Magnetic Resonance Imaging with tagging (tMRI) has long been utilized for quantifying tissue motion and strain during deformation. However, a phenomenon known as tag fading, a gradual decrease in tag visibility over time, often complicates post-processing. The first contribution of this study is to model tag fading by considering the interplay between $T_1$ relaxation and the repeated application of radio frequency (RF) pulses during serial imaging sequences. This is a factor that has been overlooked in prior research on tMRI post-processing. Further, we have observed an emerging trend of utilizing raw tagged MRI within a deep learning-based (DL) registration framework for motion estimation. In this work, we evaluate and analyze the impact of commonly used image similarity objectives in training DL registrations on raw tMRI. This is then compared with the Harmonic Phase-based approach, a traditional approach which is claimed to be robust to tag fading. Our findings, derived from both simulated images and an actual phantom scan, reveal the limitations of various similarity losses in raw tMRI and emphasize caution in registration tasks where image intensity changes over time.

A seminal paper published by Ledley and Lusted in 1959 introduced complex clinical diagnostic reasoning cases as the gold standard for the evaluation of expert medical computing systems, a standard that has held ever since. Here, we report the results of a physician evaluation of a large language model (LLM) on challenging clinical cases against a baseline of hundreds of physicians. We conduct five experiments to measure clinical reasoning across differential diagnosis generation, display of diagnostic reasoning, triage differential diagnosis, probabilistic reasoning, and management reasoning, all adjudicated by physician experts with validated psychometrics. We then report a real-world study comparing human expert and AI second opinions in randomly-selected patients in the emergency room of a major tertiary academic medical center in Boston, MA. We compared LLMs and board-certified physicians at three predefined diagnostic touchpoints: triage in the emergency room, initial evaluation by a physician, and admission to the hospital or intensive care unit. In all experiments--both vignettes and emergency room second opinions--the LLM displayed superhuman diagnostic and reasoning abilities, as well as continued improvement from prior generations of AI clinical decision support. Our study suggests that LLMs have achieved superhuman performance on general medical diagnostic and management reasoning, fulfilling the vision put forth by Ledley and Lusted, and motivating the urgent need for prospective trials.

This roadmap provides a comprehensive and forward-looking perspective on the individualized application and safety of non-ionizing radiation (NIR) dosimetry in diagnostic and therapeutic medicine. Covering a wide range of frequencies, i.e., from low-frequency to terahertz, this document provides an overview of the current state of the art and anticipates future research needs in selected key topics of NIR-based medical applications. It also emphasizes the importance of personalized dosimetry, rigorous safety evaluation, and interdisciplinary collaboration to ensure safe and effective integration of NIR technologies in modern therapy and diagnosis.

Agent-based modeling (ABM) is a powerful computational approach for studying complex biological and biomedical systems, yet its widespread use remains limited by significant computational demands. As models become increasingly sophisticated, the number of parameters and interactions rises rapidly, exacerbating the so-called curse of dimensionality and making comprehensive parameter exploration and uncertainty analyses computationally prohibitive. Surrogate modeling provides a promising solution by approximating ABM behavior through computationally efficient alternatives, greatly reducing the runtime needed for parameter estimation, sensitivity analysis, and uncertainty quantification. In this review, we examine traditional approaches for performing these tasks directly within ABMs -- providing a baseline for comparison -- and then synthesize recent developments in surrogate-assisted methodologies for biological and biomedical applications. We cover statistical, mechanistic, and machine-learning-based approaches, emphasizing emerging hybrid strategies that integrate mechanistic insights with machine learning to balance interpretability and scalability. Finally, we discuss current challenges and outline directions for future research, including the development of standardized benchmarks to enhance methodological rigor and facilitate the broad adoption of surrogate-assisted ABMs in biology and medicine.

Parkinson's disease (PD) is a common neurodegenerative disease with a high degree of heterogeneity in its clinical features, rate of progression, and change of variables over time. In this work, we present a novel data-driven, network-based Trajectory Profile Clustering (TPC) algorithm for 1) identification of PD subtypes and 2) early prediction of disease progression in individual patients. Our subtype identification is based not only on PD variables, but also on their complex patterns of progression, providing a useful tool for the analysis of large heterogenous, longitudinal data. Specifically, we cluster patients based on the similarity of their trajectories through a time series of bipartite networks connecting patients to demographic, clinical, and genetic variables. We apply this approach to demographic and clinical data from the Parkinson's Progression Markers Initiative (PPMI) dataset and identify 3 patient clusters, consistent with 3 distinct PD subtypes, each with a characteristic variable progression profile. Additionally, TPC predicts an individual patient's subtype and future disease trajectory, based on baseline assessments. Application of our approach resulted in 74% accurate subtype prediction in year 5 in a test/validation cohort. Furthermore, we show that genetic variability can be integrated seamlessly in our TPC approach. In summary, using PD as a model for chronic progressive diseases, we show that TPC leverages high-dimensional longitudinal datasets for subtype identification and early prediction of individual disease subtype. We anticipate this approach will be broadly applicable to multidimensional longitudinal datasets in diverse chronic diseases.

Association analysis (e.g., differential expression analysis) and co-expression analysis are two major classes of statistical methods for omics data. While association analysis identifies individual features linked to health conditions, co-expression analysis examines dependencies among features to uncover functional modules and regulatory interactions. However, these approaches are often conducted separately, potentially leading to statistical inference with reduced sensitivity and replicability. To address this, we propose CoReg, a new statistical framework that integrates co-expression network analysis and factor models into the covariance modeling of multivariate regression. By accounting for the dependencies among omics features, CoReg enhances the power and sensitivity of association analysis while maintaining a well-controlled false discovery rate, thereby improving replicability across omics studies. We developed computationally efficient algorithms to implement CoReg and applied it to extensive simulation studies and real-world omics data analyses. Results demonstrate that CoReg improves statistical inference accuracy and replicability compared to conventional methods.

The field of artificial intelligence (AI), regarded as one of the most enigmatic areas of science, has witnessed exponential growth in the past decade including a remarkably wide array of applications, having already impacted our everyday lives. Advances in computing power and the design of sophisticated AI algorithms have enabled computers to outperform humans in a variety of tasks, especially in the areas of computer vision and speech recognition. Yet, AI's path has never been smooth, having essentially fallen apart twice in its lifetime ('winters' of AI), both after periods of popular success ('summers' of AI). We provide a brief rundown of AI's evolution over the course of decades, highlighting its crucial moments and major turning points from inception to the present. In doing so, we attempt to learn, anticipate the future, and discuss what steps may be taken to prevent another 'winter'.

Machine learning models for continuous outcomes often yield systematically biased predictions, particularly for values that largely deviate from the mean. Specifically, predictions for large-valued outcomes tend to be negatively biased (underestimating actual values), while those for small-valued outcomes are positively biased (overestimating actual values). We refer to this linear central tendency warped bias as the "systematic bias of machine learning regression". In this paper, we first demonstrate that this systematic prediction bias persists across various machine learning regression models, and then delve into its theoretical underpinnings. To address this issue, we propose a general constrained optimization approach designed to correct this bias and develop computationally efficient implementation algorithms. Simulation results indicate that our correction method effectively eliminates the bias from the predicted outcomes. We apply the proposed approach to the prediction of brain age using neuroimaging data. In comparison to competing machine learning regression models, our method effectively addresses the longstanding issue of "systematic bias of machine learning regression" in neuroimaging-based brain age calculation, yielding unbiased predictions of brain age.

In biomedical research, validation of a new scientific discovery is tied to the reproducibility of its experimental results. However, in genomics, the definition and implementation of reproducibility still remain imprecise. Here, we argue that genomic reproducibility, defined as the ability of bioinformatics tools to maintain consistent genomics results across technical replicates, is key to generating scientific knowledge and enabling medical applications. We first discuss different concepts of reproducibility and then focus on reproducibility in the context of genomics, aiming to establish clear definitions of relevant terms. We then focus on the role of bioinformatics tools and their impact on genomic reproducibility and assess methods of evaluating bioinformatics tools in terms of genomic reproducibility. Lastly, we suggest best practices for enhancing genomic reproducibility, with an emphasis on assessing the performance of bioinformatics tools through rigorous testing across multiple technical replicates.

In biomedical research, validation of a new scientific discovery is tied to the reproducibility of its experimental results. However, in genomics, the definition and implementation of reproducibility still remain imprecise. Here, we argue that genomic reproducibility, defined as the ability of bioinformatics tools to maintain consistent genomics results across technical replicates, is key to generating scientific knowledge and enabling medical applications. We first discuss different concepts of reproducibility and then focus on reproducibility in the context of genomics, aiming to establish clear definitions of relevant terms. We then focus on the role of bioinformatics tools and their impact on genomic reproducibility and assess methods of evaluating bioinformatics tools in terms of genomic reproducibility. Lastly, we suggest best practices for enhancing genomic reproducibility, with an emphasis on assessing the performance of bioinformatics tools through rigorous testing across multiple technical replicates.

Although substance use, such as alcohol intake, is known to be associated with cognitive decline during aging, its direct influence on the central nervous system remains incompletely understood. In this study, we investigate the influence of alcohol intake frequency on reduction of brain white matter microstructural integrity in the fornix, a brain region considered a promising marker of age-related microstructural degeneration, using a large UK Biobank (UKB) cohort with extensive phenomic data reflecting a comprehensive lifestyle profile. Two major challenges arise: 1) potentially nonlinear confounding effects from phenomic variables and 2) a limited proportion of participants with complete phenomic data. To address these challenges, we develop a novel ensemble learning framework tailored for robust causal inference and introduce a data integration step to incorporate information from UKB participants with incomplete phenomic data, improving estimation efficiency. Our analysis reveals that daily alcohol intake may significantly reduce fractional anisotropy, a neuroimaging-derived measure of white matter structural integrity, in the fornix and increase systolic and diastolic blood pressure levels. Moreover, extensive numerical studies demonstrate the superiority of our method over competing approaches in terms of estimation bias, while outcome regression-based estimators may be preferred when minimizing mean squared error is prioritized.

The measurement of retinal blood flow (RBF) in capillaries can provide a powerful biomarker for the early diagnosis and treatment of ocular diseases. However, no single modality can determine capillary flowrates with high precision. Combining erythrocyte-mediated angiography (EMA) with optical coherence tomography angiography (OCTA) has the potential to achieve this goal, as EMA can measure the absolute 2D RBF of retinal microvasculature and OCTA can provide the 3D structural images of capillaries. However, multimodal retinal image registration between these two modalities remains largely unexplored. To fill this gap, we establish MEMO, the first public multimodal EMA and OCTA retinal image dataset. A unique challenge in multimodal retinal image registration between these modalities is the relatively large difference in vessel density (VD). To address this challenge, we propose a segmentation-based deep-learning framework (VDD-Reg) and a new evaluation metric (MSD), which provide robust results despite differences in vessel density. VDD-Reg consists of a vessel segmentation module and a registration module. To train the vessel segmentation module, we further designed a two-stage semi-supervised learning framework (LVD-Seg) combining supervised and unsupervised losses. We demonstrate that VDD-Reg outperforms baseline methods quantitatively and qualitatively for cases of both small VD differences (using the CF-FA dataset) and large VD differences (using our MEMO dataset). Moreover, VDD-Reg requires as few as three annotated vessel segmentation masks to maintain its accuracy, demonstrating its feasibility.

Evaluating the effects of time-varying exposures is essential for longitudinal studies. The effect estimation becomes increasingly challenging when dealing with hundreds of time-dependent confounders. We propose a Marginal Structure Ensemble Learning Model (MASE) to provide a marginal structure model (MSM)-based robust estimator under the longitudinal setting. The proposed model integrates multiple machine learning algorithms to model propensity scores and a sequence of conditional outcome means such that it becomes less sensitive to model mis-specification due to any single algorithm and allows many confounders with potential non-linear confounding effects to reduce the risk of inconsistent estimation. Extensive simulation analysis demonstrates the superiority of MASE over benchmark methods (e.g., MSM, G-computation, Targeted maximum likelihood), yielding smaller estimation bias and improved inference accuracy. We apply MASE to the adolescent cognitive development study to investigate the time-varying effects of sleep insufficiency on cognitive performance. The results reveal an aggregated negative impact of insufficient sleep on cognitive development among youth.

Chest X-ray (CXR) datasets hosted on Kaggle, though useful from a data science competition standpoint, have limited utility in clinical use because of their narrow focus on diagnosing one specific disease. In real-world clinical use, multiple diseases need to be considered since they can co-exist in the same patient. In this work, we demonstrate how federated learning (FL) can be used to make these toy CXR datasets from Kaggle clinically useful. Specifically, we train a single FL classification model (`global`) using two separate CXR datasets -- one annotated for presence of pneumonia and the other for presence of pneumothorax (two common and life-threatening conditions) -- capable of diagnosing both. We compare the performance of the global FL model with models trained separately on both datasets (`baseline`) for two different model architectures. On a standard, naive 3-layer CNN architecture, the global FL model achieved AUROC of 0.84 and 0.81 for pneumonia and pneumothorax, respectively, compared to 0.85 and 0.82, respectively, for both baseline models (p>0.05). Similarly, on a pretrained DenseNet121 architecture, the global FL model achieved AUROC of 0.88 and 0.91 for pneumonia and pneumothorax, respectively, compared to 0.89 and 0.91, respectively, for both baseline models (p>0.05). Our results suggest that FL can be used to create global `meta` models to make toy datasets from Kaggle clinically useful, a step forward towards bridging the gap from bench to bedside.

Introduction: Approximately 23 million or 30% of epilepsy patients worldwide suffer from drug-resistant epilepsy (DRE). The unpredictability of seizure occurrences, which causes safety issues as well as social concerns, restrict the lifestyles of DRE patients. Surgical solutions and EEG-based solutions are very expensive, unreliable, invasive or impractical. The goal of this research was to employ improved technologies and methods to epilepsy patient physiological data and predict seizures up to two hours before onset, enabling non-invasive, affordable seizure prediction for DRE patients. Methods: This research used a 1D Convolutional Neural Network-Based Bidirectional Long Short-Term Memory network that was trained on a diverse set of epileptic patient physiological data to predict seizures. Transfer learning was further utilized to personalize and optimize predictions for specific patients. Clinical data was retrospectively obtained for nine epilepsy patients via wearable devices over a period of about three to five days from a prospectively maintained database. The physiological data included 54 seizure occurrences and included heart rate, blood volume pulse, accelerometry, body temperature, and electrodermal activity. Results and Conclusion: A general deep-learning model trained on the physiological data with randomly sampled test data achieved an accuracy of 91.94%. However, such a generalized deep learning model had varied performances on data from unseen patients. When the general model was personalized (further trained) with patient-specific data, the personalized model achieved significantly improved performance with accuracies as high as 97%. This preliminary research shows that patient-specific personalization may be a viable approach to achieve affordable, non-invasive seizure prediction that can improve the quality of life for DRE patients.

Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). Methods: We analyzed cross-sectional data of the multi-site, international hospital-based MRI-GENetics Interface Exploration (MRI-GENIE) study (July 1, 2014- March 16, 2019) with clinical brain magnetic resonance imaging (MRI) obtained on admission for index stroke and functional outcome assessment. Post-stroke outcome was determined using the modified Rankin Scale (mRS) score (0-6; 0: asymptomatic; 6 death) recorded between 60-190 days after stroke. Demographics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke) were recorded during index admission. Results: Utilizing the data from 912 acute ischemic stroke (AIS) patients (65+/-15 years of age, 58% male, 57% history of smoking, and 65% hypertensive) in a generalized linear model, brain volume (per 155.1cm^3 ) was associated with age (beta -0.3 (per 14.4 years)), male sex (beta 1.0) and prior stroke (beta -0.2). In the multivariable outcome model, brain volume was an independent predictor of mRS (beta -0.233), with reduced odds of worse long-term functional outcomes (OR: 0.8, 95% CI 0.7-0.9) in those with larger brain volumes. Conclusions: Larger brain volume quantified on clinical MRI of AIS patients at time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of mechanisms of post-stroke recovery.

Cerebrovascular disease is a leading cause of death globally. Prevention and early intervention are known to be the most effective forms of its management. Non-invasive imaging methods hold great promises for early stratification, but at present lack the sensitivity for personalized prognosis. Resting-state functional magnetic resonance imaging (rs-fMRI), a powerful tool previously used for mapping neural activity, is available in most hospitals. Here we show that rs-fMRI can be used to map cerebral hemodynamic function and delineate impairment. By exploiting time variations in breathing pattern during rs-fMRI, deep learning enables reproducible mapping of cerebrovascular reactivity (CVR) and bolus arrive time (BAT) of the human brain using resting-state CO2 fluctuations as a natural 'contrast media'. The deep-learning network was trained with CVR and BAT maps obtained with a reference method of CO2-inhalation MRI, which included data from young and older healthy subjects and patients with Moyamoya disease and brain tumors. We demonstrate the performance of deep-learning cerebrovascular mapping in the detection of vascular abnormalities, evaluation of revascularization effects, and vascular alterations in normal aging. In addition, cerebrovascular maps obtained with the proposed method exhibited excellent reproducibility in both healthy volunteers and stroke patients. Deep-learning resting-state vascular imaging has the potential to become a useful tool in clinical cerebrovascular imaging.