Directed evolution is a versatile technique in protein engineering that mimics the process of natural selection by iteratively alternating between mutagenesis and screening in order to search for sequences that optimize a given property of interest, such as catalytic activity and binding affinity to a specified target. However, the space of possible proteins is too large to search exhaustively in the laboratory, and functional proteins are scarce in the vast sequence space. Machine learning (ML) approaches can accelerate directed evolution by learning to map protein sequences to functions without building a detailed model of the underlying physics, chemistry and biological pathways. Despite the great potentials held by these ML methods, they encounter severe challenges in identifying the most suitable sequences for a targeted function. These failures can be attributed to the common practice of adopting a high-dimensional feature representation for protein sequences and inefficient search methods. To address these issues, we propose an efficient, experimental design-oriented closed-loop optimization framework for protein directed evolution, termed ODBO, which employs a combination of novel low-dimensional protein encoding strategy and Bayesian optimization enhanced with search space prescreening via outlier detection. We further design an initial sample selection strategy to minimize the number of experimental samples for training ML models. We conduct and report four protein directed evolution experiments that substantiate the capability of the proposed framework for finding of the variants with properties of interest. We expect the ODBO framework to greatly reduce the experimental cost and time cost of directed evolution, and can be further generalized as a powerful tool for adaptive experimental design in a broader context.
We consider physics-informed neural networks (PINNs) [Raissi et al., J.~Comput. Phys. 278 (2019) 686-707] for forward physical problems. In order to find optimal PINNs configuration, we introduce a hyper-parameter optimization (HPO) procedure via Gaussian processes-based Bayesian optimization. We apply the HPO to Helmholtz equation for bounded domains and conduct a thorough study, focusing on: (i) performance, (ii) the collocation points density $r$ and (iii) the frequency $\kappa$, confirming the applicability and necessity of the method. Numerical experiments are performed in two and three dimensions, including comparison to finite element methods.
Recent years have witnessed tremendously improved efficiency of Automated Machine Learning (AutoML), especially Automated Deep Learning (AutoDL) systems, but recent work focuses on tabular, image, or NLP tasks. So far, little attention has been paid to general AutoDL frameworks for time series forecasting, despite the enormous success in applying different novel architectures to such tasks. In this paper, we propose an efficient approach for the joint optimization of neural architecture and hyperparameters of the entire data processing pipeline for time series forecasting. In contrast to common NAS search spaces, we designed a novel neural architecture search space covering various state-of-the-art architectures, allowing for an efficient macro-search over different DL approaches. To efficiently search in such a large configuration space, we use Bayesian optimization with multi-fidelity optimization. We empirically study several different budget types enabling efficient multi-fidelity optimization on different forecasting datasets. Furthermore, we compared our resulting system, dubbed \system, against several established baselines and show that it significantly outperforms all of them across several datasets.
We present Parallel Feasible Pareto Frontier Entropy Search ($\{\text{PF}\}^2$ES) -- a novel information-theoretic acquisition function for multi-objective Bayesian optimization supporting unknown constraints and batch query. Due to the complexity of characterizing the mutual information between candidate evaluations and (feasible) Pareto frontiers, existing approaches must either employ crude approximations that significantly hamper their performance or rely on expensive inference schemes that substantially increase the optimization's computational overhead. By instead using a variational lower bound, $\{\text{PF}\}^2$ES provides a low-cost and accurate estimate of the mutual information. We benchmark $\{\text{PF}\}^2$ES against other information-theoretic acquisition functions, demonstrating its competitive performance for optimization across synthetic and real-world design problems.
We consider the problem of multi-objective (MO) blackbox optimization using expensive function evaluations, where the goal is to approximate the true Pareto set of solutions while minimizing the number of function evaluations. For example, in hardware design optimization, we need to find the designs that trade-off performance, energy, and area overhead using expensive simulations. We propose a novel uncertainty-aware search framework referred to as USeMO to efficiently select the sequence of inputs for evaluation to solve this problem. The selection method of USeMO consists of solving a cheap MO optimization problem via surrogate models of the true functions to identify the most promising candidates and picking the best candidate based on a measure of uncertainty. We also provide theoretical analysis to characterize the efficacy of our approach. Our experiments on several synthetic and six diverse real-world benchmark problems show that USeMO consistently outperforms the state-of-the-art algorithms.
Optimization strategies driven by machine learning, such as Bayesian optimization, are being explored across experimental sciences as an efficient alternative to traditional design of experiment. When combined with automated laboratory hardware and high-performance computing, these strategies enable next-generation platforms for autonomous experimentation. However, the practical application of these approaches is hampered by a lack of flexible software and algorithms tailored to the unique requirements of chemical research. One such aspect is the pervasive presence of constraints in the experimental conditions when optimizing chemical processes or protocols, and in the chemical space that is accessible when designing functional molecules or materials. Although many of these constraints are known a priori, they can be interdependent, non-linear, and result in non-compact optimization domains. In this work, we extend our experiment planning algorithms Phoenics and Gryffin such that they can handle arbitrary known constraints via an intuitive and flexible interface. We benchmark these extended algorithms on continuous and discrete test functions with a diverse set of constraints, demonstrating their flexibility and robustness. In addition, we illustrate their practical utility in two simulated chemical research scenarios: the optimization of the synthesis of o-xylenyl Buckminsterfullerene adducts under constrained flow conditions, and the design of redox active molecules for flow batteries under synthetic accessibility constraints. The tools developed constitute a simple, yet versatile strategy to enable model-based optimization with known experimental constraints, contributing to its applicability as a core component of autonomous platforms for scientific discovery.
Federated Learning (FL) framework brings privacy benefits to distributed learning systems by allowing multiple clients to participate in a learning task under the coordination of a central server without exchanging their private data. However, recent studies have revealed that private information can still be leaked through shared gradient information. To further protect user's privacy, several defense mechanisms have been proposed to prevent privacy leakage via gradient information degradation methods, such as using additive noise or gradient compression before sharing it with the server. In this work, we validate that the private training data can still be leaked under certain defense settings with a new type of leakage, i.e., Generative Gradient Leakage (GGL). Unlike existing methods that only rely on gradient information to reconstruct data, our method leverages the latent space of generative adversarial networks (GAN) learned from public image datasets as a prior to compensate for the informational loss during gradient degradation. To address the nonlinearity caused by the gradient operator and the GAN model, we explore various gradient-free optimization methods (e.g., evolution strategies and Bayesian optimization) and empirically show their superiority in reconstructing high-quality images from gradients compared to gradient-based optimizers. We hope the proposed method can serve as a tool for empirically measuring the amount of privacy leakage to facilitate the design of more robust defense mechanisms.
We design and evaluate a Bayesian optimization framework for resource efficient pre-training of Transformer-based language models (TLMs). TLM pre-training requires high computational resources and introduces many unresolved design choices, such as selecting its pre-training hyperparameters. We propose a multi-armed bandit framework for the sequential selection of TLM pre-training hyperparameters, aimed at optimizing language model performance, in a resource efficient manner. We design a Thompson sampling algorithm, with a surrogate Gaussian process reward model of the Masked Language Model (MLM) pre-training objective, for its sequential minimization. Instead of MLM pre-training with fixed masking probabilities, the proposed Gaussian process-based Thompson sampling (GP-TS) accelerates pre-training by sequentially selecting masking hyperparameters that improve performance. We empirically demonstrate how GP-TS pre-trains language models efficiently, i.e., it achieves lower MLM loss in fewer epochs, across a variety of settings. In addition, GP-TS pre-trained TLMs attain competitive downstream performance, while avoiding expensive hyperparameter grid search. GP-TS provides an interactive framework for efficient and optimized TLM pre-training that, by circumventing costly hyperparameter selection, enables substantial computational savings.
Bayesian optimization (BayesOpt) is a gold standard for query-efficient continuous optimization. However, its adoption for drug design has been hindered by the discrete, high-dimensional nature of the decision variables. We develop a new approach (LaMBO) which jointly trains a denoising autoencoder with a discriminative multi-task Gaussian process head, allowing gradient-based optimization of multi-objective acquisition functions in the latent space of the autoencoder. These acquisition functions allow LaMBO to balance the explore-exploit tradeoff over multiple design rounds, and to balance objective tradeoffs by optimizing sequences at many different points on the Pareto frontier. We evaluate LaMBO on two small-molecule design tasks, and introduce new tasks optimizing \emph{in silico} and \emph{in vitro} properties of large-molecule fluorescent proteins. In our experiments LaMBO outperforms genetic optimizers and does not require a large pretraining corpus, demonstrating that BayesOpt is practical and effective for biological sequence design.
We consider Bayesian optimization of expensive-to-evaluate experiments that generate vector-valued outcomes over which a decision-maker (DM) has preferences. These preferences are encoded by a utility function that is not known in closed form but can be estimated by asking the DM to express preferences over pairs of outcome vectors. To address this problem, we develop Bayesian optimization with preference exploration, a novel framework that alternates between interactive real-time preference learning with the DM via pairwise comparisons between outcomes, and Bayesian optimization with a learned compositional model of DM utility and outcomes. Within this framework, we propose preference exploration strategies specifically designed for this task, and demonstrate their performance via extensive simulation studies.
Modern optimization strategies such as evolutionary algorithms, ant colony algorithms, Bayesian optimization techniques, etc. come with several parameters that steer their behavior during the optimization process. To obtain high-performing algorithm instances, automated algorithm configuration techniques have been developed. One of the most popular tools is irace, which evaluates configurations in sequential races, making use of iterated statistical tests to discard poorly performing configurations. At the end of the race, a set of elite configurations are selected from those survivor configurations that were not discarded, using greedy truncation selection. We study two alternative selection methods: one keeps the best survivor and selects the remaining configurations uniformly at random from the set of survivors, while the other applies entropy to maximize the diversity of the elites. These methods are tested for tuning ant colony optimization algorithms for traveling salesperson problems and the quadratic assignment problem and tuning an exact tree search solver for satisfiability problems. The experimental results show improvement on the tested benchmarks compared to the default selection of irace. In addition, the obtained results indicate that non-elitist can obtain diverse algorithm configurations, which encourages us to explore a wider range of solutions to understand the behavior of algorithms.
Bayesian optimization (BO) is a powerful approach to sample-efficient optimization of black-box objective functions. However, the application of BO to areas such as recommendation systems often requires taking the interpretability and simplicity of the configurations into consideration, a setting that has not been previously studied in the BO literature. To make BO useful for this setting, we present several regularization-based approaches that allow us to discover sparse and more interpretable configurations. We propose a novel differentiable relaxation based on homotopy continuation that makes it possible to target sparsity by working directly with $L_0$ regularization. We identify failure modes for regularized BO and develop a hyperparameter-free method, sparsity exploring Bayesian optimization (SEBO) that seeks to simultaneously maximize a target objective and sparsity. SEBO and methods based on fixed regularization are evaluated on synthetic and real-world problems, and we show that we are able to efficiently optimize for sparsity.
Autonomous Cyber-Physical Systems must often operate under uncertainties like sensor degradation and shifts in the operating conditions, which increases its operational risk. Dynamic Assurance of these systems requires designing runtime safety components like Out-of-Distribution detectors and risk estimators, which require labeled data from different operating modes of the system that belong to scenes with adverse operating conditions, sensors, and actuator faults. Collecting real-world data of these scenes can be expensive and sometimes not feasible. So, scenario description languages with samplers like random and grid search are available to generate synthetic data from simulators, replicating these real-world scenes. However, we point out three limitations in using these conventional samplers. First, they are passive samplers, which do not use the feedback of previous results in the sampling process. Second, the variables to be sampled may have constraints that are often not included. Third, they do not balance the tradeoff between exploration and exploitation, which we hypothesize is necessary for better search space coverage. We present a scene generation approach with two samplers called Random Neighborhood Search (RNS) and Guided Bayesian Optimization (GBO), which extend the conventional random search and Bayesian Optimization search to include the limitations. Also, to facilitate the samplers, we use a risk-based metric that evaluates how risky the scene was for the system. We demonstrate our approach using an Autonomous Vehicle example in CARLA simulation. To evaluate our samplers, we compared them against the baselines of random search, grid search, and Halton sequence search. Our samplers of RNS and GBO sampled a higher percentage of high-risk scenes of 83% and 92%, compared to 56%, 66% and 71% of the grid, random and Halton samplers, respectively.
Quantifying the dynamics of tumor burden reveals useful information about cancer evolution concerning treatment effects and drug resistance, which play a crucial role in advancing model-informed drug developments (MIDD) towards personalized medicine and precision oncology. The emergence of Quantum Machine Intelligence offers unparalleled insights into tumor dynamics via a quantum mechanics perspective. This paper introduces a novel hybrid quantum-classical neural architecture named $\eta-$Net that enables quantifying quantum dynamics of tumor burden concerning treatment effects. We evaluate our proposed neural solution on two major use cases, including cohort-specific and patient-specific modeling. In silico numerical results show a high capacity and expressivity of $\eta-$Net to the quantified biological problem. Moreover, the close connection to representation learning - the foundation for successes of modern AI, enables efficient transferability of empirical knowledge from relevant cohorts to targeted patients. Finally, we leverage Bayesian optimization to quantify the epistemic uncertainty of model predictions, paving the way for $\eta-$Net towards reliable AI in decision-making for clinical usages.
Multi-fidelity (gray-box) hyperparameter optimization techniques (HPO) have recently emerged as a promising direction for tuning Deep Learning methods. However, existing methods suffer from a sub-optimal allocation of the HPO budget to the hyperparameter configurations. In this work, we introduce DyHPO, a Bayesian Optimization method that learns to decide which hyperparameter configuration to train further in a dynamic race among all feasible configurations. We propose a new deep kernel for Gaussian Processes that embeds the learning curve dynamics, and an acquisition function that incorporates multi-budget information. We demonstrate the significant superiority of DyHPO against state-of-the-art hyperparameter optimization methods through large-scale experiments comprising 50 datasets (Tabular, Image, NLP) and diverse architectures (MLP, CNN/NAS, RNN).
Topic models are statistical methods that extract underlying topics from document collections. When performing topic modeling, a user usually desires topics that are coherent, diverse between each other, and that constitute good document representations for downstream tasks (e.g. document classification). In this paper, we conduct a multi-objective hyperparameter optimization of three well-known topic models. The obtained results reveal the conflicting nature of different objectives and that the training corpus characteristics are crucial for the hyperparameter selection, suggesting that it is possible to transfer the optimal hyperparameter configurations between datasets.
Bayesian optimization (BO) is a sample-efficient approach for tuning design parameters to optimize expensive-to-evaluate, black-box performance metrics. In many manufacturing processes, the design parameters are subject to random input noise, resulting in a product that is often less performant than expected. Although BO methods have been proposed for optimizing a single objective under input noise, no existing method addresses the practical scenario where there are multiple objectives that are sensitive to input perturbations. In this work, we propose the first multi-objective BO method that is robust to input noise. We formalize our goal as optimizing the multivariate value-at-risk (MVaR), a risk measure of the uncertain objectives. Since directly optimizing MVaR is computationally infeasible in many settings, we propose a scalable, theoretically-grounded approach for optimizing MVaR using random scalarizations. Empirically, we find that our approach significantly outperforms alternative methods and efficiently identifies optimal robust designs that will satisfy specifications across multiple metrics with high probability.
The early pioneering Neural Architecture Search (NAS) works were multi-trial methods applicable to any general search space. The subsequent works took advantage of the early findings and developed weight-sharing methods that assume a structured search space typically with pre-fixed hyperparameters. Despite the amazing computational efficiency of the weight-sharing NAS algorithms, it is becoming apparent that multi-trial NAS algorithms are also needed for identifying very high-performance architectures, especially when exploring a general search space. In this work, we carefully review the latest multi-trial NAS algorithms and identify the key strategies including Evolutionary Algorithm (EA), Bayesian Optimization (BO), diversification, input and output transformations, and lower fidelity estimation. To accommodate the key strategies into a single framework, we develop B2EA that is a surrogate assisted EA with two BO surrogate models and a mutation step in between. To show that B2EA is robust and efficient, we evaluate three performance metrics over 14 benchmarks with general and cell-based search spaces. Comparisons with state-of-the-art multi-trial algorithms reveal that B2EA is robust and efficient over the 14 benchmarks for three difficulty levels of target performance. The B2EA code is publicly available at \url{https://github.com/snu-adsl/BBEA}.
We present Posterior Temperature Optimized Bayesian Inverse Models (POTOBIM), an unsupervised Bayesian approach to inverse problems in medical imaging using mean-field variational inference with a fully tempered posterior. Bayesian methods exhibit useful properties for approaching inverse tasks, such as tomographic reconstruction or image denoising. A suitable prior distribution introduces regularization, which is needed to solve the ill-posed problem and reduces overfitting the data. In practice, however, this often results in a suboptimal posterior temperature, and the full potential of the Bayesian approach is not being exploited. In POTOBIM, we optimize both the parameters of the prior distribution and the posterior temperature with respect to reconstruction accuracy using Bayesian optimization with Gaussian process regression. Our method is extensively evaluated on four different inverse tasks on a variety of modalities with images from public data sets and we demonstrate that an optimized posterior temperature outperforms both non-Bayesian and Bayesian approaches without temperature optimization. The use of an optimized prior distribution and posterior temperature leads to improved accuracy and uncertainty estimation and we show that it is sufficient to find these hyperparameters per task domain. Well-tempered posteriors yield calibrated uncertainty, which increases the reliability in the predictions. Our source code is publicly available at github.com/Cardio-AI/mfvi-dip-mia.
Real-world optimization problems are generally not just black-box problems, but also involve mixed types of inputs in which discrete and continuous variables coexist. Such mixed-space optimization possesses the primary challenge of modeling complex interactions between the inputs. In this work, we propose a novel yet simple approach that entails exploiting the graph data structure to model the underlying relationship between variables, i.e., variables as nodes and interactions defined by edges. Then, a variational graph autoencoder is used to naturally take the interactions into account. We first provide empirical evidence of the existence of such graph structures and then suggest a joint framework of graph structure learning and latent space optimization to adaptively search for optimal graph connectivity. Experimental results demonstrate that our method shows remarkable performance, exceeding the existing approaches with significant computational efficiency for a number of synthetic and real-world tasks.