A Discordance-Aware Multimodal Framework with Multi-Agent Clinical Reasoning

Knee osteoarthritis (KOA) progression prediction can support patient monitoring, requiring the integration of multimodal data and multidomain expertise. Moreover, isolated risk estimates provide limited insight underlying a prediction. To automate the progression assessment workflow and reduce manual effort while providing interpretable findings and supporting evidence, we present OA-MAP, an autonomous multi-agent framework for evidence-grounded assessment of structural and pain progression in KOA. The system incorporates modality-specific agents including MRI, X-ray, and clinical agents, together with a coordinator agent. This framework can autonomously recruit specialist agents, select tools for prediction and analysis, and retrieve literature as external evidence based on user request and available patient information. An uncertainty-informed human-in-the-loop mechanism enables clinicians to review and correct intermediate findings, triggering recomputation of affected results. We evaluate the prediction models using 600 participants from the FNIH Osteoarthritis Biomarkers Consortium cohort. On the test set of 100 participants, the fusion models achieve AUROCs of 0.80 for structural progression and 0.68 for pain progression. A case study illustrates how OA-MAP combines risk estimates with intermediate findings, cross-modal conflicts, literature support, and uncertainty indicators to support interactive review.

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.

Background and objective. Conventional Deep Learning (DL) approaches for Knee Osteoarthritis (KOA) grading rely on one-hot labels, which fail to capture both the ordinal uncertainty of Kellgren--Lawrence (KL) and Calcium Pyrophosphate Deposition Disease (CPPD) severity scores and the asymmetric relationship between the two scales observed in clinical practice. Methods. We retrospectively collected 2172 knee X-ray images, including 968 radiographs jointly annotated for KL and CPPD severity. An ordinal DL framework based on soft-labelling was developed for both tasks, replacing one-hot targets with unimodal probability distributions centred on the annotated grade. Four formulations were investigated: binomial, beta, triangular, and exponential. Results. All soft-labelling strategies consistently outperformed the nominal baseline. For CPPD grading, the triangular formulation achieved the highest Quadratic Weighted Kappa (QWK) and the lowest Mean Absolute Error (MAE) (QWK = 0.796; MAE = 0.438), while the beta formulation yielded the most balanced class-wise performance considering Average MAE (AMAE) and Maximum MAE (MMAE) across classes (AMAE = 0.458; MMAE = 0.573). For KL grading, the beta-based approach provided the best overall performance, achieving the highest QWK together with the lowest MAE and class-wise errors (QWK = 0.777; MAE = 0.529; AMAE = 0.523; MMAE = 0.775). Statistical analysis demonstrated significant improvements over conventional one-hot supervision (p < 0.001).