UNesT: Local Spatial Representation Learning with Hierarchical Transformer for Efficient Medical Segmentation

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 realize 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 tissues structures. 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 anatomies of 133 structures in brain, 14 organs in abdomen, 4 hierarchical components in kidney, and inter-connected kidney 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 single network, outperforms prior state-of-the-art method SLANT27 ensembled with 27 network tiles, our model performance increases the mean DSC score of the publicly available Colin and CANDI dataset from 0.7264 to 0.7444 and from 0.6968 to 0.7025, respectively.

Longitudinal Variability Analysis on Low-dose Abdominal CT with Deep Learning-based Segmentation

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.

Compound Figure Separation of Biomedical Images: Mining Large Datasets for Self-supervised Learning

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.

Cross-scale Attention Guided Multi-instance Learning for Crohn's Disease Diagnosis with Pathological Images

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.

Pseudo-Label Guided Multi-Contrast Generalization for Non-Contrast Organ-Aware Segmentation

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.

Characterizing Renal Structures with 3D Block Aggregate Transformers

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.

Random Multi-Channel Image Synthesis for Multiplexed Immunofluorescence Imaging

Multiplex immunofluorescence (MxIF) is an emerging imaging technique that produces the high sensitivity and specificity of single-cell mapping. With a tenet of 'seeing is believing', MxIF enables iterative staining and imaging extensive antibodies, which provides comprehensive biomarkers to segment and group different cells on a single tissue section. However, considerable depletion of the scarce tissue is inevitable from extensive rounds of staining and bleaching ('missing tissue'). Moreover, the immunofluorescence (IF) imaging can globally fail for particular rounds ('missing stain''). In this work, we focus on the 'missing stain' issue. It would be appealing to develop digital image synthesis approaches to restore missing stain images without losing more tissue physically. Herein, we aim to develop image synthesis approaches for eleven MxIF structural molecular markers (i.e., epithelial and stromal) on real samples. We propose a novel multi-channel high-resolution image synthesis approach, called pixN2N-HD, to tackle possible missing stain scenarios via a high-resolution generative adversarial network (GAN). Our contribution is three-fold: (1) a single deep network framework is proposed to tackle missing stain in MxIF; (2) the proposed 'N-to-N' strategy reduces theoretical four years of computational time to 20 hours when covering all possible missing stains scenarios, with up to five missing stains (e.g., '(N-1)-to-1', '(N-2)-to-2'); and (3) this work is the first comprehensive experimental study of investigating cross-stain synthesis in MxIF. Our results elucidate a promising direction of advancing MxIF imaging with deep image synthesis.

Compound Figure Separation of Biomedical Images with Side Loss

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.

Attention-Guided Supervised Contrastive Learning for Semantic Segmentation

Contrastive learning has shown superior performance in embedding global and spatial invariant features in computer vision (e.g., image classification). However, its overall success of embedding local and spatial variant features is still limited, especially for semantic segmentation. In a per-pixel prediction task, more than one label can exist in a single image for segmentation (e.g., an image contains both cat, dog, and grass), thereby it is difficult to define 'positive' or 'negative' pairs in a canonical contrastive learning setting. In this paper, we propose an attention-guided supervised contrastive learning approach to highlight a single semantic object every time as the target. With our design, the same image can be embedded to different semantic clusters with semantic attention (i.e., coerce semantic masks) as an additional input channel. To achieve such attention, a novel two-stage training strategy is presented. We evaluate the proposed method on multi-organ medical image segmentation task, as our major task, with both in-house data and BTCV 2015 datasets. Comparing with the supervised and semi-supervised training state-of-the-art in the backbone of ResNet-50, our proposed pipeline yields substantial improvement of 5.53% and 6.09% in Dice score for both medical image segmentation cohorts respectively. The performance of the proposed method on natural images is assessed via PASCAL VOC 2012 dataset, and achieves 2.75% substantial improvement.

Multi-Contrast Computed Tomography Healthy Kidney Atlas

The construction of three-dimensional multi-modal tissue maps provides an opportunity to spur interdisciplinary innovations across temporal and spatial scales through information integration. While the preponderance of effort is allocated to the cellular level and explore the changes in cell interactions and organizations, contextualizing findings within organs and systems is essential to visualize and interpret higher resolution linkage across scales. There is a substantial normal variation of kidney morphometry and appearance across body size, sex, and imaging protocols in abdominal computed tomography (CT). A volumetric atlas framework is needed to integrate and visualize the variability across scales. However, there is no abdominal and retroperitoneal organs atlas framework for multi-contrast CT. Hence, we proposed a high-resolution CT retroperitoneal atlas specifically optimized for the kidney across non-contrast CT and early arterial, late arterial, venous and delayed contrast enhanced CT. Briefly, we introduce a deep learning-based volume of interest extraction method and an automated two-stage hierarchal registration pipeline to register abdominal volumes to a high-resolution CT atlas template. To generate and evaluate the atlas, multi-contrast modality CT scans of 500 subjects (without reported history of renal disease, age: 15-50 years, 250 males & 250 females) were processed. We demonstrate a stable generalizability of the atlas template for integrating the normal kidney variation from small to large, across contrast modalities and populations with great variability of demographics. The linkage of atlas and demographics provided a better understanding of the variation of kidney anatomy across populations.