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In recent years, deep generative models have been successfully adopted for various molecular design tasks, particularly in the life and material sciences. A critical challenge for pre-trained generative molecular design (GMD) models is to fine-tune them to be better suited for downstream design tasks aimed at optimizing specific molecular properties. However, redesigning and training an existing effective generative model from scratch for each new design task is impractical. Furthermore, the black-box nature of typical downstream tasks$\unicode{x2013}$such as property prediction$\unicode{x2013}$makes it nontrivial to optimize the generative model in a task-specific manner. In this work, we propose a novel approach for a model uncertainty-guided fine-tuning of a pre-trained variational autoencoder (VAE)-based GMD model through performance feedback in an active learning setting. The main idea is to quantify model uncertainty in the generative model, which is made efficient by working within a low-dimensional active subspace of the high-dimensional VAE parameters explaining most of the variability in the model's output. The inclusion of model uncertainty expands the space of viable molecules through decoder diversity. We then explore the resulting model uncertainty class via black-box optimization made tractable by low-dimensionality of the active subspace. This enables us to identify and leverage a diverse set of high-performing models to generate enhanced molecules. Empirical results across six target molecular properties, using multiple VAE-based generative models, demonstrate that our uncertainty-guided fine-tuning approach consistently outperforms the original pre-trained models.

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., Comment: 20 pages, 14 figures

Deep generative models have been accelerating the inverse design process in material and drug design. Unlike their counterpart property predictors in typical molecular design frameworks, generative molecular design models have seen fewer efforts on uncertainty quantification (UQ) due to computational challenges in Bayesian inference posed by their large number of parameters. In this work, we focus on the junction-tree variational autoencoder (JT-VAE), a popular model for generative molecular design, and address this issue by leveraging the low dimensional active subspace to capture the uncertainty in the model parameters. Specifically, we approximate the posterior distribution over the active subspace parameters to estimate the epistemic model uncertainty in an extremely high dimensional parameter space. The proposed UQ scheme does not require alteration of the model architecture, making it readily applicable to any pre-trained model. Our experiments demonstrate the efficacy of the AS-based UQ and its potential impact on molecular optimization by exploring the model diversity under epistemic uncertainty.

A Clinical Decision Support System (CDSS) is designed to enhance clinician decision-making by combining system-generated recommendations with medical expertise. Given the high costs, intensive labor, and time-sensitive nature of medical treatments, there is a pressing need for efficient decision support, especially in complex emergency scenarios. In these scenarios, where information can be limited, an advanced CDSS framework that leverages AI (artificial intelligence) models to effectively reduce diagnostic uncertainty has utility. Such an AI-enabled CDSS framework with quantified uncertainty promises to be practical and beneficial in the demanding context of real-world medical care. In this study, we introduce the concept of Medical Entropy, quantifying uncertainties in patient outcomes predicted by neural machine translation based on the ICD-9 code of procedures. Our experimental results not only show strong correlations between procedure and diagnosis sequences based on the simple ICD-9 code but also demonstrate the promising capacity to model trends of uncertainties during hospitalizations through a data-driven approach.

World is looking for clean and renewable energy sources that do not pollute the environment, in an attempt to reduce greenhouse gas emissions that contribute to global warming. Wind energy has significant potential to not only reduce greenhouse emission, but also meet the ever increasing demand for energy. To enable the effective utilization of wind energy, addressing the following three challenges in wind data analysis is crucial. Firstly, improving data resolution in various climate conditions to ensure an ample supply of information for assessing potential energy resources. Secondly, implementing dimensionality reduction techniques for data collected from sensors/simulations to efficiently manage and store large datasets. Thirdly, extrapolating wind data from one spatial specification to another, particularly in cases where data acquisition may be impractical or costly. We propose a deep learning based approach to achieve multi-modal continuous resolution wind data prediction from discontinuous wind data, along with data dimensionality reduction.

Network biology is an interdisciplinary field bridging computational and biological sciences that has proved pivotal in advancing the understanding of cellular functions and diseases across biological systems and scales. Although the field has been around for two decades, it remains nascent. It has witnessed rapid evolution, accompanied by emerging challenges. These challenges stem from various factors, notably the growing complexity and volume of data together with the increased diversity of data types describing different tiers of biological organization. We discuss prevailing research directions in network biology and highlight areas of inference and comparison of biological networks, multimodal data integration and heterogeneous networks, higher-order network analysis, machine learning on networks, and network-based personalized medicine. Following the overview of recent breakthroughs across these five areas, we offer a perspective on the future directions of network biology. Additionally, we offer insights into scientific communities, educational initiatives, and the importance of fostering diversity within the field. This paper establishes a roadmap for an immediate and long-term vision for network biology., Comment: 52 pages, 6 figures, 1 table

Pharmacodynamic (PD) models are mathematical models of cellular reaction networks that include drug mechanisms of action. These models are useful for studying predictive therapeutic outcomes of novel drug therapies in silico. However, PD models are known to possess significant uncertainty with respect to constituent parameter data, leading to uncertainty in the model predictions. Furthermore, experimental data to calibrate these models is often limited or unavailable for novel pathways. In this study, we present a Bayesian optimal experimental design approach for improving PD model prediction accuracy. We then apply our method using simulated experimental data to account for uncertainty in hypothetical laboratory measurements. This leads to a probabilistic prediction of drug performance and a quantitative measure of which prospective laboratory experiment will optimally reduce prediction uncertainty in the PD model. The methods proposed here provide a way forward for uncertainty quantification and guided experimental design for models of novel biological pathways.

Bayesian inference for neural networks, or Bayesian deep learning, has the potential to provide well-calibrated predictions with quantified uncertainty and robustness. However, the main hurdle for Bayesian deep learning is its computational complexity due to the high dimensionality of the parameter space. In this work, we propose a novel scheme that addresses this limitation by constructing a low-dimensional subspace of the neural network parameters-referred to as an active subspace-by identifying the parameter directions that have the most significant influence on the output of the neural network. We demonstrate that the significantly reduced active subspace enables effective and scalable Bayesian inference via either Monte Carlo (MC) sampling methods, otherwise computationally intractable, or variational inference. Empirically, our approach provides reliable predictions with robust uncertainty estimates for various regression tasks.

Understanding protein interactions and pathway knowledge is crucial for unraveling the complexities of living systems and investigating the underlying mechanisms of biological functions and complex diseases. While existing databases provide curated biological data from literature and other sources, they are often incomplete and their maintenance is labor-intensive, necessitating alternative approaches. In this study, we propose to harness the capabilities of large language models to address these issues by automatically extracting such knowledge from the relevant scientific literature. Toward this goal, in this work, we investigate the effectiveness of different large language models in tasks that involve recognizing protein interactions, identifying genes associated with pathways affected by low-dose radiation, and gene regulatory relations. We thoroughly evaluate the performance of various models, highlight the significant findings, and discuss both the future opportunities and the remaining challenges associated with this approach. The code and data are available at: https://github.com/boxorange/BioIE-LLM

The ability to replicate predictions by machine learning (ML) or artificial intelligence (AI) models and results in scientific workflows that incorporate such ML/AI predictions is driven by numerous factors. An uncertainty-aware metric that can quantitatively assess the reproducibility of quantities of interest (QoI) would contribute to the trustworthiness of results obtained from scientific workflows involving ML/AI models. In this article, we discuss how uncertainty quantification (UQ) in a Bayesian paradigm can provide a general and rigorous framework for quantifying reproducibility for complex scientific workflows. Such as framework has the potential to fill a critical gap that currently exists in ML/AI for scientific workflows, as it will enable researchers to determine the impact of ML/AI model prediction variability on the predictive outcomes of ML/AI-powered workflows. We expect that the envisioned framework will contribute to the design of more reproducible and trustworthy workflows for diverse scientific applications, and ultimately, accelerate scientific discoveries.

There are various sources of ionizing radiation exposure, where medical exposure for radiation therapy or diagnosis is the most common human-made source. Understanding how gene expression is modulated after ionizing radiation exposure and investigating the presence of any dose-dependent gene expression patterns have broad implications for health risks from radiotherapy, medical radiation diagnostic procedures, as well as other environmental exposure. In this paper, we perform a comprehensive pathway-based analysis of gene expression profiles in response to low-dose radiation exposure, in order to examine the potential mechanism of gene regulation underlying such responses. To accomplish this goal, we employ a statistical framework to determine whether a specific group of genes belonging to a known pathway display coordinated expression patterns that are modulated in a manner consistent with the radiation level. Findings in our study suggest that there exist complex yet consistent signatures that reflect the molecular response to radiation exposure, which differ between low-dose and high-dose radiation., Comment: 9 pages, 6 figures

Deep ensembles have emerged as a powerful technique for improving predictive performance and enhancing model robustness across various applications by leveraging model diversity. However, traditional deep ensemble methods are often computationally expensive and rely on deterministic models, which may limit their flexibility. Additionally, while sparse subnetworks of dense models have shown promise in matching the performance of their dense counterparts and even enhancing robustness, existing methods for inducing sparsity typically incur training costs comparable to those of training a single dense model, as they either gradually prune the network during training or apply thresholding post-training. In light of these challenges, we propose an approach for sequential ensembling of dynamic Bayesian neural subnetworks that consistently maintains reduced model complexity throughout the training process while generating diverse ensembles in a single forward pass. Our approach involves an initial exploration phase to identify high-performing regions within the parameter space, followed by multiple exploitation phases that take advantage of the compactness of the sparse model. These exploitation phases quickly converge to different minima in the energy landscape, corresponding to high-performing subnetworks that together form a diverse and robust ensemble. We empirically demonstrate that our proposed approach outperforms traditional dense and sparse deterministic and Bayesian ensemble models in terms of prediction accuracy, uncertainty estimation, out-of-distribution detection, and adversarial robustness.

Various real-world scientific applications involve the mathematical modeling of complex uncertain systems with numerous unknown parameters. Accurate parameter estimation is often practically infeasible in such systems, as the available training data may be insufficient and the cost of acquiring additional data may be high. In such cases, based on a Bayesian paradigm, we can design robust operators retaining the best overall performance across all possible models and design optimal experiments that can effectively reduce uncertainty to enhance the performance of such operators maximally. While objective-based uncertainty quantification (objective-UQ) based on MOCU (mean objective cost of uncertainty) provides an effective means for quantifying uncertainty in complex systems, the high computational cost of estimating MOCU has been a challenge in applying it to real-world scientific/engineering problems. In this work, we propose a novel scheme to reduce the computational cost for objective-UQ via MOCU based on a data-driven approach. We adopt a neural message-passing model for surrogate modeling, incorporating a novel axiomatic constraint loss that penalizes an increase in the estimated system uncertainty. As an illustrative example, we consider the optimal experimental design (OED) problem for uncertain Kuramoto models, where the goal is to predict the experiments that can most effectively enhance robust synchronization performance through uncertainty reduction. We show that our proposed approach can accelerate MOCU-based OED by four to five orders of magnitude, without any visible performance loss compared to the state-of-the-art. The proposed approach applies to general OED tasks, beyond the Kuramoto model., Comment: 14 pages, 5 figures, accepted by Engineering Applications of Artificial Intelligence

Molecular design based on generative models, such as variational autoencoders (VAEs), has become increasingly popular in recent years due to its efficiency for exploring high-dimensional molecular space to identify molecules with desired properties. While the efficacy of the initial model strongly depends on the training data, the sampling efficiency of the model for suggesting novel molecules with enhanced properties can be further enhanced via latent space optimization. In this paper, we propose a multi-objective latent space optimization (LSO) method that can significantly enhance the performance of generative molecular design (GMD). The proposed method adopts an iterative weighted retraining approach, where the respective weights of the molecules in the training data are determined by their Pareto efficiency. We demonstrate that our multi-objective GMD LSO method can significantly improve the performance of GMD for jointly optimizing multiple molecular properties., Comment: 23 pages, 9 figures

Accurate detection of infected individuals is one of the critical steps in stopping any pandemic. When the underlying infection rate of the disease is low, testing people in groups, instead of testing each individual in the population, can be more efficient. In this work, we consider noisy adaptive group testing design with specific test sensitivity and specificity that select the optimal group given previous test results based on pre-selected utility function. As in prior studies on group testing, we model this problem as a sequential Bayesian Optimal Experimental Design (BOED) to adaptively design the groups for each test. We analyze the required number of group tests when using the updated posterior on the infection status and the corresponding Mutual Information (MI) as our utility function for selecting new groups. More importantly, we study how the potential bias on the ground-truth noise of group tests may affect the group testing sample complexity., Comment: full length version for ICASSP

The need for efficient computational screening of molecular candidates that possess desired properties frequently arises in various scientific and engineering problems, including drug discovery and materials design. However, the large size of the search space containing the candidates and the substantial computational cost of high-fidelity property prediction models makes screening practically challenging. In this work, we propose a general framework for constructing and optimizing a virtual screening (HTVS) pipeline that consists of multi-fidelity models. The central idea is to optimally allocate the computational resources to models with varying costs and accuracy to optimize the return-on-computational-investment (ROCI). Based on both simulated as well as real data, we demonstrate that the proposed optimal HTVS framework can significantly accelerate screening virtually without any degradation in terms of accuracy. Furthermore, it enables an adaptive operational strategy for HTVS, where one can trade accuracy for efficiency.

Classification has been a major task for building intelligent systems as it enables decision-making under uncertainty. Classifier design aims at building models from training data for representing feature-label distributions--either explicitly or implicitly. In many scientific or clinical settings, training data are typically limited, which makes designing accurate classifiers and evaluating their classification error extremely challenging. While transfer learning (TL) can alleviate this issue by incorporating data from relevant source domains to improve learning in a different target domain, it has received little attention for performance assessment, notably in error estimation. In this paper, we fill this gap by investigating knowledge transferability in the context of classification error estimation within a Bayesian paradigm. We introduce a novel class of Bayesian minimum mean-square error (MMSE) estimators for optimal Bayesian transfer learning (OBTL), which enables rigorous evaluation of classification error under uncertainty in a small-sample setting. Using Monte Carlo importance sampling, we employ the proposed estimator to evaluate the classification accuracy of a broad family of classifiers that span diverse learning capabilities. Experimental results based on both synthetic data as well as real-world RNA sequencing (RNA-seq) data show that our proposed OBTL error estimation scheme clearly outperforms standard error estimators, especially in a small-sample setting, by tapping into the data from other relevant domains.

Recent advances in objective-based uncertainty quantification (objective-UQ) have shown that such a goal-driven approach for quantifying model uncertainty is extremely useful in real-world problems that aim at achieving specific objectives based on complex uncertain systems. Central to this objective-UQ is the concept of mean objective cost of uncertainty (MOCU), which provides effective means of quantifying the impact of uncertainty on the operational goals at hand. MOCU is especially useful for optimal experimental design (OED) as the potential efficacy of an experimental (or data acquisition) campaign can be quantified by estimating the MOCU that is expected to remain after the campaign. However, MOCU-based OED tends to be computationally expensive, which limits its practical applicability. In this paper, we propose a novel machine learning (ML) scheme that can significantly accelerate MOCU computation and expedite MOCU-based experimental design. The main idea is to use an ML model to efficiently search for the optimal robust operator under model uncertainty, a necessary step for computing MOCU. We apply the proposed ML-based OED acceleration scheme to design experiments aimed at optimally enhancing the control performance of uncertain Kuramoto oscillator models. Our results show that the proposed scheme results in up to 154-fold speed improvement without any degradation of the OED performance.

Clustering data into meaningful subsets is a major task in scientific data analysis. To date, various strategies ranging from model-based approaches to data-driven schemes, have been devised for efficient and accurate clustering. One important class of clustering methods that is of a particular interest is the class of exemplar-based approaches. This interest primarily stems from the amount of compressed information encoded in these exemplars that effectively reflect the major characteristics of the respective clusters. Affinity propagation (AP) has proven to be a powerful exemplar-based approach that refines the set of optimal exemplars by iterative pairwise message updates. However, a critical limitation is its inability to capitalize on known networked relations between data points often available for various scientific datasets. To mitigate this shortcoming, we propose geometric-AP, a novel clustering algorithm that effectively extends AP to take advantage of the network topology. Geometric-AP obeys network constraints and uses max-sum belief propagation to leverage the available network topology for generating smooth clusters over the network. Extensive performance assessment reveals a significant enhancement in the quality of the clustering results when compared to benchmark clustering schemes. Especially, we demonstrate that geometric-AP performs extremely well even in cases where the original AP fails drastically.

Various real-world applications involve modeling complex systems with immense uncertainty and optimizing multiple objectives based on the uncertain model. Quantifying the impact of the model uncertainty on the given operational objectives is critical for designing optimal experiments that can most effectively reduce the uncertainty that affect the objectives pertinent to the application at hand. In this paper, we propose the concept of mean multi-objective cost of uncertainty (multi-objective MOCU) that can be used for objective-based quantification of uncertainty for complex uncertain systems considering multiple operational objectives. We provide several illustrative examples that demonstrate the concept and strengths of the proposed multi-objective MOCU. Furthermore, we present a real-world example based on the mammalian cell cycle network to demonstrate how the multi-objective MOCU can be used for quantifying the operational impact of model uncertainty when there are multiple, possibly competing, objectives.

We consider the optimal experimental design problem for an uncertain Kuramoto model, which consists of N interacting oscillators described by coupled ordinary differential equations. The objective is to design experiments that can effectively reduce the uncertainty present in the coupling strengths between the oscillators, thereby minimizing the cost of robust control of the uncertain Kuramoto model. We demonstrate the importance of quantifying the operational impact of the potential experiments in designing optimal experiments.

Fetal neuroinflammation and prenatal stress (PS) may contribute to lifelong neurological disabilities. Astrocytes and microglia, among the brain's non-neuronal glia cell populations, play a pivotal role in neurodevelopment, predisposition to and initiation of disease throughout lifespan. One of the most common neurodevelopmental disorders manifesting between 1-4 years of age is autism spectrum disorder (ASD). A pathological glial-neuronal interplay is thought to increase the risk for clinical manifestation of ASD in at-risk children, but the mechanisms remain poorly understood and integrative, multi-scale models are needed. We propose a model that integrates the data across the scales of physiological organization, from genome to phenotype, and provides a foundation to explain the disparate findings on the genomic level. We hypothesize that via gene-environment interactions, fetal neuroinflammation and PS may reprogram glial immunometabolic phenotypes that impact neurodevelopment and neurobehavior. Drawing on genomic data from the recently published series of ovine and rodent glial transcriptome analyses with fetuses exposed to neuroinflammation or PS, we conduct an analysis on the Simons Foundation Autism Research Initiative (SFARI) Gene database. We confirm 21 gene hits. Using unsupervised statistical network analysis, we then identify six clusters of probable protein-protein interactions mapping onto the immunometabolic and stress response networks and epigenetic memory. These findings support our hypothesis. We discuss the implications for ASD etiology, early detection, and novel therapeutic approaches. We conclude with delineation of the next steps to verify our model on the individual gene level in an assumption-free manner., Comment: Supplemental Table and Data: https://github.com/martinfrasch/ASD_origins_hypothesis. arXiv admin note: text overlap with arXiv:1812.06617 | This is a different study with related research context (relevance to ASD)