Peter G. Jacobs

Phat Tran, Neville Mehta, Clara Mosquera-Lopez et al.

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.

Valentina Roquemen-Echeverri, Taisa Kushner, Peter G. Jacobs et al.

Simulating glucose dynamics in individuals with type 1 diabetes (T1D) is critical for developing personalized treatments and supporting data-driven clinical decisions. Existing models often miss key physiological aspects and are difficult to individualize. Here, we introduce physiologically-constrained neural network (NN) digital twins to simulate glucose dynamics in T1D. To ensure interpretability and physiological consistency, we first build a population-level NN state-space model aligned with a set of ordinary differential equations (ODEs) describing glucose regulation. This model is formally verified to conform to known T1D dynamics. Digital twins are then created by augmenting the population model with individual-specific models, which include personal data, such as glucose management and contextual information, capturing both inter- and intra-individual variability. We validate our approach using real-world data from the T1D Exercise Initiative study. Two weeks of data per participant were split into 5-hour sequences and simulated glucose profiles were compared to observed ones. Clinically relevant outcomes were used to assess similarity via paired equivalence t-tests with predefined clinical equivalence margins. Across 394 digital twins, glucose outcomes were equivalent between simulated and observed data: time in range (70-180 mg/dL) was 75.1$\pm$21.2% (simulated) vs. 74.4$\pm$15.4% (real; P<0.001); time below range (<70 mg/dL) 2.5$\pm$5.2% vs. 3.0$\pm$3.3% (P=0.022); and time above range (>180 mg/dL) 22.4$\pm$22.0% vs. 22.6$\pm$15.9% (P<0.001). Our framework can incorporate unmodeled factors like sleep and activity while preserving key dynamics. This approach enables personalized in silico testing of treatments, supports insulin optimization, and integrates physics-based and data-driven modeling. Code: https://github.com/mosqueralopez/T1DSim_AI