A Rubric-Guided Large Language Model Solution for Opioid Use Disorder Computable Phenotyping

Feature selection is a critical step in electronic health record (EHR)-based predictive modeling, where input variables are often high-dimensional, sparse, noisy, and redundant. Large feature sets not only increase computational burden and overfitting risk, but also make model interpretation difficult, leading to limited usefulness in clinical settings. In this study, we focus on diagnosis-related features and compare five feature selection paradigms for opioid use disorder (OUD) prediction: recurrence enrichment, NTK-motivated early gradient sensitivity, LightGBM-SHAP, Elastic Net, and large language model (LLM)-guided semantic selection. We use a unified preprocessing and evaluation framework and assess each method by downstream predictive performance, resampling stability, and representation of infrequent diagnosis codes. Our results demonstrate that performance improves with larger feature budgets with diminishing returns beyond a moderate size. NTK sensitivity provides the best overall balance of accuracy and stability, and LLM-guided selection contributes complementary clinically meaningful signals despite lower standalone performance.

Electronic health records (EHRs) may incompletely capture patient-reported factors associated with opioid use disorder (OUD). We evaluated whether survey data improve prediction of a first recorded OUD diagnosis among 267,747 All of Us participants with documented opioid exposure, including 15,287 OUD cases. We compared EHR-only and EHR+survey models across 6-, 12-, and 24-month look-back windows using logistic regression, random forest, XGBoost, LightGBM, multilayer perceptron, LSTM, GRU, and Transformer. Survey augmentation improved PR-AUC across all 24 model-window combinations by 0.0087-0.0505; the best 24-month LightGBM model improved from 0.6219 to 0.6603. Survey coverage increased with longer windows and differed by OUD status (24 months: 21.7% OUD-positive vs. 60.7% OUD-negative). Permutation analysis ranked survey features as the second most important information domain at 24 months in both evaluated models. Patient-reported data provide complementary predictive signals beyond structured EHRs while highlighting the importance of survey availability.

Opioid overdose remains a major clinical and public health burden, highlighting the need for scalable approaches to identify patients at high risk. Here, we investigate diagnosis-specific adaptation for 180-day opioid overdose risk prediction from patients' preceding one-year longitudinal ICD histories. We develop OODMAMBA and OODQWEN through continued pretraining on longitudinal diagnostic sequences followed by task-specific fine-tuning. Building on the stronger Qwen-based predictors, we further propose OVERDOSEMOE, a multi-expert framework that integrates models of different scales using complementary expert-weighting strategies. Diagnosis-specific adaptation consistently improved predictive performance over general-purpose language-model baselines, with OODQWEN achieving an AUPRC of 24.47 and an AUROC of 68.56. OVERDOSEMOE further improved discrimination and precision, achieving an AUPRC of 25.17 and an AUROC of 69.49 while outperforming the strongest single-model baselines. Among patients ranked in the top 5% of predicted risk, OVERDOSEMOE identified substantially enriched overdose risk, achieving a PPV of 25.38% while retaining meaningful recall. Evaluation on an independent MIMIC-IV cohort further demonstrated cross-cohort robustness, with complementary weighting strategies showing advantages across different performance measures. These findings demonstrate that diagnosis-specific language-model adaptation combined with multi-expert integration can improve opioid overdose risk stratification and support more robust prediction across heterogeneous electronic health record populations.