treatment planning. Despite its potential, SSM remains under-utilized in medical research due to the significant overhead associated with automatic construction methods, which demand complete, aligned shape surface representations. Additionally, optimization-based techniques rely on bias-inducing assumptions or templates and have prolonged inference times as the entire cohort is simultaneously optimized. To overcome these challenges, we introduce Point2SSM++, a principled, self-supervised deep learning approach that directly learns correspondence points from point cloud representations of anatomical shapes. Point2SSM++ is robust to misaligned and inconsistent input, providing SSM that accurately samples individual shape surfaces while effectively capturing population-level statistics. Additionally, we present principled extensions of Point2SSM++ to adapt it for dynamic spatiotemporal and multi-anatomy use cases, demonstrating the broad versatility of the Point2SSM++ framework. Furthermore, we present extensions of Point2SSM++ tailored for dynamic spatiotemporal and multi-anatomy scenarios, showcasing the broad versatility of the framework. Through extensive validation across diverse anatomies, evaluation metrics, and clinically relevant downstream tasks, we demonstrate Point2SSM++'s superiority over existing state-of-the-art deep learning models and traditional approaches. Point2SSM++ substantially enhances the feasibility of SSM generation and significantly broadens its array of potential clinical applications.

Janmesh Ukey, Tushar Kataria, Shireen Y. Elhabian

Statistical Shape Modeling (SSM) effectively analyzes anatomical variations within populations but is limited by the need for manual localization and segmentation, which relies on scarce medical expertise. Recent advances in deep learning have provided a promising approach that automatically generates statistical representations (as point distribution models or PDMs) from unsegmented images. Once trained, these deep learning-based models eliminate the need for manual segmentation for new subjects. Most deep learning methods still require manual pre-alignment of image volumes and bounding box specification around the target anatomy, leading to a partially manual inference process. Recent approaches facilitate anatomy localization but only estimate population-level statistical representations and cannot directly delineate anatomy in images. Additionally, they are limited to modeling a single anatomy. We introduce MASSM, a novel end-to-end deep learning framework that simultaneously localizes multiple anatomies, estimates population-level statistical representations, and delineates shape representations directly in image space. Our results show that MASSM, which delineates anatomy in image space and handles multiple anatomies through a multitask network, provides superior shape information compared to segmentation networks for medical imaging tasks. Estimating Statistical Shape Models (SSM) is a stronger task than segmentation, as it encodes a more robust statistical prior for the objects to be detected and delineated. MASSM allows for more accurate and comprehensive shape representations, surpassing the capabilities of traditional pixel-wise segmentation.

Tushar Kataria, Beatrice Knudsen, Shireen Y. Elhabian

Hematoxylin and eosin (H&E) staining is a gold standard for microscopic diagnosis in pathology. However, H&E staining does not capture all the diagnostic information that may be needed. To obtain additional molecular information, immunohistochemical (IHC) stains highlight proteins that mark specific cell types, such as CD3 for T-cells or CK8/18 for epithelial cells. While IHC stains are vital for prognosis and treatment guidance, they are typically only available at specialized centers and time consuming to acquire, leading to treatment delays for patients. Virtual staining, enabled by deep learning-based image translation models, provides a promising alternative by computationally generating IHC stains from H&E stained images. Although many GAN and diffusion based image to image (I2I) translation methods have been used for virtual staining, these models treat image patches as independent data points, which results in increased and more diverse data requirements for effective generation. We present ImplicitStainer, a novel approach that leverages local implicit functions to improve image translation, specifically virtual staining performance, by focusing on pixel-level predictions. This method enhances robustness to variations in dataset sizes, delivering high-quality results even with limited data. We validate our approach on two datasets using a comprehensive set of metrics and benchmark it against over fifteen state-of-the-art GAN- and diffusion based models. Full Code and models trained will be released publicly via Github upon acceptance.

Krithika Iyer, Shireen Elhabian, Sarang Joshi

Image registration is a core task in computational anatomy that establishes correspondences between images. Invertible deformable registration, which computes a deformation field and handles complex, non-linear transformations, is essential for tracking anatomical variations, especially in neuroimaging applications where inter-subject differences and longitudinal changes are key. Analyzing the deformation fields is challenging due to their non-linearity, which limits statistical analysis. However, traditional approaches for analyzing deformation fields are computationally expensive, sensitive to initialization, and prone to numerical errors, especially when the deformation is far from the identity. To address these limitations, we propose the Log-Euclidean Diffeomorphism Autoencoder (LEDA), an innovative framework designed to compute the principal logarithm of deformation fields by efficiently predicting consecutive square roots. LEDA operates within a linearized latent space that adheres to the diffeomorphisms group action laws, enhancing our model's robustness and applicability. We also introduce a loss function to enforce inverse consistency, ensuring accurate latent representations of deformation fields. Extensive experiments with the OASIS-1 dataset demonstrate the effectiveness of LEDA in accurately modeling and analyzing complex non-linear deformations while maintaining inverse consistency. Additionally, we evaluate its ability to capture and incorporate clinical variables, enhancing its relevance for clinical applications.

Hong Xu, Shireen Y. Elhabian

Particle-based shape modeling (PSM) is a popular approach to automatically quantify shape variability in populations of anatomies. The PSM family of methods employs optimization to automatically populate a dense set of corresponding particles (as pseudo landmarks) on 3D surfaces to allow subsequent shape analysis. A recent deep learning approach leverages implicit radial basis function representations of shapes to better adapt to the underlying complex geometry of anatomies. Here, we propose an adaptation of this method using a traditional optimization approach that allows more precise control over the desired characteristics of models by leveraging both an eigenshape and a correspondence loss. Furthermore, the proposed approach avoids using a black-box model and allows more freedom for particles to navigate the underlying surfaces, yielding more informative statistical models. We demonstrate the efficacy of the proposed approach to state-of-the-art methods on two real datasets and justify our choice of losses empirically.

Rachaell Nihalaani, Tushar Kataria, Jadie Adams et al.

Supervised methods for 3D anatomy segmentation demonstrate superior performance but are often limited by the availability of annotated data. This limitation has led to a growing interest in self-supervised approaches in tandem with the abundance of available un-annotated data. Slice propagation has emerged as an self-supervised approach that leverages slice registration as a self-supervised task to achieve full anatomy segmentation with minimal supervision. This approach significantly reduces the need for domain expertise, time, and the cost associated with building fully annotated datasets required for training segmentation networks. However, this shift toward reduced supervision via deterministic networks raises concerns about the trustworthiness and reliability of predictions, especially when compared with more accurate supervised approaches. To address this concern, we propose the integration of calibrated uncertainty quantification (UQ) into slice propagation methods, providing insights into the model's predictive reliability and confidence levels. Incorporating uncertainty measures enhances user confidence in self-supervised approaches, thereby improving their practical applicability. We conducted experiments on three datasets for 3D abdominal segmentation using five UQ methods. The results illustrate that incorporating UQ improves not only model trustworthiness, but also segmentation accuracy. Furthermore, our analysis reveals various failure modes of slice propagation methods that might not be immediately apparent to end-users. This study opens up new research avenues to improve the accuracy and trustworthiness of slice propagation methods.

Hong Xu, Shireen Y. Elhabian

Particle-based shape modeling (PSM) is a family of approaches that automatically quantifies shape variability across anatomical cohorts by positioning particles (pseudo landmarks) on shape surfaces in a consistent configuration. Recent advances incorporate implicit radial basis function representations as self-supervised signals to better capture the complex geometric properties of anatomical structures. However, these methods still lack self-adaptivity -- that is, the ability to automatically adjust particle configurations to local geometric features of each surface, which is essential for accurately representing complex anatomical variability. This paper introduces two mechanisms to increase surface adaptivity while maintaining consistent particle configurations: (1) a novel neighborhood correspondence loss to enable high adaptivity and (2) a geodesic correspondence algorithm that regularizes optimization to enforce geodesic neighborhood consistency. We evaluate the efficacy and scalability of our approach on challenging datasets, providing a detailed analysis of the adaptivity-correspondence trade-off and benchmarking against existing methods on surface representation accuracy and correspondence metrics.

Tushar Kataria, Shireen Y. Elhabian

Obtaining large-scale medical data, annotated or unannotated, is challenging due to stringent privacy regulations and data protection policies. In addition, annotating medical images requires that domain experts manually delineate anatomical structures, making the process both time-consuming and costly. As a result, semi-supervised methods have gained popularity for reducing annotation costs. However, the performance of semi-supervised methods is heavily dependent on the availability of unannotated data, and their effectiveness declines when such data are scarce or absent. To overcome this limitation, we propose a simple, yet effective and computationally efficient approach for medical image segmentation that leverages only existing annotations. We propose BoundarySeg , a multi-task framework that incorporates organ boundary prediction as an auxiliary task to full organ segmentation, leveraging consistency between the two task predictions to provide additional supervision. This strategy improves segmentation accuracy, especially in low data regimes, allowing our method to achieve performance comparable to or exceeding state-of-the-art semi supervised approaches all without relying on unannotated data or increasing computational demands. Code will be released upon acceptance.

Krithika Iyer, Mokshagna Sai Teja Karanam, Shireen Elhabian

Anatomy evaluation is crucial for understanding the physiological state, diagnosing abnormalities, and guiding medical interventions. Statistical shape modeling (SSM) is vital in this process. By enabling the extraction of quantitative morphological shape descriptors from MRI and CT scans, SSM provides comprehensive descriptions of anatomical variations within a population. However, the effectiveness of SSM in anatomy evaluation hinges on the quality and robustness of the shape models. While deep learning techniques show promise in addressing these challenges by learning complex nonlinear representations of shapes, existing models still have limitations and often require pre-established shape models for training. To overcome these issues, we propose Mesh2SSM++, a novel approach that learns to estimate correspondences from meshes in an unsupervised manner. This method leverages unsupervised, permutation-invariant representation learning to estimate how to deform a template point cloud into subject-specific meshes, forming a correspondence-based shape model. Additionally, our probabilistic formulation allows learning a population-specific template, reducing potential biases associated with template selection. A key feature of Mesh2SSM++ is its ability to quantify aleatoric uncertainty, which captures inherent data variability and is essential for ensuring reliable model predictions and robust decision-making in clinical tasks, especially under challenging imaging conditions. Through extensive validation across diverse anatomies, evaluation metrics, and downstream tasks, we demonstrate that Mesh2SSM++ outperforms existing methods. Its ability to operate directly on meshes, combined with computational efficiency and interpretability through its probabilistic framework, makes it an attractive alternative to traditional and deep learning-based SSM approaches.

Hong Xu, Alan Morris, Shireen Y. Elhabian

Statistical Shape Modeling (SSM) is a quantitative method for analyzing morphological variations in anatomical structures. These analyses often necessitate building models on targeted anatomical regions of interest to focus on specific morphological features. We propose an extension to \particle-based shape modeling (PSM), a widely used SSM framework, to allow shape modeling to arbitrary regions of interest. Existing methods to define regions of interest are computationally expensive and have topological limitations. To address these shortcomings, we use mesh fields to define free-form constraints, which allow for delimiting arbitrary regions of interest on shape surfaces. Furthermore, we add a quadratic penalty method to the model optimization to enable computationally efficient enforcement of any combination of cutting-plane and free-form constraints. We demonstrate the effectiveness of this method on a challenging synthetic dataset and two medical datasets.

Jadie Adams, Shireen Elhabian

We present Point2SSM, a novel unsupervised learning approach for constructing correspondence-based statistical shape models (SSMs) directly from raw point clouds. SSM is crucial in clinical research, enabling population-level analysis of morphological variation in bones and organs. Traditional methods of SSM construction have limitations, including the requirement of noise-free surface meshes or binary volumes, reliance on assumptions or templates, and prolonged inference times due to simultaneous optimization of the entire cohort. Point2SSM overcomes these barriers by providing a data-driven solution that infers SSMs directly from raw point clouds, reducing inference burdens and increasing applicability as point clouds are more easily acquired. While deep learning on 3D point clouds has seen success in unsupervised representation learning and shape correspondence, its application to anatomical SSM construction is largely unexplored. We conduct a benchmark of state-of-the-art point cloud deep networks on the SSM task, revealing their limited robustness to clinical challenges such as noisy, sparse, or incomplete input and limited training data. Point2SSM addresses these issues through an attention-based module, providing effective correspondence mappings from learned point features. Our results demonstrate that the proposed method significantly outperforms existing networks in terms of accurate surface sampling and correspondence, better capturing population-level statistics.

Hong Xu, Shireen Y. Elhabian

Statistical shape modeling (SSM) is an essential tool for analyzing variations in anatomical morphology. In a typical SSM pipeline, 3D anatomical images, gone through segmentation and rigid registration, are represented using lower-dimensional shape features, on which statistical analysis can be performed. Various methods for constructing compact shape representations have been proposed, but they involve laborious and costly steps. We propose Image2SSM, a novel deep-learning-based approach for SSM that leverages image-segmentation pairs to learn a radial-basis-function (RBF)-based representation of shapes directly from images. This RBF-based shape representation offers a rich self-supervised signal for the network to estimate a continuous, yet compact representation of the underlying surface that can adapt to complex geometries in a data-driven manner. Image2SSM can characterize populations of biological structures of interest by constructing statistical landmark-based shape models of ensembles of anatomical shapes while requiring minimal parameter tuning and no user assistance. Once trained, Image2SSM can be used to infer low-dimensional shape representations from new unsegmented images, paving the way toward scalable approaches for SSM, especially when dealing with large cohorts. Experiments on synthetic and real datasets show the efficacy of the proposed method compared to the state-of-art correspondence-based method for SSM.

Krithika Iyer, Shireen Elhabian

Statistical shape modeling is the computational process of discovering significant shape parameters from segmented anatomies captured by medical images (such as MRI and CT scans), which can fully describe subject-specific anatomy in the context of a population. The presence of substantial non-linear variability in human anatomy often makes the traditional shape modeling process challenging. Deep learning techniques can learn complex non-linear representations of shapes and generate statistical shape models that are more faithful to the underlying population-level variability. However, existing deep learning models still have limitations and require established/optimized shape models for training. We propose Mesh2SSM, a new approach that leverages unsupervised, permutation-invariant representation learning to estimate how to deform a template point cloud to subject-specific meshes, forming a correspondence-based shape model. Mesh2SSM can also learn a population-specific template, reducing any bias due to template selection. The proposed method operates directly on meshes and is computationally efficient, making it an attractive alternative to traditional and deep learning-based SSM approaches.

Jadie Adams, Shireen Elhabian

Statistical shape modeling (SSM) enables population-based quantitative analysis of anatomical shapes, informing clinical diagnosis. Deep learning approaches predict correspondence-based SSM directly from unsegmented 3D images but require calibrated uncertainty quantification, motivating Bayesian formulations. Variational information bottleneck DeepSSM (VIB-DeepSSM) is an effective, principled framework for predicting probabilistic shapes of anatomy from images with aleatoric uncertainty quantification. However, VIB is only half-Bayesian and lacks epistemic uncertainty inference. We derive a fully Bayesian VIB formulation and demonstrate the efficacy of two scalable implementation approaches: concrete dropout and batch ensemble. Additionally, we introduce a novel combination of the two that further enhances uncertainty calibration via multimodal marginalization. Experiments on synthetic shapes and left atrium data demonstrate that the fully Bayesian VIB network predicts SSM from images with improved uncertainty reasoning without sacrificing accuracy.

Tushar Kataria, Beatrice Knudsen, Shireen Elhabian

Semantic segmentation is a critical step in automated image interpretation and analysis where pixels are classified into one or more predefined semantically meaningful classes. Deep learning approaches for semantic segmentation rely on harnessing the power of annotated images to learn features indicative of these semantic classes. Nonetheless, they often fail to generalize when there is a significant domain (i.e., distributional) shift between the training (i.e., source) data and the dataset(s) encountered when deployed (i.e., target), necessitating manual annotations for the target data to achieve acceptable performance. This is especially important in medical imaging because different image modalities have significant intra- and inter-site variations due to protocol and vendor variability. Current techniques are sensitive to hyperparameter tuning and target dataset size. This paper presents an unsupervised domain adaptation approach for semantic segmentation that alleviates the need for annotating target data. Using kernel density estimation, we match the target data distribution to the source in the feature space, particularly when the number of target samples is limited (3% of the target dataset size). We demonstrate the efficacy of our proposed approach on 2 datasets, multisite prostate MRI and histopathology images.

Jadie Adams, Shireen Elhabian

Statistical Shape Modeling (SSM) is a valuable tool for investigating and quantifying anatomical variations within populations of anatomies. However, traditional correspondence-based SSM generation methods have a prohibitive inference process and require complete geometric proxies (e.g., high-resolution binary volumes or surface meshes) as input shapes to construct the SSM. Unordered 3D point cloud representations of shapes are more easily acquired from various medical imaging practices (e.g., thresholded images and surface scanning). Point cloud deep networks have recently achieved remarkable success in learning permutation-invariant features for different point cloud tasks (e.g., completion, semantic segmentation, classification). However, their application to learning SSM from point clouds is to-date unexplored. In this work, we demonstrate that existing point cloud encoder-decoder-based completion networks can provide an untapped potential for SSM, capturing population-level statistical representations of shapes while reducing the inference burden and relaxing the input requirement. We discuss the limitations of these techniques to the SSM application and suggest future improvements. Our work paves the way for further exploration of point cloud deep learning for SSM, a promising avenue for advancing shape analysis literature and broadening SSM to diverse use cases.

Wenzheng Tao, Riddhish Bhalodia, Shireen Elhabian

Statistical shape modeling is an essential tool for the quantitative analysis of anatomical populations. Point distribution models (PDMs) represent the anatomical surface via a dense set of correspondences, an intuitive and easy-to-use shape representation for subsequent applications. These correspondences are exhibited in two coordinate spaces: the local coordinates describing the geometrical features of each individual anatomical surface and the world coordinates representing the population-level statistical shape information after removing global alignment differences across samples in the given cohort. We propose a deep-learning-based framework that simultaneously learns these two coordinate spaces directly from the volumetric images. The proposed joint model serves a dual purpose; the world correspondences can directly be used for shape analysis applications, circumventing the heavy pre-processing and segmentation involved in traditional PDM models. Additionally, the local correspondences can be used for anatomy segmentation. We demonstrate the efficacy of this joint model for both shape modeling applications on two datasets and its utility in inferring the anatomical surface.

Riddhish Bhalodia, Shireen Elhabian, Ladislav Kavan et al.

In current biological and medical research, statistical shape modeling (SSM) provides an essential framework for the characterization of anatomy/morphology. Such analysis is often driven by the identification of a relatively small number of geometrically consistent features found across the samples of a population. These features can subsequently provide information about the population shape variation. Dense correspondence models can provide ease of computation and yield an interpretable low-dimensional shape descriptor when followed by dimensionality reduction. However, automatic methods for obtaining such correspondences usually require image segmentation followed by significant preprocessing, which is taxing in terms of both computation as well as human resources. In many cases, the segmentation and subsequent processing require manual guidance and anatomy specific domain expertise. This paper proposes a self-supervised deep learning approach for discovering landmarks from images that can directly be used as a shape descriptor for subsequent analysis. We use landmark-driven image registration as the primary task to force the neural network to discover landmarks that register the images well. We also propose a regularization term that allows for robust optimization of the neural network and ensures that the landmarks uniformly span the image domain. The proposed method circumvents segmentation and preprocessing and directly produces a usable shape descriptor using just 2D or 3D images. In addition, we also propose two variants on the training loss function that allows for prior shape information to be integrated into the model. We apply this framework on several 2D and 3D datasets to obtain their shape descriptors, and analyze their utility for various applications.

Riddhish Bhalodia, Shireen Elhabian, Jadie Adams et al.

Statistical shape modeling (SSM) characterizes anatomical variations in a population of shapes generated from medical images. SSM requires consistent shape representation across samples in shape cohort. Establishing this representation entails a processing pipeline that includes anatomy segmentation, re-sampling, registration, and non-linear optimization. These shape representations are then used to extract low-dimensional shape descriptors that facilitate subsequent analyses in different applications. However, the current process of obtaining these shape descriptors from imaging data relies on human and computational resources, requiring domain expertise for segmenting anatomies of interest. Moreover, this same taxing pipeline needs to be repeated to infer shape descriptors for new image data using a pre-trained/existing shape model. Here, we propose DeepSSM, a deep learning-based framework for learning the functional mapping from images to low-dimensional shape descriptors and their associated shape representations, thereby inferring statistical representation of anatomy directly from 3D images. Once trained using an existing shape model, DeepSSM circumvents the heavy and manual pre-processing and segmentation and significantly improves the computational time, making it a viable solution for fully end-to-end SSM applications. In addition, we introduce a model-based data-augmentation strategy to address data scarcity. Finally, this paper presents and analyzes two different architectural variants of DeepSSM with different loss functions using three medical datasets and their downstream clinical application. Experiments showcase that DeepSSM performs comparably or better to the state-of-the-art SSM both quantitatively and on application-driven downstream tasks. Therefore, DeepSSM aims to provide a comprehensive blueprint for deep learning-based image-to-shape models.

Praful Agrawal, Ross T. Whitaker, Shireen Y. Elhabian

Correspondence-based shape models are key to various medical imaging applications that rely on a statistical analysis of anatomies. Such shape models are expected to represent consistent anatomical features across the population for population-specific shape statistics. Early approaches for correspondence placement rely on nearest neighbor search for simpler anatomies. Coordinate transformations for shape correspondence hold promise to address the increasing anatomical complexities. Nonetheless, due to the inherent shape-level geometric complexity and population-level shape variation, the coordinate-wise correspondence often does not translate to the anatomical correspondence. An alternative, group-wise approach for correspondence placement explicitly models the trade-off between geometric description and the population's statistical compactness. However, these models achieve limited success in resolving nonlinear shape correspondence. Recent works have addressed this limitation by adopting an application-specific notion of correspondence through lifting positional data to a higher dimensional feature space. However, they heavily rely on manual expertise to create domain-specific features and consistent landmarks. This paper proposes an automated feature learning approach, using deep convolutional neural networks to extract correspondence-friendly features from shape ensembles. Further, an unsupervised domain adaptation scheme is introduced to augment the pretrained geometric features with new anatomies. Results on anatomical datasets of human scapula, femur, and pelvis bones demonstrate that features learned in supervised fashion show improved performance for correspondence estimation compared to the manual features. Further, unsupervised learning is demonstrated to learn complex anatomy features using the supervised domain adaptation from features learned on simpler anatomy.

Surojit Saha, Shireen Elhabian, Ross T. Whitaker

Mapping data from and/or onto a known family of distributions has become an important topic in machine learning and data analysis. Deep generative models (e.g., generative adversarial networks ) have been used effectively to match known and unknown distributions. Nonetheless, when the form of the target distribution is known, analytical methods are advantageous in providing robust results with provable properties. In this paper, we propose and analyze the use of nonparametric density methods to estimate the Jensen-Shannon divergence for matching unknown data distributions to known target distributions, such Gaussian or mixtures of Gaussians, in latent spaces. This analytical method has several advantages: better behavior when training sample quantity is low, provable convergence properties, and relatively few parameters, which can be derived analytically. Using the proposed method, we enforce the latent representation of an autoencoder to match a target distribution in a learning framework that we call a {\em generative encoding network}. Here, we present the numerical methods; derive the expected distribution of the data in the latent space; evaluate the properties of the latent space, sample reconstruction, and generated samples; show the advantages over the adversarial counterpart; and demonstrate the application of the method in real world.

Jadie Adams, Riddhish Bhalodia, Shireen Elhabian

Statistical shape modeling (SSM) has recently taken advantage of advances in deep learning to alleviate the need for a time-consuming and expert-driven workflow of anatomy segmentation, shape registration, and the optimization of population-level shape representations. DeepSSM is an end-to-end deep learning approach that extracts statistical shape representation directly from unsegmented images with little manual overhead. It performs comparably with state-of-the-art shape modeling methods for estimating morphologies that are viable for subsequent downstream tasks. Nonetheless, DeepSSM produces an overconfident estimate of shape that cannot be blindly assumed to be accurate. Hence, conveying what DeepSSM does not know, via quantifying granular estimates of uncertainty, is critical for its direct clinical application as an on-demand diagnostic tool to determine how trustworthy the model output is. Here, we propose Uncertain-DeepSSM as a unified model that quantifies both, data-dependent aleatoric uncertainty by adapting the network to predict intrinsic input variance, and model-dependent epistemic uncertainty via a Monte Carlo dropout sampling to approximate a variational distribution over the network parameters. Experiments show an accuracy improvement over DeepSSM while maintaining the same benefits of being end-to-end with little pre-processing.

Hong Xu, David E. Timm, Shireen Y. Elhabian

Cryogenic electron microscopy (cryo-EM) has become an enabling technology in drug discovery and in understanding molecular bases of disease by producing near-atomic resolution (less than 0.4 nm) 3D reconstructions of biological macromolecules. The imaging process required for 3D reconstructions involves a highly iterative and empirical screening process, starting with the acquisition of low magnification images of the cryo-EM grids. These images are inspected for squares that are likely to contain useful molecular signals. Potentially useful squares within the grid are then imaged at progressively higher magnifications, with the goal of identifying sub-micron areas within circular holes (bounded by the squares) for imaging at high magnification. This arduous, multi-step data acquisition process represents a bottleneck for obtaining a high throughput data collection. Here, we focus on automating the early decision making for the microscope operator, scoring low magnification images of squares, and proposing the first deep learning framework, XCryoNet, for automated cryo-EM grid screening. XCryoNet is a semi-supervised, attention-guided deep learning approach that provides explainable scoring of automatically extracted square images using limited amounts of labeled data. Results show up to 8% and 37% improvements over a fully supervised and a no-attention solution, respectively, when labeled data is scarce.

Riddhish Bhalodia, Iain Lee, Shireen Elhabian

Unsupervised representation learning via generative modeling is a staple to many computer vision applications in the absence of labeled data. Variational Autoencoders (VAEs) are powerful generative models that learn representations useful for data generation. However, due to inherent challenges in the training objective, VAEs fail to learn useful representations amenable for downstream tasks. Regularization-based methods that attempt to improve the representation learning aspect of VAEs come at a price: poor sample generation. In this paper, we explore this representation-generation trade-off for regularized VAEs and introduce a new family of priors, namely decoupled priors, or dpVAEs, that decouple the representation space from the generation space. This decoupling enables the use of VAE regularizers on the representation space without impacting the distribution used for sample generation, and thereby reaping the representation learning benefits of the regularizations without sacrificing the sample generation. dpVAE leverages invertible networks to learn a bijective mapping from an arbitrarily complex representation distribution to a simple, tractable, generative distribution. Decoupled priors can be adapted to the state-of-the-art VAE regularizers without additional hyperparameter tuning. We showcase the use of dpVAEs with different regularizers. Experiments on MNIST, SVHN, and CelebA demonstrate, quantitatively and qualitatively, that dpVAE fixes sample generation for regularized VAEs.

Riddhish Bhalodia, Shireen Y. Elhabian, Ladislav Kavan et al.

Spatial transformations are enablers in a variety of medical image analysis applications that entail aligning images to a common coordinate systems. Population analysis of such transformations is expected to capture the underlying image and shape variations, and hence these transformations are required to produce anatomically feasible correspondences. This is usually enforced through some smoothness-based generic regularization on deformation field. Alternatively, population-based regularization has been shown to produce anatomically accurate correspondences in cases where anatomically unaware (i.e., data independent) fail. Recently, deep networks have been for unsupervised image registration, these methods are computationally faster and maintains the accuracy of state of the art methods. However, these networks use smoothness penalty on deformation fields and ignores population-level statistics of the transformations. We propose a novel neural network architecture that simultaneously learns and uses the population-level statistics of the spatial transformations to regularize the neural networks for unsupervised image registration. This regularization is in the form of a bottleneck autoencoder, which encodes the population level information of the deformation fields in a low-dimensional manifold. The proposed architecture produces deformation fields that describe the population-level features and associated correspondences in an anatomically relevant manner and are statistically compact relative to the state-of-the-art approaches while maintaining computational efficiency. We demonstrate the efficacy of the proposed architecture on synthetic data sets, as well as 2D and 3D medical data.

Alessandro Ferrero, Shireen Elhabian, Ross Whitaker

Generative adversarial networks (GANs) have proven effective in modeling distributions of high-dimensional data. However, their training instability is a well-known hindrance to convergence, which results in practical challenges in their applications to novel data. Furthermore, even when convergence is reached, GANs can be affected by mode collapse, a phenomenon for which the generator learns to model only a small part of the target distribution, disregarding the vast majority of the data manifold or distribution. This paper addresses these challenges by introducing SetGAN, an adversarial architecture that processes sets of generated and real samples, and discriminates between the origins of these sets (i.e., training versus generated data) in a flexible, permutation invariant manner. We also propose a new metric to quantitatively evaluate GANs that does not require previous knowledge of the application, apart from the data itself. Using the new metric, in conjunction with the state-of-the-art evaluation methods, we show that the proposed architecture, when compared with GAN variants stemming from similar strategies, produces more accurate models of the input data in a way that is also less sensitive to hyperparameter settings.