PhysioSeq2Seq: A Hybrid Physiological Digital Twin and Sequence-to-Sequence LSTM for Long-Horizon Glucose Forecasting in Type 1 Diabetes

Abstract: Accurate long-horizon glucose forecasting is critical for automated insulin delivery systems, which help people with type 1 diabetes (T1D) manage their glucose and avoid dangerous hypoglycemia. However, standard recursive long short-term memory (LSTM) networks suffer from systematic negative bias at longer horizons due to error compounding, while purely mechanistic ordinary differential equation (ODE) models fail to generalize across individuals when parameterized at the population level. We propose PhysioSeq2Seq, a hybrid architecture that combines patient-specific physiological modeling with a sequence-to-sequence (Seq2Seq) LSTM. For each glucose segment, twin matching searches a population of 300 parameterized digital twins to identify the best-fitting physiological match from a 3-hour continuous glucose monitoring (CGM) history. The 10 internal ODE state variables of the matched twin are injected as exogenous covariates into both the encoder and decoder of the Seq2Seq LSTM. This simultaneous 48-step prediction strategy eliminates recursive error compounding, while the ODE features provide a physics-grounded constraint that bounds long-horizon drift within physiologically plausible ranges. PhysioSeq2Seq was trained on CGM and insulin data from 348 participants in the Type 1 Diabetes Exercise Initiative (T1DEXI) dataset and evaluated on 74 held-out participants. At the 240-minute horizon, PhysioSeq2Seq achieves a mean absolute error of 39.28 mg/dL and a mean error of -10.62 mg/dL, reducing bias by 13.89 mg/dL over the recursive LSTM and reducing mean absolute error by 28.62 mg/dL over the ODE-based digital twin. These results show that eliminating architectural feedback and injecting patient-matched physiological states is an effective and clinically meaningful strategy for long-horizon glucose forecasting in T1D.