Adjoint-Based Calibration and Optimal Control of Stochastic Multiscale Bioprocess Digital Twins

Digital twins of natural systems must remain aligned with physical systems that evolve over time, are only partially observed, and are typically modeled by mechanistic simulators whose parameters cannot be measured directly. In such settings, model adaptation is naturally posed as a simulation-based inference problem. However, sparse and indirect observations often fail to identify a unique and optimal calibration, leaving several simulator parameterizations compatible with the available evidence. This article presents a GFlowNet-based approach to model adaptation for digital twins of natural systems. We formulate adaptation as a generative modeling problem over complete simulator configurations, so that plausible parameterizations can be sampled with probability proportional to a reward derived from agreement between simulated and observed behavior. Using a controlled environment agriculture case study based on a mechanistic tomato model, we show that the learned policy recovers dominant regions of the adaptation landscape, retrieves strong calibration hypotheses, and preserves multiple plausible configurations under uncertainty.

Digital-twin calibration requires interaction data that is expensive to collect. We study two acquisition decisions: which trajectories to generate, and when to spend a limited budget on privileged parameter measurements. Our framework couples an excitation-oriented reinforcement learning controller, a recurrent parameter estimator with predictive uncertainty, and a budgeted query policy. In Pendulum, a Random Forest diagnostic recovers gravity only weakly from task-oriented trajectories and does not recover mass or length, while a GRU trained on excitation-oriented trajectories reaches a mean absolute error of 0.0066 with no queries. We then withdraw continuous oracle access partway through an episode, so that the twin must run on the estimator's output for the remainder. The estimator-plus-policy pipeline achieves a terminal error of 0.0092 under a three-query budget, against 0.2031 for an uncalibrated twin. In partially observable Waterworld, five controllers produce different observed error profiles across three hidden parameters, and an estimator trained on a five-controller mixture reaches online normalized errors of roughly 4-5%. These exploratory case studies are not controlled ablations, but they motivate treating trajectory design and query allocation as explicit design variables in data-scarce calibration.

Bayesian model calibration is central to digital twins and computer experiments, as it aligns model outputs with field observations by estimating calibration parameters and correcting systematic model bias. Classical Bayesian calibration introduces latent parameters and a discrepancy function to model bias, but suffers from parameter--discrepancy confounding and is typically formulated as an offline procedure under a stationary data-generating assumption. These limitations are restrictive in modern digital twin applications, where systems evolve over time and may exhibit gradual drift and abrupt regime shifts. While data assimilation methods enable sequential updates, they generally do not explicitly model systematic bias and are less effective under abrupt changes. We propose Bayesian Recursive Projected Calibration (BRPC), an online Bayesian calibration framework for streaming data under simulator mismatch and nonstationarity. BRPC extends projected calibration to the online setting by separating a discrepancy-free particle update for calibration parameters from a conditional Gaussian process update for discrepancy, preserving identifiability while enabling bias-aware adaptation under gradual system evolution. To handle abrupt changes, BRPC is integrated with restart mechanisms that detect regime shifts and reset the calibration process. We establish theoretical guarantees for both components, including tracking performance under gradual evolution and false-alarm and detection behavior for restart mechanisms. Empirical studies on synthetic and plant-simulation benchmarks show that BRPC improves calibration accuracy under gradual changes, while restart-augmented BRPC further improves robustness and predictive performance under abrupt regime shifts compared to sliding-window Bayesian calibration and data assimilation baselines.