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Purpose: Diffusion weighted MRI (dMRI) and its models of neural structure provide insight into human brain organization and variations in white matter. A recent study by McMaster, et al. showed that complex graph measures of the connectome, the graphical representation of a tractogram, vary with spatial sampling changes, but biases introduced by anisotropic voxels in the process have not been well characterized. This study uses microstructural measures (fractional anisotropy and mean diffusivity) and white matter bundle properties (bundle volume, length, and surface area) to further understand the effect of anisotropic voxels on microstructure and tractography. Methods: The statistical significance of the selected measures derived from dMRI data were assessed by comparing three white matter bundles at different spatial resolutions with 44 subjects from the Human Connectome Project Young Adult dataset scan/rescan data using the Wilcoxon Signed Rank test. The original isotropic resolution (1.25 mm isotropic) was explored with six anisotropic resolutions with 0.25 mm incremental steps in the z dimension. Then, all generated resolutions were upsampled to 1.25 mm isotropic and 1 mm isotropic. Results: There were statistically significant differences between at least one microstructural and one bundle measure at every resolution (p less than or equal to 0.05, corrected for multiple comparisons). Cohen's d coefficient evaluated the effect size of anisotropic voxels on microstructure and tractography. Conclusion: Fractional anisotropy and mean diffusivity cannot be recovered with basic up sampling from low quality data with gold standard data. However, the bundle measures from tractogram become more repeatable when voxels are resampled to 1 mm isotropic.

While typical qualitative T1-weighted magnetic resonance images reflect scanner and protocol differences, quantitative T1 mapping aims to measure T1 independent of these effects. Changes in T1 in the brain reflect chemical and physical changes in brain tissue, such as the demyelination of axons in multiple sclerosis. Magnetization-prepared two rapid acquisition gradient echo (MP2RAGE) is an acquisition protocol that allows for efficient T1 mapping with a much lower scan time per slice compared to multi-TI inversion recovery (IR) protocols. We collect and register B1-corrected MP2RAGE acquisitions with an additional inversion time (MP3RAGE) alongside multi-TI selective inversion recovery acquisitions for four subjects and find a tissue-dependent bias between the derived T1 values. We train a patch-based ResNet-18 to calibrate the MP3RAGE T1 values to the multi-TI IR T1 values, incorporating the standard deviation of T1 calculated from a Monte Carlo simulation as an additional channel. Across four folds, the error between the MP2RAGE and T1 maps varies substantially (RMSE in white matter: 0.30 +/- 0.01 seconds, subcortical gray matter: 0.26 +/- 0.02 seconds, cortical gray matter: 0.36 +/- 0.02 seconds). Our network reduces the RMSE significantly (RMSE in white matter: 0.11 +/- 0.02 seconds, subcortical gray matter: 0.10 +/- 0.02 seconds, cortical gray matter: 0.17 +/- 0.03 seconds). Adding the standard deviation channel does not substantially change the RMSE. Using limited paired training data from both sequences, we can reduce the error between quantitative imaging methods and calibrate to one of the protocols with a neural network., Comment: 20 pages, 10 figures. Submitted to Magnetic Resonance Imaging

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 na\"ive 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., Comment: 13.5 pages of manuscript content

To date, there has been no comprehensive study characterizing the effect of diffusion-weighted magnetic resonance imaging voxel resolution on the resulting connectome for high resolution subject data. Similarity in results improved with higher resolution, even after initial down-sampling. To ensure robust tractography and connectomes, resample data to 1 mm isotropic resolution.

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.

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., Comment: arXiv admin note: text overlap with arXiv:2401.05602

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.

Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 age-matched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods' effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05., Comment: 11 pages, 5 figures, to be published in SPIE Medical Imaging 2024: Image Processing

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., Comment: Revised for submission to SPIE Journal of Medical Imaging. 26 pages, 6 figures

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., Comment: 10 pages, 6 figures, 1 table, Submitted to SPIE Medical Imaging : Image Processing. San Diego, CA. February 2024

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., Comment: Submitted to SPIE Medical Imaging. San Diego, CA. February 2024

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).

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.

Multi-class cell segmentation in high-resolution Giga-pixel whole slide images (WSI) is critical for various clinical applications. Training such an AI model typically requires labor-intensive pixel-wise manual annotation from experienced domain experts (e.g., pathologists). Moreover, such annotation is error-prone when differentiating fine-grained cell types (e.g., podocyte and mesangial cells) via the naked human eye. In this study, we assess the feasibility of democratizing pathological AI deployment by only using lay annotators (annotators without medical domain knowledge). The contribution of this paper is threefold: (1) We proposed a molecular-empowered learning scheme for multi-class cell segmentation using partial labels from lay annotators; (2) The proposed method integrated Giga-pixel level molecular-morphology cross-modality registration, molecular-informed annotation, and molecular-oriented segmentation model, so as to achieve significantly superior performance via 3 lay annotators as compared with 2 experienced pathologists; (3) A deep corrective learning (learning with imperfect label) method is proposed to further improve the segmentation performance using partially annotated noisy data. From the experimental results, our learning method achieved F1 = 0.8496 using molecular-informed annotations from lay annotators, which is better than conventional morphology-based annotations (F1 = 0.7015) from experienced pathologists. Our method democratizes the development of a pathological segmentation deep model to the lay annotator level, which consequently scales up the learning process similar to a non-medical computer vision task. The official implementation and cell annotations are publicly available at https://github.com/hrlblab/MolecularEL.

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.

Tracking multiple moving objects of interest (OOI) with multiple robot systems (MRS) has been addressed by active sensing that maintains a shared belief of OOIs and plans the motion of robots to maximize the information quality. Mobility of robots enables the behavior of pursuing better visibility, which is constrained by sensor field of view (FoV) and occlusion objects. We first extend prior work to detect, maintain and share occlusion information explicitly, allowing us to generate occlusion-aware planning even if a priori semantic occlusion information is unavailable. The efficacy of active sensing approaches is often evaluated according to estimation error and information gain metrics. However, these metrics do not directly explain the level of cooperative behavior engendered by the active sensing algorithms. Next, we extract different emergent cooperative behaviors that stem from the same underlying algorithms but manifest differently under differing scenarios. In particular, we highlight and demonstrate three emergent behavior patterns in active sensing MRS: (i) Change of tracking responsibility between agents when tracking trajectories with divergent directions or due to a re-allocation of the resource among heterogeneous agents; (ii) Awareness of occlusions to a trajectory and temporal leave-and-return of the sensing agent; (iii) Sharing of local occlusion objects in MRS that subsequently improves the awareness of occlusion.

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.

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.

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.

In target tracking with mobile multi-sensor systems, sensor deployment impacts the observation capabilities and the resulting state estimation quality. Based on a partially observable Markov decision process (POMDP) formulation comprised of the observable sensor dynamics, unobservable target states, and accompanying observation laws, we present a distributed information-driven solution approach to the multi-agent target tracking problem, namely, sequential multi-agent nominal belief-state optimization (SMA-NBO). SMA-NBO seeks to minimize the expected tracking error via receding horizon control including a heuristic expected cost-to-go (HECTG). SMA-NBO incorporates a computationally efficient approximation of the target belief-state over the horizon. The agent-by-agent decision-making is capable of leveraging on-board (edge) compute for selecting (sub-optimal) target-tracking maneuvers exhibiting non-myopic cooperative fleet behavior. The optimization problem explicitly incorporates semantic information defining target occlusions from a world model. To illustrate the efficacy of our approach, a random occlusion forest environment is simulated. SMA-NBO is compared to other baseline approaches. The simulation results show SMA-NBO 1) maintains tracking performance and reduces the computational cost by replacing the calculation of the expected target trajectory with a single sample trajectory based on maximum a posteriori estimation; 2) generates cooperative fleet decision by sequentially optimizing single-agent policy with efficient usage of other agents' policy of intent; 3) aptly incorporates the multiple weighted trace penalty (MWTP) HECTG, which improves tracking performance with a computationally efficient heuristic.