Explainable Medical Image Analysis

Lung cancer is the leading cause of cancer-related mortality, with approximately 2.5 million new cases and 1.8 million deaths annually, making reliable diagnosis a clinical priority. Although deep learning models have achieved strong performance in lung cancer classification, evaluation has largely focused on predictive accuracy, leaving their decision-making processes insufficiently examined. This study compares three architecturally distinct models: a Convolutional Neural Network (CNN), a pretrained ResNet50, and a Vision Transformer (ViT), trained on the IQ-OTH/NCCD lung cancer CT dataset. Local Interpretable Model-Agnostic Explanations (LIME) were applied to investigate model reasoning. In addition to standard performance metrics, a dual-correlation framework was introduced to measure both prediction agreement and explanation agreement across model pairs. All three models achieved strong classification performance, with ResNet50 attaining 98.61% accuracy, CNN 97.91%, and ViT 93.75%, while all achieved ROC-AUC scores of 0.99. Prediction correlations exceeded 0.99 across all model pairs, indicating highly consistent outputs. However, LIME explanation correlations remained below 0.26, revealing substantial differences in the image regions used to reach those predictions. Analysis of misclassified samples further identified a consistent spatial pattern: incorrect predictions were associated with attention outside the lung parenchyma, whereas correct predictions focused primarily within lung regions. These findings demonstrate that prediction agreement is a poor proxy for reasoning consistency, and that interpretability evaluation must be treated as an independent validation criterion alongside predictive performance in clinical AI systems.

Interpretability is essential for trustworthy medical image diagnosis. However, existing concept-driven interpretable methods have key limitations: Concept Bottleneck Models (CBMs) require scoring all predefined concepts at inference time and for manual intervention, imposing a substantial burden on clinicians, while rationale-based generative approaches often select concepts by class discriminability, which can drift from diagnostic ontologies. To address these issues, we propose Neuro-Symbolic Rule Distillation (NeRD), a framework that produces efficient, ontology-grounded reasoning chains that are sufficient yet non-redundant, without manually crafting diagnostic rules. Experiments on two skin datasets demonstrate strong diagnostic performance and interpretability, and blinded expert evaluation confirms the clinical plausibility of NeRD rationales. Our method further enables a first expert-in-the-loop study for Multimodal Chain-of-Thought-based diagnosis, achieving efficient and effective concept-level intervention.

Diabetic Retinopathy (DR) is an aggressive retinal disease and a leading cause of global blindness, yet its clinical management is currently hindered by the black-box nature of diagnostic AI. While deep learning models achieve high classification accuracy, there is a critical lack of explainability methods capable of detailing the exact anatomical landmarks and lesion distributions that lead to a clinical decision for DR. Therefore, we propose HSQ-VLM, a novel quadrant segmentation pipeline on fundus images that utilizes a Landmark-Anchored Cartesian Cross-Attention mechanism to unify visual feature extraction with structured clinical reasoning. Unlike traditional methods that rely on arbitrary image partitioning, our pipeline implements 4-quadrant Topological Latent Partitioning (TLP) to dynamically align retinal features with a fovea-centered coordinate system. This allows the Vision-Language Model to generate natural language reports that quantify pathology with anatomical precision. On a dataset of 3,500 high-resolution fundus images, this innovative methodology achieved a lesion detection sensitivity of 99.6% for hemorrhages and 96.4% for microaneurysms, while demonstrating a significant reduction in boundary-ambiguity errors compared to standard segmentation baselines.

Strabismus is a common ocular disorder that requires fine-grained subtype diagnosis for individualized treatment planning. However, existing deep learning methods mainly provide diagnostic predictions without transparent reasoning, while recent large vision-language models (LVLMs), although promising for joint image understanding and report generation, remain highly prone to hallucination in this evidence-sensitive and rule-driven medical task. To address these challenges, we propose MAGIS, an evidence-based Multi-AGent reasoning for Interpretable Strabismus diagnosis framework. MAGIS transforms black-box end-to-end generation into a structured diagnostic process consisting of candidate hypothesis generation, dual-evidence constrained context, evidence-based corrective verification, and report generation. Specifically, we introduce a Dual-Evidence Constrained Context (DECC) mechanism that jointly organizes visual evidence from the photograph of the nine cardinal positions of gaze and evidence-based clinical diagnostic rules into a constrained context for reliable diagnostic reasoning. We further develop an Evidence-Based Corrective Verification (EBCV) mechanism that verifies whether the current diagnostic hypothesis is supported by visual evidence, heatmap-based visual cues, and evidence-based clinical diagnostic rules. Hypothesis refinement is triggered when inconsistency is detected. Experiments on a fine-grained strabismus benchmark demonstrate that MAGIS not only significantly outperforms other state-of-the-art diagnostic systems, improving the weighted F1 score from 72.0% to 91.3%, but also substantially improves the clinical reliability (consistency, alignment, and completeness) of generated diagnostic reports. These results demonstrate that MAGIS provides an effective solution for building accurate, evidence-based, and clinically interpretable strabismus diagnosis systems.

Explanations of multiple instance learning (MIL) models are widely used for validation and discovery in digital histopathology. Existing methods primarily rely on heatmaps that highlight influential regions but do not explain how evidence from different tissue regions is combined to produce a prediction. This limits interpretability, especially when decisions depend on interactions between tissue features. We introduce Symbolic explainable MIL (Symb-xMIL), a post-hoc explanation framework that quantifies how a MIL model's behavior aligns with human-readable decision rules, expressed as logical relationships (e.g., AND, OR, NOT) between input features. These alignment scores reveal semantic patterns underlying the model's predictions. We evaluate Symb-xMIL on synthetic and real-world histopathology datasets. On synthetic MIL data, Symb-xMIL reliably recovers ground-truth logical rules. In a clinical tumor detection task, the best-aligned rules uncover heterogeneous decision patterns and expose hidden model errors. On an HPV-prediction task on TCGA-HNSCC, a cohort of head and neck cancer, our framework refines patient survival stratification beyond HPV status with potential clinical relevance. Overall, Symb-xMIL extends MIL explainability beyond visual attribution toward structured, rule-based reasoning, enabling more transparent and semantically grounded interpretation of model predictions.

Purpose: To develop an interpretable and trustworthy AI framework that combines deep learning based MRI Osteoarthritis Knee Score (MOAKS) prediction with interpretable statistical modeling to study structure-pain relationships at scale using data from the Osteoarthritis Initiative (OAI). Materials and Methods: We first developed a deep learning framework to predict MOAKS features directly from knee MRIs and incorporated conformal prediction to provide prediction uncertainty quantification. This uncertainty-aware strategy enables explicit filtering of model outputs, retaining only high-confidence MOAKS predictions at the knee level. Second, we applied a longitudinal latent class mixed model (LCMM) to examine associations between key structural abnormalities and four complementary knee pain measurements. Results: Among the three MRI-defined abnormalities (i.e., bone marrow lesions (BML), cartilage loss (CART), and meniscal extrusion (ME)), our framework substantially improved the Matthews correlation coefficient (MCC) and some other metrics. For example, MCC increased from 0.69 to 0.91 for BML, from 0.45 to 0.80 for CART, and from 0.59 to 0.89 for ME. Using these high-confidence predictions, we expanded the sample size to 2,175 knees for the LCMM analysis. Two distinct pain trajectories were identified (rapid and stable pain progression). The estimated odds ratios (95% CI) for the rapid progression group were 1.62 (1.12-2.35) for BML, 1.83 (1.24-2.70) for CART loss, and 2.50 (1.75-3.57) for ME. Conclusion: These results highlight the importance of these structural abnormalities as risk factors for pain and functional progression in osteoarthritis.

Longitudinal medical visual question answering (VQA) requires reasoning about anatomical differences between an image of a current time point and an image of a referred time point. We propose an attention-guided encoder-decoder for this task with chest X-rays. Instead of conventional direct contrast, we propose to include a lightweight affine registration module to reduce nuisance motion by co-registering the current image to the reference image with a small registration regularizer. The registered image pair is fed into the image encoder, followed by a frozen DINO-based mask generator and a trainable adaptive mask generator to produce masks applied to the original image pairs. The masked image pairs are again fed into the image encoder and concatenated with text features as the input to a multimodal transformer-based decoder to generate final answers. To facilitate learning stabilization and clarify the change signal, inspired by DINO-v3, we include additional auxiliary objectives, including a mask rebuilding loss, a pairwise Gram-style consistency loss, and a KoLeo uniformity loss, which enhances the geometry of the representation. On the Medical-Diff-VQA benchmark, the model delivers strong BLEU, ROUGE-L, CIDEr, and METEOR scores while offering intrinsic interpretability through the shared saliency mask. These results support saliency-conditioned generation with mild pre-alignment as a principled framework for longitudinal reasoning in medical VQA. Our training strategy also illustrates the potential of a paradigm in utilizing image foundation models in biomedicine: optimizing both supervised and unsupervised learning objectives simultaneously.

Whether attention maps from pathology foundation models capture genuine biology remains unknown, yet this question is critical for clinical trust and regulatory approval. We propose a spatial transcriptomics-based framework for orthogonal, hypothesis-free evaluation of attention and apply it to five pathology foundation models (CONCH v1.5, UNI v2, Virchow2, GigaPath, H-Optimus-1) and a ResNet50 baseline. Using attention-based multiple instance learning, we train single-task and multi-task models to predict five molecular alterations in glioblastoma on the CPTAC cohort, validate on an independent TCGA cohort, and evaluate biological coherence of attention maps against 87 transcriptional signatures using co-registered Visium spatial transcriptomics data from 18 samples. Internally, no single encoder dominates across all tasks, and external validation inverts internal performance rankings. Attention maps show a five-fold enrichment gradient from pathways (Cohen's d=0.329) to individual genes (d=0.055), indicating that attention captures emergent multi-gene transcriptional programs rather than individual molecular events. Spatially smooth attention maps do not imply biological coherence, and different encoders attend to distinct biological compartments. Our framework provides objective, quantitative assessment of what foundation models learn from histopathology, moving the field beyond qualitative saliency map review.

While multimodal deep learning has advanced medical imaging analysis, existing black-box systems \textcolor{black}{may remain confined to isolated tasks, often overlooking} the trust-sensitive nature of clinical diagnosis as a multi-task process. We propose IMT-CXR (Interpretable Multi-task Transformer for Chest X-ray Analysis), a framework that emulates radiologists' diagnostic workflow through three evidence-driven stages: 1) Disease recognition; 2) Attribute characterization (e.g., size, location, severity quantification); 3) Evidence-integrated report generation with traceable decision pathways. The framework employs a unified transformer architecture optimized via medical-domain instruction tuning, sequentially executing four clinical tasks: multi-label disease classification, lesion localization, anatomical segmentation, and radiology report generation. Experimental validation demonstrates competitive performance on ten CXR benchmarks under direct inference and fine-tuning settings. In a blinded evaluation of 160 historical reports from four medical centers, three radiologists rated 66% of AI-generated reports as comparable to or surpassing original clinical reports in diagnostic clarity, highlighting the framework's translational potential. By establishing traceable diagnostic pathways from anatomical findings to conclusions, this work bridges the gap between AI technical metrics and clinical utility, advancing trustworthy AI systems in medical imaging.

Deep learning has revolutionized medical image analysis, delivering exceptional diagnostic accuracy across diverse applications. Yet, the lack of interpretability in its decision-making hinders clinical adoption, particularly in high-stakes medical contexts where transparency is paramount for trustworthiness. For example, in Placenta Accreta Spectrum (PAS), subtle cues in ultrasound imaging challenge reliable diagnosis, rendering black-box models untrustworthy for accurate scoring. To address this, Concept Bottleneck Models (CBMs) offer a promising avenue by embedding clinically meaningful intermediate concepts into the diagnosis pipeline, enabling clinicians to scrutinize and refine model outputs. However, conventional CBMs falter in capturing complex inter-concept dependencies and demand costly, expert-driven concept annotations, limiting their scalability. This study introduces a novel semi-supervised CBM framework designed for medical imaging, which leverages dual-level hypergraph learning to model high-order concept dependencies and generate domain-adaptive pseudo-labels. Our approach achieves superior interpretability and performance by integrating a concept-level hypergraph for enhanced reasoning and an image-level hypergraph for robust pseudo-label generation. Experiments on a newly annotated PAS ultrasound dataset and a breast ultrasound public dataset demonstrate the effectiveness of the proposed concept label-efficient interpretable framework. Its universality is further validated on the dermoscopic image dataset SkinCon. The code is available at https://github.com/scott-yjyang/HyperCBM.

Two-sample testing is a fundamental tool for detecting distributional differences across scientific domains, but classical tests (including kernel-based tests) can be ineffective on high-dimensional structured data such as images. Recent deep two-sample tests improve sensitivity in these settings by learning informative representations, yet they provide limited insight into which data features drive rejection of the null hypothesis $H_0$. To address this issue, we propose a counterfactual explanation framework for deep two-sample testing that generates sample-level edits moving observations from a source group toward a target group while explicitly reducing the discrepancy measured by the test. Our method combines a diffusion autoencoder with a pretrained deep two-sample test model and optimizes a maximum mean discrepancy (MMD) objective in the test model's representation space to produce plausible counterfactuals. We quantify distribution-level effects through changes in the test statistic and the resulting two-sample p-values. We evaluate the method on synthetic 2D shape datasets and two MRI cohorts. Across both settings, the counterfactual transformations consistently increase p-values relative to the original samples, indicating that the edited source set becomes statistically closer to the target distribution under the test. We measure minimality using LPIPS to ensure the counterfactuals remain close to the original samples. The resulting edits provide interpretable evidence of the features associated with the detected group differences. On MRI, the localized changes are consistent with known anatomical differences between cohorts.

Latent reasoning enables reasoning over continuous hidden states rather than explicit tokens, avoiding the language bottleneck and inference overhead of chain-of-thought for medical VQA. However, existing methods suffer from modality collapse, insufficient visual supervision, and train-inference mismatch. Moreover, their opaque latent states offer no interpretability, which is critical in clinical applications. We propose VITAL, a latent-space reasoning framework for medical MLLMs with visual-semantic dual supervision: an auxiliary text decoder reconstructs reasoning chains from latent states, while a visual projector regresses ROI features from a frozen, independent medical vision encoder. Both modules are discarded at inference with zero overhead, yet can be re-attached post-hoc for dual interpretability, providing textual and visual explanations of the reasoning process without sacrificing efficiency. We construct a 61K dataset spanning 9 imaging modalities, exceeding prior medical visual latent reasoning datasets by an order of magnitude. Experiments on 7 benchmarks show that VITAL consistently and substantially outperforms the backbone, all latent reasoning baselines, and medical MLLMs trained on far larger data, achieving state-of-the-art results competitive with trillion-parameter proprietary models.

Introduction. Early detection of malignant skin lesions is critical for prognosis, yet dermatologist shortages in Russian regions limit screening coverage. Mobile dermoscopy clinical decision support systems (CDSS) offer a promising approach, with model interpretability and standardised patient routing remaining key barriers to adoption. Aim. To develop a quantitative interpretability assessment method for cascade deep learning models and a three-zone patient routing algorithm, and to conduct a preliminary single-centre prospective clinical validation of the Melanoscope AI CDSS in Russian outpatient practice. Material and methods. Two-stage cascade classification of dermoscopic images; attention map visualisation (attention rollout for ViT and Swin; Grad-CAM for ConvNeXt and EfficientNetV2); quantitative IoU-based agreement assessment between activation maps and expert annotations; prospective single-centre validation across four "Melanoma Day" sessions (Orel, Russia, June 2025 - April 2026). Results. On 176 patients: agreement with expert assessment 88.6%; no false negatives among 5 malignant lesions (95% CI: 47.8-100.0%); specificity 88.3%. Three melanomas and two basal cell carcinomas were histologically confirmed; six dysplastic naevi placed under follow-up. Mean IoU (n=180): ViT - 0.69; Swin - 0.64; ConvNeXt - 0.53; EfficientNetV2 - 0.51. Routing thresholds: P<0.15 / 0.15-0.50 / >=0.50. Conclusion. No false negatives were observed; specificity was 88.3%, supporting screening use. The integrated cascade classification, attention map visualisation with IoU assessment, and three-zone routing provide reproducible, interpretable clinical decision support adaptable to varying resource levels.

Weakly-supervised classification of whole-slide images with attention-based multiple instance learning (ABMIL) on top of foundation features now reaches near-saturation on Camelyon16 slide-level performance, but the corresponding attention maps are an imperfect localization signal: in clinical interpretation, a model that classifies correctly without firing on the actual lesion is hard to trust. We address this gap with cellular sheaves, which equip each vertex and edge of a graph with a finite-dimensional vector space and consistent linear maps between them, providing a principled way to detect local disagreement on graph-structured data. We apply cellular sheaves to weakly-supervised tumour localization on whole-slide images, combining a sheaf disagreement field with ABMIL. The natural training objective, encouraging consistency between similar features, produces a disagreement field that tracks tissue-level texture rather than diagnostic content. We propose attention-conditional consistency, which uses the classifier's attention to define which neighbouring patches should agree. Joint training of the classifier and the sheaf under this objective produces a disagreement field with patch-level AUC 0.940 on Camelyon16 and raises the attention head from its ABMIL-alone level of 0.717 to 0.953. Two-stage ablation with the classifier frozen at its ABMIL values reaches only 0.727 on the disagreement field and leaves attention at 0.717, confirming that the gain comes from the projector co-adapting under both objectives, not from the loss change in isolation. The trained model transfers without retraining to annotated slides from Camelyon17, maintaining Delta AUC 0.932 +/- 0.083 and attention AUC 0.955 +/- 0.099. The result is an attention map and a sheaf-disagreement map that fire on the same diagnostic regions, giving clinicians two complementary explanations for each slide-level prediction.

Pre-trained Vision Transformers (ViTs) are increasingly deployed for medical image classification. However, correcting their inevitable failure cases in dynamic clinical scenarios poses a critical challenge. Conventional fine-tuning approaches inherently suffer from catastrophic forgetting, severely degrading previously acquired diagnostic capabilities. Such instability fundamentally compromises clinical safety. Addressing this vulnerability requires an active, controllable, and reliable intervention mechanism that is both theoretically grounded and inherently interpretable. To this end, we propose X-Edit (eXact, eXplicit, and eXplainable Editing), an efficient null-space model editing framework. X-Edit transitions the editing process from iterative gradient-based optimization to a theoretically grounded, closed-form solution. Specifically, we first explicitly localize the influential layers via causal tracing governing the erroneous prediction. Subsequently, we construct an orthogonal null-space projection matrix from a curated anchor set. By geometrically constraining the exact parameter update strictly within this null space, we provide mathematical guarantees that the intervention rectifies targeted errors without perturbing established diagnostic representations. Extensive evaluations on six medical imaging benchmarks demonstrate that X-Edit comprehensively suppresses catastrophic forgetting while achieving superior edit success rates. Our code is available at https://github.com/HenryLau7/X-Edit.

Retinal imaging provides a non-invasive window into systemic microvascular health and has emerged as a potential biomarker for systemic diseases. However, whether retinal features encode biologically meaningful systemic signals that can be reliably interpreted using explainable artificial intelligence (XAI) remains unclear. An explainable multi-task deep learning framework was developed to investigate associations between retinal microvascular features and systemic abnormalities in Type 2 Diabetes Mellitus. A total of 11,011 fundus images from 2,719 individuals were analysed using a shared neural network with task-specific heads for glycaemic status, kidney abnormality, and multi-system involvement. Model interpretability was evaluated using Gradient-weighted Class Activation Mapping (Grad-CAM), anatomical masking, and vessel alignment analysis. The framework demonstrated task-dependent predictive performance, with the best discrimination observed for kidney abnormality (AUC up to 0.63), whereas glycaemic status prediction showed limited performance (AUC = 0.49-0.61). Explainability analyses consistently localized model attention to retinal vessels and peripapillary regions. Masking experiments showed that occlusion of vascular regions caused the greatest performance decline, indicating that retinal vessels were the primary predictive source. Different architectures exhibited heterogeneous attention patterns, suggesting multiple representational pathways for systemic signal encoding. This pilot study demonstrates that retinal microvascular features contain measurable signals associated with systemic abnormalities, particularly microvascular damage. By integrating multi-task learning with quantitative XAI validation, this framework advances retinal imaging toward interpretable digital biomarkers for systemic risk stratification in diabetes.

Effective pre-polysomnography screening for obstructive sleep apnea-hypopnea syndrome (OSAHS) requires combining clinical risk factors with visible craniofacial and neck cues. Directly prompting general-purpose multimodal foundation models for medical yes/no decisions can yield unstable, poorly calibrated outputs. We propose EviOSAHS, an evidence-grounded multimodal reasoning framework that separates image-only anatomical evidence acquisition from final clinical adjudication. Each frontal facial image is decomposed into seven fixed anatomical queries covering the neck, chin, mouth, face/neck fat, lower jaw, midface, and nose. Visual responses are converted into structured evidence cards recording target anatomy, visibility, risk direction, evidence strength, confidence, and a concise summary. These cards are combined with a cleaned clinical profile only in the final stage, where a large language model performs balanced binary screening adjudication. We evaluated EviOSAHS on a 642-subject cohort, mapping normal subjects to screening-negative and mild, moderate, or severe OSAHS subjects to screening-positive. EviOSAHS achieved 88.47% accuracy, 94.86% sensitivity, 93.74% F1-score, and a 5.14% false-negative rate, outperforming clinical-only prompting, direct multimodal prompting, and naive two-stage pipelines under a unified protocol. Ablations showed that seven-question visual decomposition and balanced final adjudication were critical to the high-sensitivity operating point. A question-level audit of 4,494 visual outputs showed a 100% structured parse rate and 93.88% high-visibility rate. EviOSAHS provides an auditable, high-sensitivity workflow for binary pre-polysomnography OSAHS screening, but should be viewed as a triage assistant rather than a diagnostic system. Prospective validation, external testing, and calibrated operating-point control are needed before clinical deployment.

Accurate segmentation of brain tumour sub-regions from multi-parametric MRI is critical for treatment planning yet remains challenging due to morphological variability, class imbalance, and overlapping appearances of tumour regions across imaging sequences. We propose SegGuidedNet, a three-dimensional residual encoder--decoder network introducing a novel SegAttentionGate module that explicitly supervises the decoder to produce spatially discriminative attention maps for each tumour sub-region necrotic core, peritumoral oedema, and enhancing tumour via a lightweight auxiliary loss, adding less than 0.2% parameter overhead. This sub-region supervision maintains decoder discriminability between visually ambiguous classes while providing free-of-cost spatial interpretability at inference without any post-hoc explanation method. Evaluated independently on BraTS2021 and BraTS2023 GLI across 251 held-out subjects each, SegGuidedNet achieves mean Dice of 0.905 (ET= 0.873, TC=0.906, WT=0.935) and 0.897 (ET=0.859, TC=0.902, WT=0.931) respectively, surpassing ensemble-based nnU-Net and HNF-Netv2 as a single model and approaching Swin UNETR a 10-model ensemble within 2--4 Dice points at a fraction of the inference cost. The consistency of results across two benchmark editions further confirms the generalisability of the proposed approach, offering competitive accuracy with built-in interpretability in a lightweight, clinically practical framework.

Visual Question Answering (VQA) holds great promise for clinical support, particularly in ophthalmology, where retinal fundus photography is essential for diagnosis. However, ophthalmic VQA benchmarks primarily emphasize answer accuracy, neglecting the explicit visual evidence necessary for clinical interpretability. In this work, we introduce FundusGround, a new benchmark for clinically interpretable ophthalmic VQA with spatially-grounded lesion evidence. Specifically, we propose a three-stage pipeline that collects 10,719 fundus images with 15,595 image-level meticulously annotated lesions. To ensure anatomical consistency and clinical validity, all lesions are spatially localized using the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, enabling standardized mapping to nine clinically meaningful retinal regions. Built upon this structured lesion evidence, 72,706 questions are then generated spanning four formats: open-ended, closed-ended, single-choice, and multiple-choice. We further benchmark multiple general- and medical- large vision-language models using dual metrics for answer accuracy and lesion-level reasoning. The experiments demonstrate that incorporating lesion-level visual evidence consistently improves model performance and transparency, highlighting the necessity of explicit spatial grounding for reliable and explainable ophthalmic VQA.

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, $K$ learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype $\times$ pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.

Large Vision Language Models (LVLMs) show promise in medical applications, but their inability to faithfully ground responses in visual evidence raises serious concerns about clinical trustworthiness. While visual attribution methods are widely used to explain LVLM predictions, whether these explanations actually reflect the visual evidence underlying the model's decision is largely unverified, since ground-truth annotations for internal model reasoning are typically unavailable. We address this question for chest X-ray (CXR) reasoning by developing a causal evaluation framework that retains only CXR-VQA samples for which the expert-annotated region is verified, via counterfactual editing, to be causally responsible for the model's prediction. Using this framework across 11 attribution methods, six open-source LVLMs, and two output modes (direct answer and step-by-step reasoning), we find that existing attribution methods often fail to identify the evidence used by LVLMs. To address this failure, we propose MedFocus, a concept-based attribution method that localizes clinically meaningful anatomical regions via unbalanced optimal transport and measures their causal effect on model outputs through targeted interventions. MedFocus produces spatial, concept-level, and token-level attributions and substantially outperforms prior methods, taking a step toward more trustworthy attribution for medical LVLMs. Our data and code are available at https://github.com/gzxiong/medfocus/.

Multiple instance learning (MIL) is the standard approach for whole-slide image (WSI) classification and survival prediction, where attention-based models ag gregate patch features into slide-level predictions. These models treat attention weights as evidence for their predictions, but attention is optimized for classi fication, not for identifying which patches actually support the diagnosis. This conflation leads to three failures: selected patches are insufficient (keeping them alone drops Macro-F1 by 0.078), unnecessary (removing them barely changes the prediction), and unrecoverable (continuous attention scores disagree with discrete patch subsets used at inference). The central premise is that evidence quality should be optimized directly through explicit criteria- Sufficiency, Necessity, and Recov erability (S/N/R)- rather than inherited as a byproduct of classification. GCE-MIL is a backbone-agnostic wrapper implemented through three injection modes and three evidence components: a grounding mechanism that aligns selection with domain-specific concepts, noisy-OR coverage that acts as a differentiable proxy for interventional evidence search, and threshold-plus-repair recovery that converts continuous selectors into discrete subsets through marginal-guided repair. Across 9 backbones and 9 datasets (81 configurations), GCE-MIL improves average Macro-F1 by 0.024 and C-index by 0.014, reduces the continuous-discrete gap by 4-7, and increases complement degradation by 2-4. With optional tile prefiltering after discrete recovery, inference runs up to 5 faster while retaining 0.989 full-bag utility.

Manual Pap smear analysis for cervical cancer screening is limited by inter-observer variability, time constraints, and restricted expert availability. Although convolutional neural networks (CNNs) have automated cervical cell classification, they remain limited in modeling long-range spatial dependencies and often lack clinical interpretability. In this study, Vision Transformer (ViT) architectures were systematically optimized to enhance automated cervical cancer screening, which resulted in improved interpretability. The Herlev dataset (917 images: 242 normal, 675 abnormal) was utilized to optimize ViT-Tiny, a lightweight Vision Transformer architecture designed for reduced computational complexity, through a comprehensive evaluation of augmentation strategies, class weighting, and hyperparameters. The optimal configuration achieved 94.9%-95.2% cross-validation accuracy, in which random horizontal flipping and class weighting (0.7 x 1.3) were identified as most effective. Gradient-weighted Class Activation Mapping (Grad-CAM) analysis confirmed that model attention corresponded to clinically relevant morphological features, which include nuclear regions, cell boundaries, and chromatin texture, which align with cytopathological criteria. These findings indicate that Vision Transformers can deliver accurate and interpretable decision support for cervical cancer screening, which fulfills both clinical performance and transparency requirements essential for medical AI deployment.

Accurate intraoperative and postoperative diagnosis of spread through air spaces (STAS) is essential for guiding surgical decisions and postoperative management in lung cancer. However, histopathological assessment is labor-intensive and is prone to missed or incorrect diagnoses. We propose a Diffusion Attention Expert Model (DAEM) to detect STAS in frozen sections (FSs) and paraffin sections (PSs). Its diffusion attention expert module leverages full attention aggregation to learn multi-scale features from histopathological images, while a dual-branch architecture strengthens multi-scale feature representation. On an internal dataset, DAEM achieves AUCs of 0.8946 for FSs and 0.9112 for PSs. Validation on external multi-center datasets from eight institutions demonstrates strong generalizability and interpretability. Using tumor microenvironment (TME) features in PSs, we further enable semi-automatic measurement of STAS location and its distance from the primary tumor. Several quantitative TME metrics are identified as potential biomarkers for STAS, including micropapillary-type STAS. Overall, DAEM offers a clinically actionable framework for STAS assessment by enabling accurate and interpretable detection on FSs and PSs, supporting postoperative risk stratification through quantitative TME-based analysis.

Disease screening is critical for early detection and timely intervention in clinical practice. However, most current screening models for medical images suffer from limited interpretability and suboptimal performance. They often lack effective mechanisms to reference historical cases or provide transparent reasoning pathways. To address these challenges, we introduce EviScreen, an evidential reasoning framework for disease screening that leverages region-level evidence from historical cases. The proposed EviScreen offers retrospection interpretability through regional evidence retrieved from dual knowledge banks. Using this evidential mechanism, the subsequent evidence-aware reasoning module makes predictions using both the current case and evidence from historical cases, thereby enhancing disease screening performance. Furthermore, rather than relying on post-hoc saliency maps, EviScreen enhances localization interpretability by leveraging abnormality maps derived from contrastive retrieval. Our method achieves superior performance on our carefully established benchmarks for real-world disease screening, yielding notably higher specificity at clinical-level recall. Code is publicly available at https://github.com/DopamineLcy/EviScreen.

Dermatological diagnosis requires integrating fine-grained visual perception with expert clinical knowledge. Although Multimodal Large Language Models (MLLMs) facilitate interactive medical image analysis, their application in dermatology is hindered by insufficient domain-specific grounding and hallucinations. To address these issues, we propose DermAgent, a collaborative multi-tool agent that orchestrates seven specialized vision and language modules within a Plan-Execute-Reflect framework. DermAgent delivers stepwise, traceable diagnostic reasoning through three core components. First, it employs complementary visual perception tools for comprehensive morphological description, dermoscopic concept annotation, and disease diagnosis. Second, to overcome the lack of domain prior, a dual-modality retrieval module anchors every prediction in external evidence by cross-referencing 413,210 diagnosed image cases and 3,199 clinical guideline chunks. To further mitigate hallucinations, a deterministic critic module conducts strict post-hoc auditing via confidence, coverage, and conflict gates, automatically detecting inter-source disagreements to trigger targeted self-correction. Extensive experiments on five dermatology benchmarks demonstrate that DermAgent consistently outperforms state-of-the-art MLLMs and medical agent baselines across zero-shot fine-grained disease diagnosis, concept annotation, and clinical captioning tasks, exceeding GPT-4o by 17.6% in skin disease diagnostic accuracy and 3.15% in captioning ROUGE-L. Our code is available at https://github.com/YizeezLiu/DermAgent.

Concept Bottleneck Models (CBMs) offer interpretable alternatives to black-box predictors by introducing human-relatable concepts before the final output. However, existing CBMs struggle to verify whether predicted concepts correspond to the correct visual evidence, limiting their reliability. We propose a fine-grained CBM framework that grounds each concept in localized visual evidence, enabling direct inspection of where and how concepts are encoded. This design allows users to interpret predictions and verify that the model learns intended concepts rather than spurious correlations. Experiments on medical imaging benchmarks show that our learned concept space is information-complete and achieves predictive performance comparable to standard CBMs, while substantially improving transparency. Unlike post-hoc attribution methods, our framework validates both the presence and correctness of concept representations, bridging interpretability with verifiability. Our approach enhances the trustworthiness of CBMs and establishes a principled mechanism for human-model interaction at the concept level, paving the way toward more reliable and clinically actionable concept-based learning systems.

While interpretable prototype networks offer compelling case-based reasoning for clinical diagnostics, their raw continuous outputs lack the semantic structure required for medical documentation. Bridging this gap via standard Retrieval-Augmented Generation (RAG) routinely triggers ``retrieval sycophancy,'' where Large Language Models (LLMs) hallucinate post-hoc rationalizations to align with visual predictions. We introduce ProtoMedAgent, a framework that formalizes multimodal clinical reporting as an iterative, zero-gradient test-time optimization problem over a strict neuro-symbolic bottleneck. Operating on a frozen prototype backbone, we distill latent visual and tabular features into a discrete semantic memory. Online generation is strictly constrained by exact set-theoretic differentials and a reflective Scribe-Critic loop, mathematically precluding unsupported narrative claims. To safely bound data disclosure, we introduce a semantic privacy gate governed by $k$-anonymity and $\ell$-diversity. Evaluated on a 4,160-patient clinical cohort, ProtoMedAgent achieves 91.2% Comparison Set Faithfulness where it fundamentally outperforms standard RAG (46.2%). ProtoMedAgent additionally leverages a binding $\ell$-diversity phase transition to systematically reduce artifact-level membership inference risks by an absolute 9.8%.

Transthoracic echocardiography (TTE) is the first-line imaging modality for diagnosing bicuspid aortic valve (BAV), yet diagnostic performance varies with operator expertise and image quality. We developed an explainable AI model that distinguishes BAV from tricuspid aortic valves (TAV) using routinely acquired parasternal long-axis (PLAX) cine loops. A multi-backbone video ensemble was trained and evaluated using a leakage-aware, stratified outer cross-validation protocol on $N{=}90$ patient studies (48 BAV, 42 TAV). Across fixed outer splits and 10 random seeds, the calibrated stacked ensemble achieved an outer-CV F1-score of $0.907$ and recall of $0.877$. Frame-level Grad-CAM localized salient evidence to the aortic root and leaflet plane, while globally aggregated SHAP values quantified each video backbone's contribution to the stacked prediction, enabling transparent, case-level auditability. These findings indicate that PLAX-based video ensembles can support reliable BAV/TAV classification from routine echocardiographic cine loops and may facilitate earlier detection in non-specialist or resource-limited clinical settings.

Retinal diagnosis is inherently bilateral: clinicians compare homologous structures across eyes (e.g., optic disc asymmetry), yet most deep models operate on monocular representations. We investigate whether explicit structural correspondence improves diagnosis, and propose Anatomy-Slot to operationalize this hypothesis. Anatomy-Slot introduces an unsupervised anatomical bottleneck by decomposing patch tokens into a set of emergent, structurally-coherent slots that correspond to anatomical regions, then aligning these slots across eyes via bidirectional cross-attention. On ODIR-5K with $n=10$ seeds, the method improves AUC by $4.2$ points over a matched ViT-L baseline (95% CIs; Wilcoxon signed-rank test, $W=0$, $p=0.002$). Pairing disruption and stress testing under Gaussian noise provide controlled tests of correspondence dependence and robustness under corruption. We further report quantitative optic disc grounding on REFUGE and cross-attention localization analysis. Beyond the reported gains, these results indicate that object-centric anatomical correspondence offers a principled path toward interpretable diagnostic systems aligned with clinical bilateral comparison.