An Interpretable Deep Learning Framework for Discovery and Clinical Validation of Deep Radiomic Signatures in Tumor Classification

Deep learning has achieved remarkable performance in medical image segmentation, yet it suffers from critical limitations: mathematical intractability, substantial parameter requirements, and lack of clinical interpretability. We propose RadiomicNet, a novel two-stream hybrid architecture that enhances standard deep learning by integrating handcrafted radiomics features directly into the segmentation learning process. The key contribution is the Radiomics Attention Gate (RAG), which leverages Gray-Level Co-occurrence Matrix (GLCM) and Local Binary Pattern (LBP) features to modulate skip-connection attention in a lightweight MobileNetV2-based encoder-decoder, providing ante-hoc interpretability without post-hoc approximations. A novel Radiomics Consistency Loss further enforces alignment between texture complexity and prediction uncertainty, reducing Expected Calibration Error (ECE) from 0.142 to 0.118. RadiomicNet achieves a Dice Similarity Coefficient (DSC) of 0.763 +/- 0.231 on the Breast Ultrasound Images (BUSI) dataset and 0.854 +/- 0.112 on Kvasir-SEG, outperforming U-KAN by 1.2% and 1.8%, respectively (p < 0.05, Wilcoxon signed-rank test), with only 3.27M parameters, 9.5x fewer than standard U-Net and 4.3x fewer than U-KAN. Gradient-based feature importance analysis reveals that GLCM dissimilarity (15.24%), GLCM energy (14.56%), and LBP entropy (11.49%) are the dominant radiomics cues, providing clinically meaningful explanations for segmentation decisions. The proposed approach demonstrates that compact, interpretable models grounded in domain knowledge can deliver state-of-the-art segmentation performance with substantially reduced computational overhead.

The opaque nature of deep learning models remains a significant barrier to their clinical adoption in medical imaging. This paper presents a multimodal explainability framework that bridges the gap between convolutional neural network (CNN) predictions and clinically actionable insights for brain tumor classification, leveraging large language models (LLMs) to deliver human-interpretable diagnostic narratives. The proposed framework operates through three coupled stages. First, nine CNN architectures are extended with a dual-output hybrid formulation that simultaneously optimises a classification head and a segmentation head, enabling spatially richer feature learning. Second, visual saliency attribution methods, namely Grad-CAM, Grad-CAM++, and ScoreCAM, are applied to generate class-discriminative heatmaps, which are subsequently refined into binary tumor masks via an adaptive percentile thresholding pipeline. Third, the resulting masks are mapped onto the Harvard-Oxford cortical atlas to translate pixel-level evidence into named neuroanatomical structures, and the extracted findings are encoded into a structured JSON file that conditions three LLMs (Grok3, Mistral, and LLaMA) to generate coherent, radiological-style diagnostic reports. Evaluated on a dataset of 4,834 contrast-enhanced T1-weighted brain MRI images spanning three tumor classes, InceptionResNetV2 achieved the highest classification performance and Grad-CAM++ yielded the best segmentation overlap. Among the language models, Grok3 led in lexical diversity and coherence, while LLaMA achieved the highest readability score. By integrating visual, anatomical, and linguistic modalities into a unified pipeline, the framework produces explanations that are technically grounded and meaningfully interpretable, advancing the transparency and clinical accountability of artificial intelligence assisted brain tumor diagnosis.

Background: Radiogenomics allows identification of radiological biomarkers for genomic phenotypes. In glioblastoma, these biomarkers could potentially complement patient stratification strategies. We aim to develop and analytically validate radiological biomarkers that capture immune cell signatures within IDH-wildtype glioblastoma microenvironment using radiogenomic analysis. Methods: This was a retrospective multicenter study using curated open-access anonymized imaging and genomic data from TCGA-GBM, CPTAC, IvyGAP, REMBRANDT and CGGA datasets. Imaging data consisted of MRI-based radiomic features extracted from necrotic core, enhancing and edema regions of deep learning-based auto-segmented tumors. Radiomic feature selections were performed using nested cross-validated LASSO. Support vector machine and ensemble models were trained using seventeen immune and cell-specific score labels extracted from deconvoluted transcriptomic data using pan-cancer and glioblastoma immune signature matrices as reference standards. Seventeen classifier models trained in three cross-cohort strategies were validated on three held-out datasets assessing stability and generalizability. Results: One-hundred-and-seventy-six patients were included in the study. The immune-related radiomic signatures obtained after feature selection were shape, first order and higher order radiomic features. Models predicting macrophage subtype immune signature showed stable mean performance on balanced accuracy (0.67) and precision (0.89) metrics for three independent holdout datasets with ensemble model outperforming support vector machine model. Conclusion: Radiogenomic models non-invasively predicted the macrophage subtype M0 immune signature in IDH-wildtype glioblastoma. These biomarkers have the potential to stratify patients for immunotherapy within prospective glioblastoma clinical trials.