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Current generative models for drug discovery primarily use molecular docking as an oracle to guide the generation of active compounds. However, such models are often not useful in practice because even compounds with high docking scores do not consistently show experimental activity. More accurate methods for activity prediction exist, such as molecular dynamics based binding free energy calculations, but they are too computationally expensive to use in a generative model. To address this challenge, we propose Multi-Fidelity Latent space Active Learning (MF-LAL), a generative modeling framework that integrates a set of oracles with varying cost-accuracy tradeoffs. Unlike previous approaches that separately learn the surrogate model and generative model, MF-LAL combines the generative and multi-fidelity surrogate models into a single framework, allowing for more accurate activity prediction and higher quality samples. We train MF-LAL with a novel active learning algorithm to further reduce computational cost. Our experiments on two disease-relevant proteins show that MF-LAL produces compounds with significantly better binding free energy scores than other single and multi-fidelity approaches., Comment: 10 pages, 4 figures. arXiv admin note: text overlap with arXiv:2402.10387

Accurate uncertainty quantification of large language models (LLMs) provides credibility measure over their outputs. However, fine-tuned LLMs often struggle with overconfidence in uncertain predictions due to the limitations in the models' ability to generalize with limited data. Existing parameter efficient fine-tuning (PEFT) uncertainty quantification methods for LLMs focus on post fine-tuning stage and fall short of calibrating epistemic uncertainty. To address these limitations, we propose Functional-Level Uncertainty Quantification for Calibrated Fine-Tuning (UQ4CT), which captures and calibrates epistemic uncertainty over the space of functions that map input prompts to outputs. We implement UQ4CT during the fine-tuning stage via a mixture-of-experts framework that hierarchically decomposes the functional space. We demonstrate that UQ4CT reduces Expected Calibration Error (ECE) by more than $25\%$ while maintaining high accuracy across $5$ benchmarks. Even under distribution shift, UQ4CT maintains superior ECE performance with high accuracy, showcasing improved generalizability.

Online black-box optimization (BBO) aims to optimize an objective function by iteratively querying a black-box oracle in a sample-efficient way. While prior studies focus on forward approaches such as Gaussian Processes (GPs) to learn a surrogate model for the unknown objective function, they struggle with steering clear of out-of-distribution and invalid designs in scientific discovery tasks. Recently, inverse modeling approaches that map the objective space to the design space with conditional diffusion models have demonstrated impressive capability in learning the data manifold. However, these approaches proceed in an offline fashion with pre-collected data. How to design inverse approaches for online BBO to actively query new data and improve the sample efficiency remains an open question. In this work, we propose Diffusion-BBO, a sample-efficient online BBO framework leveraging the conditional diffusion model as the inverse surrogate model. Diffusion-BBO employs a novel acquisition function Uncertainty-aware Exploration (UaE) to propose scores in the objective space for conditional sampling. We theoretically prove that Diffusion-BBO with UaE achieves a near-optimal solution for online BBO. We also empirically demonstrate that Diffusion-BBO with UaE outperforms existing online BBO baselines across 6 scientific discovery tasks.

Multi-fidelity surrogate modeling aims to learn an accurate surrogate at the highest fidelity level by combining data from multiple sources. Traditional methods relying on Gaussian processes can hardly scale to high-dimensional data. Deep learning approaches utilize neural network based encoders and decoders to improve scalability. These approaches share encoded representations across fidelities without including corresponding decoder parameters. This hinders inference performance, especially in out-of-distribution scenarios when the highest fidelity data has limited domain coverage. To address these limitations, we propose Multi-fidelity Residual Neural Processes (MFRNP), a novel multi-fidelity surrogate modeling framework. MFRNP explicitly models the residual between the aggregated output from lower fidelities and ground truth at the highest fidelity. The aggregation introduces decoders into the information sharing step and optimizes lower fidelity decoders to accurately capture both in-fidelity and cross-fidelity information. We show that MFRNP significantly outperforms state-of-the-art in learning partial differential equations and a real-world climate modeling task. Our code is published at: https://github.com/Rose-STL-Lab/MFRNP, Comment: A novel probabilistic inference approach for scalable multi-fidelity surrogate modeling

Addressing real-world optimization problems becomes particularly challenging when analytic objective functions or constraints are unavailable. While numerous studies have addressed the issue of unknown objectives, limited research has focused on scenarios where feasibility constraints are not given explicitly. Overlooking these constraints can lead to spurious solutions that are unrealistic in practice. To deal with such unknown constraints, we propose to perform optimization within the data manifold using diffusion models. To constrain the optimization process to the data manifold, we reformulate the original optimization problem as a sampling problem from the product of the Boltzmann distribution defined by the objective function and the data distribution learned by the diffusion model. Depending on the differentiability of the objective function, we propose two different sampling methods. For differentiable objectives, we propose a two-stage framework that begins with a guided diffusion process for warm-up, followed by a Langevin dynamics stage for further correction. For non-differentiable objectives, we propose an iterative importance sampling strategy using the diffusion model as the proposal distribution. Comprehensive experiments on a synthetic dataset, six real-world black-box optimization datasets, and a multi-objective molecule optimization dataset show that our method achieves better or comparable performance with previous state-of-the-art baselines.

Current generative models for drug discovery primarily use molecular docking to evaluate the quality of generated compounds. However, such models are often not useful in practice because even compounds with high docking scores do not consistently show experimental activity. More accurate methods for activity prediction exist, such as molecular dynamics based binding free energy calculations, but they are too computationally expensive to use in a generative model. We propose a multi-fidelity approach, Multi-Fidelity Bind (MFBind), to achieve the optimal trade-off between accuracy and computational cost. MFBind integrates docking and binding free energy simulators to train a multi-fidelity deep surrogate model with active learning. Our deep surrogate model utilizes a pretraining technique and linear prediction heads to efficiently fit small amounts of high-fidelity data. We perform extensive experiments and show that MFBind (1) outperforms other state-of-the-art single and multi-fidelity baselines in surrogate modeling, and (2) boosts the performance of generative models with markedly higher quality compounds., Comment: 9 pages, 4 figures

We address the problem of learning Granger causality from asynchronous, interdependent, multi-type event sequences. In particular, we are interested in discovering instance-level causal structures in an unsupervised manner. Instance-level causality identifies causal relationships among individual events, providing more fine-grained information for decision-making. Existing work in the literature either requires strong assumptions, such as linearity in the intensity function, or heuristically defined model parameters that do not necessarily meet the requirements of Granger causality. We propose Instance-wise Self-Attentive Hawkes Processes (ISAHP), a novel deep learning framework that can directly infer the Granger causality at the event instance level. ISAHP is the first neural point process model that meets the requirements of Granger causality. It leverages the self-attention mechanism of the transformer to align with the principles of Granger causality. We empirically demonstrate that ISAHP is capable of discovering complex instance-level causal structures that cannot be handled by classical models. We also show that ISAHP achieves state-of-the-art performance in proxy tasks involving type-level causal discovery and instance-level event type prediction.

To balance quality and cost, various domain areas of science and engineering run simulations at multiple levels of sophistication. Multi-fidelity active learning aims to learn a direct mapping from input parameters to simulation outputs at the highest fidelity by actively acquiring data from multiple fidelity levels. However, existing approaches based on Gaussian processes are hardly scalable to high-dimensional data. Deep learning-based methods often impose a hierarchical structure in hidden representations, which only supports passing information from low-fidelity to high-fidelity. These approaches can lead to the undesirable propagation of errors from low-fidelity representations to high-fidelity ones. We propose a novel framework called Disentangled Multi-fidelity Deep Bayesian Active Learning (D-MFDAL), which learns the surrogate models conditioned on the distribution of functions at multiple fidelities. On benchmark tasks of learning deep surrogates of partial differential equations including heat equation, Poisson's equation and fluid simulations, our approach significantly outperforms state-of-the-art in prediction accuracy and sample efficiency.

Science and engineering fields use computer simulation extensively. These simulations are often run at multiple levels of sophistication to balance accuracy and efficiency. Multi-fidelity surrogate modeling reduces the computational cost by fusing different simulation outputs. Cheap data generated from low-fidelity simulators can be combined with limited high-quality data generated by an expensive high-fidelity simulator. Existing methods based on Gaussian processes rely on strong assumptions of the kernel functions and can hardly scale to high-dimensional settings. We propose Multi-fidelity Hierarchical Neural Processes (MF-HNP), a unified neural latent variable model for multi-fidelity surrogate modeling. MF-HNP inherits the flexibility and scalability of Neural Processes. The latent variables transform the correlations among different fidelity levels from observations to latent space. The predictions across fidelities are conditionally independent given the latent states. It helps alleviate the error propagation issue in existing methods. MF-HNP is flexible enough to handle non-nested high dimensional data at different fidelity levels with varying input and output dimensions. We evaluate MF-HNP on epidemiology and climate modeling tasks, achieving competitive performance in terms of accuracy and uncertainty estimation. In contrast to deep Gaussian Processes with only low-dimensional (< 10) tasks, our method shows great promise for speeding up high-dimensional complex simulations (over 7000 for epidemiology modeling and 45000 for climate modeling).

Electron microscopy is widely used to explore defects in crystal structures, but human detecting of defects is often time-consuming, error-prone, and unreliable, and is not scalable to large numbers of images or real-time analysis. In this work, we discuss the application of machine learning approaches to find the location and geometry of different defect clusters in irradiated steels. We show that a deep learning based Faster R-CNN analysis system has a performance comparable to human analysis with relatively small training data sets. This study proves the promising ability to apply deep learning to assist the development of automated microscopy data analysis even when multiple features are present and paves the way for fast, scalable, and reliable analysis systems for massive amounts of modern electron microscopy data.

Videos captured using Transmission Electron Microscopy (TEM) can encode details regarding the morphological and temporal evolution of a material by taking snapshots of the microstructure sequentially. However, manual analysis of such video is tedious, error-prone, unreliable, and prohibitively time-consuming if one wishes to analyze a significant fraction of frames for even videos of modest length. In this work, we developed an automated TEM video analysis system for microstructural features based on the advanced object detection model called YOLO and tested the system on an in-situ ion irradiation TEM video of dislocation loops formed in a FeCrAl alloy. The system provides analysis of features observed in TEM including both static and dynamic properties using the YOLO-based defect detection module coupled to a geometry analysis module and a dynamic tracking module. Results show that the system can achieve human comparable performance with an F1 score of 0.89 for fast, consistent, and scalable frame-level defect analysis. This result is obtained on a real but exceptionally clean and stable data set and more challenging data sets may not achieve this performance. The dynamic tracking also enabled evaluation of individual defect evolution like per defect growth rate at a fidelity never before achieved using common human analysis methods. Our work shows that automatically detecting and tracking interesting microstructures and properties contained in TEM videos is viable and opens new doors for evaluating materials dynamics.

Stochastic simulations such as large-scale, spatiotemporal, age-structured epidemic models are computationally expensive at fine-grained resolution. While deep surrogate models can speed up the simulations, doing so for stochastic simulations and with active learning approaches is an underexplored area. We propose Interactive Neural Process (INP), a deep Bayesian active learning framework for learning deep surrogate models to accelerate stochastic simulations. INP consists of two components, a spatiotemporal surrogate model built upon Neural Process (NP) family and an acquisition function for active learning. For surrogate modeling, we develop Spatiotemporal Neural Process (STNP) to mimic the simulator dynamics. For active learning, we propose a novel acquisition function, Latent Information Gain (LIG), calculated in the latent space of NP based models. We perform a theoretical analysis and demonstrate that LIG reduces sample complexity compared with random sampling in high dimensions. We also conduct empirical studies on three complex spatiotemporal simulators for reaction diffusion, heat flow, and infectious disease. The results demonstrate that STNP outperforms the baselines in the offline learning setting and LIG achieves the state-of-the-art for Bayesian active learning.

Deep learning is gaining increasing popularity for spatiotemporal forecasting. However, prior works have mostly focused on point estimates without quantifying the uncertainty of the predictions. In high stakes domains, being able to generate probabilistic forecasts with confidence intervals is critical to risk assessment and decision making. Hence, a systematic study of uncertainty quantification (UQ) methods for spatiotemporal forecasting is missing in the community. In this paper, we describe two types of spatiotemporal forecasting problems: regular grid-based and graph-based. Then we analyze UQ methods from both the Bayesian and the frequentist point of view, casting in a unified framework via statistical decision theory. Through extensive experiments on real-world road network traffic, epidemics, and air quality forecasting tasks, we reveal the statistical and computational trade-offs for different UQ methods: Bayesian methods are typically more robust in mean prediction, while confidence levels obtained from frequentist methods provide more extensive coverage over data variations. Computationally, quantile regression type methods are cheaper for a single confidence interval but require re-training for different intervals. Sampling based methods generate samples that can form multiple confidence intervals, albeit at a higher computational cost., Comment: arXiv admin note: text overlap with arXiv:2102.06684

We introduce DeepGLEAM, a hybrid model for COVID-19 forecasting. DeepGLEAM combines a mechanistic stochastic simulation model GLEAM with deep learning. It uses deep learning to learn the correction terms from GLEAM, which leads to improved performance. We further integrate various uncertainty quantification methods to generate confidence intervals. We demonstrate DeepGLEAM on real-world COVID-19 mortality forecasting tasks.