Digital Twin Calibration for Biological System-of-Systems: Cell Culture Manufacturing Process

Biomanufacturing innovation relies on an efficient design of experiments (DoE) to optimize processes and product quality. Traditional DoE methods, ignoring the underlying bioprocessing mechanisms, often suffer from a lack of interpretability and sample efficiency. This limitation motivates us to create a new optimal learning approach that can guide a sequential DoEs for digital twin model calibration. In this study, we consider a multi-scale mechanistic model for cell culture process, also known as Biological Systems-of-Systems (Bio-SoS), as our digital twin. This model with modular design, composed of sub-models, allows us to integrate data across various production processes. To calibrate the Bio-SoS digital twin, we evaluate the mean squared error of model prediction and develop a computational approach to quantify the impact of parameter estimation error of individual sub-models on the prediction accuracy of digital twin, which can guide sample-efficient and interpretable DoEs.

SiGeo: Sub-One-Shot NAS via Information Theory and Geometry of Loss Landscape

Neural Architecture Search (NAS) has become a widely used tool for automating neural network design. While one-shot NAS methods have successfully reduced computational requirements, they often require extensive training. On the other hand, zero-shot NAS utilizes training-free proxies to evaluate a candidate architecture's test performance but has two limitations: (1) inability to use the information gained as a network improves with training and (2) unreliable performance, particularly in complex domains like RecSys, due to the multi-modal data inputs and complex architecture configurations. To synthesize the benefits of both methods, we introduce a "sub-one-shot" paradigm that serves as a bridge between zero-shot and one-shot NAS. In sub-one-shot NAS, the supernet is trained using only a small subset of the training data, a phase we refer to as "warm-up." Within this framework, we present SiGeo, a proxy founded on a novel theoretical framework that connects the supernet warm-up with the efficacy of the proxy. Extensive experiments have shown that SiGeo, with the benefit of warm-up, consistently outperforms state-of-the-art NAS proxies on various established NAS benchmarks. When a supernet is warmed up, it can achieve comparable performance to weight-sharing one-shot NAS methods, but with a significant reduction ($\sim 60$\%) in computational costs.

Compressed domain vibration detection and classification for distributed acoustic sensing

Distributed acoustic sensing (DAS) is a novel enabling technology that can turn existing fibre optic networks to distributed acoustic sensors. However, it faces the challenges of transmitting, storing, and processing massive streams of data which are orders of magnitude larger than that collected from point sensors. The gap between intensive data generated by DAS and modern computing system with limited reading/writing speed and storage capacity imposes restrictions on many applications. Compressive sensing (CS) is a revolutionary signal acquisition method that allows a signal to be acquired and reconstructed with significantly fewer samples than that required by Nyquist-Shannon theorem. Though the data size is greatly reduced in the sampling stage, the reconstruction of the compressed data is however time and computation consuming. To address this challenge, we propose to map the feature extractor from Nyquist-domain to compressed-domain and therefore vibration detection and classification can be directly implemented in compressed-domain. The measured results show that our framework can be used to reduce the transmitted data size by 70% while achieves 99.4% true positive rate (TPR) and 0.04% false positive rate (TPR) along 5 km sensing fibre and 95.05% classification accuracy on a 5-class classification task.

Variance Reduction based Experience Replay for Policy Optimization

For reinforcement learning on complex stochastic systems where many factors dynamically impact the output trajectories, it is desirable to effectively leverage the information from historical samples collected in previous iterations to accelerate policy optimization. Classical experience replay allows agents to remember by reusing historical observations. However, the uniform reuse strategy that treats all observations equally overlooks the relative importance of different samples. To overcome this limitation, we propose a general variance reduction based experience replay (VRER) framework that can selectively reuse the most relevant samples to improve policy gradient estimation. This selective mechanism can adaptively put more weight on past samples that are more likely to be generated by the current target distribution. Our theoretical and empirical studies show that the proposed VRER can accelerate the learning of optimal policy and enhance the performance of state-of-the-art policy optimization approaches.

Dynamic Bayesian Network Auxiliary ABC-SMC for Hybrid Model Bayesian Inference to Accelerate Biomanufacturing Process Mechanism Learning and Robust Control

Driven by the critical needs of biomanufacturing 4.0, we present a probabilistic knowledge graph hybrid model characterizing complex spatial-temporal causal interdependencies of underlying bioprocessing mechanisms. It can faithfully capture the important properties, including nonlinear reactions, partially observed state, and nonstationary dynamics. Given limited process observations, we derive a posterior distribution quantifying model uncertainty, which can facilitate mechanism learning and support robust process control. To avoid evaluation of intractable likelihood, Approximate Bayesian Computation sampling with Sequential Monte Carlo (ABC-SMC) is developed to approximate the posterior distribution. Given high stochastic and model uncertainties, it is computationally expensive to match process output trajectories. Therefore, we propose a linear Gaussian dynamic Bayesian network (LG-DBN) auxiliary likelihood-based ABC-SMC algorithm. Through matching observed and simulated summary statistics, the proposed approach can dramatically reduce the computation cost and improve the posterior distribution approximation.

Variance Reduction based Partial Trajectory Reuse to Accelerate Policy Gradient Optimization

We extend the idea underlying the success of green simulation assisted policy gradient (GS-PG) to partial historical trajectory reuse for infinite-horizon Markov Decision Processes (MDP). The existing GS-PG method was designed to learn from complete episodes or process trajectories, which limits its applicability to low-data environment and online process control. In this paper, the mixture likelihood ratio (MLR) based policy gradient estimation is used to leverage the information from historical state decision transitions generated under different behavioral policies. We propose a variance reduction experience replay (VRER) approach that can intelligently select and reuse most relevant transition observations, improve the policy gradient estimation accuracy, and accelerate the learning of optimal policy. Then we create a process control strategy by incorporating VRER with the state-of-the-art step-based policy optimization approaches such as actor-critic method and proximal policy optimizations. The empirical study demonstrates that the proposed policy gradient methodology can significantly outperform the existing policy optimization approaches.

Opportunities of Hybrid Model-based Reinforcement Learning for Cell Therapy Manufacturing Process Control

Driven by the key challenges of cell therapy manufacturing, including high complexity, high uncertainty, and very limited process observations, we propose a hybrid model-based reinforcement learning (RL) to efficiently guide process control. We first create a probabilistic knowledge graph (KG) hybrid model characterizing the risk- and science-based understanding of biomanufacturing process mechanisms and quantifying inherent stochasticity, e.g., batch-to-batch variation. It can capture the key features, including nonlinear reactions, nonstationary dynamics, and partially observed state. This hybrid model can leverage existing mechanistic models and facilitate learning from heterogeneous process data. A computational sampling approach is used to generate posterior samples quantifying model uncertainty. Then, we introduce hybrid model-based Bayesian RL, accounting for both inherent stochasticity and model uncertainty, to guide optimal, robust, and interpretable dynamic decision making. Cell therapy manufacturing examples are used to empirically demonstrate that the proposed framework can outperform the classical deterministic mechanistic model assisted process optimization.

Is "my favorite new movie" my favorite movie? Probing the Understanding of Recursive Noun Phrases

Recursive noun phrases (NPs) have interesting semantic properties. For example, "my favorite new movie" is not necessarily "my favorite movie", whereas "my new favorite movie" is. This is common sense to humans, yet it is unknown whether pre-trained language models have such knowledge. We introduce the Recursive Noun Phrase Challenge (RNPC), a challenge set targeting the understanding of recursive NPs. When evaluated on our dataset, state-of-the-art Transformer models only achieve around chance performance. Still, we show that such knowledge is learnable with appropriate data. We further probe the models for relevant linguistic features that can be learned from our tasks, including modifier semantic category and modifier scope. Finally, models trained on RNPC achieve strong zero-shot performance on an extrinsic Harm Detection task, showing the usefulness of the understanding of recursive NPs in downstream applications. All code and data will be released at https://github.com/veronica320/Recursive-NPs.

Green Simulation Assisted Policy Gradient to Accelerate Stochastic Process Control

This study is motivated by the critical challenges in the biopharmaceutical manufacturing, including high complexity, high uncertainty, and very limited process data. Each experiment run is often very expensive. To support the optimal and robust process control, we propose a general green simulation assisted policy gradient (GS-PG) framework for both online and offline learning settings. Basically, to address the key limitations of state-of-art reinforcement learning (RL), such as sample inefficiency and low reliability, we create a mixture likelihood ratio based policy gradient estimation that can leverage on the information from historical experiments conducted under different inputs, including process model coefficients and decision policy parameters. Then, to accelerate the learning of optimal and robust policy, we further propose a variance reduction based sample selection method that allows GS-PG to intelligently select and reuse most relevant historical trajectories. The selection rule automatically updates the samples to be reused during the learning of process mechanisms and the search for optimal policy. Our theoretical and empirical studies demonstrate that the proposed framework can perform better than the state-of-art policy gradient approach and accelerate the optimal robust process control for complex stochastic systems under high uncertainty.

Reinforcement Learning Assisted Oxygen Therapy for COVID-19 Patients Under Intensive Care

Patients with severe Coronavirus disease 19 (COVID-19) typically require supplemental oxygen as an essential treatment. We developed a machine learning algorithm, based on a deep Reinforcement Learning (RL), for continuous management of oxygen flow rate for critical ill patients under intensive care, which can identify the optimal personalized oxygen flow rate with strong potentials to reduce mortality rate relative to the current clinical practice. Basically, we modeled the oxygen flow trajectory of COVID-19 patients and their health outcomes as a Markov decision process. Based on individual patient characteristics and health status, a reinforcement learning based oxygen control policy is learned and real-time recommends the oxygen flow rate to reduce the mortality rate. We assessed the performance of proposed methods through cross validation by using a retrospective cohort of 1,372 critically ill patients with COVID-19 from New York University Langone Health ambulatory care with electronic health records from April 2020 to January 2021. The mean mortality rate under the RL algorithm is lower than standard of care by 2.57% (95% CI: 2.08- 3.06) reduction (P<0.001) from 7.94% under the standard of care to 5.37 % under our algorithm and the averaged recommended oxygen flow rate is 1.28 L/min (95% CI: 1.14-1.42) lower than the rate actually delivered to patients. Thus, the RL algorithm could potentially lead to better intensive care treatment that can reduce mortality rate, while saving the oxygen scarce resources. It can reduce the oxygen shortage issue and improve public health during the COVID-19 pandemic.