Improving Clinical Target Volume Segmentation Accuracy using Anatomical Priors and Active Learning for the AGITG TOPGEAR Clinical Trial

Training deep learning-based medical image segmentation models is challenging with limited curated datasets. For AGITG TOPGEAR, a gastric cancer trial, the Clinical Target Volume (CTV) is complex and defined by multiple anatomical landmarks, making upfront training data preparation difficult for an automated contour QA segmentation model. We investigate anatomical priors, derived from surrounding organ segmentations, to provide spatial context and improve TOPGEAR CTV segmentation accuracy. We also evaluate active learning, iteratively expanding the training dataset by selecting cases expected to improve performance. One hundred TOPGEAR CT scans were retrospectively analyzed. An initial set of 10 expert-contoured cases was used to train an nnU-Net model. TotalSegmentator generated a voxel-wise anatomical prior map from surrounding structures as an additional input channel. Active learning was simulated over four iterations, selecting cases by model uncertainty and segmentation performance. All models used five-fold cross-validation for an ensemble uncertainty measure. Evaluation used a hold-out testing set of 50 cases. The anatomical prior improved CTV segmentation accuracy, increasing mean Dice Similarity Coefficient (DSC) from 0.84 to 0.86. Active learning similarly improved performance to 0.86, with greatest benefit in the final round. Combining the anatomical prior with active learning achieved the highest accuracy, with a DSC of 0.87. Model uncertainty correlated with DSC, supporting its use in identifying suboptimal predictions and guiding active learning. Anatomical priors and active learning each improved CTV segmentation accuracy and generalizability, with their combination achieving the best performance, supporting integration into segmentation model development for automated contour QA in radiotherapy clinical trials.

Spending Scarce Confirmatory PET Measurements: Target-Aligned Validation in A4/LEARN

Anti-amyloid therapies and blood-based biomarkers are changing Alzheimer disease workups into a two-stage measurement workflow: screen broadly with cheaper information, then spend scarce confirmatory amyloid measurements where they support the decision that will be reported. Amyloid positron-emission tomography (PET) remains one such protocol measurement for amyloid burden, but PET slots, trial budgets, and payer-facing evidence packages are finite. This paper asks a deliberately operational question: when is simple transparent PET validation enough, and when is a fitted residual-uncertainty score worth the added complexity? For a weighted protocol target, the first-order value of validating subject i is the product of target influence and residual protocol uncertainty. Generic uncertainty sampling uses only the second factor and can spend PET measurements on subjects that are hard to predict but weak for the scientific, clinical, or commercial claim. We apply this rule to the A4/LEARN PET archive, treating observed PET as a design laboratory for scarce-confirmation studies. For the primary APOE4 carrier versus non-carrier contrast in Centiloid 24-or-higher PET positivity, simple APOE4-balanced validation recovers nearly all of the target-specific gain: at PET budget 200, the confidence-interval width ratio relative to random validation is 0.923 for APOE4 balancing and 0.914 for target-specific scoring, while generic uncertainty sampling is 0.980. Other targets behave differently: target-specific scoring gives larger gains for an age-slope analysis and for cutoff-indexed PET positivity. The practical message is simple: spend scarce protocol measurements according to the claim being validated, not only according to prediction uncertainty.

CytoFormer: A Molecularly Supervised Cell Foundation Model for Histopathology Cell Classification

Identifying cell types directly from routine haematoxylin and eosin (H&E) histology would enable single-cell analysis at scale, but training such models has relied on manual pathologist annotations, which are slow, expensive and unreliable for many cell types. We instead supervise morphology with molecules. Imaging-based spatial transcriptomics profiles individual cells in situ on a section that can afterwards be stained with H&E, so that molecular identity and morphology are observed for the same physical cell. We assembled 81 such paired Xenium sections spanning 16 organs, derived per-cell labels by clustering, marker-gene annotation, organ-wise human review and quality control, and mapped them onto the cell types commonly reported in each organ. This yielded 15.4 million cells, each with a paired H&E image patch and one of 23 cell types, on which we trained CytoFormer, a cell foundation model with a multi-task, per-organ classification head. On spatially held-out tissue CytoFormer reached an accuracy of 0.85 and a macro-F1 of 0.78 across all 16 organs, and its predictions reproduced the tissue architecture of an entire held-out section. The representation also transfers: with the encoder frozen, a linear head on CytoFormer features performed better than six pathology foundation models on four expert-annotated benchmarks, including on organs and cell types that were not part of pretraining. Finally, in an interactive active-learning setting, CytoFormer's embeddings are markedly more label-efficient than existing pathology foundation models, detecting normal epithelium amid look-alike tumour with an F1 of 0.82 from only a few annotations and leading the strongest baseline by 0.13 in F1. CytoFormer turns paired H&E and spatial transcriptomics into a reusable, label-efficient representation for cell-level analysis of routine histology.

SUGFW+: An Uncertainty-guided Feature Weighting Framework for Cold Start Active Adaptation of SAM in Medical Image Segmentation

Cold Start Active Learning (CSAL) is important in improving the performance of a medical image segmentation model with low annotation budget by querying a small subset for annotation from an unlabeled training set. Existing CSAL methods typically rely on inefficient dataset-specific Self-Supervised Learning (SSL) to map the unlabeled images into a feature space for sample selection. Recently, the advent of foundation models such as the Segment Anything Model (SAM) offer a promising alternative as the pre-trained model can provide strong generalizable feature embeddings, and allow high performance in downstream tasks after fine-tuning (adaptation). However, how to systematically exploit SAM's inherent embeddings for cold-start sample selection during adaptation with low annotation budget remains underexplored. To address this, we propose an extended SAM-based Uncertainty-guided Feature Weighting (SUGFW+) framework for CSAL and adaptation of SAM. Specifically, it leverages the SAM for Patch-level Feature and Uncertainty Calculation (PFUC), and introduces a Patch-based Global Distinct Representation (PGDR) module that aggregates patch-level embeddings into highly discriminative, uncertainty-aware image-level features. These features are then utilized by a Greedy Selection with Cluster and Uncertainty (GSCU) strategy to combine diversity and uncertainty during sample selection. Unlike prior CSAL methods that decouple sample selection from model training, SUGFW+ tightly integrates these two stages via an Uncertainty-Prompted Fine-Tuning (UPFT) process of SAM in model training. Extensive experiments on four public datasets demonstrate that SUGFW+ achieves state-of-the-art performance against existing CSAL methods. Code is available at https://github.com/HiLab-git/SUGFW-plus.

ScreenShot: A Foundation Model for Few-Shot Combination Drug Screening

Treating patients with combinations of drugs reduces the risk of resistance to any individual drug. Finding effective combinations is difficult because the large search space makes combinatorial screens prohibitively expensive, time consuming, and often technically infeasible. Predictive models can fill this gap, yet existing methods typically require molecular profiling of each sample and per-cohort training, limiting their applicability when time and tissue are scarce. To address this challenge, we introduce ScreenShot, a hierarchical transformer pretrained on 40 drug screening datasets covering 3,700 drugs and 6,000 biological samples, whose architecture mirrors the nested structure of screening data. Given a few-shot context of observations from a new patient, ScreenShot predicts the response of the sample to combination therapies through in-context learning, operating directly on functional measurements with no fine-tuning and no molecular profiling. On four held-out datasets, ScreenShot outperforms all baselines in both prediction accuracy and identification of selectively effective treatments. ScreenShot's internal representations are directly useful for experimental design: we use them to drive a weighted k-means++ active learning strategy that selects which experiments to run, achieving the same hit detection as uniform screening with a third of the budget. Source code and interactive dashboard: https://github.com/tansey-lab/screenshot.

Foundation Model-Enabled Efficient Data Sampling (FEEDS): A label-efficient training strategy for pan-cancer, multi-tracer PET/CT datasets

Automated lesion segmentation in whole-body PET/CT imaging can assist clinicians with cancer detection, staging, and treatment planning across radiotracers and cancer types. However, training lesion segmentation models that capture variations in lesion size, distribution, and appearance requires large annotated datasets, whose creation is both time- and expertise-intensive. As a result, models trained on limited labeled PET/CT data often lack the accuracy and generalizability needed for clinical use. We present FEEDS (Foundation model-Enabled Efficient Data Sampling), a label- and compute-efficient learning strategy that uses vision foundation model embeddings to select the most informative and diverse unlabeled cases for expert annotation. Unlike unsupervised, semi-supervised, and active learning approaches, FEEDS is a one-step training paradigm requiring only a limited, representative training set, making it label- and compute-efficient. We train and validate FEEDS using the AutoPET-III dataset. We test its accuracy and generalizability on three held-out sets: AutoPET-III, DeepPSMA, and an internal Dartmouth-Hitchcock Medical Center dataset. We evaluate clinical utility at the voxel, lesion, and anatomic region level to assess performance in high-risk areas and treatment planning utility. FEEDS outperforms random-sampling-based labeling, pseudolabel-based semi-supervised learning, and training with limited labeled data alone. It generalizes across all three test sets, FDG and PSMA tracers, and multiple diseases, matching fully-labeled (100\%) training performance with 70\% less annotation burden. FEEDS addresses the challenge of label scarcity in an automatic lesion segmentation framework by providing a practical approach for constructing representative and diverse annotation queues from large, unannotated clinical repositories.

How Many Labels Are Enough? ALDA: Active Learning Deployment Advisor for Medical Image Classification

Active learning (AL) promises to reduce the cost of medical imaging projects by lowering the number of clinical labels required. However, practical deployment requires committing to a sampling strategy before the full annotation budget is spent, and choosing the wrong strategy can increase rather than decrease costs. We propose Active-Learning Deployment Advisor (ALDA), a deployment-oriented framework for AL method selection under clinical performance constraints. Given a short pilot phase, ALDA fits a parametric learning-curve model to each candidate strategy, estimates whether that strategy is expected to reach a required clinical performance target, and predicts the number of expert annotations needed to do so. In addition to absolute annotation cost, ALDA introduces a deployment window that quantifies the sensitivity of this cost estimate to uncertainty in the clinical threshold. The final recommendation follows a risk-aware rule: among strategies with near-optimal predicted cost, ALDA prefers the strategy with the narrowest deployment window, the most robust to threshold revisions. Experiments on four medical imaging classification domains show that ALDA predicts the deployment-optimal method from a pilot of 15-30% of the intended budget and reduces annotation costs by up to 82% compared with a poor strategy choice. Rather than introducing a new sampling heuristic, ALDA provides a practical decision layer that answers a deployment-critical question: how many labels are enough?

Unifying Active Learning and Semi-Supervised Learning for Medical Image Segmentation

In practical settings, medical image segmentation models are often developed with limited annotated data rather than fully labeled datasets. Training frequently begins in ultra-low labeled regimes where only a small number of volumes are annotated. In such scenarios, practitioners must simultaneously decide which cases to annotate and how to best use the remaining unlabeled data. Although active learning (AL) and semi-supervised learning (SSL) both target annotation scarcity, they are typically designed and optimized independently, resulting in objective mismatch and unstable training during early-stage "cold start" conditions. We propose RegAL, a unified active semi-supervised framework governed by a shared topology-aware Pareto optimization that couples sample acquisition with unlabeled data utilization. RegAL evaluates images along three complementary axes, voxel-wise uncertainty, feature diversity, and a novel topological consistency metric, to select anatomically informative edge cases for annotation. On the other hand, the same criteria are used to identify geometrically stable atlas candidates for diffeomorphic registration-guided augmentation to train a self-supervised Mean Teacher segmentation network. Across BraTS 2021, dHCP, and ProstateX, RegAL remains stable with few labeled volumes and consistently outperforms state-of-the-art AL, SSL, and active semi-supervised baselines across Dice and boundary-distance (ASD, HD95) metrics under extreme annotation scarcity.

Active few-shot segmentation by reinforcing data selection

Few-shot learning enables medical image segmentation models to adapt to new tasks using only a small number of labelled examples. However, adaptation performance depends strongly on which examples are selected for the support set. Effective support sets should capture relevant variation within the target domain and be informative for adaptation, with constituent samples providing complementary information. Despite this, existing active data selection approaches largely prioritise samples individually and do not explicitly account for interactions between examples. In this work, we propose a reinforcement learning framework for support-set selection in few-shot medical image segmentation, enabling support sets to be optimised jointly rather than through independent sample scoring. Given a pool of unlabelled candidate images, an agent directly predicts a support set that maximises downstream segmentation performance. Experiments on a cross-institutional pelvic MRI dataset demonstrate improvements over random selection and current state-of-the-art methods. Our findings highlight the importance of support-set complementarity for effective adaptation and demonstrate the potential of reinforcement learning for optimising adaptation sets.

Slide-Level Active Learning Reduces Annotation Burden in H&E images

Deep learning-based segmentation of histopathology whole-slide images (WSIs) requires large amounts of pixel-level annotations, which are costly and time-consuming to obtain. Active learning (AL) has been proposed to reduce this effort, but existing methods exhibit three key limitations. Uncertainty estimation is unreliable on partially annotated WSIs, patch-level acquisition is inconsistent with slide-level annotation workflows, and class imbalance in multi-class settings is not explicitly addressed. To address these challenges, we propose SHAL (Slide-level Hybrid Active Learning), a patient-level AL framework for annotation-efficient multi-class histopathology segmentation. SHAL integrates three complementary components: a foreground-aware strategy that suppresses bias from unlabeled background regions, a stage-adaptive mechanism that hybridizes predictive entropy and epistemic uncertainty across learning stages, and a class-aware strategy that prioritizes diagnostically relevant tissue classes. SHAL is evaluated on the TCGA colorectal cancer dataset. It achieves the highest Macro Dice at the full annotation budget (0.846) and reaches Dice greater than or equal to 0.80 using only 26 percent of the budget (50 of 190 slides), whereas competing methods reach this threshold only at 37 percent (70 slides). Across five independent external cohorts, SHAL attains the highest mean external Macro Dice (0.815) and the smallest internal-to-external generalization gap among all methods (0.025 at Round 3 and 0.026 at the full budget). The results indicate that patient-level hybrid uncertainty acquisition reduces annotation cost without sacrificing cross-domain generalization in computational pathology.

Transformer-Based Active Learning for Data-Efficient Vaccine Epitope Selection in PRRS

High-fidelity molecular docking simulations can produce biologically relevant estimates of epitope-receptor binding affinity but are computationally expensive and therefore limit the number of candidates that can be screened for vaccine design. In this work, we evaluate machine learning (ML) approaches where variants of active learning are used to classify instances of high binding affinity between 9-mer epitopes and a well-conserved swine leukocyte antigen (SLA) receptor in the context of Porcine Reproductive and Respiratory Syndrome (PRRS). We use an internally generated dataset of 80 epitope-SLA docking affinities, each requiring more than 48 hours of high-performance computing (HPC). Multiple model families (linear, MLP, CNN, and a small transformer) are trained under strict low-data conditions within a pool-based active learning loop. In each case, optimal model configurations are identified by conducting large-scale hyperparameter optimization over the combined space of model architecture, training configuration, acquisition policy, and ensemble decision rules. To mitigate the effects of data subsample selection, each candidate configuration is evaluated by averaging performance over many randomized and balanced training and validation data subsets. Across experiments, transformer-based sequence models consistently emerged as the best-performing architecture, with active incremental learning yielding significant improvement over a baseline random sample acquisition strategy. Under moderate training data availability (N=30), the optimized ML-model configuration outperforms a standard baseline trained on twice the amount of data. Under higher training data availability (N=60), the same configuration achieves a peak accuracy of 86.8%, consistent with an upper bound of 85% classification accuracy based on two independent estimates of conformational noise.

Mask to Concept: Auto-Promptable SAM3 via Efficient Test-Time Concept Embedding Search for Few-Shot Annotation

Transforming foundation segmentation models from human-prompted tools into auto-promptable annotators is critical for scalable medical data annotation. Current methods commonly depend on external feature matchers or auxiliary networks to automate geometric prompting, but introducing architectural overhead and limiting performance scalability. Although SAM3 natively supports concept segmentation via reusable text prompts, its direct use in medical imaging is hindered by a lack of fine-grained clinical knowledge and the ambiguity of human-written descriptions. In this work, we propose Mask to Concept (M2C), an efficient framework that adapts SAM3 for medical few-shot annotation without external modules, parameter retraining, or manual text engineering. Using only a few labeled images, M2C enables SAM3 to automatically search for transferable visual concepts entirely within its frozen architecture: it initializes a learnable concept embedding, uses it to prompt segmentation, and updates the embedding by gradients of minimizing the concept segmentation error. We further introduce a Hybrid Uncertainty Estimation (HUE) module that calculates the prediction entropy and maps concept predictions back to the box prompts, measuring concept-geometry prompting inconsistency. Highly uncertain samples are flagged actively for human correction, and the corrected masks are then fed back to M2C to continuously search for more precise concept embeddings, forming a self-enhancing annotation loop with minimal expert effort. Experiments on medical segmentation benchmarks show that our method achieves SOTA few-shot segmentation performance and outstanding annotation efficiency, offering a practical and efficient pathway toward scalable medical image labeling. Codes are at https://github.com/Huster-Hq/M2C.

One-Shot Data Selection for Medical Image Classification via Graph Coverage

Training medical image classifiers on entire datasets is wasteful when annotation budgets are limited: not all samples contribute equally, yet acquiring expert labels is expensive. Active learning reduces annotation cost through iterative querying, but assumes repeated access to an oracle and requires multiple rounds of model training. One-shot geometry-based methods such as facility location avoid retraining but operate on pairwise distances that ignore the local structure of the data manifold. We propose a graph-based one-shot selection method that operates entirely on frozen foundation model embeddings. Given embeddings from a pretrained encoder, we construct a k-nearest neighbor graph over all training samples and derive a two-term coverage kernel from the heat diffusion kernel, capturing both direct and two-hop neighborhood relationships. Greedy facility location on this kernel selects class-balanced subsets that maximize coverage of the data manifold. The two-term kernel matches the full spectral heat kernel in selection behavior while reducing computation to sparse matrix operations with a single hyperparameter. We evaluate on five MedMNIST datasets spanning histopathology, radiology, and microscopy, comparing against both training-dynamics and geometry-based baselines. Our method achieves the highest balanced accuracy on nine of ten dataset-ratio conditions, with the largest gains on class-imbalanced datasets where global graph construction captures cross-class structure that per-class methods miss, all without any model training during selection. Code is available at https://github.com/zahiriddin-rustamov/graph-coverage-selection.

Dataset-Aware Cold-Start Active Learning for Annotation-Efficient 3D Medical Image Segmentation

Deep learning for 3D medical image segmentation requires extensive manual annotations, a major bottleneck in volumetric medical imaging. Active learning aims to reduce this burden by selecting informative samples for annotation, but most methods assume that an initial labeled set is already available. This leaves the cold-start problem largely unresolved: how to select the first volumes from a fully unlabeled pool before any task-specific model is trained. We propose CSCS, a Curriculum-Stratified Cold-Start framework that adapts initial sample selection to the structure of the unlabeled dataset. CSCS combines two self-supervised, label-free signals: local typicality, measuring representativeness in the embedding space, and reconstruction-based uncertainty, used as a proxy for sample difficulty. These signals are combined through a weighted geometric score, where the weighting is determined by a closed-form pacing rule based on the effective annotation budget and the Difficulty-Coverage Ratio, a pool-level statistic measuring the alignment between difficulty and representativeness. We evaluate CSCS on four 3D medical image segmentation benchmarks: BraTS, FeTA, Spleen, and an in-house fetal MRI dataset. Using nnU-Net as downstream segmentation model, CSCS shows consistently competitive performance across datasets and annotation budgets, with the strongest gains in low-to-mid annotation regimes. These results suggest that dataset-aware cold-start initialization can improve the robustness of active learning for 3D medical image segmentation by adapting sample selection to the geometry of the unlabeled pool.

cAPM: Continual AI-Assisted Pace-Mapping with Active Learning

Ventricular tachycardia is a life-threatening rhythm disorder and a major cause of sudden cardiac death. Pace-mapping is a clinical procedure for identifying the intervention target during catheter ablation of VT. It requires clinicians to pace different sites in the ventricles and rapidly interpret the resulting electrocardiograms to determine where to pace next or whether a target site has been identified. Active learning AI models have been proposed to guide clinicians to the next pacing site, showing promise in reducing the number of pacing sites and improving the efficiency of pace-mapping. Existing methods require retraining each target without the ability to transfer knowledge across multiple VTs within the same patient or across patients. We introduce cAPM for continuous AI-assisted pace-mapping to capture and transfer knowledge accumulated from past pace-mapping data to reduce the number of pace-mapping data needed for future target VTs. This is made possible by a task-agnostic surrogate neural network that learns the mapping from pacing sites to 12-lead ECG morphology, an active-learning strategy that refines this surrogate model by selecting the most informative pacing site for each target, and a continual learning strategy to do so sequentially while retaining knowledge from prior targets. Evaluated on an in-silico testbed consisting of sequentially-presented localization tasks across different physiological conditions and ventricular geometries, cAPM with and without replay of past data samples achieved an 81% probability of localizing within clinical tolerance (5 mm accuracy) using 4.5 pace-mapping sites, compared to the state-of-the-art active-learning method achieving 38% probability using 13.7 pacing sites. These results provide a strong basis for preparing cAPM towards in-vivo preclinical and clinical studies where it can be used to guide pace-mapping.

XSSR: Cross-Domain Self-Supervised Representative Selection for Efficient Annotation in Medical Image Segmentation

Acquiring labeled medical image data is resource-intensive and a challenge further exacerbated in cross-domain scenarios where source and target datasets differ in imaging equipment, population, or clinical site. This study introduces XSSR (Cross-Domain Self-Supervised Representative Selection), a framework designed to minimize annotation effort in the target domain while maintaining robust segmentation performance. XSSR comprises three stages: first, a Masked Autoencoder (MAE) is trained on unlabeled source data to establish a shared embedding space without requiring target labels; second, a greedy selection algorithm scores unlabeled target samples based on a composite density, novelty, and diversity criterion; and third, a U-Net segmentation model is trained exclusively on the selected subset. The novelty-diversity trade-off parameter, alpha, is automatically calibrated by minimizing embedding-space coverage, eliminating manual tuning. We evaluate XSSR on three public benchmarks: Chest X-ray, RIGA+ retinal fundus imaging, and multi-site Prostate MRI, each under a fixed 5% annotation budget. XSSR achieves 99.3% of full-data performance on Chest X-ray using only 22 labeled samples, surpasses random selection by up to 2.5 Dice points on Prostate MRI, and consistently outperforms the CoreSet baseline by 0.4 to 1.2 Dice points across all datasets. Ablation studies indicate that diversity is the most influential scoring component, and per-site analysis shows that performance correlates with scanner similarity to the source domain.