Longitudinal Medical Image Analysis

Longitudinal models forecast how a patient's imaging state evolves, but accuracy does not show whether the patient's observed trajectory drives the prediction. A population-average forecast may be useful but cannot establish a patient-specific world-model claim. We introduce Patient, Place, Prior (P$^3$), an audit asking whether a forecast benefits from the patient's longitudinal imaging history (Patient), benefits from patient-matched externally supplied spatial support (Place), and gains predictive value beyond a population-average prediction under matched support and context (Prior). We also propose Cancer JEPA, a one-step model that forecasts frozen representations of future breast dynamic contrast-enhanced MRI examinations during neoadjuvant therapy. It adds a lesion-constrained neural correction, trained with an occlusion-based latent objective, to a patient-conditioned low-complexity reduced-rank regression baseline. This factorization permits a post-hoc P$^3$ audit of the frozen model. In a validation cohort previously used in development, forecast error is lower when the neural correction receives the patient's history rather than another patient's and patient-matched lesion occupancy maps rather than substituted maps. However, the descriptive 95% interval comparing the correction computed from patient history with the population-average neural correction includes zero. P$^3$ thus separates input use from evidence of patient-specific predictive value beyond a population-level pattern.

Multi-tumor segmentation is important for early cancer detection and allows radiologists to visualize, verify, and understand AI predictions. However, tumor segmentation masks are expensive, time-consuming, and unavailable for many tumor types in public data. Instead, hospitals have vast, readily available data that can guide segmentation: radiology reports, longitudinal images, and multi-phase images. We use this readily available data to substitute for tumor masks in training AI for tumor segmentation. To this end, we propose a new architecture, RT-Super. It has a teacher network, which analyzes the patient's longitudinal images and reports to create high-quality tumor masks. These masks train a student network, which sees a single image and no report. At inference, when longitudinal images and reports are unavailable, we use the student. RT-Super uses a new CNN-Transformer architecture and novel Consistency Losses that exploit tumor location consistency across longitudinal images. We train RT-Super to segment esophagus, uterus and spleen tumors, which have few or no public masks. Even without training masks, RT-Super can segment these tumors and surpass public AI models. Overall, we demonstrate that learning from longitudinal images, multi-phase images, and reports can overcome mask scarcity and advance multi-cancer detection and segmentation. Code: https://github.com/MrGiovanni/RT-Super

Medical vision-language pre-training largely follows a visit-level image-report matching paradigm, aligning paired images and reports at individual visits. While effective for static cross-modal correspondence, this paradigm provides limited supervision for longitudinal clinical change, such as whether abnormalities improve, remain stable, or worsen over time. Learning such change is challenging because temporal semantics are implicit in free-text reports, and different abnormalities within the same patient may evolve asynchronously or even in opposite directions. We propose MedCTA, which reframes medical vision-language pre-training from visit-level cross-modal matching to learning clinical change. Rather than compressing a patient history into a single temporal representation, MedCTA models clinical change at two complementary scopes. At the abnormality scope, clinically grounded queries construct abnormality-conditioned visual and textual trajectories to capture heterogeneous abnormality evolution. At the patient-course scope, global image and report sequences are modeled to capture overall clinical progression beyond any individual abnormality. Structured trend supervision is extracted from longitudinal reports by an offline LLM parser, removing the need for manual temporal annotations. Combined with static image-report alignment, MedCTA learns representations that preserve visit-level cross-modal correspondence while encoding longitudinal change semantics. Experiments on temporal image classification, image-text retrieval, and zero-shot classification show consistent gains over strong medical vision-language baselines.

A diffusion model can predict a follow-up medical scan from a baseline, but a clinician needs a per-voxel map of where that prediction can be trusted. Many such maps approximate the diagonal of the Tweedie posterior covariance, and are evaluated against another approximation of it, so whether the estimator or the target limits them is unclear. We compute the exact diagonal on six checkpoints across fourteen model-corpus conditions. Hutchinson at M=200 tracks it at rank agreement of at least 0.92 everywhere, yet in four of the fourteen the exact diagonal is anti-correlated with the denoising error, reaching -0.13, so a faithful estimator reproduces that reversal. All four are real-image conditions; on the models' own samples the reversal does not appear, so evaluating on generated samples flatters this family. What limits these maps is the target, not the estimator. We then introduce Tweedie Probe-Tangent (T-PT), a gradient-free residual probe that corrupts one model-supported prediction repeatedly and measures the voxel-wise variance of the denoiser's response. T-PT reads a different functional of the same Jacobian, and its exact second-order form ranks with the diagonal wherever the diagonal reverses; at thirty probes it returns a map too unstable to reproduce that ranking, while Hutchinson at M=5 already reproduces it, so T-PT there is not evidence against the reversal. We offer it as an instrument, not a better approximation. On brain MRI at full resolution, where every Jacobian-based estimator we test runs out of memory, T-PT leads a twenty-chain Monte-Carlo ensemble on five of eight endpoints inside tissue and trails it on none, at 16x fewer network evaluations; over the whole volume the ensemble leads, and fifty chains close the tissue gap. On lung CT the ensemble is ahead throughout. Both lose most of their discrimination where the change is, which remains open.

Foundation model embeddings of screening mammograms may encode pre-diagnostic tissue change without task-specific adaptation. We tested whether embeddings move faster along a data-derived "cancer direction" in women later biopsied for cancer than in matched screen-negative controls, and whether this depends on pretraining domain. We studied 1,773 biopsied women (785 malignant, 988 biopsy-negative) and 1,773 matched controls, each with at least two annual screening exams before their index exam. An identical pipeline was applied to four 2D models: Mammo-CLIP (MC, out-of-distribution mammography), HOPPR (in-distribution mammography), MedImageInsight (MII, general medical imaging), and BiomedCLIP (biomedical vision-language pretraining on literature figures). Breast-level embeddings quantified longitudinal movement along the cancer direction. We compared cases and controls using a between-patient design with complementary mixed-effects analysis, and biopsied versus healthy contralateral breasts within patients. Under matched modality in MII embedding space, malignant cases drifted significantly faster than controls in the first two screening intervals preceding the index exam; biopsy-negative cases showed significance only in the first. MC differences were significant in the first interval for both biopsy groups. Within-patient comparisons showed a broadly similar pattern, with MC significance extending to the second interval in both groups and HOPPR showing significance at interval 1. BiomedCLIP showed no significant differences in either design or biopsy group. Overall, directional embedding velocity emerges as a property of clinically grounded rather than general biomedical pretraining, showing that foundation model embeddings can encode pre-diagnostic mammographic change without task-specific adaptation.

Forecasting anatomical changes such as tumor growth and neurodegeneration is a challenging generative vision task. Morphological evolution is subtle relative to static anatomy, highly patient-specific, and inherently stochastic. Existing methods struggle with several issues: deterministic networks ignore biological stochasticity, while standard diffusion models require computationally prohibitive multi-pass sampling to quantify uncertainty. We propose MUMINS (Metadata-conditioned Uncertainty-aware Medical Image Next-state Synthesis), an efficient diffusion framework that jointly diffuses a baseline scan and its follow-up residual, summed to synthesize the follow-up scan, while concurrently predicting a spatial uncertainty map, in a single reverse diffusion process. Conditioned on the time interval and relevant metadata, it preserves fine-grained anatomy by dynamically re-injecting the baseline as a soft anchor at every denoising step, and a negative-log-likelihood head learns the uncertainty map to explicitly flag error-prone regions. Designed without organ-specific heuristics, the same architecture is reused across anatomies via separate, dataset-specific retraining. Extensive evaluations demonstrate that dataset-specific retraining of MUMINS matches or outperforms dedicated, domain-specific state-of-the-art methods on lung CT (PNG) and brain MRI (OASIS-3). Project page: https://github.com/aolivtous/MUMINS.

Recent advances in angiographic imaging have enabled longitudinal visualization of the microvasculature. Image processing pipelines based on vessel graphs are able to resolve subtle temporal changes at the level of individual blood vessels. However, current strategies for graph extraction, refinement, and matching are highly sensitive, with even minuscule differences in the underlying segmentation map resulting in substantially different vessel graphs. These artifacts severely inhibit the ability to accurately match sequential vessel graphs of the same subject over time. To address this problem, we propose a strategy that matches graphs before jointly refining them. Specifically, we perform an early matching after basic graph extraction before removing spurious bulges and merging junctions in both graphs using joint information. In experiments with complex retinal vessel graphs, we demonstrate that this strategy results in a higher matched area without graph fragmentation compared to separate or no refinement, respectively.

Post-treatment MRI in patients with glioma provides serial observations for updating patient-specific tumor-state proxy estimates, but variable appearances and trajectories complicate forecasting. We formulate forecasting as an observation-aware digital-twin update in which an intermediate observation anchors the patient-specific state. Among 203 patients and 594 follow-up time points, a predefined no-new-treatment criterion retained 120 of 236 candidate triplets, split into 81/24/15 training/validation/test triplets at the patient level. Each time point was represented by a continuous voxel-wise tumor-state proxy map in [0,1] derived from MRI lesion labels. A SegMamba-based single-step forecaster predicted update proposals from multimodal source-state tensors. Observation-Anchored Selective Assimilation (OASA) retained the observed intermediate proxy as the state anchor and selectively applied updates through a validation-selected tiered case-level rule and voxel-wise soft gate. We compared initial-scan forecasting, rollout without assimilation, latest-observation persistence, direct prediction, OASA, OASA + calibration, and morphological dilation. Checkpoints, OASA rules, and calibration thresholds were selected using validation data only. Across three seeds on 15 held-out test triplets, OASA maintained Dice at $\tau$ = 0.2 comparable to persistence (0.6071 $\pm$ 0.0025 vs. 0.6070) while yielding numerically higher Dice at $\tau$ = 0.5 (0.4269 $\pm$ 0.0079 vs. 0.3981), with a small RMSE increase. Calibration increased Dice at $\tau$ = 0.2 to 0.6178 $\pm$ 0.0025, increased false-positive (FP) support (11,836$\rightarrow$18,663), and reduced false-negative (FN) support (22,107$\rightarrow$17,536). This reflects near-threshold support calibration rather than improved biological predictive capability. Code is publicly available at https://github.com/jsudg436/longitudinal-proxy-forecasting.

Modelling how a disease progresses over time requires longitudinal imaging cohorts, which are scarce and small, whereas cross-sectional data -- one image per participant -- is abundant. Self-supervised pre-training on such data offers a way to bridge this gap, but it is unclear which strategy best supports progression modelling, or how that answer depends on the amount of labelled longitudinal data. We study this for age-related macular degeneration (AMD), pre-training encoders on the large cross-sectional NAKO cohort and predicting time to late AMD on the longitudinal AREDS dataset. We compare in-house self-supervised encoders against a general-purpose (DINOv2) and a domain-specific (RETFound) foundation model, across contrastive, masked-autoencoding, and self-distillation objectives, under frozen and fine-tuned protocols, and across labelled training sets from 100 to 32,250 examples. Which model performs best depends on how the encoder is used. When the encoder is frozen and labels are few -- the regime typical of longitudinal cohorts -- pre-trained representations reach clinically reasonable discrimination from a few hundred labelled samples, while models trained from scratch do not; this advantage fades under fine-tuning. Transfer is governed by the self-supervision objective rather than corpus scale or domain match, so that an encoder pre-trained on a modest cross-sectional cohort matches or exceeds a far larger in-domain foundation model. Together, these results offer a practical recipe for building progression models where longitudinal data is scarce: a frozen self-supervised encoder with a lightweight survival head.

Brain age estimation has become a popular research proxy for assessing brain health and disease, yet longitudinal trajectories of brain ageing are still poorly defined, and clinical use is limited. Building on existing Siamese longitudinal frameworks, we develop Brain-Predicted Age Acceleration (Brain-PACE) to directly estimate the pace of structural brain ageing from paired T1-weighted MRI. Brain-PACE identified accelerated ageing in $42.6$% of participants with mild cognitive impairment. Faster Brain-PACE was associated with greater functional and cognitive impairment (FAQ; $r=0.35$, ADAS13; $r=0.30$, CDR-SB; $r=0.32$) and greater regional tau burden in the posterior cingulate ($r=0.59$), precuneus ($r=0.47$), and entorhinal cortex ($r=0.37$). These associations were stronger than those observed when pace was calculated indirectly from repeated cross-sectional brain age estimates, suggesting that direct longitudinal modelling captures complementary information relevant to ongoing pathological change. Methodologically, Brain-PACE extends the LILAC framework by combining spatial attention with soft label distribution learning and a Cram'er distance objective, improving probabilistic performance and reducing prediction bias while providing measures of predictive uncertainty. Together, these findings support Brain-PACE as a complementary longitudinal imaging phenotype with sensitivity to relevant clinical and biological changes in early neurodegeneration.

Longitudinal characterization of multiple sclerosis (MS) lesions remains constrained by the lack of frameworks capable of establishing consistent instance-level correspondences across time. Conventional segmentation approaches produce semantic lesion masks at each visit and therefore fail to capture the complex instance temporal patterns associated with lesion appearance, disappearance, splitting, or merging. This study presents a comparative evaluation of five strategies for automated tracking of spinal cord MS lesions in longitudinal MRI data from a multi-site cohort. The investigated strategies rely either on deformable registration or on a spinal anatomical reference system, and encompass overlap-based matching, coordinate-based Hungarian algorithm, gradient-boosted classification, and Siamese model classification. Tracking accuracy is quantified using instance-level true positives, false positives, and false negatives, allowing to assess the presence of one-to-many and many-to-one associations. Results show best performance for the registration-based overlap method. This study provides the first systematic analysis of lesion-instance correspondence in the spinal cord and outlines the strengths and limitations of registration-based and registration-free paradigms for longitudinal MS assessment. The code is available at http://github.com/ivadomed/longitudinal-sc-ms-lesion-tracking .

We present a unified computational approach to tensor-based morphometry in detecting the brain surface shape differences between two clinical groups based on magnetic resonance images. Our approach is novel in a sense that we combined surface modeling, surface data smoothing and statistical analysis in a coherent unified mathematical framework. The cerebral cortex has the topology of a 2D highly convoluted sheet. Between two different clinical groups, the local surface area and curvature of the cortex may differ. It is highly likely that such surface shape differences are not uniform over the whole cortex. By computing how such surface metrics differ, the regions of the most rapid structural differences can be localized. To increase the signal to noise ratio, diffusion smoothing based on the explicit estimation of Laplace-Beltrami operator has been developed and applied to the surface metrics. As an illustration, we demonstrate how this new tensor-based surface morphometry can be applied in localizing the cortical regions of the gray matter tissue growth and loss in the brain images longitudinally collected in the group of children.

Neuroradiologists rarely read a brain MRI in isolation, yet automated brain-MRI report generation has been built almost entirely for single studies. Temporal analysis has been explored on chest radiography and chest CT, but to our knowledge, longitudinal reporting for brain MRI, where interval change is often subtle and spatially distributed, remains unaddressed. We present BrainDiff, the first longitudinal vision-language system for brain MRI. BrainDiff outperforms both frontier general-purpose and single-study neuroimaging models on the same patient pairs. Moreover, BrainDiff retains 91% of internal RadGraph-XL entity+relation F1 (rg_er) on an external, cross-hospital cohort. Beyond the system, we contribute three analyses. First, we identify two independent grounding levers: a counterfactual objective with prior-report dropout, which increases measured image reliance by ~47%, and a staged curriculum. Together, these interventions raise image reliance 2.5-fold from the baseline. Second, we provide a factorial over prior-report availability and image identity, isolating a visual contribution of +0.0387 rg_er, which grows when the prior report is withheld. Third, a cheap change-decodability test for candidate backbones shows that interval change is decodable far more weakly than single-study pathology (0.60 vs. 0.77 AUROC). Code is publicly available at https://github.com/jhuldr/BrainDiff.

Recent radiology multi-modal language models have made substantial progress in chest X-ray report generation, visual question answering, and temporal reasoning. While longitudinal chest X-ray interpretation compares sequential examinations to describe change, visual grounding aims to connect clinical language with localized image evidence. Although longitudinal modeling and visual grounding have each advanced radiology language models, how localized visual evidence can support longitudinal interpretation remains under-explored. We introduce CheXGround, a region-grounded longitudinal chest X-ray language model that represents paired studies through corresponding anatomical regions. CheXGround extracts anatomical regions from current and prior radiographs, encodes them as temporally enhanced Region-of-Interest (ROI) tokens, and combines them with global temporal image context during generation. To connect these region tokens with clinical text, we propose Temporal Region--Phrase Alignment, a pretraining objective that aligns temporal anatomical representations with localized report phrases. We evaluate CheXGround on single-study and longitudinal Visual Question Answering (VQA), longitudinal findings generation, temporal grounded VQA, and anatomical grounding. Across these tasks, CheXGround improves clinical language quality, temporal reasoning, and localization accuracy over recent baselines. Our results suggest that organizing longitudinal evidence at the anatomical level is a strong representation for grounded radiology language modeling. Project page: https://adonaydem.github.io/chexground-website

Magnetic Resonance Imaging (MRI) interpretation is fundamental to clinical decision-making, requiring radiologists to integrate multi-view anatomical planes across sequential timepoints while precisely localizing interval changes. However, existing vision-language benchmarks remain confined to single-timepoint, single-view interpretation, failing to capture the temporal-spatial reasoning essential to radiologic practice. We introduce the Time-Aware Multi-View MRI Benchmark, an evaluation framework unifying multi-view anatomical input, temporal reasoning across longitudinal scans, and structured localization guidance. The benchmark comprises 3,920 expert-verified question-answer pairs derived from 890 patients across over 3,200 longitudinal MRI timepoints, drawn from seven clinical cohorts covering glioblastoma, neurodegeneration, vestibular schwannoma, and brain metastases, in open-ended, multiple-choice, and binary formats, requiring models to identify anatomical regions of maximal change, characterize progression across sequences and views, and provide structured guidance specifying boundaries, imaging features, and confounders. Experiments across 16 vision-language models reveal moderate temporal alignment but systematic failure on change direction recognition and volumetric quantification, while multi-view inputs improve spatial localization yet degrade temporal reasoning in compact architectures. Our benchmark provides a systematic framework for evaluating progression tracking, interval change localization, and temporal ordering, which are essential for clinical deployment. Code, evaluation splits, and the dataset are available at: https://github.com/wafaAlghallabi/Time-Aware-MRI.

In medical imaging, the clinical value of Computed Tomography (CT) lies not only in depicting current disease status, but crucially in enabling longitudinal comparison of serial scans to determine disease evolution, a process that underpins response assessment, recurrence detection, and ongoing patient management. Yet, despite this central role of temporal comparison in clinical decision-making, existing medical foundation models remain largely confined to single-study understanding, leaving temporally grounded cross-examination insufficiently addressed. To address this gap, we study longitudinal imaging difference reporting, a task in which a model takes two temporally separated scans from the same patient and generates a clinically meaningful report describing interval changes between them. We introduce CT-$Δ$Bench, a dedicated benchmark for this task with patient-level splitting to prevent information leakage. To better evaluate this task beyond surface-level text similarity, we further develop change-aware metrics specifically designed to capture clinically meaningful longitudinal changes, and conduct an independent physician validation to assess the reliability of the synthesized references and event extraction pipeline. We also compare direct paired-CT reasoning with an indirect two-stage pipeline that first generates single-timepoint reports and then performs textual differencing. Finally, we propose DeltaMed, a baseline model for direct paired-CT difference reporting, and train it on the benchmark training set. Together, these contributions lay the groundwork for temporally aware medical foundation models that better reflect real-world longitudinal clinical reasoning.

Age-related Macular Degeneration (AMD) is the major cause of blindness in the Western world. Its late dry phase is characterised by irreversible atrophic areas, namely Geographic Atrophy (GA). Longitudinal Fundus Autofluorescence (FAF) image acquisitions are currently the main tool for assessing lesion growth over time at the image level. However, due to its highly individualised progression, the evolution of late AMD remains poorly understood. In this work, we propose using Implicit Neural Representations (INRs) to model GA progression at the individual level in a low-data setting. Our approach generates both FAF and GA segmentation at both past and future time points. Among the comparison models, our method achieves competitive segmentation quality across different scenarios, yielding the lowest Mean Absolute Error (MAE) for the GA lesion area and the highest DICE score, without sacrificing FAF image quality. The code is available at https://github.com/SimoneSarrocco/ga-progression-with-inrs.

Alzheimer's disease (AD) progression is a longitudinal process with subtle pathological cues in the early stages. Yet, computational constraints have limited most neuroimaging models to either compromise spatial information or limit the number of longitudinal scans. We aim to overcome this bottleneck and fully leverage high-resolution, variable-length T1w structural MRI (4D sMRI) scan sequences. We introduce Parcel2Progression (P2P), a Longitudinal Transformer Framework which tackles this challenge using an Atlas-guided Parcel Encoder that tokenizes 3D scans into a set of richer anatomically grounded representations. A Longitudinal Transformer then integrates irregular, arbitrary-length longitudinal visits with patient age. This synergy delivers two key advantages: (1) parcel-specific interpretability, and (2) computational tractability for long-term analysis, which scales linearly with the number of scans compared to a naive quadratic 4D ViT cost. P2P outperforms prior works and baselines in both MCI (Mild Cognitive Impairment) to AD conversion prediction and AD vs. CN (Cognitively Normal) classification tasks across ADNI, AIBL, and MIRIAD datasets. Leveraging longitudinal scans boosts performance over single-scan baselines by up to 5% and 7% in balanced accuracy for AD classification and MCI conversion prediction tasks, respectively. Interpretability analysis using parcel saliencies and attention rollouts reveals clinically consistent atrophy patterns in AD and MCI subjects. We also demonstrate the frameworks' reliability in anomaly detection using a synthetic dataset, and test the model's generalizability for other neurodegenerative diseases like Frontotemporal Dementia.

Longitudinal MRI enables sensitive measurement of structural brain change for studying aging and neurodegenerative disease. Deformable image registration is a key tool for estimating such change by computing a dense deformation that captures geometric differences between longitudinal scans. However, MRI scanners introduce geometric distortions that vary across acquisition systems and protocols, such as gradient non-linearity (GNL) distortion. Existing registration methods estimate a single field that conflates biological and technical effects, potentially biasing downstream morphometric measurements if distortions remain (partially) uncorrected. We propose $\texttt{DisMorph}$, a registration framework trained entirely on synthetic data that explicitly decomposes longitudinal deformation into technical and anatomical transforms. It predicts two dense deformations, each encoding one effect. During training, a novel generative model synthesizes both effects separately to provide disentanglement supervision, while domain randomization promotes generalization across imaging protocols. We evaluate our method in three complementary settings. On simulated data with known ground truth, our method detects anatomical change more accurately and consistently than conventional registration. On real image pairs that differ only by GNL distortion, our method assigns most geometric change to the distortion field, demonstrating specificity in the absence of anatomical change. On longitudinal Alzheimer's disease (AD) pairs, our method detects anatomical change in AD-related brain structures while identifying residual distortion left after standard correction. By disentangling MRI-induced distortion from biological change in the longitudinal deformation, our method paves the way for more accurate longitudinal morphometry in clinical settings where maintaining acquisition consistency is challenging.

Pathologic complete response (pCR) is an important endpoint in neoadjuvant chemotherapy (NAC) for breast cancer, and predicting pCR from imaging during treatment could support treatment response assessment. Many existing imaging-based approaches rely on a single static timepoint, which fails to capture changes that occur during treatment. In this work, we present a longitudinal framework that combines a frozen 3D foundation encoder (Pillar-0) with our Temporal Dynamics Network (TDN) to predict treatment response from serial Dynamic Contrast-Enhanced (DCE) MRI acquired across four clinical timepoints from pre-treatment to pre-surgery. The TDN combines time-aware volumetric embeddings with clinical and treatment data to predict pCR. Evaluated on 982 patients from the combined I-SPY2 and ACRIN-6698 cohort, the proposed model achieves strong performance across all reported metrics when longitudinal 3D imaging is fused with clinical data (test AUROC: 73.6%, balanced accuracy: 69.1%). While clinical variables provide the strongest individual predictive signal, longitudinal 3D imaging contributes complementary information when fused with clinical data, improving pCR prediction. Our source code is available at: https://github.com/omarftt/longitudinal_temporal_pillar.

There has been a tremendous amount of image processing and machine learning research to measure and classify disease progression from live optical coherence tomography (OCT) imaging of the retina. The images considered here are large, complex, three-dimensional (3-D) and difficult to visualize effectively. Many current supervised machine learning approaches, \emph{e.g.} neural networks, are non-metric meaning that any features or measurements generated can introduce systematic distortion that may be correlated with underlying non-meaningful physiological differences. Here we present a metric learning approach using the normalized compression distance (NCD) combined with anisotropic structure-enhancing filters to quantify and visualize the principal differences among a collection of 3-D retinal images. We validate the NCD-measured structural differences between pairs of images against the physician-measured change in visual field function, achieving a prediction error of $\sim$ 0.5 dB, more accurate than non-metric deep learning approaches. The normalized compression vectors (NCV) are proposed as a feature set measuring visual differences among a collection of 3-D microscopy images. The utility of the NCV for visualizing and measuring patterns of change is demonstrated for a human with moderate non-progressing glaucoma and for a non-human primate model using intraocular pressure setting manipulation. We conclude with a brief simulation of non-metric embedding features, \emph{e.g.} from neural networks, introducing class-correlated statistical distortion.

Computed tomography (CT) is widely used for clinical diagnosis and longitudinal follow-up, yet automatically generating accurate and complete radiology reports from three-dimensional (3D) CT remains challenging. Existing methods improve fine-grained correspondence between images and text by modeling anatomical regions, but remain centered on the current examination. Consequently, patient-specific longitudinal changes within individual regions remain insufficiently modeled. Meanwhile, interval changes are often distributed across multiple anatomical regions, complicating a coherent assessment of the overall longitudinal state. We propose Anatomically Localized Temporal Evidence Representation (ALTER) to address these limitations. Global Prior Integration (GPI) incorporates the prior CT and report to establish historical context for the current examination. Regional Proxy Differencing (RPD) enables each current anatomical region to retrieve a historical proxy from a single shared encoding of the prior volume and to derive localized interval evidence. Interval Change Fusion (ICF) further combines current abnormality states with region-distributed differences, converting their joint representation into change-aware soft prompts that guide report generation. ALTER achieves state-of-the-art results on most evaluation metrics across the RadGenome-ChestCT validation and CTRG-Chest-548K test sets. Code and data preprocessing details are available at https://github.com/peytonkarlie/ALTER/tree/main.

Predicting how a subcortical structure's shape will evolve from a few prior scans could support prognosis and clinical-trial enrichment. Existing longitudinal mesh predictors either extrapolate shape trajectories via high-dimensional embeddings or regress vertex deformations directly. We instead predict the surface's intrinsic geometry in continuous time: a single per-structure graph network predicts the future per-vertex first fundamental form (metric tensor) for an arbitrary causal multiple-visit history and an arbitrary prediction horizon, conditioned on a Fourier encoding of the lead time. The predicted metric is decoded into a surface by a differentiable As-Rigid-As-Possible solver, and the model is trained end-to-end on the rigid-aligned vertex error. Training through the reconstruction keeps the decoded prediction a valid surface and consistently improves it. On 14 subcortical structures from the ADNI dataset, the proposed mesh evolution model (MT-GNN) predicts best among the evaluated methods at every horizon ($-2.29\%$ mean vertex error vs. the temporal mean, $p{=}6.1{\times}10^{-5}$, beating it on 14/14 structures), ahead of geodesic shape regression (DCM, $-0.19\%$) and a mesh transformer (TransforMesh, $-0.45\%$; $p{=}1.2{\times}10^{-4}$), with the lead widening as the horizon grows.

Longitudinal multiparametric MRI is central to follow-up imaging in oncology, yet real-world clinical data are characterised by missing sequences, heterogeneous acquisition protocols, and varying spatial resolutions across time points. We propose a patient-specific conditional implicit neural representation (INR) that models multimodal longitudinal MRI as a continuous function of world coordinates, time, and modality conditioning. The model is trained with stochastic modality dropout to handle incomplete data, and its continuous coordinate-space formulation enables both spatial and temporal interpolation without resampling to a fixed voxel grid. A self-consistency-based confidence estimator is derived from cross-modal reconstruction performance at inference time. We evaluate the framework on longitudinal MRI from paediatric brain tumour patients, demonstrating statistically significant improvements over linear interpolation for T1CE and FLAIR (p < 0.05), with mean MS-SSIM of 0.95 $\pm$ 0.02 for T1CE. Predicted confidence correlates strongly with true reconstruction quality (Pearson r up to 0.996), suggesting reliable deployment potential in heterogeneous clinical settings.

Head-and-neck (HN) proton therapy is highly sensitive to anatomical change over a 4-to-6-week course, as tumor shrinkage, weight loss, and setup variation can misposition the Bragg peak near critical organs such as the parotids, oral cavity, brainstem, and spinal cord, leading to target underdosing or organ-at-risk overdosing. Online adaptive proton therapy replans on the anatomy of the day, yet standard workflows rely on offline replanning that requires repeated CT acquisition and roughly a week of preparation, adding burden, cost, and delay. We investigate whether a patient's treatment-day anatomy can be predicted before image acquisition by transferring longitudinal change from a population database. We propose a digital-twin framework built on a pretrained foundation-model deformable registration network used without patient-specific training. A first registration aligns a prior patient's planning CT to the target and carries the prior's during-treatment quality assurance CT (QACT) into the target frame; a second registration estimates the prior's planning-to-QACT change, which is then applied to the target's own planning CT to synthesize predicted CTs (pdCTs) with propagated contours. Using 88 HN patients, each with a planning CT and three QACTs, we show that pdCTs better match treatment-day anatomy than the static planning CT. Compared with the planning CT alone, normalized cross-correlation improves by 22.8%, Dice for organs-at-risk by 20.2%, and CT-number error decreases by 23.4%. Gains are largest for patients with major anatomical change and negligible when anatomy is stable. This cross-patient motion transfer leverages the digital-twin concept to anticipate treatment-day anatomy, enabling personalized online adaptive proton therapy without repeated imaging.

In clinical practice, patients often undergo multiple imaging examinations over successive visits, yielding longitudinal data. Modeling such temporal information is crucial for reliable assessment of disease progression and treatment response. However, despite the rapid advancement of multimodal large language models (MLLMs), longitudinal medical visual reasoning remains largely underexplored. To fill this gap, we propose LoMeVQA, a comprehensive benchmark consisting of 206K longitudinal visual question answering (VQA) pairs for temporal medical image analysis. LoMeVQA covers five tasks: progress classification, progress description, progress report generation, differential region grounding, and differential region description. To construct the dataset, we develop an automated pipeline that (1) organizes patient records chronologically, (2) extracts clinically meaningful entities via a medical knowledge graph, and (3) models their temporal evolution to guide large language models in generating high-quality longitudinal VQA pairs. Extensive evaluations demonstrate that both general-purpose and medical-domain MLLMs perform poorly on LoMeVQA, revealing substantial limitations in temporal reasoning. To address these limitations, we introduce MedLong-8B, which achieves state-of-the-art performance across all tasks. Beyond benchmarking, we conduct detailed analyses that uncover key failure modes and shed light on how to improve longitudinal medical visual reasoning. Our data is available at: https://github.com/pepperbubble/LoMeVQA

Predicting future structural MRI of a brain is challenging because longitudinal changes are often subtle and confined to specific anatomical regions, while most subject-specific brain structure remains stable over time. An effective model should therefore preserve global brain structural consistency while remaining sensitive to fine-grained disease progression. Existing latent-space-based methods improve computational efficiency, but suffer from information loss during their compression-reconstruction procedure. In contrast, direct voxel-space methods avoid latent reconstruction but commonly use a unified prediction pathway to model brain structure and progression-related changes. Subtle local changes may therefore be overshadowed by the dominant stable brain structure. To address these challenges, we propose ProgFormer, a hierarchical voxel-space Diffusion Transformer for longitudinal brain MRI prediction. ProgFormer uses a coarse pathway to perform the primary volumetric prediction from 3D patch tokens. This pathway models overall brain structure and longitudinal context. The fine pathway then uses the coarse representations as spatio-temporal grounding for voxel-level refinement within individual patches. The two pathways jointly estimate a velocity field directly in voxel space through conditional flow matching, enabling end-to-end prediction without a separately learned image autoencoder. The predicted future scan is then generated from Gaussian noise by integrating the estimated velocity field over a sequence of Euler steps. Extensive experimental results on three widely used benchmarks, ADNI, AIBL, and OASIS, under both pairwise and trajectory settings demonstrate favourable performance compared against several state-of-the-art methods.

Rigorous dataset partitioning is a foundational, yet frequently overlooked, prerequisite for reliable deep learning in longitudinal medical imaging. Naively shuffling small clinical cohorts routinely introduces covariate shifts and temporal sampling imbalances across training, validation, and test subsets, exposing downstream models to out-of-distribution evaluation. We address this vulnerability with an auditable Tripartite Dataset Analytics Framework that systematically characterizes spatial grid integrity, multi-parametric intensity fingerprints, and longitudinal temporal trajectories, quantifying the heavy-tailed feature dispersion and irregular, episodic sampling intervals typical of real-world clinical cohorts. Building on this characterization, we formalize an unsupervised spatio-temporal cohort-balancing standard operating procedure (SOP) that combines elbow-optimized K-means clustering over a standardized, six-dimensional joint intensity-temporal feature space with intra-cluster proportionate stratified sampling. On a longitudinal, contrast-enhanced $T1$-weighted brain MRI cohort (N=149), the protocol reduces the maximum cross-subset intensity bias from 34.1% under conventional random shuffling to under 2.1%, while aligning longitudinal follow-up intervals closely around the population mean. Monte Carlo stress testing across ten random seeds and three split configurations confirms that this alignment remains tightly bounded, in clear contrast to the substantial variability of random partitioning. The resulting protocol offers a reproducible, generalizable procedure for cohort engineering in variable-length longitudinal clinical imaging workflows.

Longitudinal medical imaging captures temporal evolution of lesions, yet extracting the underlying dynamical parameters governing this evolution remains challenging. We propose an inverse Bayesian framework for inferring lesion dynamics from longitudinal spectral CT. We decompose spectral feature ($x$) evolution into three components: \begin{equation*} \frac{dx_i}{dt} = A_i x_i + B \cdot n + C \cdot Δx_{\text{sat}} \end{equation*} where $A_i$ captures intrinsic dynamics (lesion-autonomous evolution), $B$ captures local environment tumour burden (organ tumour burden through satellite count coupling), and $C$ captures environment/satellite state change (i.e., whether surrounding lesions move similarly or not). We demonstrate the framework on photon-counting NSCLC CT data from metastases, recovering distinct dynamical regimes: lung lesions exhibit significant satellite count coupling ($B=-0.34$, $p<0.05$) suggesting competitive dynamics, while liver lesions show synergistic satellite behaviour coupling ($C\approx+1.0$, $p<0.05$). Synthetic validation confirms parameter recovery, and cross-coupling analysis validates that our method detects non-zero coupling when present. This work establishes inverse dynamical inference as a principled methodology for extracting interpretable parameters from longitudinal imaging, moving beyond static feature extraction toward mechanistic characterisation of lesion behaviour. The code and data are available at: https://github.com/lukasf98/inverse-bayesian-inference

Active surveillance (AS) is the preferred strategy for favorable-risk prostate cancer, yet current protocols rely on scheduled repeat biopsies, most of which reveal no progression and are unnecessary. Existing risk-stratification tools operate on single time-point imaging or depend on explicit lesion segmentation, limiting their ability to capture longitudinal change and excluding patients without an MRI-visible lesion. In this study, we propose an end-to-end temporal and multimodal model for predicting pathological progression during AS without lesion segmentation. We encode each serial scan with a pretrained 3D MRI foundation model and introduce a temporal attention gate that recalibrates the multi-visit features to amplify focal imaging changes associated with progression. The gated imaging representation is then fused with clinical variables in a multimodal framework to estimate the probability of progression. Validated on a longitudinal AS cohort, our approach consistently outperforms competing baselines and performs comparably to the radiologist assessment representing current clinical practice. It maintains high negative predictive value while achieving higher positive predictive value, demonstrating its potential to safely reduce unnecessary biopsies during surveillance.