EpiEvolve: Self-Evolving Agents for Streaming Pandemic Forecasting under Regime Shifts

Probabilistic forecasting of infectious diseases is crucial for public health but relies on labor-intensive manual model curation by expert modeling teams. This bespoke development bottlenecks scalability to granular geographic resolutions or emerging pathogens. Here, we present an autonomous system using Large Language Model (LLM)-guided tree search to iteratively generate, evaluate, and optimize executable forecasting software. In a fully prospective, real-time evaluation during the 2025-2026 US respiratory season, the system autonomously discovered methodologically diverse models for influenza, COVID-19, and respiratory syncytial virus (RSV). Aggregating these machine-generated models yielded an ensemble that consistently matched or outperformed the gold-standard, human-curated Centers for Disease Control and Prevention (CDC) hub ensembles out-of-sample. The system successfully navigated data-scarce "cold start" scenarios for RSV. Moreover, controlled retrospective ablations revealed that optimizing log-scale distance metrics prevents reward hacking, while an automated judge-in-the-loop ensures structural fidelity to complex scientific theories. By autonomously translating epidemiological theory into accurate, transparent code, this framework overcomes the modeling labor bottleneck, enabling rapid deployment of expert-level disease forecasting at unprecedented scales.

Weekly influenza surveillance counts guide vaccine distribution and public-health alerts, yet they are hard to forecast. Each region offers only a few seasons, waves shift in timing and height every year, and information that helps while a wave grows misleads after its peak, whereas last season's shape stays informative for a year. Existing epidemic graph models and general forecasters read a short fixed window and treat all past information alike, so they neither exploit earlier seasons nor discard stale associations when the epidemic phase changes. To address these limitations, we propose TERN, a forecaster built around a delta-rule fast-weight memory that decays channel-wise and erases along a learned address under gates driven by local epidemic-phase features, combined with an explicit seasonal reference and online adaptation. On three Cola-GNN influenza benchmarks, TERN outperformed epidemic graph models and general forecasters, matched or exceeded seasonal references, and a controlled comparison confirmed the contribution of the memory itself.

Epidemic forecasting faces a fundamental challenge: human behavior dynamically responds to disease spread, creating feedback loops that induce distribution shifts at policy intervention points. This renders data-driven models unreliable under distribution shift. We propose \textbf{SL-BiLEM} (Structured Learnable Behavior-in-the-Loop Epidemic Model), leveraging physical constraints as regularization for robust extrapolation. The framework decomposes effective transmission as $β_{\text{eff}}(t,g) = β_0(g) \times m_{\text{policy}}(t) \times m_{\text{media}}(t) \times m_{\text{comp}}(t,g)$, where monotonicity, smoothness, and bounded-jump constraints on the learned compliance function maintain predictive validity under novel policy regimes. Beyond forecasting, SL-BiLEM enables counterfactual analysis for intervention decision support. We validate forecasting on three real-world datasets (cruise ship, school influenza, and school-district COVID-19 surveillance) and evaluate counterfactual recovery on synthetic benchmarks with known ground truth. SL-BiLEM demonstrates: (1) 76% improvement over neural-mechanistic baselines, with only 53% OOD degradation versus 1142% for neural baselines under policy-induced shift; (2) 100% bootstrap CI coverage across 27 synthetic counterfactual experiments; and (3) Treatment Effect Accuracy exceeding 0.85. These results establish SL-BiLEM as an interpretable tool for public health decision-makers seeking accurate prediction and principled intervention planning.