Samuel W. Remedios

Lianrui Zuo, Yihao Liu, Yuan Xue et al.

The lack of standardization is a prominent issue in magnetic resonance (MR) imaging. This often causes undesired contrast variations in the acquired images due to differences in hardware and acquisition parameters. In recent years, image synthesis-based MR harmonization with disentanglement has been proposed to compensate for the undesired contrast variations. Despite the success of existing methods, we argue that three major improvements can be made. First, most existing methods are built upon the assumption that multi-contrast MR images of the same subject share the same anatomy. This assumption is questionable, since different MR contrasts are specialized to highlight different anatomical features. Second, these methods often require a fixed set of MR contrasts for training (e.g., both T1-weighted and T2-weighted images), limiting their applicability. Lastly, existing methods are generally sensitive to imaging artifacts. In this paper, we present Harmonization with Attention-based Contrast, Anatomy, and Artifact Awareness (HACA3), a novel approach to address these three issues. HACA3 incorporates an anatomy fusion module that accounts for the inherent anatomical differences between MR contrasts. Furthermore, HACA3 is also robust to imaging artifacts and can be trained and applied to any set of MR contrasts. HACA3 is developed and evaluated on diverse MR datasets acquired from 21 sites with varying field strengths, scanner platforms, and acquisition protocols. Experiments show that HACA3 achieves state-of-the-art performance under multiple image quality metrics. We also demonstrate the applicability and versatility of HACA3 on downstream tasks including white matter lesion segmentation and longitudinal volumetric analyses.

Samuel W. Remedios, Shuo Han, Yuan Xue et al.

In 2D multi-slice magnetic resonance (MR) acquisition, the through-plane signals are typically of lower resolution than the in-plane signals. While contemporary super-resolution (SR) methods aim to recover the underlying high-resolution volume, the estimated high-frequency information is implicit via end-to-end data-driven training rather than being explicitly stated and sought. To address this, we reframe the SR problem statement in terms of perfect reconstruction filter banks, enabling us to identify and directly estimate the missing information. In this work, we propose a two-stage approach to approximate the completion of a perfect reconstruction filter bank corresponding to the anisotropic acquisition of a particular scan. In stage 1, we estimate the missing filters using gradient descent and in stage 2, we use deep networks to learn the mapping from coarse coefficients to detail coefficients. In addition, the proposed formulation does not rely on external training data, circumventing the need for domain shift correction. Under our approach, SR performance is improved particularly in "slice gap" scenarios, likely due to the constrained solution space imposed by the framework.

Samuel W. Remedios, Zhangxing Bian, Shuwen Wei et al.

Diffusion models are the current state-of-the-art for solving inverse problems in imaging. Their impressive generative capability allows them to approximate sampling from a prior distribution, which alongside a known likelihood function permits posterior sampling without retraining the model. While recent methods have made strides in advancing the accuracy of posterior sampling, the majority focuses on single-image inverse problems. However, for modalities such as magnetic resonance imaging (MRI), it is common to acquire multiple complementary measurements, each low-resolution along a different axis. In this work, we generalize common diffusion-based inverse single-image problem solvers for multi-image super-resolution (MISR) MRI. We show that the DPS likelihood correction allows an exactly-separable gradient decomposition across independently acquired measurements, enabling MISR without constructing a joint operator, modifying the diffusion model, or increasing network function evaluations. We derive MISR versions of DPS, DMAP, DPPS, and diffusion-based PnP/ADMM, and demonstrate substantial gains over SISR across $4\times/8\times/16\times$ anisotropic degradations. Our results achieve state-of-the-art super-resolution of anisotropic MRI volumes and, critically, enable reconstruction of near-isotropic anatomy from routine 2D multi-slice acquisitions, which are otherwise highly degraded in orthogonal views.

Zhangxing Bian, Shuwen Wei, Samuel W. Remedios et al.

Tagged MRI enables tracking internal tissue motion non-invasively. It encodes motion by modulating anatomy with periodic tags, which deform along with tissue. However, the entanglement between anatomy, tags and motion poses significant challenges for post-processing. The existence of tags and imaging blur hinders downstream tasks such as segmenting anatomy. Tag fading, due to T1-relaxation, disrupts the brightness constancy assumption for motion tracking. For decades, these challenges have been handled in isolation and sub-optimally. In contrast, we introduce a blind and nonlinear inverse framework for tagged MRI that, for the first time, unifies these tasks: anatomical image recovery, high-resolution cine image synthesis, and motion estimation. At its core, the synergy of MR physics and generative priors enables us to blindly estimate the unknown forward imaging models and high-resolution underlying anatomy, while simultaneously tracking 3D diffeomorphic Lagrangian motion over time. Experiments on tagged brain MRI demonstrate that our approach yields high-resolution anatomy images, cine images, and more accurate motion than specialized methods.

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.

Jinwei Zhang, Lianrui Zuo, Blake E. Dewey et al.

Automated segmentation of multiple sclerosis (MS) lesions using multicontrast magnetic resonance (MR) images improves efficiency and reproducibility compared to manual delineation, with deep learning (DL) methods achieving state-of-the-art performance. However, these DL-based methods have yet to simultaneously optimize in-domain accuracy and out-of-domain generalization when trained on a single source with limited data, or their performance has been unsatisfactory. To fill this gap, we propose a method called UNISELF, which achieves high accuracy within a single training domain while demonstrating strong generalizability across multiple out-of-domain test datasets. UNISELF employs a novel test-time self-ensembled lesion fusion to improve segmentation accuracy, and leverages test-time instance normalization (TTIN) of latent features to address domain shifts and missing input contrasts. Trained on the ISBI 2015 longitudinal MS segmentation challenge training dataset, UNISELF ranks among the best-performing methods on the challenge test dataset. Additionally, UNISELF outperforms all benchmark methods trained on the same ISBI training data across diverse out-of-domain test datasets with domain shifts and missing contrasts, including the public MICCAI 2016 and UMCL datasets, as well as a private multisite dataset. These test datasets exhibit domain shifts and/or missing contrasts caused by variations in acquisition protocols, scanner types, and imaging artifacts arising from imperfect acquisition. Our code is available at https://github.com/uponacceptance.

Samuel W. Remedios, Aaron Carass, Jerry L. Prince et al.

The purpose of this study is to present and compare three denoising diffusion probabilistic models (DDPMs) that generate 3D $T_1$-weighted MRI human brain images. Three DDPMs were trained using 80,675 image volumes from 42,406 subjects spanning 38 publicly available brain MRI datasets. These images had approximately 1 mm isotropic resolution and were manually inspected by three human experts to exclude those with poor quality, field-of-view issues, and excessive pathology. The images were minimally preprocessed to preserve the visual variability of the data. Furthermore, to enable the DDPMs to produce images with natural orientation variations and inhomogeneity, the images were neither registered to a common coordinate system nor bias field corrected. Evaluations included segmentation, Frechet Inception Distance (FID), and qualitative inspection. Regarding results, all three DDPMs generated coherent MR brain volumes. The velocity and flow prediction models achieved lower FIDs than the sample prediction model. However, all three models had higher FIDs compared to real images across multiple cohorts. In a permutation experiment, the generated brain regional volume distributions differed statistically from real data. However, the velocity and flow prediction models had fewer statistically different volume distributions in the thalamus and putamen. In conclusion this work presents and releases the first 3D non-latent diffusion model for brain data without skullstripping or registration. Despite the negative results in statistical testing, the presented DDPMs are capable of generating high-resolution 3D $T_1$-weighted brain images. All model weights and corresponding inference code are publicly available at https://github.com/piksl-research/medforj .

Samuel W. Remedios, Shuwen Wei, Shuo Han et al.

In clinical imaging, magnetic resonance (MR) image volumes are often acquired as stacks of 2D slices with decreased scan times, improved signal-to-noise ratio, and image contrasts unique to 2D MR pulse sequences. While this is sufficient for clinical evaluation, automated algorithms designed for 3D analysis perform poorly on multi-slice 2D MR volumes, especially those with thick slices and gaps between slices. Super-resolution (SR) methods aim to address this problem, but previous methods do not address all of the following: slice profile shape estimation, slice gap, domain shift, and non-integer or arbitrary upsampling factors. In this paper, we propose ECLARE (Efficient Cross-planar Learning for Anisotropic Resolution Enhancement), a self-SR method that addresses each of these factors. ECLARE uses a slice profile estimated from the multi-slice 2D MR volume, trains a network to learn the mapping from low-resolution to high-resolution in-plane patches from the same volume, and performs SR with anti-aliasing. We compared ECLARE to cubic B-spline interpolation, SMORE, and other contemporary SR methods. We used realistic and representative simulations so that quantitative performance against ground truth can be computed, and ECLARE outperformed all other methods in both signal recovery and downstream tasks. Importantly, as ECLARE does not use external training data it cannot suffer from domain shift between training and testing. Our code is open-source and available at https://www.github.com/sremedios/eclare.

Carlos A. Rivas, Jinwei Zhang, Shuwen Wei et al.

Unique identification of multiple sclerosis (MS) white matter lesions (WMLs) is important to help characterize MS progression. WMLs are routinely identified from magnetic resonance images (MRIs) but the resultant total lesion load does not correlate well with EDSS; whereas mean unique lesion volume has been shown to correlate with EDSS. Our approach builds on prior work by incorporating Hessian matrix computation from lesion probability maps before using the random walker algorithm to estimate the volume of each unique lesion. Synthetic images demonstrate our ability to accurately count the number of lesions present. The takeaways, are: 1) that our method correctly identifies all lesions including many that are missed by previous methods; 2) we can better separate confluent lesions; and 3) we can accurately capture the total volume of WMLs in a given probability map. This work will allow new more meaningful statistics to be computed from WMLs in brain MRIs

Zejun Wu, Samuel W. Remedios, Blake E. Dewey et al.

Anisotropic low-resolution (LR) magnetic resonance (MR) images are fast to obtain but hinder automated processing. We propose to use denoising diffusion probabilistic models (DDPMs) to super-resolve these 2D-acquired LR MR slices. This paper introduces AniRes2D, a novel approach combining DDPM with a residual prediction for 2D super-resolution (SR). Results demonstrate that AniRes2D outperforms several other DDPM-based models in quantitative metrics, visual quality, and out-of-domain evaluation. We use a trained AniRes2D to super-resolve 3D volumes slice by slice, where comparative quantitative results and reduced skull aliasing are achieved compared to a recent state-of-the-art self-supervised 3D super-resolution method. Furthermore, we explored the use of noise conditioning augmentation (NCA) as an alternative augmentation technique for DDPM-based SR models, but it was found to reduce performance. Our findings contribute valuable insights to the application of DDPMs for SR of anisotropic MR images.

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.

Zhangxing Bian, Shuwen Wei, Xiao Liang et al.

Magnetic resonance (MR) tagging is an imaging technique for noninvasively tracking tissue motion in vivo by creating a visible pattern of magnetization saturation (tags) that deforms with the tissue. Due to longitudinal relaxation and progression to steady-state, the tags and tissue brightnesses change over time, which makes tracking with optical flow methods error-prone. Although Fourier methods can alleviate these problems, they are also sensitive to brightness changes as well as spectral spreading due to motion. To address these problems, we introduce the brightness-invariant tracking estimation (BRITE) technique for tagged MRI. BRITE disentangles the anatomy from the tag pattern in the observed tagged image sequence and simultaneously estimates the Lagrangian motion. The inherent ill-posedness of this problem is addressed by leveraging the expressive power of denoising diffusion probabilistic models to represent the probabilistic distribution of the underlying anatomy and the flexibility of physics-informed neural networks to estimate biologically-plausible motion. A set of tagged MR images of a gel phantom was acquired with various tag periods and imaging flip angles to demonstrate the impact of brightness variations and to validate our method. The results show that BRITE achieves more accurate motion and strain estimates as compared to other state of the art methods, while also being resistant to tag fading.

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.

Anqi Feng, Zhangxing Bian, Samuel W. Remedios et al.

Accurate thalamic nuclei segmentation is crucial for understanding neurological diseases, brain functions, and guiding clinical interventions. However, the optimal inputs for segmentation remain unclear. This study systematically evaluates multiple MRI contrasts, including MPRAGE and FGATIR sequences, quantitative PD and T1 maps, and multiple T1-weighted images at different inversion times (multi-TI), to determine the most effective inputs. For multi-TI images, we employ a gradient-based saliency analysis with Monte Carlo dropout and propose an Overall Importance Score to select the images contributing most to segmentation. A 3D U-Net is trained on each of these configurations. Results show that T1 maps alone achieve strong quantitative performance and superior qualitative outcomes, while PD maps offer no added value. These findings underscore the value of T1 maps as a reliable and efficient input among the evaluated options, providing valuable guidance for optimizing imaging protocols when thalamic structures are of clinical or research interest.

Samuel W. Remedios, Zihao Wu, Camilo Bermudez et al.

Multiple instance learning (MIL) is a supervised learning methodology that aims to allow models to learn instance class labels from bag class labels, where a bag is defined to contain multiple instances. MIL is gaining traction for learning from weak labels but has not been widely applied to 3D medical imaging. MIL is well-suited to clinical CT acquisitions since (1) the highly anisotropic voxels hinder application of traditional 3D networks and (2) patch-based networks have limited ability to learn whole volume labels. In this work, we apply MIL with a deep convolutional neural network to identify whether clinical CT head image volumes possess one or more large hemorrhages (> 20cm$^3$), resulting in a learned 2D model without the need for 2D slice annotations. Individual image volumes are considered separate bags, and the slices in each volume are instances. Such a framework sets the stage for incorporating information obtained in clinical reports to help train a 2D segmentation approach. Within this context, we evaluate the data requirements to enable generalization of MIL by varying the amount of training data. Our results show that a training size of at least 400 patient image volumes was needed to achieve accurate per-slice hemorrhage detection. Over a five-fold cross-validation, the leading model, which made use of the maximum number of training volumes, had an average true positive rate of 98.10%, an average true negative rate of 99.36%, and an average precision of 0.9698. The models have been made available along with source code to enabled continued exploration and adaption of MIL in CT neuroimaging.

Camilo Bermudez, Justin Blaber, Samuel W. Remedios et al.

Generalizability is an important problem in deep neural networks, especially in the context of the variability of data acquisition in clinical magnetic resonance imaging (MRI). Recently, the Spatially Localized Atlas Network Tiles (SLANT) approach has been shown to effectively segment whole brain non-contrast T1w MRI with 132 volumetric labels. Enhancing generalizability of SLANT would enable broader application of volumetric assessment in multi-site studies. Transfer learning (TL) is commonly used to update the neural network weights for local factors; yet, it is commonly recognized to risk degradation of performance on the original validation/test cohorts. Here, we explore TL by data augmentation to address these concerns in the context of adapting SLANT to anatomical variation and scanning protocol. We consider two datasets: First, we optimize for age with 30 T1w MRI of young children with manually corrected volumetric labels, and accuracy of automated segmentation defined relative to the manually provided truth. Second, we optimize for acquisition with 36 paired datasets of pre- and post-contrast clinically acquired T1w MRI, and accuracy of the post-contrast segmentations assessed relative to the pre-contrast automated assessment. For both studies, we augment the original TL step of SLANT with either only the new data or with both original and new data. Over baseline SLANT, both approaches yielded significantly improved performance (signed rank tests; pediatric: 0.89 vs. 0.82 DSC, p<0.001; contrast: 0.80 vs 0.76, p<0.001). The performance on the original test set decreased with the new-data only transfer learning approach, so data augmentation was superior to strict transfer learning.