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Estimated brain age from magnetic resonance image (MRI) and its deviation from chronological age can provide early insights into potential neurodegenerative diseases, supporting early detection and implementation of prevention strategies. Diffusion MRI (dMRI), a widely used modality for brain age estimation, presents an opportunity to build an earlier biomarker for neurodegenerative disease prediction because it captures subtle microstructural changes that precede more perceptible macrostructural changes. However, the coexistence of macro- and micro-structural information in dMRI raises the question of whether current dMRI-based brain age estimation models are leveraging the intended microstructural information or if they inadvertently rely on the macrostructural information. To develop a microstructure-specific brain age, we propose a method for brain age identification from dMRI that minimizes the model's use of macrostructural information by non-rigidly registering all images to a standard template. Imaging data from 13,398 participants across 12 datasets were used for the training and evaluation. We compare our brain age models, trained with and without macrostructural information minimized, with an architecturally similar T1-weighted (T1w) MRI-based brain age model and two state-of-the-art T1w MRI-based brain age models that primarily use macrostructural information. We observe difference between our dMRI-based brain age and T1w MRI-based brain age across stages of neurodegeneration, with dMRI-based brain age being older than T1w MRI-based brain age in participants transitioning from cognitively normal (CN) to mild cognitive impairment (MCI), but younger in participants already diagnosed with Alzheimer's disease (AD). Approximately 4 years before MCI diagnosis, dMRI-based brain age yields better performance than T1w MRI-based brain ages in predicting transition from CN to MCI.

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.

Proper quality control (QC) is time consuming when working with large-scale medical imaging datasets, yet necessary, as poor-quality data can lead to erroneous conclusions or poorly trained machine learning models. Most efforts to reduce data QC time rely on outlier detection, which cannot capture every instance of algorithm failure. Thus, there is a need to visually inspect every output of data processing pipelines in a scalable manner. We design a QC pipeline that allows for low time cost and effort across a team setting for a large database of diffusion weighted and structural magnetic resonance images. Our proposed method satisfies the following design criteria: 1.) a consistent way to perform and manage quality control across a team of researchers, 2.) quick visualization of preprocessed data that minimizes the effort and time spent on the QC process without compromising the condition or caliber of the QC, and 3.) a way to aggregate QC results across pipelines and datasets that can be easily shared. In addition to meeting these design criteria, we also provide information on what a successful output should be and common occurrences of algorithm failures for various processing pipelines. Our method reduces the time spent on QC by a factor of over 20 when compared to naively opening outputs in an image viewer and demonstrate how it can facilitate aggregation and sharing of QC results within a team. While researchers must spend time on robust visual QC of data, there are mechanisms by which the process can be streamlined and efficient., Comment: 22 pages, 12 figures, 1 table, 6 supplemental figures

An incomplete field-of-view (FOV) in diffusion magnetic resonance imaging (dMRI) can severely hinder the volumetric and bundle analyses of whole-brain white matter connectivity. Although existing works have investigated imputing the missing regions using deep generative models, it remains unclear how to specifically utilize additional information from paired multi-modality data and whether this can enhance the imputation quality and be useful for downstream tractography. To fill this gap, we propose a novel framework for imputing dMRI scans in the incomplete part of the FOV by integrating the learned diffusion features in the acquired part of the FOV to the complete brain anatomical structure. We hypothesize that by this design the proposed framework can enhance the imputation performance of the dMRI scans and therefore be useful for repairing whole-brain tractography in corrupted dMRI scans with incomplete FOV. We tested our framework on two cohorts from different sites with a total of 96 subjects and compared it with a baseline imputation method that treats the information from T1w and dMRI scans equally. The proposed framework achieved significant improvements in imputation performance, as demonstrated by angular correlation coefficient (p < 1E-5), and in downstream tractography accuracy, as demonstrated by Dice score (p < 0.01). Results suggest that the proposed framework improved imputation performance in dMRI scans by specifically utilizing additional information from paired multi-modality data, compared with the baseline method. The imputation achieved by the proposed framework enhances whole brain tractography, and therefore reduces the uncertainty when analyzing bundles associated with neurodegenerative., Comment: 20 pages; 8 figures

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

Coronary artery calcium (CAC) is highly predictive of cardiovascular events. While millions of chest CT scans are performed annually in the United States, CAC is not routinely quantified from scans done for non-cardiac purposes. A deep learning algorithm was developed using 446 expert segmentations to automatically quantify CAC on non-contrast, non-gated CT scans (AI-CAC). Our study differs from prior works as we leverage imaging data across the Veterans Affairs national healthcare system, from 98 medical centers, capturing extensive heterogeneity in imaging protocols, scanners, and patients. AI-CAC performance on non-gated scans was compared against clinical standard ECG-gated CAC scoring. Non-gated AI-CAC differentiated zero vs. non-zero and less than 100 vs. 100 or greater Agatston scores with accuracies of 89.4% (F1 0.93) and 87.3% (F1 0.89), respectively, in 795 patients with paired gated scans within a year of a non-gated CT scan. Non-gated AI-CAC was predictive of 10-year all-cause mortality (CAC 0 vs. >400 group: 25.4% vs. 60.2%, Cox HR 3.49, p < 0.005), and composite first-time stroke, MI, or death (CAC 0 vs. >400 group: 33.5% vs. 63.8%, Cox HR 3.00, p < 0.005). In a screening dataset of 8,052 patients with low-dose lung cancer-screening CTs (LDCT), 3,091/8,052 (38.4%) individuals had AI-CAC >400. Four cardiologists qualitatively reviewed LDCT images from a random sample of >400 AI-CAC patients and verified that 527/531 (99.2%) would benefit from lipid-lowering therapy. To the best of our knowledge, this is the first non-gated CT CAC algorithm developed across a national healthcare system, on multiple imaging protocols, without filtering intra-cardiac hardware, and compared against a strong gated CT reference. We report superior performance relative to previous CAC algorithms evaluated against paired gated scans that included patients with intra-cardiac hardware.

Curating, processing, and combining large-scale medical imaging datasets from national studies is a non-trivial task due to the intense computation and data throughput required, variability of acquired data, and associated financial overhead. Existing platforms or tools for large-scale data curation, processing, and storage have difficulty achieving a viable cost-to-scale ratio of computation speed for research purposes, either being too slow or too expensive. Additionally, management and consistency of processing large data in a team-driven manner is a non-trivial task. We design a BIDS-compliant method for an efficient and robust data processing pipeline of large-scale diffusion-weighted and T1-weighted MRI data compatible with low-cost, high-efficiency computing systems. Our method accomplishes automated querying of data available for processing and process running in a consistent and reproducible manner that has long-term stability, while using heterogenous low-cost computational resources and storage systems for efficient processing and data transfer. We demonstrate how our organizational structure permits efficiency in a semi-automated data processing pipeline and show how our method is comparable in processing time to cloud-based computation while being almost 20 times more cost-effective. Our design allows for fast data throughput speeds and low latency to reduce the time for data transfer between storage servers and computation servers, achieving an average of 0.60 Gb/s compared to 0.33 Gb/s for using cloud-based processing methods. The design of our workflow engine permits quick process running while maintaining flexibility to adapt to newly acquired data.

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.

Estimating heterogeneous treatment effects is important to tailor treatments to those individuals who would most likely benefit. However, conditional average treatment effect predictors may often be trained on one population but possibly deployed on different, possibly unknown populations. We use methodology for learning multi-accurate predictors to post-process CATE T-learners (differenced regressions) to become robust to unknown covariate shifts at the time of deployment. The method works in general for pseudo-outcome regression, such as the DR-learner. We show how this approach can combine (large) confounded observational and (smaller) randomized datasets by learning a confounded predictor from the observational dataset, and auditing for multi-accuracy on the randomized controlled trial. We show improvements in bias and mean squared error in simulations with increasingly larger covariate shift, and on a semi-synthetic case study of a parallel large observational study and smaller randomized controlled experiment. Overall, we establish a connection between methods developed for multi-distribution learning and achieve appealing desiderata (e.g. external validity) in causal inference and machine learning.

Purpose: In diffusion MRI (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field-of-view (FOV). This work aims to develop a method for imputing the missing slices directly from existing dMRI scans with an incomplete FOV. We hypothesize that the imputed image with complete FOV can improve the whole-brain tractography for corrupted data with incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable dMRI data, enabling subsequent tractography analyses that would otherwise be challenging or unattainable with corrupted data. Approach: We propose a framework based on a deep generative model that estimates the absent brain regions in dMRI scans with incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWI) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWI outside of incomplete FOV. Results: For evaluating the imputed slices, on the WRAP dataset the proposed framework achieved PSNRb0=22.397, SSIMb0=0.905, PSNRb1300=22.479, SSIMb1300=0.893; on the NACC dataset it achieved PSNRb0=21.304, SSIMb0=0.892, PSNRb1300=21.599, SSIMb1300= 0.877. The proposed framework improved the tractography accuracy, as demonstrated by an increased average Dice score for 72 tracts (p < 0.001) on both the WRAP and NACC datasets. Conclusions: Results suggest that the proposed framework achieved sufficient imputation performance in dMRI data with incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer's Disease., Comment: 20 pages, 11 figures

The demand for precise information on DRAM microarchitectures and error characteristics has surged, driven by the need to explore processing in memory, enhance reliability, and mitigate security vulnerability. Nonetheless, DRAM manufacturers have disclosed only a limited amount of information, making it difficult to find specific information on their DRAM microarchitectures. This paper addresses this gap by presenting more rigorous findings on the microarchitectures of commodity DRAM chips and their impacts on the characteristics of activate-induced bitflips (AIBs), such as RowHammer and RowPress. The previous studies have also attempted to understand the DRAM microarchitectures and associated behaviors, but we have found some of their results to be misled by inaccurate address mapping and internal data swizzling, or lack of a deeper understanding of the modern DRAM cell structure. For accurate and efficient reverse-engineering, we use three tools: AIBs, retention time test, and RowCopy, which can be cross-validated. With these three tools, we first take a macroscopic view of modern DRAM chips to uncover the size, structure, and operation of their subarrays, memory array tiles (MATs), and rows. Then, we analyze AIB characteristics based on the microscopic view of the DRAM microarchitecture, such as 6F^2 cell layout, through which we rectify misunderstandings regarding AIBs and discover a new data pattern that accelerates AIBs. Lastly, based on our findings at both macroscopic and microscopic levels, we identify previously unknown AIB vulnerabilities and propose a simple yet effective protection solution., Comment: To appear at the 51st IEEE/ACM International Symposium on Computer Architecture (ISCA)

Diffusion MRI (dMRI) streamline tractography, the gold standard for in vivo estimation of brain white matter (WM) pathways, has long been considered indicative of macroscopic relationships with WM microstructure. However, recent advances in tractography demonstrated that convolutional recurrent neural networks (CoRNN) trained with a teacher-student framework have the ability to learn and propagate streamlines directly from T1 and anatomical contexts. Training for this network has previously relied on high-resolution dMRI. In this paper, we generalize the training mechanism to traditional clinical resolution data, which allows generalizability across sensitive and susceptible study populations. We train CoRNN on a small subset of the Baltimore Longitudinal Study of Aging (BLSA), which better resembles clinical protocols. Then, we define a metric, termed the epsilon ball seeding method, to compare T1 tractography and traditional diffusion tractography at the streamline level. Under this metric, T1 tractography generated by CoRNN reproduces diffusion tractography with approximately two millimeters of error.

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: Published in SPIE Journal of Medical Imaging (https://doi.org/10.1117/1.JMI.11.6.064004). 27 pages, 6 figures