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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/wholebrainSeg.

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Diffusion magnetic resonance imaging (dMRI) offers the ability to assess subvoxel brain microstructure through the extraction of biomarkers like fractional anisotropy, as well as to unveil brain connectivity by reconstructing white matter fiber trajectories. However, accurate analysis becomes challenging at the interface between cerebrospinal fluid and white matter, where the MRI signal originates from both the cerebrospinal fluid and the white matter partial volume. The presence of free water partial volume effects introduces a substantial bias in estimating diffusion properties, thereby limiting the clinical utility of DWI. Moreover, current mathematical models often lack applicability to single-shell acquisitions commonly encountered in clinical settings. Without appropriate regularization, direct model fitting becomes impractical. We propose a novel voxel-based deep learning method for mapping and correcting free-water partial volume contamination in DWI to address these limitations. This approach leverages data-driven techniques to reliably infer plausible free-water volumes across different diffusion MRI acquisition schemes, including single-shell acquisitions. Our evaluation demonstrates that the introduced methodology consistently produces more consistent and plausible results than previous approaches. By effectively mitigating the impact of free water partial volume effects, our approach enhances the accuracy and reliability of DWI analysis for single-shell dMRI, thereby expanding its applications in assessing brain microstructure and connectivity.

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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 ± 0.15 (prevalence 0.03 ± 0.01) and 0.47 ± 0.1 (prevalence 0.07 ± 0.02) respectively on virtual H&E. This approach represents a promising step towards automating annotation in digital pathology.

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Purpose: In brain diffusion magnetic resonance imaging (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field of view (FOV). We aim 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 a complete FOV can improve whole-brain tractography for corrupted data with an incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable brain 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 an incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWIs) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWIs in the incomplete part of the FOV. Results: For evaluating the imputed slices, on the Wisconsin Registry for Alzheimer's Prevention (WRAP) dataset, the proposed framework achieved PSNR b 0 = 22.397 , SSIM b 0 = 0.905 , PSNR b 1300 = 22.479 , and SSIM b 1300 = 0.893 ; on the National Alzheimer's Coordinating Center (NACC) dataset, it achieved PSNR b 0 = 21.304 , SSIM b 0 = 0.892 , PSNR b 1300 = 21.599 , and SSIM b 1300 = 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 brain dMRI data with an incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with an extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer's disease.

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Crohn's disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identify a distinct epithelial cell type in both terminal ileum and ascending colon (hereon as 'LND') with high expression of LCN2, NOS2, and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, are rare in non-IBD controls but expand in active CD, and actively interact with immune cells and specifically express IBD/CD susceptibility genes, suggesting a possible function in CD immunopathogenesis. Furthermore, we discover early and late LND subpopulations with different origins and developmental potential. A higher ratio of late-to-early LND cells correlates with better response to anti-TNF treatment. Our findings thus suggest a potential pathogenic role for LND cells in both Crohn's ileitis and colitis.

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Multiplex immunofluorescence (MxIF) is an advanced molecular imaging technique that can simultaneously provide biologists with multiple (i.e., more than 20) molecular markers on a single histological tissue section. Unfortunately, due to imaging restrictions, the more routinely used hematoxylin and eosin (H&E) stain is typically unavailable with MxIF on the same tissue section. As biological H&E staining is not feasible, previous efforts have been made to obtain H&E whole slide image (WSI) from MxIF via deep learning empowered virtual staining. However, the tiling effect is a long-lasting problem in high-resolution WSI-wise synthesis. The MxIF to H&E synthesis is no exception. Limited by computational resources, the cross-stain image synthesis is typically performed at the patch-level. Thus, discontinuous intensities might be visually identified along with the patch boundaries assembling all individual patches back to a WSI. In this work, we propose a deep learning based unpaired high-resolution image synthesis method to obtain virtual H&E WSIs from MxIF WSIs (each with 27 markers/stains) with reduced tiling effects. Briefly, we first extend the CycleGAN framework by adding simultaneous nuclei and mucin segmentation supervision as spatial constraints. Then, we introduce a random walk sliding window shifting strategy during the optimized inference stage, to alleviate the tiling effects. The validation results show that our spatially constrained synthesis method achieves a 56% performance gain for the downstream cell segmentation task. The proposed inference method reduces the tiling effects by using 50% fewer computation resources without compromising performance. The proposed random sliding window inference method is a plug-and-play module, which can be generalized for other high-resolution WSI image synthesis applications. The source code with our proposed model are available at https://github.com/MASILab/RandomWalkSlidingWindow.git.

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INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

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Prenatal alcohol exposure (PAE) occurs in ~11% of North American pregnancies and is the most common known cause of neurodevelopmental disabilities such as fetal alcohol spectrum disorder (FASD; ~2-5% prevalence). PAE has been consistently associated with smaller gray matter volumes in children, adolescents, and adults. A small number of longitudinal studies show altered gray matter development trajectories in late childhood/early adolescence, but patterns in early childhood and potential sex differences have not been characterized in young children. Using longitudinal T1-weighted MRI, the present study characterized gray matter volume development in young children with PAE (N = 42, 84 scans, ages 3-8 years) compared to unexposed children (N = 127, 450 scans, ages 2-8.5 years). Overall, we observed altered global and regional gray matter development trajectories in the PAE group, wherein they had attenuated age-related increases and more volume decreases relative to unexposed children. Moreover, we found more pronounced sex differences in children with PAE; females with PAE having the smallest gray matter volumes and the least age-related changes of all groups. This pattern of altered development may indicate reduced brain plasticity and/or accelerated maturation and may underlie the cognitive/behavioral difficulties often experienced by children with PAE. In conjunction with previous research on older children, adolescents, and adults with PAE, our results suggest that gray matter volume differences associated with PAE vary by age and may become more apparent in older children.

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Purpose: 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 leads to different organs/tissues being captured. Approach: 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. Results: Our experiments on 2608 volumetric CT data from two in-house datasets and 50 subjects from the 2015 Multi-Atlas Abdomen Labeling Challenge Beyond the Cranial Vault (BTCV) dataset 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 dataset, which contains longitudinal single abdominal slices, and confirmed that our method can harmonize the slice positional variance in terms of visceral fat area. Conclusion: 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.

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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., 20× 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.

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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.

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Purpose: Diffusion-weighted magnetic resonance imaging (DW-MRI) is a critical imaging method for capturing and modeling tissue microarchitecture at a millimeter scale. A common practice to model the measured DW-MRI signal is via fiber orientation distribution function (fODF). This function is the essential first step for the downstream tractography and connectivity analyses. With recent advantages in data sharing, large-scale multisite DW-MRI datasets are being made available for multisite studies. However, measurement variabilities (e.g., inter- and intrasite variability, hardware performance, and sequence design) are inevitable during the acquisition of DW-MRI. Most existing model-based methods [e.g., constrained spherical deconvolution (CSD)] and learning-based methods (e.g., deep learning) do not explicitly consider such variabilities in fODF modeling, which consequently leads to inferior performance on multisite and/or longitudinal diffusion studies. Approach: In this paper, we propose a data-driven deep CSD method to explicitly constrain the scan-rescan variabilities for a more reproducible and robust estimation of brain microstructure from repeated DW-MRI scans. Specifically, the proposed method introduces a three-dimensional volumetric scanner-invariant regularization scheme during the fODF estimation. We study the Human Connectome Project (HCP) young adults test-retest group as well as the MASiVar dataset (with inter- and intrasite scan/rescan data). The Baltimore Longitudinal Study of Aging dataset is employed for external validation. Results: From the experimental results, the proposed data-driven framework outperforms the existing benchmarks in repeated fODF estimation. By introducing the contrastive loss with scan/rescan data, the proposed method achieved a higher consistency while maintaining higher angular correlation coefficients with the CSD modeling. The proposed method is assessing the downstream connectivity analysis and shows increased performance in distinguishing subjects with different biomarkers. Conclusion: We propose a deep CSD method to explicitly reduce the scan-rescan variabilities, so as to model a more reproducible and robust brain microstructure from repeated DW-MRI scans. The plug-and-play design of the proposed approach is potentially applicable to a wider range of data harmonization problems in neuroimaging.

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Rapid developments in machine vision technology have impacted a variety of applications, such as medical devices and autonomous driving systems. These achievements, however, typically necessitate digital neural networks with the downside of heavy computational requirements and consequent high energy consumption. As a result, real-time decision-making is hindered when computational resources are not readily accessible. Here we report a meta-imager designed to work together with a digital back end to offload computationally expensive convolution operations into high-speed, low-power optics. In this architecture, metasurfaces enable both angle and polarization multiplexing to create multiple information channels that perform positively and negatively valued convolution operations in a single shot. We use our meta-imager for object classification, achieving 98.6% accuracy in handwritten digits and 88.8% accuracy in fashion images. Owing to its compactness, high speed and low power consumption, our approach could find a wide range of applications in artificial intelligence and machine vision applications.

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Imaging findings inconsistent with those expected at specific chronological age ranges may serve as early indicators of neurological disorders and increased mortality risk. Estimation of chronological age, and deviations from expected results, from structural magnetic resonance imaging (MRI) data has become an important proxy task for developing biomarkers that are sensitive to such deviations. Complementary to structural analysis, diffusion tensor imaging (DTI) has proven effective in identifying age-related microstructural changes within the brain white matter, thereby presenting itself as a promising additional modality for brain age prediction. Although early studies have sought to harness DTI's advantages for age estimation, there is no evidence that the success of this prediction is owed to the unique microstructural and diffusivity features that DTI provides, rather than the macrostructural features that are also available in DTI data. Therefore, we seek to develop white-matter-specific age estimation to capture deviations from normal white matter aging. Specifically, we deliberately disregard the macrostructural information when predicting age from DTI scalar images, using two distinct methods. The first method relies on extracting only microstructural features from regions of interest (ROIs). The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are non-linearly registered and warped to a template to minimize macrostructural variations. When tested on unseen data, the first method yields mean absolute error (MAE) of 6.11 ± 0.19 years for cognitively normal participants and MAE of 6.62 ± 0.30 years for cognitively impaired participants, while the second method achieves MAE of 4.69 ± 0.23 years for cognitively normal participants and MAE of 4.96 ± 0.28 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction.

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Rationale: Skeletal muscle fat infiltration progresses with aging and is worsened among individuals with a history of cigarette smoking. Many negative impacts of smoking on muscles are likely reversible with smoking cessation. Objectives: To determine if the progression of skeletal muscle fat infiltration with aging is altered by smoking cessation among lung cancer screening participants. Methods: This was a secondary analysis based on the National Lung Screening Trial. Skeletal muscle attenuation in Hounsfield unit (HU) was derived from the baseline and follow-up low-dose CT scans using a previously validated artificial intelligence algorithm. Lower attenuation indicates greater fatty infiltration. Linear mixed-effects models were constructed to evaluate the associations between smoking status and the muscle attenuation trajectory. Measurements and Main Results: Of 19,019 included participants (age: 61 years, 5 [SD]; 11,290 males), 8,971 (47.2%) were actively smoking cigarettes. Accounting for body mass index, pack-years, percent emphysema, and other confounding factors, actively smoking predicted a lower attenuation in both males (ß0 =-0.88 HU, P<.001) and females (ß0 =-0.69 HU, P<.001), and an accelerated muscle attenuation decline-rate in males (ß1=-0.08 HU/y, P<.05). Age-stratified analyses indicated that the accelerated muscle attenuation decline associated with smoking likely occurred at younger age, especially in females. Conclusions: Among lung cancer screening participants, active cigarette smoking was associated with greater skeletal muscle fat infiltration in both males and females, and accelerated muscle adipose accumulation rate in males. These findings support the important role of smoking cessation in preserving muscle health.

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Multiplex immunofluorescence (MxIF) is an emerging imaging technology whose downstream molecular analytics highly rely upon the effectiveness of cell segmentation. In practice, multiple membrane markers (e.g., NaKATPase, PanCK and ß-catenin) are employed to stain membranes for different cell types, so as to achieve a more comprehensive cell segmentation since no single marker fits all cell types. However, prevalent watershed-based image processing might yield inferior capability for modeling complicated relationships between markers. For example, some markers can be misleading due to questionable stain quality. In this paper, we propose a deep learning based membrane segmentation method to aggregate complementary information that is uniquely provided by large scale MxIF markers. We aim to segment tubular membrane structure in MxIF data using global (membrane markers z-stack projection image) and local (separate individual markers) information to maximize topology preservation with deep learning. Specifically, we investigate the feasibility of four SOTA 2D deep networks and four volumetric-based loss functions. We conducted a comprehensive ablation study to assess the sensitivity of the proposed method with various combinations of input channels. Beyond using adjusted rand index (ARI) as the evaluation metric, which was inspired by the clDice, we propose a novel volumetric metric that is specific for skeletal structure, denoted as clDiceSKEL. In total, 80 membrane MxIF images were manually traced for 5-fold cross-validation. Our model outperforms the baseline with a 20.2% and 41.3% increase in clDiceSKEL and ARI performance, which is significant (p<0.05) using the Wilcoxon signed rank test. Our work explores a promising direction for advancing MxIF imaging cell segmentation with deep learning membrane segmentation. Tools are available at https://github.com/MASILab/MxIF_Membrane_Segmentation.

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Crohn's disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohn's ileitis and Crohn's colitis and identify novel biomarkers associated with disease activity and treatment response.

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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. 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. Code, pre-trained models, and use case pipeline are available at: https://github.com/MASILab/UNesT.

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With the confounding effects of demographics across large-scale imaging surveys, substantial variation is demonstrated with the volumetric structure of orbit and eye anthropometry. Such variability increases the level of difficulty to localize the anatomical features of the eye organs for populational analysis. To adapt the variability of eye organs with stable registration transfer, we propose an unbiased eye atlas template followed by a hierarchical coarse-to-fine approach to provide generalized eye organ context across populations. Furthermore, we retrieved volumetric scans from 1842 healthy patients for generating an eye atlas template with minimal biases. Briefly, we select 20 subject scans and use an iterative approach to generate an initial unbiased template. We then perform metric-based registration to the remaining samples with the unbiased template and generate coarse registered outputs. The coarse registered outputs are further leveraged to train a deep probabilistic network, which aims to refine the organ deformation in unsupervised setting. Computed tomography (CT) scans of 100 de-identified subjects are used to generate and evaluate the unbiased atlas template with the hierarchical pipeline. The refined registration shows the stable transfer of the eye organs, which were well-localized in the high-resolution (0.5 mm3) atlas space and demonstrated a significant improvement of 2.37% Dice for inverse label transfer performance. The subject-wise qualitative representations with surface rendering successfully demonstrate the transfer details of the organ context and showed the applicability of generalizing the morphological variation across patients.

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In lung cancer screening, estimation of future lung cancer risk is usually guided by demographics and smoking status. The role of constitutional profiles of human body, a.k.a. body habitus, is increasingly understood to be important, but has not been integrated into risk models. Chest low dose computed tomography (LDCT) is the standard imaging study in lung cancer screening, with the capability to discriminate differences in body composition and organ arrangement in the thorax. We hypothesize that the primary phenotypes identified using lung screening chest LDCT can form a representation of body habitus and add predictive power for lung cancer risk stratification. In this pilot study, we evaluated the feasibility of body habitus image-based phenotyping on a large lung screening LDCT dataset. A thoracic imaging manifold was estimated based on an intensity-based pairwise (dis)similarity metric for pairs of spatial normalized chest LDCT images. We applied the hierarchical clustering method on this manifold to identify the primary phenotypes. Body habitus features of each identified phenotype were evaluated and associated with future lung cancer risk using time-to-event analysis. We evaluated the method on the baseline LDCT scans of 1,200 male subjects sampled from National Lung Screening Trial. Five primary phenotypes were identified, which were associated with highly distinguishable clinical and body habitus features. Time-to-event analysis against future lung cancer incidences showed two of the five identified phenotypes were associated with elevated future lung cancer risks (HR=1.61, 95% CI = [1.08, 2.38], p=0.019; HR=1.67, 95% CI = [0.98, 2.86], p=0.057). These results indicated that it is feasible to capture the body habitus by image-base phenotyping using lung screening LDCT and the learned body habitus representation can potentially add value for future lung cancer risk stratification.