arXiv subjects

Daniel C. Alexander

Publications and source records attributed to Daniel C. Alexander.

At least 37 records · Page 2Linked to original sources

arXiv2025

Deep generative priors for 3D brain analysis

Diffusion models have recently emerged as powerful generative models in medical imaging. However, it remains a major challenge to combine these data-driven models with domain knowledge to guide brain imaging problems. In neuroimaging, Bayesian inverse problems have long provided a successful framework for inference tasks, where incorporating domain knowledge of the imaging process enables robust performance without requiring extensive training data. However, the anatomical modeling component of these approaches typically relies on classical mathematical priors that often fail to capture the complex structure of brain anatomy. In this work, we present the first general-purpose application of diffusion models as priors for solving a wide range of medical imaging inverse problems. Our approach leverages a score-based diffusion prior trained extensively on diverse brain MRI data, paired with flexible forward models that capture common image processing tasks such as super-resolution, bias field correction, inpainting, and combinations thereof. We further demonstrate how our framework can refine outputs from existing deep learning methods to improve anatomical fidelity. Experiments on heterogeneous clinical and research MRI data show that our method achieves state-of-the-art performance producing consistent, high-quality solutions without requiring paired training datasets. These results highlight the potential of diffusion priors as versatile tools for brain MRI analysis.

cs.CV↗

arXiv2025

HalluGen: Synthesizing Realistic and Controllable Hallucinations for Evaluating Image Restoration

Generative models are prone to hallucinations: plausible but incorrect structures absent in the ground truth. This issue is problematic in image restoration for safety-critical domains such as medical imaging, industrial inspection, and remote sensing, where such errors undermine reliability and trust. For example, in low-field MRI, widely used in resource-limited settings, restoration models are essential for enhancing low-quality scans, yet hallucinations can lead to serious diagnostic errors. Progress has been hindered by a circular dependency: evaluating hallucinations requires labeled data, yet such labels are costly and subjective. We introduce HalluGen, a diffusion-based framework that synthesizes realistic hallucinations with controllable type, location, and severity, producing perceptually realistic but semantically incorrect outputs (segmentation IoU drops from 0.86 to 0.36). Using HalluGen, we construct the first large-scale hallucination dataset comprising 4,350 annotated images derived from 1,450 brain MR images for low-field enhancement, enabling systematic evaluation of hallucination detection and mitigation. We demonstrate its utility in two applications: (1) benchmarking image quality metrics and developing Semantic Hallucination Assessment via Feature Evaluation (SHAFE), a feature-based metric with soft-attention pooling that improves hallucination sensitivity over traditional metrics; and (2) training reference-free hallucination detectors that generalize to real restoration failures. Together, HalluGen and its open dataset establish the first scalable foundation for evaluating hallucinations in safety-critical image restoration.

cs.CV↗

arXiv2025

LLM enhanced graph inference for long-term disease progression modelling

Understanding the interactions between biomarkers among brain regions during neurodegenerative disease is essential for unravelling the mechanisms underlying disease progression. For example, pathophysiological models of Alzheimer's Disease (AD) typically describe how variables, such as regional levels of toxic proteins, interact spatiotemporally within a dynamical system driven by an underlying biological substrate, often based on brain connectivity. However, current methods grossly oversimplify the complex relationship between brain connectivity by assuming a single-modality brain connectome as the disease-spreading substrate. This leads to inaccurate predictions of pathology spread, especially during the long-term progression period. Meanhwile, other methods of learning such a graph in a purely data-driven way face the identifiability issue due to lack of proper constraint. We thus present a novel framework that uses Large Language Models (LLMs) as expert guides on the interaction of regional variables to enhance learning of disease progression from irregularly sampled longitudinal patient data. By leveraging LLMs' ability to synthesize multi-modal relationships and incorporate diverse disease-driving mechanisms, our method simultaneously optimizes 1) the construction of long-term disease trajectories from individual-level observations and 2) the biologically-constrained graph structure that captures interactions among brain regions with better identifiability. We demonstrate the new approach by estimating the pathology propagation using tau-PET imaging data from an Alzheimer's disease cohort. The new framework demonstrates superior prediction accuracy and interpretability compared to traditional approaches while revealing additional disease-driving factors beyond conventional connectivity measures.

cs.AI↗

arXiv2025

CoCoLIT: ControlNet-Conditioned Latent Image Translation for MRI to Amyloid PET Synthesis

Synthesizing amyloid PET scans from the more widely available and accessible structural MRI modality offers a promising, cost-effective approach for large-scale Alzheimer's Disease (AD) screening. This is motivated by evidence that, while MRI does not directly detect amyloid pathology, it may nonetheless encode information correlated with amyloid deposition that can be uncovered through advanced modeling. However, the high dimensionality and structural complexity of 3D neuroimaging data pose significant challenges for existing MRI-to-PET translation methods. Modeling the cross-modality relationship in a lower-dimensional latent space can simplify the learning task and enable more effective translation. As such, we present CoCoLIT (ControlNet-Conditioned Latent Image Translation), a diffusion-based latent generative framework that incorporates three main innovations: (1) a novel Weighted Image Space Loss (WISL) that improves latent representation learning and synthesis quality; (2) a theoretical and empirical analysis of Latent Average Stabilization (LAS), an existing technique used in similar generative models to enhance inference consistency; and (3) the introduction of ControlNet-based conditioning for MRI-to-PET translation. We evaluate CoCoLIT's performance on publicly available datasets and find that our model significantly outperforms state-of-the-art methods on both image-based and amyloid-related metrics. Notably, in amyloid-positivity classification, CoCoLIT outperforms the second-best method with improvements of +10.5% on the internal dataset and +23.7% on the external dataset. The code and models of our approach are available at https://github.com/brAIn-science/CoCoLIT.

eess.IV↗

arXiv2025

Connectomics Informed by Large Language Models

Tractography is a unique method for mapping white matter connections in the brain, but tractography algorithms suffer from an inherent trade-off between sensitivity and specificity that limits accuracy. Incorporating prior knowledge of white matter anatomy is an effective strategy for improving accuracy and has been successful for reducing false positives and false negatives in bundle-mapping protocols. However, it is challenging to scale this approach for connectomics due to the difficulty in synthesising information relating to many thousands of possible connections. In this work, we develop and evaluate a pipeline using large language models (LLMs) to generate quantitative priors for connectomics, based on their knowledge of neuroanatomy. We benchmark our approach against an evaluation set derived from a gold-standard tractography atlas, identifying prompting techniques to elicit accurate connectivity information from the LLMs. We further identify strategies for incorporating external knowledge sources into the pipeline, which can provide grounding for the LLM and improve accuracy. Finally, we demonstrate how the LLM-derived priors can augment existing tractography filtering approaches by identifying true-positive connections to retain during the filtering process. We show that these additional connections can improve the accuracy of a connectome-based model of pathology spread, which provides supporting evidence that the connections preserved by the LLM are valid.

cs.CE↗

arXiv2025

Generalist versus Specialist Vision Foundation Models for Ocular Disease and Oculomics

Medical foundation models, pre-trained with large-scale clinical data, demonstrate strong performance in diverse clinically relevant applications. RETFound, trained on nearly one million retinal images, exemplifies this approach in applications with retinal images. However, the emergence of increasingly powerful and multifold larger generalist foundation models such as DINOv2 and DINOv3 raises the question of whether domain-specific pre-training remains essential, and if so, what gap persists. To investigate this, we systematically evaluated the adaptability of DINOv2 and DINOv3 in retinal image applications, compared to two specialist RETFound models, RETFound-MAE and RETFound-DINOv2. We assessed performance on ocular disease detection and systemic disease prediction using two adaptation strategies: fine-tuning and linear probing. Data efficiency and adaptation efficiency were further analysed to characterise trade-offs between predictive performance and computational cost. Our results show that although scaling generalist models yields strong adaptability across diverse tasks, RETFound-DINOv2 consistently outperforms these generalist foundation models in ocular-disease detection and oculomics tasks, demonstrating stronger generalisability and data efficiency. These findings suggest that specialist retinal foundation models remain the most effective choice for clinical applications, while the narrowing gap with generalist foundation models suggests that continued data and model scaling can deliver domain-relevant gains and position them as strong foundations for future medical foundation models.

eess.IV↗

arXiv2025

A Modality-agnostic Multi-task Foundation Model for Human Brain Imaging

Recent learning-based approaches have made astonishing advances in calibrated medical imaging like computerized tomography (CT), yet they struggle to generalize in uncalibrated modalities -- notably magnetic resonance (MR) imaging, where performance is highly sensitive to the differences in MR contrast, resolution, and orientation. This prevents broad applicability to diverse real-world clinical protocols. Here we introduce BrainFM, a modality-agnostic, multi-task vision foundation model for human brain imaging. With the proposed "mild-to-severe" intra-subject generation and "real-synth" mix-up training strategy, BrainFM is resilient to the appearance of acquired images (e.g., modality, contrast, deformation, resolution, artifacts), and can be directly applied to five fundamental brain imaging tasks, including image synthesis for CT and T1w/T2w/FLAIR MRI, anatomy segmentation, scalp-to-cortical distance, bias field estimation, and registration. We evaluate the efficacy of BrainFM on eleven public datasets, and demonstrate its robustness and effectiveness across all tasks and input modalities. Code is available at https://github.com/jhuldr/BrainFM.

cs.CV↗

arXiv2025

Decoding Gray Matter: large-scale analysis of brain cell morphometry to inform microstructural modeling of diffusion MR signals

The structure of grey matter has long been a key focus in neuroscience, as cell morphology varies by type and can be affected by neurological conditions. Understanding these variations is essential for studying brain function and disease. Diffusion-weighted MRI (dMRI) is a powerful non-invasive tool for examining cellular microstructure in vivo. However, for dMRI to accurately reflect cellular features, it is crucial to determine which aspects of morphology influence its measurements. Proper interpretation of dMRI data depends on understanding its sensitivity to different cellular characteristics. Despite growing interest in cellular morphology, there has been no systematic report on the key features defining different neural cell types. To address this, we analyzed over 11,500 three-dimensional cellular reconstructions across three species and nine cell types, establishing reference values for critical morphological traits. These traits fall into three categories: structural features that define the cell's skeletal framework, shape features that describe spatial organization, and topological features that break down cellular structure to distinguish cell types. Beyond reporting these reference values, we examine their relevance for dMRI, identifying which neural features dMRI can detect and which cell types may be distinguishable. To complement the statistical analysis, we also provide high resolution 3D surface meshes representative of each cell type and species. This work provides essential benchmarks for grey matter research, offering new guidelines on linking neuroimaging measurements to neurobiology. These reference values will be a valuable resource for neuroscientists and neuroimaging researchers, aiding in the interpretation of imaging data and the refinement of brain tissue models.

physics.bio-ph↗

arXiv2025

Impact of Clinical Image Quality on Efficient Foundation Model Finetuning

Foundation models in medical imaging have shown promising label efficiency, achieving high performance on downstream tasks using only a fraction of the annotated data otherwise required. In this study, we evaluate this potential in the context of prostate multiparametric MRI using ProFound, a recently developed domain-specific vision foundation model pretrained on large-scale prostate MRI datasets. We investigate the impact of variable image quality on the label-efficient finetuning, by quantifying the generalisability of the finetuned models. We conduct a comprehensive set of experiments by systematically varying the ratios of high- and low-quality images in the finetuning and evaluation sets. Our findings indicate that image quality distribution and its finetune-and-test mismatch significantly affect model performance. In particular: a) Varying the ratio of high- to low-quality images between finetuning and test sets leads to notable differences in downstream performance; and b) The presence of sufficient high-quality images in the finetuning set is critical for maintaining strong performance, whilst the importance of matched finetuning and testing distribution varies between different downstream tasks, such as automated radiology reporting and prostate cancer detection. Importantly, experimental results also show that, although finetuning requires significantly less labeled data compared to training from scratch when the quality ratio is consistent, this label efficiency is not independent of the image quality distribution. For example, we show cases that, without sufficient high-quality images in finetuning, finetuned models may fail to outperform those without pretraining.

cs.CV↗

arXiv2025

A Stage-Aware Mixture of Experts Framework for Neurodegenerative Disease Progression Modelling

The long-term progression of neurodegenerative diseases is commonly conceptualized as a spatiotemporal diffusion process that consists of a graph diffusion process across the structural brain connectome and a localized reaction process within brain regions. However, modeling this progression remains challenging due to 1) the scarcity of longitudinal data obtained through irregular and infrequent subject visits and 2) the complex interplay of pathological mechanisms across brain regions and disease stages, where traditional models assume fixed mechanisms throughout disease progression. To address these limitations, we propose a novel stage-aware Mixture of Experts (MoE) framework that explicitly models how different contributing mechanisms dominate at different disease stages through time-dependent expert weighting.Data-wise, we utilize an iterative dual optimization method to properly estimate the temporal position of individual observations, constructing a co hort-level progression trajectory from irregular snapshots. Model-wise, we enhance the spatial component with an inhomogeneous graph neural diffusion model (IGND) that allows diffusivity to vary based on node states and time, providing more flexible representations of brain networks. We also introduce a localized neural reaction module to capture complex dynamics beyond standard processes.The resulting IGND-MoE model dynamically integrates these components across temporal states, offering a principled way to understand how stage-specific pathological mechanisms contribute to progression. The stage-wise weights yield novel clinical insights that align with literature, suggesting that graph-related processes are more influential at early stages, while other unknown physical processes become dominant later on.

cs.LG↗

arXiv2025

Tackling Hallucination from Conditional Models for Medical Image Reconstruction with DynamicDPS

Hallucinations are spurious structures not present in the ground truth, posing a critical challenge in medical image reconstruction, especially for data-driven conditional models. We hypothesize that combining an unconditional diffusion model with data consistency, trained on a diverse dataset, can reduce these hallucinations. Based on this, we propose DynamicDPS, a diffusion-based framework that integrates conditional and unconditional diffusion models to enhance low-quality medical images while systematically reducing hallucinations. Our approach first generates an initial reconstruction using a conditional model, then refines it with an adaptive diffusion-based inverse problem solver. DynamicDPS skips early stage in the reverse process by selecting an optimal starting time point per sample and applies Wolfe's line search for adaptive step sizes, improving both efficiency and image fidelity. Using diffusion priors and data consistency, our method effectively reduces hallucinations from any conditional model output. We validate its effectiveness in Image Quality Transfer for low-field MRI enhancement. Extensive evaluations on synthetic and real MR scans, including a downstream task for tissue volume estimation, show that DynamicDPS reduces hallucinations, improving relative volume estimation by over 15% for critical tissues while using only 5% of the sampling steps required by baseline diffusion models. As a model-agnostic and fine-tuning-free approach, DynamicDPS offers a robust solution for hallucination reduction in medical imaging. The code will be made publicly available upon publication.

eess.IV↗

arXiv2025

Analysis of Image-and-Text Uncertainty Propagation in Multimodal Large Language Models with Cardiac MR-Based Applications

Multimodal large language models (MLLMs) can process and integrate information from multimodality sources, such as text and images. However, interrelationship among input modalities, uncertainties due to individual uni-modal data and potential clinical applications following such an uncertainty decomposition are yet fully understood in the context of large-scale MLLMs. In this work, we propose a multimodal uncertainty propagation model (MUPM) based on uncertainty propagation, to characterise the relationship among the uncertainties arising from image-only, text-only, and joint image-text variations in MLLM inputs. Using real clinical data consisting of cardiac MR scans and digital health records, we describe that MUPMs can be optimised robustly with a few samples. We then show that the fitted MUPMs are generalisable across different input data distributions and, perhaps surprisingly, across different downstream tasks. Such a transferability may be explained by the shared pretraining, comparatively light MLLM fine-tuning, along with the low-dimensional nature of the MUPMs. More importantly, this learned transferability, quantifying the relationship between these uncertainties, led to direct clinical applications in which uncertainties may be estimated and thus analysed robustly for varying data or even a novel set of cardiac disease prediction tasks. In addition, we show experimentally the efficiency in multimodal data required for estimating the overall uncertainty and its ability to identify redundant factors, both of which are considered practical yet clinically useful applications with the proposed MUPMs. Codes are available at https://github.com/yucheng722/MUPM.

cs.CV↗

arXiv2025

A computationally frugal open-source foundation model for thoracic disease detection in lung cancer screening programs

Low-dose computed tomography (LDCT) imaging employed in lung cancer screening (LCS) programs is increasing in uptake worldwide. LCS programs herald a generational opportunity to simultaneously detect cancer and non-cancer-related early-stage lung disease. Yet these efforts are hampered by a shortage of radiologists to interpret scans at scale. Here, we present TANGERINE, a computationally frugal, open-source vision foundation model for volumetric LDCT analysis. Designed for broad accessibility and rapid adaptation, TANGERINE can be fine-tuned off the shelf for a wide range of disease-specific tasks with limited computational resources and training data. Relative to models trained from scratch, TANGERINE demonstrates fast convergence during fine-tuning, thereby requiring significantly fewer GPU hours, and displays strong label efficiency, achieving comparable or superior performance with a fraction of fine-tuning data. Pretrained using self-supervised learning on over 98,000 thoracic LDCTs, including the UK's largest LCS initiative to date and 27 public datasets, TANGERINE achieves state-of-the-art performance across 14 disease classification tasks, including lung cancer and multiple respiratory diseases, while generalising robustly across diverse clinical centres. By extending a masked autoencoder framework to 3D imaging, TANGERINE offers a scalable solution for LDCT analysis, departing from recent closed, resource-intensive models by combining architectural simplicity, public availability, and modest computational requirements. Its accessible, open-source lightweight design lays the foundation for rapid integration into next-generation medical imaging tools that could transform LCS initiatives, allowing them to pivot from a singular focus on lung cancer detection to comprehensive respiratory disease management in high-risk populations.

eess.IV↗

arXiv2025

Brain Latent Progression: Individual-based Spatiotemporal Disease Progression on 3D Brain MRIs via Latent Diffusion

The growing availability of longitudinal Magnetic Resonance Imaging (MRI) datasets has facilitated Artificial Intelligence (AI)-driven modeling of disease progression, making it possible to predict future medical scans for individual patients. However, despite significant advancements in AI, current methods continue to face challenges including achieving patient-specific individualization, ensuring spatiotemporal consistency, efficiently utilizing longitudinal data, and managing the substantial memory demands of 3D scans. To address these challenges, we propose Brain Latent Progression (BrLP), a novel spatiotemporal model designed to predict individual-level disease progression in 3D brain MRIs. The key contributions in BrLP are fourfold: (i) it operates in a small latent space, mitigating the computational challenges posed by high-dimensional imaging data; (ii) it explicitly integrates subject metadata to enhance the individualization of predictions; (iii) it incorporates prior knowledge of disease dynamics through an auxiliary model, facilitating the integration of longitudinal data; and (iv) it introduces the Latent Average Stabilization (LAS) algorithm, which (a) enforces spatiotemporal consistency in the predicted progression at inference time and (b) allows us to derive a measure of the uncertainty for the prediction at the global and voxel level. We train and evaluate BrLP on 11,730 T1-weighted (T1w) brain MRIs from 2,805 subjects and validate its generalizability on an external test set comprising 2,257 MRIs from 962 subjects. Our experiments compare BrLP-generated MRI scans with real follow-up MRIs, demonstrating state-of-the-art accuracy compared to existing methods. The code is publicly available at: https://github.com/LemuelPuglisi/BrLP.

cs.CV↗

arXiv2025

Unscrambling disease progression at scale: fast inference of event permutations with optimal transport

Disease progression models infer group-level temporal trajectories of change in patients' features as a chronic degenerative condition plays out. They provide unique insight into disease biology and staging systems with individual-level clinical utility. Discrete models consider disease progression as a latent permutation of events, where each event corresponds to a feature becoming measurably abnormal. However, permutation inference using traditional maximum likelihood approaches becomes prohibitive due to combinatoric explosion, severely limiting model dimensionality and utility. Here we leverage ideas from optimal transport to model disease progression as a latent permutation matrix of events belonging to the Birkhoff polytope, facilitating fast inference via optimisation of the variational lower bound. This enables a factor of 1000 times faster inference than the current state of the art and, correspondingly, supports models with several orders of magnitude more features than the current state of the art can consider. Experiments demonstrate the increase in speed, accuracy and robustness to noise in simulation. Further experiments with real-world imaging data from two separate datasets, one from Alzheimer's disease patients, the other age-related macular degeneration, showcase, for the first time, pixel-level disease progression events in the brain and eye, respectively. Our method is low compute, interpretable and applicable to any progressive condition and data modality, giving it broad potential clinical utility.

cs.LG↗

arXiv2025

4D VQ-GAN: Synthesising Medical Scans at Any Time Point for Personalised Disease Progression Modelling of Idiopathic Pulmonary Fibrosis

Understanding the progression trajectories of diseases is crucial for early diagnosis and effective treatment planning. This is especially vital for life-threatening conditions such as Idiopathic Pulmonary Fibrosis (IPF), a chronic, progressive lung disease with a prognosis comparable to many cancers. Computed tomography (CT) imaging has been established as a reliable diagnostic tool for IPF. Accurately predicting future CT scans of early-stage IPF patients can aid in developing better treatment strategies, thereby improving survival outcomes. In this paper, we propose 4D Vector Quantised Generative Adversarial Networks (4D-VQ-GAN), a model capable of generating realistic CT volumes of IPF patients at any time point. The model is trained using a two-stage approach. In the first stage, a 3D-VQ-GAN is trained to reconstruct CT volumes. In the second stage, a Neural Ordinary Differential Equation (ODE) based temporal model is trained to capture the temporal dynamics of the quantised embeddings generated by the encoder in the first stage. We evaluate different configurations of our model for generating longitudinal CT scans and compare the results against ground truth data, both quantitatively and qualitatively. For validation, we conduct survival analysis using imaging biomarkers derived from generated CT scans and achieve a C-index comparable to that of biomarkers derived from the real CT scans. The survival analysis results demonstrate the potential clinical utility inherent to generated longitudinal CT scans, showing that they can reliably predict survival outcomes.

eess.IV↗

arXiv2024

A 3D deep learning classifier and its explainability when assessing coronary artery disease

Early detection and diagnosis of coronary artery disease (CAD) could save lives and reduce healthcare costs. The current clinical practice is to perform CAD diagnosis through analysing medical images from computed tomography coronary angiography (CTCA). Most current approaches utilise deep learning methods but require centerline extraction and multi-planar reconstruction. These indirect methods are not designed in a clinician-friendly manner, and they complicate the interventional procedure. Furthermore, the current deep learning methods do not provide exact explainability and limit the usefulness of these methods to be deployed in clinical settings. In this study, we first propose a 3D Resnet-50 deep learning model to directly classify normal subjects and CAD patients on CTCA images, then we demonstrate a 2D modified U-Net model can be subsequently employed to segment the coronary arteries. Our proposed approach outperforms the state-of-the-art models by 21.43% in terms of classification accuracy. The classification model with focal loss provides a better and more focused heat map, and the segmentation model provides better explainability than the classification-only model. The proposed holistic approach not only provides a simpler and clinician-friendly solution but also good classification accuracy and exact explainability for CAD diagnosis.

eess.IV↗

arXiv2024

MRI Parameter Mapping via Gaussian Mixture VAE: Breaking the Assumption of Independent Pixels

We introduce and demonstrate a new paradigm for quantitative parameter mapping in MRI. Parameter mapping techniques, such as diffusion MRI and quantitative MRI, have the potential to robustly and repeatably measure biologically-relevant tissue maps that strongly relate to underlying microstructure. Quantitative maps are calculated by fitting a model to multiple images, e.g. with least-squares or machine learning. However, the overwhelming majority of model fitting techniques assume that each voxel is independent, ignoring any co-dependencies in the data. This makes model fitting sensitive to voxelwise measurement noise, hampering reliability and repeatability. We propose a self-supervised deep variational approach that breaks the assumption of independent pixels, leveraging redundancies in the data to effectively perform data-driven regularisation of quantitative maps. We demonstrate that our approach outperforms current model fitting techniques in dMRI simulations and real data. Especially with a Gaussian mixture prior, our model enables sharper quantitative maps, revealing finer anatomical details that are not presented in the baselines. Our approach can hence support the clinical adoption of parameter mapping methods such as dMRI and qMRI.

eess.IV↗