Offline Model-Based Optimization: Comprehensive Review

Offline optimization is a fundamental challenge in science and engineering, where the goal is to optimize black-box functions using only offline datasets. This setting is particularly relevant when querying the objective function is prohibitively expensive or infeasible, with applications spanning protein engineering, material discovery, neural architecture search, and beyond. The main difficulty lies in accurately estimating the objective landscape beyond the available data, where extrapolations are fraught with significant epistemic uncertainty. This uncertainty can lead to objective hacking(reward hacking), exploiting model inaccuracies in unseen regions, or other spurious optimizations that yield misleadingly high performance estimates outside the training distribution. Recent advances in model-based optimization(MBO) have harnessed the generalization capabilities of deep neural networks to develop offline-specific surrogate and generative models. Trained with carefully designed strategies, these models are more robust against out-of-distribution issues, facilitating the discovery of improved designs. Despite its growing impact in accelerating scientific discovery, the field lacks a comprehensive review. To bridge this gap, we present the first thorough review of offline MBO. We begin by formalizing the problem for both single-objective and multi-objective settings and by reviewing recent benchmarks and evaluation metrics. We then categorize existing approaches into two key areas: surrogate modeling, which emphasizes accurate function approximation in out-of-distribution regions, and generative modeling, which explores high-dimensional design spaces to identify high-performing designs. Finally, we examine the key challenges and propose promising directions for advancement in this rapidly evolving field including safe control of superintelligent systems.

Optimistic Interior Point Methods for Sequential Hypothesis Testing by Betting

The technique of "testing by betting" frames nonparametric sequential hypothesis testing as a multiple-round game, where a player bets on future observations that arrive in a streaming fashion, accumulates wealth that quantifies evidence against the null hypothesis, and rejects the null once the wealth exceeds a specified threshold while controlling the false positive error. Designing an online learning algorithm that achieves a small regret in the game can help rapidly accumulate the bettor's wealth, which in turn can shorten the time to reject the null hypothesis under the alternative $H_1$. However, many of the existing works employ the Online Newton Step (ONS) to update within a halved decision space to avoid a gradient explosion issue, which is potentially conservative for rapid wealth accumulation. In this paper, we introduce a novel strategy utilizing interior-point methods in optimization that allows updates across the entire interior of the decision space without the risk of gradient explosion. Our approach not only maintains strong statistical guarantees but also facilitates faster null hypothesis rejection in critical scenarios, overcoming the limitations of existing approaches.

HODDI: A Dataset of High-Order Drug-Drug Interactions for Computational Pharmacovigilance

Drug-side effect research is vital for understanding adverse reactions arising in complex multi-drug therapies. However, the scarcity of higher-order datasets that capture the combinatorial effects of multiple drugs severely limits progress in this field. Existing resources such as TWOSIDES primarily focus on pairwise interactions. To fill this critical gap, we introduce HODDI, the first Higher-Order Drug-Drug Interaction Dataset, constructed from U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) records spanning the past decade, to advance computational pharmacovigilance. HODDI contains 109,744 records involving 2,506 unique drugs and 4,569 unique side effects, specifically curated to capture multi-drug interactions and their collective impact on adverse effects. Comprehensive statistical analyses demonstrate HODDI's extensive coverage and robust analytical metrics, making it a valuable resource for studying higher-order drug relationships. Evaluating HODDI with multiple models, we found that simple Multi-Layer Perceptron (MLP) can outperform graph models, while hypergraph models demonstrate superior performance in capturing complex multi-drug interactions, further validating HODDI's effectiveness. Our findings highlight the inherent value of higher-order information in drug-side effect prediction and position HODDI as a benchmark dataset for advancing research in pharmacovigilance, drug safety, and personalized medicine. The dataset and codes are available at https://github.com/TIML-Group/HODDI.

3DMolFormer: A Dual-channel Framework for Structure-based Drug Discovery

Structure-based drug discovery, encompassing the tasks of protein-ligand docking and pocket-aware 3D drug design, represents a core challenge in drug discovery. However, no existing work can deal with both tasks to effectively leverage the duality between them, and current methods for each task are hindered by challenges in modeling 3D information and the limitations of available data. To address these issues, we propose 3DMolFormer, a unified dual-channel transformer-based framework applicable to both docking and 3D drug design tasks, which exploits their duality by utilizing docking functionalities within the drug design process. Specifically, we represent 3D pocket-ligand complexes using parallel sequences of discrete tokens and continuous numbers, and we design a corresponding dual-channel transformer model to handle this format, thereby overcoming the challenges of 3D information modeling. Additionally, we alleviate data limitations through large-scale pre-training on a mixed dataset, followed by supervised and reinforcement learning fine-tuning techniques respectively tailored for the two tasks. Experimental results demonstrate that 3DMolFormer outperforms previous approaches in both protein-ligand docking and pocket-aware 3D drug design, highlighting its promising application in structure-based drug discovery. The code is available at: https://github.com/HXYfighter/3DMolFormer .

Fast and Interpretable Mixed-Integer Linear Program Solving by Learning Model Reduction

By exploiting the correlation between the structure and the solution of Mixed-Integer Linear Programming (MILP), Machine Learning (ML) has become a promising method for solving large-scale MILP problems. Existing ML-based MILP solvers mainly focus on end-to-end solution learning, which suffers from the scalability issue due to the high dimensionality of the solution space. Instead of directly learning the optimal solution, this paper aims to learn a reduced and equivalent model of the original MILP as an intermediate step. The reduced model often corresponds to interpretable operations and is much simpler, enabling us to solve large-scale MILP problems much faster than existing commercial solvers. However, current approaches rely only on the optimal reduced model, overlooking the significant preference information of all reduced models. To address this issue, this paper proposes a preference-based model reduction learning method, which considers the relative performance (i.e., objective cost and constraint feasibility) of all reduced models on each MILP instance as preferences. We also introduce an attention mechanism to capture and represent preference information, which helps improve the performance of model reduction learning tasks. Moreover, we propose a SetCover based pruning method to control the number of reduced models (i.e., labels), thereby simplifying the learning process. Evaluation on real-world MILP problems shows that 1) compared to the state-of-the-art model reduction ML methods, our method obtains nearly 20% improvement on solution accuracy, and 2) compared to the commercial solver Gurobi, two to four orders of magnitude speedups are achieved.

ParetoFlow: Guided Flows in Multi-Objective Optimization

In offline multi-objective optimization (MOO), we leverage an offline dataset of designs and their associated labels to simultaneously minimize multiple objectives. This setting more closely mirrors complex real-world problems compared to single-objective optimization. Recent works mainly employ evolutionary algorithms and Bayesian optimization, with limited attention given to the generative modeling capabilities inherent in such data. In this study, we explore generative modeling in offline MOO through flow matching, noted for its effectiveness and efficiency. We introduce ParetoFlow, specifically designed to guide flow sampling to approximate the Pareto front. Traditional predictor (classifier) guidance is inadequate for this purpose because it models only a single objective. In response, we propose a multi-objective predictor guidance module that assigns each sample a weight vector, representing a weighted distribution across multiple objective predictions. A local filtering scheme is introduced to address non-convex Pareto fronts. These weights uniformly cover the entire objective space, effectively directing sample generation towards the Pareto front. Since distributions with similar weights tend to generate similar samples, we introduce a neighboring evolution module to foster knowledge sharing among neighboring distributions. This module generates offspring from these distributions, and selects the most promising one for the next iteration. Our method achieves state-of-the-art performance across various tasks.

Efficient and Robust Continual Graph Learning for Graph Classification in Biology

Graph classification is essential for understanding complex biological systems, where molecular structures and interactions are naturally represented as graphs. Traditional graph neural networks (GNNs) perform well on static tasks but struggle in dynamic settings due to catastrophic forgetting. We present Perturbed and Sparsified Continual Graph Learning (PSCGL), a robust and efficient continual graph learning framework for graph data classification, specifically targeting biological datasets. We introduce a perturbed sampling strategy to identify critical data points that contribute to model learning and a motif-based graph sparsification technique to reduce storage needs while maintaining performance. Additionally, our PSCGL framework inherently defends against graph backdoor attacks, which is crucial for applications in sensitive biological contexts. Extensive experiments on biological datasets demonstrate that PSCGL not only retains knowledge across tasks but also enhances the efficiency and robustness of graph classification models in biology.

Online Detecting LLM-Generated Texts via Sequential Hypothesis Testing by Betting

Developing algorithms to differentiate between machine-generated texts and human-written texts has garnered substantial attention in recent years. Existing methods in this direction typically concern an offline setting where a dataset containing a mix of real and machine-generated texts is given upfront, and the task is to determine whether each sample in the dataset is from a large language model (LLM) or a human. However, in many practical scenarios, sources such as news websites, social media accounts, or on other forums publish content in a streaming fashion. Therefore, in this online scenario, how to quickly and accurately determine whether the source is an LLM with strong statistical guarantees is crucial for these media or platforms to function effectively and prevent the spread of misinformation and other potential misuse of LLMs. To tackle the problem of online detection, we develop an algorithm based on the techniques of sequential hypothesis testing by betting that not only builds upon and complements existing offline detection techniques but also enjoys statistical guarantees, which include a controlled false positive rate and the expected time to correctly identify a source as an LLM. Experiments were conducted to demonstrate the effectiveness of our method.

LLM-TS Integrator: Integrating LLM for Enhanced Time Series Modeling

Time series~(TS) modeling is essential in dynamic systems like weather prediction and anomaly detection. Recent studies utilize Large Language Models (LLMs) for TS modeling, leveraging their powerful pattern recognition capabilities. These methods primarily position LLMs as the predictive backbone, often omitting the mathematical modeling within traditional TS models, such as periodicity. However, disregarding the potential of LLMs also overlooks their pattern recognition capabilities. To address this gap, we introduce \textit{LLM-TS Integrator}, a novel framework that effectively integrates the capabilities of LLMs into traditional TS modeling. Central to this integration is our \textit{mutual information} module. The core of this \textit{mutual information} module is a traditional TS model enhanced with LLM-derived insights for improved predictive abilities. This enhancement is achieved by maximizing the mutual information between traditional model's TS representations and LLM's textual representation counterparts, bridging the two modalities. Moreover, we recognize that samples vary in importance for two losses: traditional prediction and mutual information maximization. To address this variability, we introduce the \textit{sample reweighting} module to improve information utilization. This module assigns dual weights to each sample: one for prediction loss and another for mutual information loss, dynamically optimizing these weights via bi-level optimization. Our method achieves state-of-the-art or comparable performance across five mainstream TS tasks, including short-term and long-term forecasting, imputation, classification, and anomaly detection.

A Simple yet Effective Subway Self-positioning Method based on Aerial-view Sleeper Detection

With the rapid development of urban underground rail vehicles,subway positioning, which plays a fundamental role in the traffic navigation and collision avoidance systems, has become a research hot-spot these years. Most current subway positioning methods rely on localization beacons densely pre-installed alongside the railway tracks, requiring massive costs for infrastructure and maintenance, while commonly lacking flexibility and anti-interference ability. In this paper, we propose a low-cost and real-time visual-assisted self-localization framework to address the robust and convenient positioning problem for subways. Firstly, we perform aerial view rail sleeper detection based on the fast and efficient YOLOv8n network. The detection results are then used to achieve real-time correction of mileage values combined with geometric positioning information, obtaining precise subway locations. Front camera Videos for subway driving scenes along a 6.9 km route are collected and annotated from the simulator for validation of the proposed method. Experimental results show that our aerial view sleeper detection algorithm can efficiently detect sleeper positions with F1-score of 0.929 at 1111 fps, and that the proposed positioning framework achieves a mean percentage error of 0.1\%, demonstrating its continuous and high-precision self-localization capability.