Uncertainty-Aware Adaptation of Large Language Models for Protein-Protein Interaction Analysis

Identification of protein-protein interactions (PPIs) helps derive cellular mechanistic understanding, particularly in the context of complex conditions such as neurodegenerative disorders, metabolic syndromes, and cancer. Large Language Models (LLMs) have demonstrated remarkable potential in predicting protein structures and interactions via automated mining of vast biomedical literature; yet their inherent uncertainty remains a key challenge for deriving reproducible findings, critical for biomedical applications. In this study, we present an uncertainty-aware adaptation of LLMs for PPI analysis, leveraging fine-tuned LLaMA-3 and BioMedGPT models. To enhance prediction reliability, we integrate LoRA ensembles and Bayesian LoRA models for uncertainty quantification (UQ), ensuring confidence-calibrated insights into protein behavior. Our approach achieves competitive performance in PPI identification across diverse disease contexts while addressing model uncertainty, thereby enhancing trustworthiness and reproducibility in computational biology. These findings underscore the potential of uncertainty-aware LLM adaptation for advancing precision medicine and biomedical research.

Epidemiological Model Calibration via Graybox Bayesian Optimization

In this study, we focus on developing efficient calibration methods via Bayesian decision-making for the family of compartmental epidemiological models. The existing calibration methods usually assume that the compartmental model is cheap in terms of its output and gradient evaluation, which may not hold in practice when extending them to more general settings. Therefore, we introduce model calibration methods based on a "graybox" Bayesian optimization (BO) scheme, more efficient calibration for general epidemiological models. This approach uses Gaussian processes as a surrogate to the expensive model, and leverages the functional structure of the compartmental model to enhance calibration performance. Additionally, we develop model calibration methods via a decoupled decision-making strategy for BO, which further exploits the decomposable nature of the functional structure. The calibration efficiencies of the multiple proposed schemes are evaluated based on various data generated by a compartmental model mimicking real-world epidemic processes, and real-world COVID-19 datasets. Experimental results demonstrate that our proposed graybox variants of BO schemes can efficiently calibrate computationally expensive models and further improve the calibration performance measured by the logarithm of mean square errors and achieve faster performance convergence in terms of BO iterations. We anticipate that the proposed calibration methods can be extended to enable fast calibration of more complex epidemiological models, such as the agent-based models.

Path-Guided Particle-based Sampling

Particle-based Bayesian inference methods by sampling from a partition-free target (posterior) distribution, e.g., Stein variational gradient descent (SVGD), have attracted significant attention. We propose a path-guided particle-based sampling~(PGPS) method based on a novel Log-weighted Shrinkage (LwS) density path linking an initial distribution to the target distribution. We propose to utilize a Neural network to learn a vector field motivated by the Fokker-Planck equation of the designed density path. Particles, initiated from the initial distribution, evolve according to the ordinary differential equation defined by the vector field. The distribution of these particles is guided along a density path from the initial distribution to the target distribution. The proposed LwS density path allows for an efficient search of modes of the target distribution while canonical methods fail. We theoretically analyze the Wasserstein distance of the distribution of the PGPS-generated samples and the target distribution due to approximation and discretization errors. Practically, the proposed PGPS-LwS method demonstrates higher Bayesian inference accuracy and better calibration ability in experiments conducted on both synthetic and real-world Bayesian learning tasks, compared to baselines, such as SVGD and Langevin dynamics, etc.

Hyperparameter Tuning Through Pessimistic Bilevel Optimization

Automated hyperparameter search in machine learning, especially for deep learning models, is typically formulated as a bilevel optimization problem, with hyperparameter values determined by the upper level and the model learning achieved by the lower-level problem. Most of the existing bilevel optimization solutions either assume the uniqueness of the optimal training model given hyperparameters or adopt an optimistic view when the non-uniqueness issue emerges. Potential model uncertainty may arise when training complex models with limited data, especially when the uniqueness assumption is violated. Thus, the suitability of the optimistic view underlying current bilevel hyperparameter optimization solutions is questionable. In this paper, we propose pessimistic bilevel hyperparameter optimization to assure appropriate outer-level hyperparameters to better generalize the inner-level learned models, by explicitly incorporating potential uncertainty of the inner-level solution set. To solve the resulting computationally challenging pessimistic bilevel optimization problem, we develop a novel relaxation-based approximation method. It derives pessimistic solutions with more robust prediction models. In our empirical studies of automated hyperparameter search for binary linear classifiers, pessimistic solutions have demonstrated better prediction performances than optimistic counterparts when we have limited training data or perturbed testing data, showing the necessity of considering pessimistic solutions besides existing optimistic ones.

LoRA-BERT: a Natural Language Processing Model for Robust and Accurate Prediction of long non-coding RNAs

Long non-coding RNAs (lncRNAs) serve as crucial regulators in numerous biological processes. Although they share sequence similarities with messenger RNAs (mRNAs), lncRNAs perform entirely different roles, providing new avenues for biological research. The emergence of next-generation sequencing technologies has greatly advanced the detection and identification of lncRNA transcripts and deep learning-based approaches have been introduced to classify long non-coding RNAs (lncRNAs). These advanced methods have significantly enhanced the efficiency of identifying lncRNAs. However, many of these methods are devoid of robustness and accuracy due to the extended length of the sequences involved. To tackle this issue, we have introduced a novel pre-trained bidirectional encoder representation called LoRA-BERT. LoRA-BERT is designed to capture the importance of nucleotide-level information during sequence classification, leading to more robust and satisfactory outcomes. In a comprehensive comparison with commonly used sequence prediction tools, we have demonstrated that LoRA-BERT outperforms them in terms of accuracy and efficiency. Our results indicate that, when utilizing the transformer model, LoRA-BERT achieves state-of-the-art performance in predicting both lncRNAs and mRNAs for human and mouse species. Through the utilization of LoRA-BERT, we acquire valuable insights into the traits of lncRNAs and mRNAs, offering the potential to aid in the comprehension and detection of diseases linked to lncRNAs in humans.

Understanding Uncertainty-based Active Learning Under Model Mismatch

Instead of randomly acquiring training data points, Uncertainty-based Active Learning (UAL) operates by querying the label(s) of pivotal samples from an unlabeled pool selected based on the prediction uncertainty, thereby aiming at minimizing the labeling cost for model training. The efficacy of UAL critically depends on the model capacity as well as the adopted uncertainty-based acquisition function. Within the context of this study, our analytical focus is directed toward comprehending how the capacity of the machine learning model may affect UAL efficacy. Through theoretical analysis, comprehensive simulations, and empirical studies, we conclusively demonstrate that UAL can lead to worse performance in comparison with random sampling when the machine learning model class has low capacity and is unable to cover the underlying ground truth. In such situations, adopting acquisition functions that directly target estimating the prediction performance may be beneficial for improving the performance of UAL.

GFlowNet Training by Policy Gradients

Generative Flow Networks (GFlowNets) have been shown effective to generate combinatorial objects with desired properties. We here propose a new GFlowNet training framework, with policy-dependent rewards, that bridges keeping flow balance of GFlowNets to optimizing the expected accumulated reward in traditional Reinforcement-Learning (RL). This enables the derivation of new policy-based GFlowNet training methods, in contrast to existing ones resembling value-based RL. It is known that the design of backward policies in GFlowNet training affects efficiency. We further develop a coupled training strategy that jointly solves GFlowNet forward policy training and backward policy design. Performance analysis is provided with a theoretical guarantee of our policy-based GFlowNet training. Experiments on both simulated and real-world datasets verify that our policy-based strategies provide advanced RL perspectives for robust gradient estimation to improve GFlowNet performance.

Learning Flexible Time-windowed Granger Causality Integrating Heterogeneous Interventional Time Series Data

Granger causality, commonly used for inferring causal structures from time series data, has been adopted in widespread applications across various fields due to its intuitive explainability and high compatibility with emerging deep neural network prediction models. To alleviate challenges in better deciphering causal structures unambiguously from time series, the use of interventional data has become a practical approach. However, existing methods have yet to be explored in the context of imperfect interventions with unknown targets, which are more common and often more beneficial in a wide range of real-world applications. Additionally, the identifiability issues of Granger causality with unknown interventional targets in complex network models remain unsolved. Our work presents a theoretically-grounded method that infers Granger causal structure and identifies unknown targets by leveraging heterogeneous interventional time series data. We further illustrate that learning Granger causal structure and recovering interventional targets can mutually promote each other. Comparative experiments demonstrate that our method outperforms several robust baseline methods in learning Granger causal structure from interventional time series data.

Hierarchical Neural Operator Transformer with Learnable Frequency-aware Loss Prior for Arbitrary-scale Super-resolution

In this work, we present an arbitrary-scale super-resolution (SR) method to enhance the resolution of scientific data, which often involves complex challenges such as continuity, multi-scale physics, and the intricacies of high-frequency signals. Grounded in operator learning, the proposed method is resolution-invariant. The core of our model is a hierarchical neural operator that leverages a Galerkin-type self-attention mechanism, enabling efficient learning of mappings between function spaces. Sinc filters are used to facilitate the information transfer across different levels in the hierarchy, thereby ensuring representation equivalence in the proposed neural operator. Additionally, we introduce a learnable prior structure that is derived from the spectral resizing of the input data. This loss prior is model-agnostic and is designed to dynamically adjust the weighting of pixel contributions, thereby balancing gradients effectively across the model. We conduct extensive experiments on diverse datasets from different domains and demonstrate consistent improvements compared to strong baselines, which consist of various state-of-the-art SR methods.

Towards Invariant Time Series Forecasting in Smart Cities

In the transformative landscape of smart cities, the integration of the cutting-edge web technologies into time series forecasting presents a pivotal opportunity to enhance urban planning, sustainability, and economic growth. The advancement of deep neural networks has significantly improved forecasting performance. However, a notable challenge lies in the ability of these models to generalize well to out-of-distribution (OOD) time series data. The inherent spatial heterogeneity and domain shifts across urban environments create hurdles that prevent models from adapting and performing effectively in new urban environments. To tackle this problem, we propose a solution to derive invariant representations for more robust predictions under different urban environments instead of relying on spurious correlation across urban environments for better generalizability. Through extensive experiments on both synthetic and real-world data, we demonstrate that our proposed method outperforms traditional time series forecasting models when tackling domain shifts in changing urban environments. The effectiveness and robustness of our method can be extended to diverse fields including climate modeling, urban planning, and smart city resource management.