Shunxing Bao

Ho Hin Lee, Shunxing Bao, Yuankai Huo et al.

The recent 3D medical ViTs (e.g., SwinUNETR) achieve the state-of-the-art performances on several 3D volumetric data benchmarks, including 3D medical image segmentation. Hierarchical transformers (e.g., Swin Transformers) reintroduced several ConvNet priors and further enhanced the practical viability of adapting volumetric segmentation in 3D medical datasets. The effectiveness of hybrid approaches is largely credited to the large receptive field for non-local self-attention and the large number of model parameters. In this work, we propose a lightweight volumetric ConvNet, termed 3D UX-Net, which adapts the hierarchical transformer using ConvNet modules for robust volumetric segmentation. Specifically, we revisit volumetric depth-wise convolutions with large kernel size (e.g. starting from $7\times7\times7$) to enable the larger global receptive fields, inspired by Swin Transformer. We further substitute the multi-layer perceptron (MLP) in Swin Transformer blocks with pointwise depth convolutions and enhance model performances with fewer normalization and activation layers, thus reducing the number of model parameters. 3D UX-Net competes favorably with current SOTA transformers (e.g. SwinUNETR) using three challenging public datasets on volumetric brain and abdominal imaging: 1) MICCAI Challenge 2021 FLARE, 2) MICCAI Challenge 2021 FeTA, and 3) MICCAI Challenge 2022 AMOS. 3D UX-Net consistently outperforms SwinUNETR with improvement from 0.929 to 0.938 Dice (FLARE2021) and 0.867 to 0.874 Dice (Feta2021). We further evaluate the transfer learning capability of 3D UX-Net with AMOS2022 and demonstrates another improvement of $2.27\%$ Dice (from 0.880 to 0.900). The source code with our proposed model are available at https://github.com/MASILab/3DUX-Net.

Xin Yu, Qi Yang, Yucheng Tang et al.

2D low-dose single-slice abdominal computed tomography (CT) slice enables direct measurements of body composition, which are critical to quantitatively characterizing health relationships on aging. However, longitudinal analysis of body composition changes using 2D abdominal slices is challenging due to positional variance between longitudinal slices acquired in different years. To reduce the positional variance, we extend the conditional generative models to our C-SliceGen that takes an arbitrary axial slice in the abdominal region as the condition and generates a defined vertebral level slice by estimating the structural changes in the latent space. Experiments on 1170 subjects from an in-house dataset and 50 subjects from BTCV MICCAI Challenge 2015 show that our model can generate high quality images in terms of realism and similarity. External experiments on 20 subjects from the Baltimore Longitudinal Study of Aging (BLSA) dataset that contains longitudinal single abdominal slices validate that our method can harmonize the slice positional variance in terms of muscle and visceral fat area. Our approach provides a promising direction of mapping slices from different vertebral levels to a target slice to reduce positional variance for single slice longitudinal analysis. The source code is available at: https://github.com/MASILab/C-SliceGen.

Ruining Deng, Can Cui, Lucas W. Remedios et al.

Multi-instance learning (MIL) is widely used in the computer-aided interpretation of pathological Whole Slide Images (WSIs) to solve the lack of pixel-wise or patch-wise annotations. Often, this approach directly applies "natural image driven" MIL algorithms which overlook the multi-scale (i.e. pyramidal) nature of WSIs. Off-the-shelf MIL algorithms are typically deployed on a single-scale of WSIs (e.g., 20x magnification), while human pathologists usually aggregate the global and local patterns in a multi-scale manner (e.g., by zooming in and out between different magnifications). In this study, we propose a novel cross-scale attention mechanism to explicitly aggregate inter-scale interactions into a single MIL network for Crohn's Disease (CD), which is a form of inflammatory bowel disease. The contribution of this paper is two-fold: (1) a cross-scale attention mechanism is proposed to aggregate features from different resolutions with multi-scale interaction; and (2) differential multi-scale attention visualizations are generated to localize explainable lesion patterns. By training ~250,000 H&E-stained Ascending Colon (AC) patches from 20 CD patient and 30 healthy control samples at different scales, our approach achieved a superior Area under the Curve (AUC) score of 0.8924 compared with baseline models. The official implementation is publicly available at https://github.com/hrlblab/CS-MIL.

Qi Yang, Xin Yu, Ho Hin Lee et al.

Objective: Thigh muscle group segmentation is important for assessment of muscle anatomy, metabolic disease and aging. Many efforts have been put into quantifying muscle tissues with magnetic resonance (MR) imaging including manual annotation of individual muscles. However, leveraging publicly available annotations in MR images to achieve muscle group segmentation on single slice computed tomography (CT) thigh images is challenging. Method: We propose an unsupervised domain adaptation pipeline with self-training to transfer labels from 3D MR to single CT slice. First, we transform the image appearance from MR to CT with CycleGAN and feed the synthesized CT images to a segmenter simultaneously. Single CT slices are divided into hard and easy cohorts based on the entropy of pseudo labels inferenced by the segmenter. After refining easy cohort pseudo labels based on anatomical assumption, self-training with easy and hard splits is applied to fine tune the segmenter. Results: On 152 withheld single CT thigh images, the proposed pipeline achieved a mean Dice of 0.888(0.041) across all muscle groups including sartorius, hamstrings, quadriceps femoris and gracilis. muscles Conclusion: To our best knowledge, this is the first pipeline to achieve thigh imaging domain adaptation from MR to CT. The proposed pipeline is effective and robust in extracting muscle groups on 2D single slice CT thigh images.The container is available for public use at https://github.com/MASILab/DA_CT_muscle_seg

Shunxing Bao, Sichen Zhu, Vasantha L Kolachala et al.

Crohn's disease (CD) is a chronic and relapsing inflammatory condition that affects segments of the gastrointestinal tract. CD activity is determined by histological findings, particularly the density of neutrophils observed on Hematoxylin and Eosin stains (H&E) imaging. However, understanding the broader morphometry and local cell arrangement beyond cell counting and tissue morphology remains challenging. To address this, we characterize six distinct cell types from H&E images and develop a novel approach for the local spatial signature of each cell. Specifically, we create a 10-cell neighborhood matrix, representing neighboring cell arrangements for each individual cell. Utilizing t-SNE for non-linear spatial projection in scatter-plot and Kernel Density Estimation contour-plot formats, our study examines patterns of differences in the cellular environment associated with the odds ratio of spatial patterns between active CD and control groups. This analysis is based on data collected at the two research institutes. The findings reveal heterogeneous nearest-neighbor patterns, signifying distinct tendencies of cell clustering, with a particular focus on the rectum region. These variations underscore the impact of data heterogeneity on cell spatial arrangements in CD patients. Moreover, the spatial distribution disparities between the two research sites highlight the significance of collaborative efforts among healthcare organizations. All research analysis pipeline tools are available at https://github.com/MASILab/cellNN.

Ruining Deng, Can Cui, Quan Liu et al.

The segment anything model (SAM) was released as a foundation model for image segmentation. The promptable segmentation model was trained by over 1 billion masks on 11M licensed and privacy-respecting images. The model supports zero-shot image segmentation with various segmentation prompts (e.g., points, boxes, masks). It makes the SAM attractive for medical image analysis, especially for digital pathology where the training data are rare. In this study, we evaluate the zero-shot segmentation performance of SAM model on representative segmentation tasks on whole slide imaging (WSI), including (1) tumor segmentation, (2) non-tumor tissue segmentation, (3) cell nuclei segmentation. Core Results: The results suggest that the zero-shot SAM model achieves remarkable segmentation performance for large connected objects. However, it does not consistently achieve satisfying performance for dense instance object segmentation, even with 20 prompts (clicks/boxes) on each image. We also summarized the identified limitations for digital pathology: (1) image resolution, (2) multiple scales, (3) prompt selection, and (4) model fine-tuning. In the future, the few-shot fine-tuning with images from downstream pathological segmentation tasks might help the model to achieve better performance in dense object segmentation.

Tianyuan Yao, Chang Qu, Jun Long et al.

With the rapid development of self-supervised learning (e.g., contrastive learning), the importance of having large-scale images (even without annotations) for training a more generalizable AI model has been widely recognized in medical image analysis. However, collecting large-scale task-specific unannotated data at scale can be challenging for individual labs. Existing online resources, such as digital books, publications, and search engines, provide a new resource for obtaining large-scale images. However, published images in healthcare (e.g., radiology and pathology) consist of a considerable amount of compound figures with subplots. In order to extract and separate compound figures into usable individual images for downstream learning, we propose a simple compound figure separation (SimCFS) framework without using the traditionally required detection bounding box annotations, with a new loss function and a hard case simulation. Our technical contribution is four-fold: (1) we introduce a simulation-based training framework that minimizes the need for resource extensive bounding box annotations; (2) we propose a new side loss that is optimized for compound figure separation; (3) we propose an intra-class image augmentation method to simulate hard cases; and (4) to the best of our knowledge, this is the first study that evaluates the efficacy of leveraging self-supervised learning with compound image separation. From the results, the proposed SimCFS achieved state-of-the-art performance on the ImageCLEF 2016 Compound Figure Separation Database. The pretrained self-supervised learning model using large-scale mined figures improved the accuracy of downstream image classification tasks with a contrastive learning algorithm. The source code of SimCFS is made publicly available at https://github.com/hrlblab/ImageSeperation.

Ruining Deng, Can Cui, Lucas W. Remedios et al.

Analyzing high resolution whole slide images (WSIs) with regard to information across multiple scales poses a significant challenge in digital pathology. Multi-instance learning (MIL) is a common solution for working with high resolution images by classifying bags of objects (i.e. sets of smaller image patches). However, such processing is typically performed at a single scale (e.g., 20x magnification) of WSIs, disregarding the vital inter-scale information that is key to diagnoses by human pathologists. In this study, we propose a novel cross-scale MIL algorithm to explicitly aggregate inter-scale relationships into a single MIL network for pathological image diagnosis. The contribution of this paper is three-fold: (1) A novel cross-scale MIL (CS-MIL) algorithm that integrates the multi-scale information and the inter-scale relationships is proposed; (2) A toy dataset with scale-specific morphological features is created and released to examine and visualize differential cross-scale attention; (3) Superior performance on both in-house and public datasets is demonstrated by our simple cross-scale MIL strategy. The official implementation is publicly available at https://github.com/hrlblab/CS-MIL.

Xin Yu, Yucheng Tang, Qi Yang et al.

Whole brain segmentation with magnetic resonance imaging (MRI) enables the non-invasive measurement of brain regions, including total intracranial volume (TICV) and posterior fossa volume (PFV). Enhancing the existing whole brain segmentation methodology to incorporate intracranial measurements offers a heightened level of comprehensiveness in the analysis of brain structures. Despite its potential, the task of generalizing deep learning techniques for intracranial measurements faces data availability constraints due to limited manually annotated atlases encompassing whole brain and TICV/PFV labels. In this paper, we enhancing the hierarchical transformer UNesT for whole brain segmentation to achieve segmenting whole brain with 133 classes and TICV/PFV simultaneously. To address the problem of data scarcity, the model is first pretrained on 4859 T1-weighted (T1w) 3D volumes sourced from 8 different sites. These volumes are processed through a multi-atlas segmentation pipeline for label generation, while TICV/PFV labels are unavailable. Subsequently, the model is finetuned with 45 T1w 3D volumes from Open Access Series Imaging Studies (OASIS) where both 133 whole brain classes and TICV/PFV labels are available. We evaluate our method with Dice similarity coefficients(DSC). We show that our model is able to conduct precise TICV/PFV estimation while maintaining the 132 brain regions performance at a comparable level. Code and trained model are available at: https://github.com/MASILab/UNesT/tree/main/wholebrainSeg.

Xin Yu, Qi Yang, Yucheng Tang et al.

Two-dimensional single-slice abdominal computed tomography (CT) provides a detailed tissue map with high resolution allowing quantitative characterization of relationships between health conditions and aging. However, longitudinal analysis of body composition changes using these scans is difficult due to positional variation between slices acquired in different years, which leading to different organs/tissues captured. To address this issue, we propose C-SliceGen, which takes an arbitrary axial slice in the abdominal region as a condition and generates a pre-defined vertebral level slice by estimating structural changes in the latent space. Our experiments on 2608 volumetric CT data from two in-house datasets and 50 subjects from the 2015 Multi-Atlas Abdomen Labeling Challenge dataset (BTCV) Challenge demonstrate that our model can generate high-quality images that are realistic and similar. We further evaluate our method's capability to harmonize longitudinal positional variation on 1033 subjects from the Baltimore Longitudinal Study of Aging (BLSA) dataset, which contains longitudinal single abdominal slices, and confirmed that our method can harmonize the slice positional variance in terms of visceral fat area. This approach provides a promising direction for mapping slices from different vertebral levels to a target slice and reducing positional variance for single-slice longitudinal analysis. The source code is available at: https://github.com/MASILab/C-SliceGen.

Ho Hin Lee, Yucheng Tang, Riqiang Gao et al.

Non-contrast computed tomography (NCCT) is commonly acquired for lung cancer screening, assessment of general abdominal pain or suspected renal stones, trauma evaluation, and many other indications. However, the absence of contrast limits distinguishing organ in-between boundaries. In this paper, we propose a novel unsupervised approach that leverages pairwise contrast-enhanced CT (CECT) context to compute non-contrast segmentation without ground-truth label. Unlike generative adversarial approaches, we compute the pairwise morphological context with CECT to provide teacher guidance instead of generating fake anatomical context. Additionally, we further augment the intensity correlations in 'organ-specific' settings and increase the sensitivity to organ-aware boundary. We validate our approach on multi-organ segmentation with paired non-contrast & contrast-enhanced CT scans using five-fold cross-validation. Full external validations are performed on an independent non-contrast cohort for aorta segmentation. Compared with current abdominal organs segmentation state-of-the-art in fully supervised setting, our proposed pipeline achieves a significantly higher Dice by 3.98% (internal multi-organ annotated), and 8.00% (external aorta annotated) for abdominal organs segmentation. The code and pretrained models are publicly available at https://github.com/MASILab/ContrastMix.

Yanfan Zhu, Yash Singh, Khaled Younis et al.

Topological data analysis (TDA) uncovers crucial properties of objects in medical imaging. Methods based on persistent homology have demonstrated their advantages in capturing topological features that traditional deep learning methods cannot detect in both radiology and pathology. However, previous research primarily focused on 2D image analysis, neglecting the comprehensive 3D context. In this paper, we propose an innovative 3D TDA approach that incorporates the concept of superpixels to transform 3D medical image features into point cloud data. By Utilizing Optimized Gaussian Coefficient, the proposed 3D TDA method, for the first time, efficiently generate holistic Persistence Images for 3D volumetric data. Our 3D TDA method exhibits superior performance on the MedMNist3D dataset when compared to other traditional methods, showcasing its potential effectiveness in modeling 3D persistent homology-based topological analysis when it comes to classification tasks. The source code is publicly available at https://github.com/hrlblab/TopologicalDataAnalysis3D.

Ho Hin Lee, Yucheng Tang, Han Liu et al.

Recent studies have demonstrated the superior performance of introducing ``scan-wise" contrast labels into contrastive learning for multi-organ segmentation on multi-phase computed tomography (CT). However, such scan-wise labels are limited: (1) a coarse classification, which could not capture the fine-grained ``organ-wise" contrast variations across all organs; (2) the label (i.e., contrast phase) is typically manually provided, which is error-prone and may introduce manual biases of defining phases. In this paper, we propose a novel data-driven contrastive loss function that adapts the similar/dissimilar contrast relationship between samples in each minibatch at organ-level. Specifically, as variable levels of contrast exist between organs, we hypothesis that the contrast differences in the organ-level can bring additional context for defining representations in the latent space. An organ-wise contrast correlation matrix is computed with mean organ intensities under one-hot attention maps. The goal of adapting the organ-driven correlation matrix is to model variable levels of feature separability at different phases. We evaluate our proposed approach on multi-organ segmentation with both non-contrast CT (NCCT) datasets and the MICCAI 2015 BTCV Challenge contrast-enhance CT (CECT) datasets. Compared to the state-of-the-art approaches, our proposed contrastive loss yields a substantial and significant improvement of 1.41% (from 0.923 to 0.936, p-value$<$0.01) and 2.02% (from 0.891 to 0.910, p-value$<$0.01) on mean Dice scores across all organs with respect to NCCT and CECT cohorts. We further assess the trained model performance with the MICCAI 2021 FLARE Challenge CECT datasets and achieve a substantial improvement of mean Dice score from 0.927 to 0.934 (p-value$<$0.01). The code is available at: https://github.com/MASILab/DCC_CL

Haoju Leng, Ruining Deng, Shunxing Bao et al.

When dealing with giga-pixel digital pathology in whole-slide imaging, a notable proportion of data records holds relevance during each analysis operation. For instance, when deploying an image analysis algorithm on whole-slide images (WSI), the computational bottleneck often lies in the input-output (I/O) system. This is particularly notable as patch-level processing introduces a considerable I/O load onto the computer system. However, this data management process could be further paralleled, given the typical independence of patch-level image processes across different patches. This paper details our endeavors in tackling this data access challenge by implementing the Adaptable IO System version 2 (ADIOS2). Our focus has been constructing and releasing a digital pathology-centric pipeline using ADIOS2, which facilitates streamlined data management across WSIs. Additionally, we've developed strategies aimed at curtailing data retrieval times. The performance evaluation encompasses two key scenarios: (1) a pure CPU-based image analysis scenario ("CPU scenario"), and (2) a GPU-based deep learning framework scenario ("GPU scenario"). Our findings reveal noteworthy outcomes. Under the CPU scenario, ADIOS2 showcases an impressive two-fold speed-up compared to the brute-force approach. In the GPU scenario, its performance stands on par with the cutting-edge GPU I/O acceleration framework, NVIDIA Magnum IO GPU Direct Storage (GDS). From what we know, this appears to be among the initial instances, if any, of utilizing ADIOS2 within the field of digital pathology. The source code has been made publicly available at https://github.com/hrlblab/adios.

Xin Yu, Yucheng Tang, Qi Yang et al.

Metabolic health is increasingly implicated as a risk factor across conditions from cardiology to neurology, and efficiency assessment of body composition is critical to quantitatively characterizing these relationships. 2D low dose single slice computed tomography (CT) provides a high resolution, quantitative tissue map, albeit with a limited field of view. Although numerous potential analyses have been proposed in quantifying image context, there has been no comprehensive study for low-dose single slice CT longitudinal variability with automated segmentation. We studied a total of 1816 slices from 1469 subjects of Baltimore Longitudinal Study on Aging (BLSA) abdominal dataset using supervised deep learning-based segmentation and unsupervised clustering method. 300 out of 1469 subjects that have two year gap in their first two scans were pick out to evaluate longitudinal variability with measurements including intraclass correlation coefficient (ICC) and coefficient of variation (CV) in terms of tissues/organs size and mean intensity. We showed that our segmentation methods are stable in longitudinal settings with Dice ranged from 0.821 to 0.962 for thirteen target abdominal tissues structures. We observed high variability in most organ with ICC<0.5, low variability in the area of muscle, abdominal wall, fat and body mask with average ICC>0.8. We found that the variability in organ is highly related to the cross-sectional position of the 2D slice. Our efforts pave quantitative exploration and quality control to reduce uncertainties in longitudinal analysis.

Can Cui, Ruining Deng, Quan Liu et al.

The Segment Anything Model (SAM) is a recently proposed prompt-based segmentation model in a generic zero-shot segmentation approach. With the zero-shot segmentation capacity, SAM achieved impressive flexibility and precision on various segmentation tasks. However, the current pipeline requires manual prompts during the inference stage, which is still resource intensive for biomedical image segmentation. In this paper, instead of using prompts during the inference stage, we introduce a pipeline that utilizes the SAM, called all-in-SAM, through the entire AI development workflow (from annotation generation to model finetuning) without requiring manual prompts during the inference stage. Specifically, SAM is first employed to generate pixel-level annotations from weak prompts (e.g., points, bounding box). Then, the pixel-level annotations are used to finetune the SAM segmentation model rather than training from scratch. Our experimental results reveal two key findings: 1) the proposed pipeline surpasses the state-of-the-art (SOTA) methods in a nuclei segmentation task on the public Monuseg dataset, and 2) the utilization of weak and few annotations for SAM finetuning achieves competitive performance compared to using strong pixel-wise annotated data.

Ho Hin Lee, Quan Liu, Shunxing Bao et al.

With the inspiration of vision transformers, the concept of depth-wise convolution revisits to provide a large Effective Receptive Field (ERF) using Large Kernel (LK) sizes for medical image segmentation. However, the segmentation performance might be saturated and even degraded as the kernel sizes scaled up (e.g., $21\times 21\times 21$) in a Convolutional Neural Network (CNN). We hypothesize that convolution with LK sizes is limited to maintain an optimal convergence for locality learning. While Structural Re-parameterization (SR) enhances the local convergence with small kernels in parallel, optimal small kernel branches may hinder the computational efficiency for training. In this work, we propose RepUX-Net, a pure CNN architecture with a simple large kernel block design, which competes favorably with current network state-of-the-art (SOTA) (e.g., 3D UX-Net, SwinUNETR) using 6 challenging public datasets. We derive an equivalency between kernel re-parameterization and the branch-wise variation in kernel convergence. Inspired by the spatial frequency in the human visual system, we extend to vary the kernel convergence into element-wise setting and model the spatial frequency as a Bayesian prior to re-parameterize convolutional weights during training. Specifically, a reciprocal function is leveraged to estimate a frequency-weighted value, which rescales the corresponding kernel element for stochastic gradient descent. From the experimental results, RepUX-Net consistently outperforms 3D SOTA benchmarks with internal validation (FLARE: 0.929 to 0.944), external validation (MSD: 0.901 to 0.932, KiTS: 0.815 to 0.847, LiTS: 0.933 to 0.949, TCIA: 0.736 to 0.779) and transfer learning (AMOS: 0.880 to 0.911) scenarios in Dice Score.

Xin Yu, Yucheng Tang, Yinchi Zhou et al.

Efficiently quantifying renal structures can provide distinct spatial context and facilitate biomarker discovery for kidney morphology. However, the development and evaluation of the transformer model to segment the renal cortex, medulla, and collecting system remains challenging due to data inefficiency. Inspired by the hierarchical structures in vision transformer, we propose a novel method using a 3D block aggregation transformer for segmenting kidney components on contrast-enhanced CT scans. We construct the first cohort of renal substructures segmentation dataset with 116 subjects under institutional review board (IRB) approval. Our method yields the state-of-the-art performance (Dice of 0.8467) against the baseline approach of 0.8308 with the data-efficient design. The Pearson R achieves 0.9891 between the proposed method and manual standards and indicates the strong correlation and reproducibility for volumetric analysis. We extend the proposed method to the public KiTS dataset, the method leads to improved accuracy compared to transformer-based approaches. We show that the 3D block aggregation transformer can achieve local communication between sequence representations without modifying self-attention, and it can serve as an accurate and efficient quantification tool for characterizing renal structures.

Can Cui, Yaohong Wang, Shunxing Bao et al.

Many anomaly detection approaches, especially deep learning methods, have been recently developed to identify abnormal image morphology by only employing normal images during training. Unfortunately, many prior anomaly detection methods were optimized for a specific "known" abnormality (e.g., brain tumor, bone fraction, cell types). Moreover, even though only the normal images were used in the training process, the abnormal images were often employed during the validation process (e.g., epoch selection, hyper-parameter tuning), which might leak the supposed ``unknown" abnormality unintentionally. In this study, we investigated these two essential aspects regarding universal anomaly detection in medical images by (1) comparing various anomaly detection methods across four medical datasets, (2) investigating the inevitable but often neglected issues on how to unbiasedly select the optimal anomaly detection model during the validation phase using only normal images, and (3) proposing a simple decision-level ensemble method to leverage the advantage of different kinds of anomaly detection without knowing the abnormality. The results of our experiments indicate that none of the evaluated methods consistently achieved the best performance across all datasets. Our proposed method enhanced the robustness of performance in general (average AUC 0.956).

Muhao Liu, Chenyang Qi, Shunxing Bao et al.

The segmentation of kidney layer structures, including cortex, outer stripe, inner stripe, and inner medulla within human kidney whole slide images (WSI) plays an essential role in automated image analysis in renal pathology. However, the current manual segmentation process proves labor-intensive and infeasible for handling the extensive digital pathology images encountered at a large scale. In response, the realm of digital renal pathology has seen the emergence of deep learning-based methodologies. However, very few, if any, deep learning based approaches have been applied to kidney layer structure segmentation. Addressing this gap, this paper assesses the feasibility of performing deep learning based approaches on kidney layer structure segmetnation. This study employs the representative convolutional neural network (CNN) and Transformer segmentation approaches, including Swin-Unet, Medical-Transformer, TransUNet, U-Net, PSPNet, and DeepLabv3+. We quantitatively evaluated six prevalent deep learning models on renal cortex layer segmentation using mice kidney WSIs. The empirical results stemming from our approach exhibit compelling advancements, as evidenced by a decent Mean Intersection over Union (mIoU) index. The results demonstrate that Transformer models generally outperform CNN-based models. By enabling a quantitative evaluation of renal cortical structures, deep learning approaches are promising to empower these medical professionals to make more informed kidney layer segmentation.

Xueyuan Li, Ruining Deng, Yucheng Tang et al.

Precise identification of multiple cell classes in high-resolution Giga-pixel whole slide imaging (WSI) is critical for various clinical scenarios. Building an AI model for this purpose typically requires pixel-level annotations, which are often unscalable and must be done by skilled domain experts (e.g., pathologists). However, these annotations can be prone to errors, especially when distinguishing between intricate cell types (e.g., podocytes and mesangial cells) using only visual inspection. Interestingly, a recent study showed that lay annotators, when using extra immunofluorescence (IF) images for reference (referred to as molecular-empowered learning), can sometimes outperform domain experts in labeling. Despite this, the resource-intensive task of manual delineation remains a necessity during the annotation process. In this paper, we explore the potential of bypassing pixel-level delineation by employing the recent segment anything model (SAM) on weak box annotation in a zero-shot learning approach. Specifically, we harness SAM's ability to produce pixel-level annotations from box annotations and utilize these SAM-generated labels to train a segmentation model. Our findings show that the proposed SAM-assisted molecular-empowered learning (SAM-L) can diminish the labeling efforts for lay annotators by only requiring weak box annotations. This is achieved without compromising annotation accuracy or the performance of the deep learning-based segmentation. This research represents a significant advancement in democratizing the annotation process for training pathological image segmentation, relying solely on non-expert annotators.

Franklin Hu, Ruining Deng, Shunxing Bao et al.

Segmentation of microvascular structures, such as arterioles, venules, and capillaries, from human kidney whole slide images (WSI) has become a focal point in renal pathology. Current manual segmentation techniques are time-consuming and not feasible for large-scale digital pathology images. While deep learning-based methods offer a solution for automatic segmentation, most suffer from a limitation: they are designed for and restricted to training on single-site, single-scale data. In this paper, we present Omni-Seg, a novel single dynamic network method that capitalizes on multi-site, multi-scale training data. Unique to our approach, we utilize partially labeled images, where only one tissue type is labeled per training image, to segment microvascular structures. We train a singular deep network using images from two datasets, HuBMAP and NEPTUNE, across different magnifications (40x, 20x, 10x, and 5x). Experimental results indicate that Omni-Seg outperforms in terms of both the Dice Similarity Coefficient (DSC) and Intersection over Union (IoU). Our proposed method provides renal pathologists with a powerful computational tool for the quantitative analysis of renal microvascular structures.

Ho Hin Lee, Quan Liu, Qi Yang et al.

The application of 3D ViTs to medical image segmentation has seen remarkable strides, somewhat overshadowing the budding advancements in Convolutional Neural Network (CNN)-based models. Large kernel depthwise convolution has emerged as a promising technique, showcasing capabilities akin to hierarchical transformers and facilitating an expansive effective receptive field (ERF) vital for dense predictions. Despite this, existing core operators, ranging from global-local attention to large kernel convolution, exhibit inherent trade-offs and limitations (e.g., global-local range trade-off, aggregating attentional features). We hypothesize that deformable convolution can be an exploratory alternative to combine all advantages from the previous operators, providing long-range dependency, adaptive spatial aggregation and computational efficiency as a foundation backbone. In this work, we introduce 3D DeformUX-Net, a pioneering volumetric CNN model that adeptly navigates the shortcomings traditionally associated with ViTs and large kernel convolution. Specifically, we revisit volumetric deformable convolution in depth-wise setting to adapt long-range dependency with computational efficiency. Inspired by the concepts of structural re-parameterization for convolution kernel weights, we further generate the deformable tri-planar offsets by adapting a parallel branch (starting from $1\times1\times1$ convolution), providing adaptive spatial aggregation across all channels. Our empirical evaluations reveal that the 3D DeformUX-Net consistently outperforms existing state-of-the-art ViTs and large kernel convolution models across four challenging public datasets, spanning various scales from organs (KiTS: 0.680 to 0.720, MSD Pancreas: 0.676 to 0.717, AMOS: 0.871 to 0.902) to vessels (e.g., MSD hepatic vessels: 0.635 to 0.671) in mean Dice.

Aravind R. Krishnan, Kaiwen Xu, Thomas Li et al.

The reconstruction kernel in computed tomography (CT) generation determines the texture of the image. Consistency in reconstruction kernels is important as the underlying CT texture can impact measurements during quantitative image analysis. Harmonization (i.e., kernel conversion) minimizes differences in measurements due to inconsistent reconstruction kernels. Existing methods investigate harmonization of CT scans in single or multiple manufacturers. However, these methods require paired scans of hard and soft reconstruction kernels that are spatially and anatomically aligned. Additionally, a large number of models need to be trained across different kernel pairs within manufacturers. In this study, we adopt an unpaired image translation approach to investigate harmonization between and across reconstruction kernels from different manufacturers by constructing a multipath cycle generative adversarial network (GAN). We use hard and soft reconstruction kernels from the Siemens and GE vendors from the National Lung Screening Trial dataset. We use 50 scans from each reconstruction kernel and train a multipath cycle GAN. To evaluate the effect of harmonization on the reconstruction kernels, we harmonize 50 scans each from Siemens hard kernel, GE soft kernel and GE hard kernel to a reference Siemens soft kernel (B30f) and evaluate percent emphysema. We fit a linear model by considering the age, smoking status, sex and vendor and perform an analysis of variance (ANOVA) on the emphysema scores. Our approach minimizes differences in emphysema measurement and highlights the impact of age, sex, smoking status and vendor on emphysema quantification.

Yinchi Zhou, Ho Hin Lee, Yucheng Tang et al.

With the substantial diversity in population demographics, such as differences in age and body composition, the volumetric morphology of pancreas varies greatly, resulting in distinctive variations in shape and appearance. Such variations increase the difficulty at generalizing population-wide pancreas features. A volumetric spatial reference is needed to adapt the morphological variability for organ-specific analysis. Here, we proposed a high-resolution computed tomography (CT) atlas framework specifically optimized for the pancreas organ across multi-contrast CT. We introduce a deep learning-based pre-processing technique to extract the abdominal region of interests (ROIs) and leverage a hierarchical registration pipeline to align the pancreas anatomy across populations. Briefly, DEEDs affine and non-rigid registration are performed to transfer patient abdominal volumes to a fixed high-resolution atlas template. To generate and evaluate the pancreas atlas template, multi-contrast modality CT scans of 443 subjects (without reported history of pancreatic disease, age: 15-50 years old) are processed. Comparing with different registration state-of-the-art tools, the combination of DEEDs affine and non-rigid registration achieves the best performance for the pancreas label transfer across all contrast phases. We further perform external evaluation with another research cohort of 100 de-identified portal venous scans with 13 organs labeled, having the best label transfer performance of 0.504 Dice score in unsupervised setting. The qualitative representation (e.g., average mapping) of each phase creates a clear boundary of pancreas and its distinctive contrast appearance. The deformation surface renderings across scales (e.g., small to large volume) further illustrate the generalizability of the proposed atlas template.

Zhiyuan Li, Chenyu Gao, Praitayini Kanakaraj et al.

An incomplete field-of-view (FOV) in diffusion magnetic resonance imaging (dMRI) can severely hinder the volumetric and bundle analyses of whole-brain white matter connectivity. Although existing works have investigated imputing the missing regions using deep generative models, it remains unclear how to specifically utilize additional information from paired multi-modality data and whether this can enhance the imputation quality and be useful for downstream tractography. To fill this gap, we propose a novel framework for imputing dMRI scans in the incomplete part of the FOV by integrating the learned diffusion features in the acquired part of the FOV to the complete brain anatomical structure. We hypothesize that by this design the proposed framework can enhance the imputation performance of the dMRI scans and therefore be useful for repairing whole-brain tractography in corrupted dMRI scans with incomplete FOV. We tested our framework on two cohorts from different sites with a total of 96 subjects and compared it with a baseline imputation method that treats the information from T1w and dMRI scans equally. The proposed framework achieved significant improvements in imputation performance, as demonstrated by angular correlation coefficient (p < 1E-5), and in downstream tractography accuracy, as demonstrated by Dice score (p < 0.01). Results suggest that the proposed framework improved imputation performance in dMRI scans by specifically utilizing additional information from paired multi-modality data, compared with the baseline method. The imputation achieved by the proposed framework enhances whole brain tractography, and therefore reduces the uncertainty when analyzing bundles associated with neurodegenerative.

Lucas W. Remedios, Han Liu, Samuel W. Remedios et al.

Multimodal fusion promises better pancreas segmentation. However, where to perform fusion in models is still an open question. It is unclear if there is a best location to fuse information when analyzing pairs of imperfectly aligned images. Two main alignment challenges in this pancreas segmentation study are 1) the pancreas is deformable and 2) breathing deforms the abdomen. Even after image registration, relevant deformations are often not corrected. We examine how early through late fusion impacts pancreas segmentation. We used 353 pairs of T2-weighted (T2w) and T1-weighted (T1w) abdominal MR images from 163 subjects with accompanying pancreas labels. We used image registration (deeds) to align the image pairs. We trained a collection of basic UNets with different fusion points, spanning from early to late, to assess how early through late fusion influenced segmentation performance on imperfectly aligned images. We assessed generalization of fusion points on nnUNet. The single-modality T2w baseline using a basic UNet model had a Dice score of 0.73, while the same baseline on the nnUNet model achieved 0.80. For the basic UNet, the best fusion approach occurred in the middle of the encoder (early/mid fusion), which led to a statistically significant improvement of 0.0125 on Dice score compared to the baseline. For the nnUNet, the best fusion approach was naïve image concatenation before the model (early fusion), which resulted in a statistically significant Dice score increase of 0.0021 compared to baseline. Fusion in specific blocks can improve performance, but the best blocks for fusion are model specific, and the gains are small. In imperfectly registered datasets, fusion is a nuanced problem, with the art of design remaining vital for uncovering potential insights. Future innovation is needed to better address fusion in cases of imperfect alignment of abdominal image pairs.

Lucas W. Remedios, Leon Y. Cai, Samuel W. Remedios et al.

Deep learning has made great strides in medical imaging, enabled by hardware advances in GPUs. One major constraint for the development of new models has been the saturation of GPU memory resources during training. This is especially true in computational pathology, where images regularly contain more than 1 billion pixels. These pathological images are traditionally divided into small patches to enable deep learning due to hardware limitations. In this work, we explore whether the shared GPU/CPU memory architecture on the M1 Ultra systems-on-a-chip (SoCs) recently released by Apple, Inc. may provide a solution. These affordable systems (less than \$5000) provide access to 128 GB of unified memory (Mac Studio with M1 Ultra SoC). As a proof of concept for gigapixel deep learning, we identified tissue from background on gigapixel areas from whole slide images (WSIs). The model was a modified U-Net (4492 parameters) leveraging large kernels and high stride. The M1 Ultra SoC was able to train the model directly on gigapixel images (16000$\times$64000 pixels, 1.024 billion pixels) with a batch size of 1 using over 100 GB of unified memory for the process at an average speed of 1 minute and 21 seconds per batch with Tensorflow 2/Keras. As expected, the model converged with a high Dice score of 0.989 $\pm$ 0.005. Training up until this point took 111 hours and 24 minutes over 4940 steps. Other high RAM GPUs like the NVIDIA A100 (largest commercially accessible at 80 GB, $\sim$\$15000) are not yet widely available (in preview for select regions on Amazon Web Services at \$40.96/hour as a group of 8). This study is a promising step towards WSI-wise end-to-end deep learning with prevalent network architectures.

Xin Yu, Qi Yang, Yinchi Zhou et al.

Transformer-based models, capable of learning better global dependencies, have recently demonstrated exceptional representation learning capabilities in computer vision and medical image analysis. Transformer reformats the image into separate patches and realizes global communication via the self-attention mechanism. However, positional information between patches is hard to preserve in such 1D sequences, and loss of it can lead to sub-optimal performance when dealing with large amounts of heterogeneous tissues of various sizes in 3D medical image segmentation. Additionally, current methods are not robust and efficient for heavy-duty medical segmentation tasks such as predicting a large number of tissue classes or modeling globally inter-connected tissue structures. To address such challenges and inspired by the nested hierarchical structures in vision transformer, we proposed a novel 3D medical image segmentation method (UNesT), employing a simplified and faster-converging transformer encoder design that achieves local communication among spatially adjacent patch sequences by aggregating them hierarchically. We extensively validate our method on multiple challenging datasets, consisting of multiple modalities, anatomies, and a wide range of tissue classes, including 133 structures in the brain, 14 organs in the abdomen, 4 hierarchical components in the kidneys, inter-connected kidney tumors and brain tumors. We show that UNesT consistently achieves state-of-the-art performance and evaluate its generalizability and data efficiency. Particularly, the model achieves whole brain segmentation task complete ROI with 133 tissue classes in a single network, outperforming prior state-of-the-art method SLANT27 ensembled with 27 networks.

Ho Hin Lee, Quan Liu, Shunxing Bao et al.

In contrast to vision transformers, which model long-range dependencies through global self-attention, large kernel convolutions provide a more efficient and scalable alternative, particularly in high-resolution 3D volumetric settings. However, naively increasing kernel size often leads to optimization instability and degradation in performance. Motivated by the spatial bias observed in effective receptive fields (ERFs), we hypothesize that different kernel elements converge at variable rates during training. To support this, we derive a theoretical connection between element-wise gradients and first-order optimization, showing that structurally re-parameterized convolution blocks inherently induce spatially varying learning rates. Building on this insight, we introduce Rep3D, a 3D convolutional framework that incorporates a learnable spatial prior into large kernel training. A lightweight two-stage modulation network generates a receptive-biased scaling mask, adaptively re-weighting kernel updates and enabling local-to-global convergence behavior. Rep3D adopts a plain encoder design with large depthwise convolutions, avoiding the architectural complexity of multi-branch compositions. We evaluate Rep3D on five challenging 3D segmentation benchmarks and demonstrate consistent improvements over state-of-the-art baselines, including transformer-based and fixed-prior re-parameterization methods. By unifying spatial inductive bias with optimization-aware learning, Rep3D offers an interpretable, and scalable solution for 3D medical image analysis. The source code is publicly available at https://github.com/leeh43/Rep3D.

Ruining Deng, Quan Liu, Can Cui et al.

Panoramic image segmentation in computational pathology presents a remarkable challenge due to the morphologically complex and variably scaled anatomy. For instance, the intricate organization in kidney pathology spans multiple layers, from regions like the cortex and medulla to functional units such as glomeruli, tubules, and vessels, down to various cell types. In this paper, we propose a novel Hierarchical Adaptive Taxonomy Segmentation (HATs) method, which is designed to thoroughly segment panoramic views of kidney structures by leveraging detailed anatomical insights. Our approach entails (1) the innovative HATs technique which translates spatial relationships among 15 distinct object classes into a versatile "plug-and-play" loss function that spans across regions, functional units, and cells, (2) the incorporation of anatomical hierarchies and scale considerations into a unified simple matrix representation for all panoramic entities, (3) the adoption of the latest AI foundation model (EfficientSAM) as a feature extraction tool to boost the model's adaptability, yet eliminating the need for manual prompt generation in conventional segment anything model (SAM). Experimental findings demonstrate that the HATs method offers an efficient and effective strategy for integrating clinical insights and imaging precedents into a unified segmentation model across more than 15 categories. The official implementation is publicly available at https://github.com/hrlblab/HATs.

Tianyuan Yao, Chang Qu, Quan Liu et al.

Unsupervised learning algorithms (e.g., self-supervised learning, auto-encoder, contrastive learning) allow deep learning models to learn effective image representations from large-scale unlabeled data. In medical image analysis, even unannotated data can be difficult to obtain for individual labs. Fortunately, national-level efforts have been made to provide efficient access to obtain biomedical image data from previous scientific publications. For instance, NIH has launched the Open-i search engine that provides a large-scale image database with free access. However, the images in scientific publications consist of a considerable amount of compound figures with subplots. To extract and curate individual subplots, many different compound figure separation approaches have been developed, especially with the recent advances in deep learning. However, previous approaches typically required resource extensive bounding box annotation to train detection models. In this paper, we propose a simple compound figure separation (SimCFS) framework that uses weak classification annotations from individual images. Our technical contribution is three-fold: (1) we introduce a new side loss that is designed for compound figure separation; (2) we introduce an intra-class image augmentation method to simulate hard cases; (3) the proposed framework enables an efficient deployment to new classes of images, without requiring resource extensive bounding box annotations. From the results, the SimCFS achieved a new state-of-the-art performance on the ImageCLEF 2016 Compound Figure Separation Database. The source code of SimCFS is made publicly available at https://github.com/hrlblab/ImageSeperation.

Ruining Deng, Quan Liu, Shunxing Bao et al.

Weakly supervised learning has been rapidly advanced in biomedical image analysis to achieve pixel-wise labels (segmentation) from image-wise annotations (classification), as biomedical images naturally contain image-wise labels in many scenarios. The current weakly supervised learning algorithms from the computer vision community are largely designed for focal objects (e.g., dogs and cats). However, such algorithms are not optimized for diffuse patterns in biomedical imaging (e.g., stains and fluorescence in microscopy imaging). In this paper, we propose a novel class-aware codebook learning (CaCL) algorithm to perform weakly supervised learning for diffuse image patterns. Specifically, the CaCL algorithm is deployed to segment protein expressed brush border regions from histological images of human duodenum. Our contribution is three-fold: (1) we approach the weakly supervised segmentation from a novel codebook learning perspective; (2) the CaCL algorithm segments diffuse image patterns rather than focal objects; and (3) the proposed algorithm is implemented in a multi-task framework based on Vector Quantised-Variational AutoEncoder (VQ-VAE) via joint image reconstruction, classification, feature embedding, and segmentation. The experimental results show that our method achieved superior performance compared with baseline weakly supervised algorithms. The code is available at https://github.com/ddrrnn123/CaCL.

Yuankai Huo, Zhoubing Xu, Yunxi Xiong et al.

Detailed whole brain segmentation is an essential quantitative technique, which provides a non-invasive way of measuring brain regions from a structural magnetic resonance imaging (MRI). Recently, deep convolution neural network (CNN) has been applied to whole brain segmentation. However, restricted by current GPU memory, 2D based methods, downsampling based 3D CNN methods, and patch-based high-resolution 3D CNN methods have been the de facto standard solutions. 3D patch-based high resolution methods typically yield superior performance among CNN approaches on detailed whole brain segmentation (>100 labels), however, whose performance are still commonly inferior compared with multi-atlas segmentation methods (MAS) due to the following challenges: (1) a single network is typically used to learn both spatial and contextual information for the patches, (2) limited manually traced whole brain volumes are available (typically less than 50) for training a network. In this work, we propose the spatially localized atlas network tiles (SLANT) method to distribute multiple independent 3D fully convolutional networks (FCN) for high-resolution whole brain segmentation. To address the first challenge, multiple spatially distributed networks were used in the SLANT method, in which each network learned contextual information for a fixed spatial location. To address the second challenge, auxiliary labels on 5111 initially unlabeled scans were created by multi-atlas segmentation for training. Since the method integrated multiple traditional medical image processing methods with deep learning, we developed a containerized pipeline to deploy the end-to-end solution. From the results, the proposed method achieved superior performance compared with multi-atlas segmentation methods, while reducing the computational time from >30 hours to 15 minutes (https://github.com/MASILab/SLANTbrainSeg).

Yuankai Huo, Zhoubing Xu, Hyeonsoo Moon et al.

A key limitation of deep convolutional neural networks (DCNN) based image segmentation methods is the lack of generalizability. Manually traced training images are typically required when segmenting organs in a new imaging modality or from distinct disease cohort. The manual efforts can be alleviated if the manually traced images in one imaging modality (e.g., MRI) are able to train a segmentation network for another imaging modality (e.g., CT). In this paper, we propose an end-to-end synthetic segmentation network (SynSeg-Net) to train a segmentation network for a target imaging modality without having manual labels. SynSeg-Net is trained by using (1) unpaired intensity images from source and target modalities, and (2) manual labels only from source modality. SynSeg-Net is enabled by the recent advances of cycle generative adversarial networks (CycleGAN) and DCNN. We evaluate the performance of the SynSeg-Net on two experiments: (1) MRI to CT splenomegaly synthetic segmentation for abdominal images, and (2) CT to MRI total intracranial volume synthetic segmentation (TICV) for brain images. The proposed end-to-end approach achieved superior performance to two stage methods. Moreover, the SynSeg-Net achieved comparable performance to the traditional segmentation network using target modality labels in certain scenarios. The source code of SynSeg-Net is publicly available (https://github.com/MASILab/SynSeg-Net).

Yuankai Huo, Zhoubing Xu, Katherine Aboud et al.

Whole brain segmentation on a structural magnetic resonance imaging (MRI) is essential in non-invasive investigation for neuroanatomy. Historically, multi-atlas segmentation (MAS) has been regarded as the de facto standard method for whole brain segmentation. Recently, deep neural network approaches have been applied to whole brain segmentation by learning random patches or 2D slices. Yet, few previous efforts have been made on detailed whole brain segmentation using 3D networks due to the following challenges: (1) fitting entire whole brain volume into 3D networks is restricted by the current GPU memory, and (2) the large number of targeting labels (e.g., > 100 labels) with limited number of training 3D volumes (e.g., < 50 scans). In this paper, we propose the spatially localized atlas network tiles (SLANT) method to distribute multiple independent 3D fully convolutional networks to cover overlapped sub-spaces in a standard atlas space. This strategy simplifies the whole brain learning task to localized sub-tasks, which was enabled by combing canonical registration and label fusion techniques with deep learning. To address the second challenge, auxiliary labels on 5111 initially unlabeled scans were created by MAS for pre-training. From empirical validation, the state-of-the-art MAS method achieved mean Dice value of 0.76, 0.71, and 0.68, while the proposed method achieved 0.78, 0.73, and 0.71 on three validation cohorts. Moreover, the computational time reduced from > 30 hours using MAS to ~15 minutes using the proposed method. The source code is available online https://github.com/MASILab/SLANTbrainSeg

Chenyu Gao, Michael E. Kim, Karthik Ramadass et al.

Estimated brain age from magnetic resonance image (MRI) and its deviation from chronological age can provide early insights into potential neurodegenerative diseases, supporting early detection and implementation of prevention strategies. Diffusion MRI (dMRI) presents an opportunity to build an earlier biomarker for neurodegenerative disease prediction because it captures subtle microstructural changes that precede more perceptible macrostructural changes. However, the coexistence of macro- and micro-structural information in dMRI raises the question of whether current dMRI-based brain age estimation models are leveraging the intended microstructural information or if they inadvertently rely on the macrostructural information. To develop a microstructure-specific brain age, we propose a method for brain age identification from dMRI that mitigates the model's use of macrostructural information by non-rigidly registering all images to a standard template. Imaging data from 13,398 participants across 12 datasets were used for the training and evaluation. We compare our brain age models, trained with and without macrostructural information mitigated, with an architecturally similar T1-weighted (T1w) MRI-based brain age model and two recent, popular, openly available T1w MRI-based brain age models that primarily use macrostructural information. We observe difference between our dMRI-based brain age and T1w MRI-based brain age across stages of neurodegeneration, with dMRI-based brain age being older than T1w MRI-based brain age in participants transitioning from cognitively normal (CN) to mild cognitive impairment (MCI), but younger in participants already diagnosed with Alzheimer's disease (AD). Furthermore, dMRI-based brain age may offer advantages over T1w MRI-based brain age in predicting the transition from CN to MCI up to five years before diagnosis.

Lucas W. Remedios, Shunxing Bao, Samuel W. Remedios et al.

Understanding the way cells communicate, co-locate, and interrelate is essential to understanding human physiology. Hematoxylin and eosin (H&E) staining is ubiquitously available both for clinical studies and research. The Colon Nucleus Identification and Classification (CoNIC) Challenge has recently innovated on robust artificial intelligence labeling of six cell types on H&E stains of the colon. However, this is a very small fraction of the number of potential cell classification types. Specifically, the CoNIC Challenge is unable to classify epithelial subtypes (progenitor, endocrine, goblet), lymphocyte subtypes (B, helper T, cytotoxic T), or connective subtypes (fibroblasts, stromal). In this paper, we propose to use inter-modality learning to label previously un-labelable cell types on virtual H&E. We leveraged multiplexed immunofluorescence (MxIF) histology imaging to identify 14 subclasses of cell types. We performed style transfer to synthesize virtual H&E from MxIF and transferred the higher density labels from MxIF to these virtual H&E images. We then evaluated the efficacy of learning in this approach. We identified helper T and progenitor nuclei with positive predictive values of $0.34 \pm 0.15$ (prevalence $0.03 \pm 0.01$) and $0.47 \pm 0.1$ (prevalence $0.07 \pm 0.02$) respectively on virtual H&E. This approach represents a promising step towards automating annotation in digital pathology.

Xueyuan Li, Can Cui, Ruining Deng et al.

Purpose: Recent developments in computational pathology have been driven by advances in Vision Foundation Models, particularly the Segment Anything Model (SAM). This model facilitates nuclei segmentation through two primary methods: prompt-based zero-shot segmentation and the use of cell-specific SAM models for direct segmentation. These approaches enable effective segmentation across a range of nuclei and cells. However, general vision foundation models often face challenges with fine-grained semantic segmentation, such as identifying specific nuclei subtypes or particular cells. Approach: In this paper, we propose the molecular-empowered All-in-SAM Model to advance computational pathology by leveraging the capabilities of vision foundation models. This model incorporates a full-stack approach, focusing on: (1) annotation-engaging lay annotators through molecular-empowered learning to reduce the need for detailed pixel-level annotations, (2) learning-adapting the SAM model to emphasize specific semantics, which utilizes its strong generalizability with SAM adapter, and (3) refinement-enhancing segmentation accuracy by integrating Molecular-Oriented Corrective Learning (MOCL). Results: Experimental results from both in-house and public datasets show that the All-in-SAM model significantly improves cell classification performance, even when faced with varying annotation quality. Conclusions: Our approach not only reduces the workload for annotators but also extends the accessibility of precise biomedical image analysis to resource-limited settings, thereby advancing medical diagnostics and automating pathology image analysis.

Yanfan Zhu, Issac Lyngaas, Murali Gopalakrishnan Meena et al.

Recent advancements in AI models are structured to retain user interactions, which could inadvertently include sensitive healthcare data. In the healthcare field, particularly when radiologists use AI-driven diagnostic tools hosted on online platforms, there is a risk that medical imaging data may be repurposed for future AI training without explicit consent, spotlighting critical privacy and intellectual property concerns around healthcare data usage. Addressing these privacy challenges, a novel approach known as Unlearnable Examples (UEs) has been introduced, aiming to make data unlearnable to deep learning models. A prominent method within this area, called Unlearnable Clustering (UC), has shown improved UE performance with larger batch sizes but was previously limited by computational resources. To push the boundaries of UE performance with theoretically unlimited resources, we scaled up UC learning across various datasets using Distributed Data Parallel (DDP) training on the Summit supercomputer. Our goal was to examine UE efficacy at high-performance computing (HPC) levels to prevent unauthorized learning and enhance data security, particularly exploring the impact of batch size on UE's unlearnability. Utilizing the robust computational capabilities of the Summit, extensive experiments were conducted on diverse datasets such as Pets, MedMNist, Flowers, and Flowers102. Our findings reveal that both overly large and overly small batch sizes can lead to performance instability and affect accuracy. However, the relationship between batch size and unlearnability varied across datasets, highlighting the necessity for tailored batch size strategies to achieve optimal data protection. Our results underscore the critical role of selecting appropriate batch sizes based on the specific characteristics of each dataset to prevent learning and ensure data security in deep learning applications.

Lucas W. Remedios, Shunxing Bao, Samuel W. Remedios et al.

Understanding the way cells communicate, co-locate, and interrelate is essential to furthering our understanding of how the body functions. H&E is widely available, however, cell subtyping often requires expert knowledge and the use of specialized stains. To reduce the annotation burden, AI has been proposed for the classification of cells on H&E. For example, the recent Colon Nucleus Identification and Classification (CoNIC) Challenge focused on labeling 6 cell types on H&E of the colon. However, the CoNIC Challenge was unable to classify epithelial subtypes (progenitor, enteroendocrine, goblet), lymphocyte subtypes (B, helper T, cytotoxic T), and connective subtypes (fibroblasts). We use inter-modality learning to label previously un-labelable cell types on H&E. We take advantage of multiplexed immunofluorescence (MxIF) histology to label 14 cell subclasses. We performed style transfer on the same MxIF tissues to synthesize realistic virtual H&E which we paired with the MxIF-derived cell subclassification labels. We evaluated the efficacy of using a supervised learning scheme where the input was realistic-quality virtual H&E and the labels were MxIF-derived cell subclasses. We assessed our model on private virtual H&E and public real H&E. On virtual H&E, we were able to classify helper T cells and epithelial progenitors with positive predictive values of $0.34 \pm 0.15$ (prevalence $0.03 \pm 0.01$) and $0.47 \pm 0.1$ (prevalence $0.07 \pm 0.02$) respectively, when using ground truth centroid information. On real H&E we could classify helper T cells and epithelial progenitors with upper bound positive predictive values of $0.43 \pm 0.03$ (parent class prevalence 0.21) and $0.94 \pm 0.02$ (parent class prevalence 0.49) when using ground truth centroid information. This is the first work to provide cell type classification for helper T and epithelial progenitor nuclei on H&E.

Ho Hin Lee, Adam M. Saunders, Michael E. Kim et al.

Purpose: Eye morphology varies significantly across the population, especially for the orbit and optic nerve. These variations limit the feasibility and robustness of generalizing population-wise features of eye organs to an unbiased spatial reference. Approach: To tackle these limitations, we propose a process for creating high-resolution unbiased eye atlases. First, to restore spatial details from scans with a low through-plane resolution compared to a high in-plane resolution, we apply a deep learning-based super-resolution algorithm. Then, we generate an initial unbiased reference with an iterative metric-based registration using a small portion of subject scans. We register the remaining scans to this template and refine the template using an unsupervised deep probabilistic approach that generates a more expansive deformation field to enhance the organ boundary alignment. We demonstrate this framework using magnetic resonance images across four different tissue contrasts, generating four atlases in separate spatial alignments. Results: For each tissue contrast, we find a significant improvement using the Wilcoxon signed-rank test in the average Dice score across four labeled regions compared to a standard registration framework consisting of rigid, affine, and deformable transformations. These results highlight the effective alignment of eye organs and boundaries using our proposed process. Conclusions: By combining super-resolution preprocessing and deep probabilistic models, we address the challenge of generating an eye atlas to serve as a standardized reference across a largely variable population.

Lucas W. Remedios, Chloe Cho, Trent M. Schwartz et al.

Purpose: Understanding how the pancreas changes is critical for detecting deviations in type 2 diabetes and other pancreatic disease. We measure pancreas size and shape using morphological measurements from ages 0 to 90. Our goals are to 1) identify reliable clinical imaging modalities for AI-based pancreas measurement, 2) establish normative morphological aging trends, and 3) detect potential deviations in type 2 diabetes. Approach: We analyzed a clinically acquired dataset of 2533 patients imaged with abdominal CT or MRI. We resampled the scans to 3mm isotropic resolution, segmented the pancreas using automated methods, and extracted 13 morphological pancreas features across the lifespan. First, we assessed CT and MRI measurements to determine which modalities provide consistent lifespan trends. Second, we characterized distributions of normative morphological patterns stratified by age group and sex. Third, we used GAMLSS regression to model pancreas morphology trends in 1350 patients matched for age, sex, and type 2 diabetes status to identify any deviations from normative aging associated with type 2 diabetes. Results: When adjusting for confounders, the aging trends for 10 of 13 morphological features were significantly different between patients with type 2 diabetes and non-diabetic controls (p < 0.05 after multiple comparisons corrections). Additionally, MRI appeared to yield different pancreas measurements than CT using our AI-based method. Conclusions: We provide lifespan trends demonstrating that the size and shape of the pancreas is altered in type 2 diabetes using 675 control patients and 675 diabetes patients. Moreover, our findings reinforce that the pancreas is smaller in type 2 diabetes. Additionally, we contribute a reference of lifespan pancreas morphology from a large cohort of non-diabetic control patients in a clinical setting.

Lucas W. Remedios, Chloe Cho, Trent M. Schwartz et al.

Purpose: Although elevated BMI is a well-known risk factor for type 2 diabetes, the disease's presence in some lean adults and absence in others with obesity suggests that detailed body composition may uncover abdominal phenotypes of type 2 diabetes. With AI, we can now extract detailed measurements of size, shape, and fat content from abdominal structures in 3D clinical imaging at scale. This creates an opportunity to empirically define body composition signatures linked to type 2 diabetes risk and protection using large-scale clinical data. Approach: To uncover BMI-specific diabetic abdominal patterns from clinical CT, we applied our design four times: once on the full cohort (n = 1,728) and once on lean (n = 497), overweight (n = 611), and obese (n = 620) subgroups separately. Briefly, our experimental design transforms abdominal scans into collections of explainable measurements through segmentation, classifies type 2 diabetes through a cross-validated random forest, measures how features contribute to model-estimated risk or protection through SHAP analysis, groups scans by shared model decision patterns (clustering from SHAP) and links back to anatomical differences (classification). Results: The random-forests achieved mean AUCs of 0.72-0.74. There were shared type 2 diabetes signatures in each group; fatty skeletal muscle, older age, greater visceral and subcutaneous fat, and a smaller or fat-laden pancreas. Univariate logistic regression confirmed the direction of 14-18 of the top 20 predictors within each subgroup (p < 0.05). Conclusions: Our findings suggest that abdominal drivers of type 2 diabetes may be consistent across weight classes.

Aravind R. Krishnan, Thomas Z. Li, Lucas W. Remedios et al.

Reconstruction kernels in computed tomography (CT) affect spatial resolution and noise characteristics, introducing systematic variability in quantitative imaging measurements such as emphysema quantification. Choosing an appropriate kernel is therefore essential for consistent quantitative analysis. We propose a multipath cycleGAN model for CT kernel harmonization, trained on a mixture of paired and unpaired data from a low-dose lung cancer screening cohort. The model features domain-specific encoders and decoders with a shared latent space and uses discriminators tailored for each domain.We train the model on 42 kernel combinations using 100 scans each from seven representative kernels in the National Lung Screening Trial (NLST) dataset. To evaluate performance, 240 scans from each kernel are harmonized to a reference soft kernel, and emphysema is quantified before and after harmonization. A general linear model assesses the impact of age, sex, smoking status, and kernel on emphysema. We also evaluate harmonization from soft kernels to a reference hard kernel. To assess anatomical consistency, we compare segmentations of lung vessels, muscle, and subcutaneous adipose tissue generated by TotalSegmentator between harmonized and original images. Our model is benchmarked against traditional and switchable cycleGANs. For paired kernels, our approach reduces bias in emphysema scores, as seen in Bland-Altman plots (p<0.05). For unpaired kernels, harmonization eliminates confounding differences in emphysema (p>0.05). High Dice scores confirm preservation of muscle and fat anatomy, while lung vessel overlap remains reasonable. Overall, our shared latent space multipath cycleGAN enables robust harmonization across paired and unpaired CT kernels, improving emphysema quantification and preserving anatomical fidelity.

Juming Xiong, Muyang Li, Ruining Deng et al.

Video endoscopy represents a major advance in the investigation of gastrointestinal diseases. Reviewing endoscopy videos often involves frequent adjustments and reorientations to piece together a complete view, which can be both time-consuming and prone to errors. Image stitching techniques address this issue by providing a continuous and complete visualization of the examined area. However, endoscopic images, particularly those of the esophagus, present unique challenges. The smooth surface, lack of distinct feature points, and non-horizontal orientation complicate the stitching process, rendering traditional feature-based methods often ineffective for these types of images. In this paper, we propose a novel preprocessing pipeline designed to enhance endoscopic image stitching through advanced computational techniques. Our approach converts endoscopic video data into continuous 2D images by following four key steps: (1) keyframe selection, (2) image rotation adjustment to correct distortions, (3) surface unwrapping using polar coordinate transformation to generate a flat image, and (4) feature point matching enhanced by Adaptive Histogram Equalization for improved feature detection. We evaluate stitching quality through the assessment of valid feature point match pairs. Experiments conducted on 20 pediatric endoscopy videos demonstrate that our method significantly improves image alignment and stitching quality compared to traditional techniques, laying a robust foundation for more effective panoramic image creation.

Lianrui Zuo, Xin Yu, Dingjie Su et al.

Body composition analysis provides valuable insights into aging, disease progression, and overall health conditions. Due to concerns of radiation exposure, two-dimensional (2D) single-slice computed tomography (CT) imaging has been used repeatedly for body composition analysis. However, this approach introduces significant spatial variability that can impact the accuracy and robustness of the analysis. To mitigate this issue and facilitate body composition analysis, this paper presents a novel method to generate 3D CT volumes from limited number of 2D slices using a latent diffusion model (LDM). Our approach first maps 2D slices into a latent representation space using a variational autoencoder. An LDM is then trained to capture the 3D context of a stack of these latent representations. To accurately interpolate intermediateslices and construct a full 3D volume, we utilize body part regression to determine the spatial location and distance between the acquired slices. Experiments on both in-house and public 3D abdominal CT datasets demonstrate that the proposed method significantly enhances body composition analysis compared to traditional 2D-based analysis, with a reduced error rate from 23.3% to 15.2%.

Lianrui Zuo, Kaiwen Xu, Dingjie Su et al.

The interconnection between the human lungs and other organs, such as the liver and kidneys, is crucial for understanding the underlying risks and effects of lung diseases and improving patient care. However, most research chest CT imaging is focused solely on the lungs due to considerations of cost and radiation dose. This restricted field of view (FOV) in the acquired images poses challenges to comprehensive analysis and hinders the ability to gain insights into the impact of lung diseases on other organs. To address this, we propose SCOPE (Spatial Coverage Optimization with Prior Encoding), a novel approach to capture the inter-organ relationships from CT images and extend the FOV of chest CT images. Our approach first trains a variational autoencoder (VAE) to encode 2D axial CT slices individually, then stacks the latent representations of the VAE to form a 3D context for training a latent diffusion model. Once trained, our approach extends the FOV of CT images in the z-direction by generating new axial slices in a zero-shot manner. We evaluated our approach on the National Lung Screening Trial (NLST) dataset, and results suggest that it effectively extends the FOV to include the liver and kidneys, which are not completely covered in the original NLST data acquisition. Quantitative results on a held-out whole-body dataset demonstrate that the generated slices exhibit high fidelity with acquired data, achieving an SSIM of 0.81.

Xin Yu, Qi Yang, Han Liu et al.

2D single-slice abdominal computed tomography (CT) enables the assessment of body habitus and organ health with low radiation exposure. However, single-slice data necessitates the use of 2D networks for segmentation, but these networks often struggle to capture contextual information effectively. Consequently, even when trained on identical datasets, 3D networks typically achieve superior segmentation results. In this work, we propose a novel 3D-to-2D distillation framework, leveraging pre-trained 3D models to enhance 2D single-slice segmentation. Specifically, we extract the prediction distribution centroid from the 3D representations, to guide the 2D student by learning intra- and inter-class correlation. Unlike traditional knowledge distillation methods that require the same data input, our approach employs unpaired 3D CT scans with any contrast to guide the 2D student model. Experiments conducted on 707 subjects from the single-slice Baltimore Longitudinal Study of Aging (BLSA) dataset demonstrate that state-of-the-art 2D multi-organ segmentation methods can benefit from the 3D teacher model, achieving enhanced performance in single-slice multi-organ segmentation. Notably, our approach demonstrates considerable efficacy in low-data regimes, outperforming the model trained with all available training subjects even when utilizing only 200 training subjects. Thus, this work underscores the potential to alleviate manual annotation burdens.

Chenyu Gao, Shunxing Bao, Michael Kim et al.

Purpose: In diffusion MRI (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field-of-view (FOV). This work aims to develop a method for imputing the missing slices directly from existing dMRI scans with an incomplete FOV. We hypothesize that the imputed image with complete FOV can improve the whole-brain tractography for corrupted data with incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable dMRI data, enabling subsequent tractography analyses that would otherwise be challenging or unattainable with corrupted data. Approach: We propose a framework based on a deep generative model that estimates the absent brain regions in dMRI scans with incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWI) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWI outside of incomplete FOV. Results: For evaluating the imputed slices, on the WRAP dataset the proposed framework achieved PSNRb0=22.397, SSIMb0=0.905, PSNRb1300=22.479, SSIMb1300=0.893; on the NACC dataset it achieved PSNRb0=21.304, SSIMb0=0.892, PSNRb1300=21.599, SSIMb1300= 0.877. The proposed framework improved the tractography accuracy, as demonstrated by an increased average Dice score for 72 tracts (p < 0.001) on both the WRAP and NACC datasets. Conclusions: Results suggest that the proposed framework achieved sufficient imputation performance in dMRI data with incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer's Disease.