iLENS: Interpretable LLM-Guided Mixture-of-Experts for Neuroimaging Survival Analysis

Individualized Alzheimer's disease (AD) progression prediction requires models that use irregular visits, account for censoring, avoid diagnostic leakage, and provide calibrated horizon risks. We propose PROgression-aware MultI-horizon Survival Estimation for Alzheimer's Disease (PROMISE-AD), a leakage-safe survival framework for predicting conversion from cognitively normal (CN) to mild cognitive impairment (MCI) and from MCI to AD dementia using ADNI/TADPOLE tabular histories. PROMISE-AD converts pre-index visits into tokens with standardized measurements, missingness masks, longitudinal changes, time-normalized slopes, visit timing, and non-diagnostic categorical attributes. A temporal Transformer fuses global, attention-pooled, and latest-visit representations to estimate a progression score and latent discrete-time mixture hazards. Training combines survival likelihood, horizon-specific focal risk loss, progression ranking, hazard smoothness, and mixture-balance regularization, followed by validation-set isotonic calibration for 1-, 2-, 3-, and 5-year risks. In held-out testing across three seeds, PROMISE-AD achieved an integrated Brier score (IBS) of 0.085 $\pm$ 0.012, C-index of 0.808 $\pm$ 0.015, and mean time-dependent AUC of 0.840 $\pm$ 0.081 for CN-to-MCI conversion, yielding the lowest IBS among compared methods. For MCI-to-AD conversion, PROMISE-AD achieved the highest C-index (0.894 $\pm$ 0.018) and near-ceiling 5-year discrimination (AUROC 0.997 $\pm$ 0.003; AUPRC 0.999 $\pm$ 0.001), although some baselines had lower IBS. Ablations and interpretability supported longitudinal change features, fused temporal representations, mixture hazards, cognitive and functional measures, APOE4 status, and recent conversion-proximal visits. These findings suggest that progression-aware survival modeling can provide interpretable multi-horizon AD conversion risk estimates.

Survival prediction plays a central role for healthcare providers and clinical researchers. Accurate risk stratification enables early intervention and improved patient management. Most existing deep survival models learn one common feature representation for all patients, which may hide important differences between patient subgroups. In contrast, a Mixture-of-Experts (MoE) framework allows different parts of the model to focus on different patient patterns, leading to more individualized representations. Therefore, in this work, we propose a mixture-of-experts enhanced adaptive deep clustering survival framework (AdaCSM) for modeling such heterogeneous survival patterns. We introduce a routing-based expert mechanism that enables conditional specialization within a parametric survival modeling framework. The proposed architecture allocates patients to specialized risk predictors dynamically while preserving the patient survival and subtype clustering objectives. We compare our method with state-of-the-art survival and deep clustering models on multiple real-world longitudinal clinical cohorts spanning diverse disease domains. The proposed method demonstrates improved predictive performance and leads to interpretable results in survival analysis.

Objective: Survival analysis is central to medical prediction, yet large language models (LLMs) are rarely used as end-to-end survival models because censoring prevents straightforward supervised fine-tuning. Here we present LLMSurvival, a framework that enables censoring-aware survival analysis with unmodified LLMs operating directly on tabular clinical data. Materials and Methods: LLMSurvival reformulates time-to-event prediction as pairwise ranking among comparable subjects, and derives test-time risk by aggregating comparisons against anchor individuals from the training cohort. Results: Across two clinical tasks (ICU mortality prediction in MIMIC-IV and fragility fracture prediction in a NewYork-Presbyterian/Weill Cornell Medicine cohort), LLMSurvival improves overall concordance over Cox proportional hazards modeling by 3.1% for ICU mortality and 0.5% for fracture risk, 2.1% on average for ICU mortality and 2.8% for fracture risk over three established deep learning survival models. Discussion: The results show that survival modeling with censoring can be made compatible with LLM fine-tuning through comparison-based reformulation. The framework demonstrates high portability and superior performance over expert curated scores like SAPS-II and FRAX scores across diverse clinical context. Furthermore, the framework supports local deployment, as compact, publicly available base models provide sufficient performance. Conclusion: The LLMSurvival framework serves as a proof of concept for an integrated, censoring-conscious approach to survival analysis via LLMs.