Enzyme design plays a crucial role in both industrial production and biology. However, this field faces challenges due to the lack of comprehensive benchmarks and the complexity of enzyme design tasks, leading to a dearth of systematic research. Consequently, computational enzyme design is relatively overlooked within the broader protein domain and remains in its early stages. In this work, we address these challenges by introducing MetaEnzyme, a staged and unified enzyme design framework. We begin by employing a cross-modal structure-to-sequence transformation architecture, as the feature-driven starting point to obtain initial robust protein representation. Subsequently, we leverage domain adaptive techniques to generalize specific enzyme design tasks under low-resource conditions. MetaEnzyme focuses on three fundamental low-resource enzyme redesign tasks: functional design (FuncDesign), mutation design (MutDesign), and sequence generation design (SeqDesign). Through novel unified paradigm and enhanced representation capabilities, MetaEnzyme demonstrates adaptability to diverse enzyme design tasks, yielding outstanding results. Wet lab experiments further validate these findings, reinforcing the efficacy of the redesign process.
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Identifying dense subgraphs called quasi-cliques is pivotal in various graph mining tasks across domains like biology, social networks, and e-commerce. However, recent algorithms still suffer from efficiency issues when mining large quasi-cliques in massive and complex graphs. Our key insight is that vertices within a quasi-clique exhibit similar neighborhoods to some extent. Based on this, we introduce NBSim and FastNBSim, efficient algorithms that find near-maximum quasi-cliques by exploiting vertex neighborhood similarity. FastNBSim further uses MinHash approximations to reduce the time complexity for similarity computation. Empirical evaluation on 10 real-world graphs shows that our algorithms deliver up to three orders of magnitude speedup versus the state-of-the-art algorithms, while ensuring high-quality quasi-clique extraction.
The goal of the 22nd International Workshop on Data Mining in Bioinformatics (BIOKDD 2023) is to encourage KDD researchers to solve the numerous problems and challenges in Bioinformatics using Data Mining technologies. Based on the organizers' expertise and communities, BIOKDD 2023 features the theme "Large-Scale Data-Driven Methods for Bioinformatics". This theme encourages the use of high-performance computing (HPC) to support the training of large machine learning models for problems in Bioinformatics and Computational Biology. The key goal is to accelerate the convergence between Data Mining and Bioinformatics communities to expedite discoveries in basic biology, medicine and healthcare. The goal of the 23rd International Workshop on Data Mining in Bioinformatics (BIOKDD 2024) is to encourage KDD researchers to solve the numerous problems and challenges in Bioinformatics using Data Mining technologies. Based on the organizers' expertise and communities, BIOKDD 2024 features the theme "Advancing Bioinformatics with LLMs and GenAI". This theme encourages the use of large language models and generative artificial intelligence to solve problems in Bioinformatics and Computational Biology. The key goal is to accelerate the convergence between Data Mining and Bioinformatics communities to expedite discoveries in basic biology, medicine and healthcare.
Graph plays a significant role in representing and analyzing complex relationships in real-world applications such as citation networks, social networks, and biological data. Graph intelligence is rapidly becoming a crucial aspect of understanding and exploiting the intricate interconnections within graph data. Recently, large language models (LLMs) and prompt learning techniques have pushed graph intelligence forward, outperforming traditional Graph Neural Network (GNN) pre-training methods and setting new benchmarks for performance. In this tutorial, we begin by offering a comprehensive review and analysis of existing methods that integrate LLMs with graphs. We introduce existing works based on a novel taxonomy that classifies them into three distinct categories according to the roles of LLMs in graph tasks: as enhancers, predictors, or alignment components. Secondly, we introduce a new learning method that utilizes prompting on graphs, offering substantial potential to enhance graph transfer capabilities across diverse tasks and domains. We discuss existing works on graph prompting within a unified framework and introduce our developed tool for executing a variety of graph prompting tasks. Additionally, we discuss the applications of combining Graphs, LLMs, and prompt learning across various tasks, such as urban computing, recommendation systems, and anomaly detection. This lecture-style tutorial is an extension of our original work published in IJCAI 2024[44] and arXiv[77] with the invitation of KDD24.
Independent and identically distributed (i.i.d.) data is essential to many data analysis and modeling techniques. In the medical domain, collecting data from multiple sites or institutions is a common strategy that guarantees sufficient clinical diversity, determined by the decentralized nature of medical data. However, data from various sites are easily biased by the local environment or facilities, thereby violating the i.i.d. rule. A common strategy is to harmonize the site bias while retaining important biological information. The ComBat is among the most popular harmonization approaches and has recently been extended to handle distributed sites. However, when faced with situations involving newly joined sites in training or evaluating data from unknown/unseen sites, ComBat lacks compatibility and requires retraining with data from all the sites. The retraining leads to significant computational and logistic overhead that is usually prohibitive. In this work, we develop a novel Cluster ComBat harmonization algorithm, which leverages cluster patterns of the data in different sites and greatly advances the usability of ComBat harmonization. We use extensive simulation and real medical imaging data from ADNI to demonstrate the superiority of the proposed approach. Our codes are provided in https://github.com/illidanlab/distributed-cluster-harmonization.
Pseudo-cliques (subgraphs with almost all possible edges) have many applications. But they do not satisfy the convertible antimonotone constraint (as we prove here). So, it is hard to reduce the search space of pseudo-cliques and list them efficiently. To our knowledge, only two exact algorithms, namely, ODES and PCE, were proposed for this purpose, but both have high execution times. Here, we present an exact algorithm named Fast Pseudo-Clique Enumerator (FPCE). It employs some pruning techniques we derived to reduce the search space. Our experiment on 15 real and 16 synthetic graphs shows that (i) on real graphs, FPCE is, on average, 38.6 and 6.5 times faster than ODES and PCE, respectively, whereas (ii) on synthetic graphs, FPCE is, on average, 39.7 and 3.1 times faster than ODES and PCE, respectively. We apply FPCE and a popular heuristic method on a PPI network to identify pseudo-cliques. FPCE outputs match with more known protein complexes, are more accurate, and are biologically more significant - suggesting that the exact computation of pseudo-cliques may give better insights. For its speed, FPCE is a suitable choice in such cases.
Social dilemmasare situations of inter-dependent decision making in which individualrationality can lead to outcomes with poor social qualities. The ubiquity of social dilem-mas in social, biological, and computational systems has generated substantial researchacross these diverse disciplines into the study of mechanisms for avoiding deficient outcomes by promoting and maintaining mutual cooperation. Much of this research is focused on studying how individuals faced with a dilemma can learn to cooperate by adapting their behaviours according to their past experience. In particular, three types of learning approaches have been studied: evolutionary game-theoretic learning, reinforcement learning, and best-response learning. This article is a comprehensive integrated survey of these learning approaches in the context of dilemma games. We formally introduce dilemma games and their inherent challenges. We then outline the three learning approaches and, for eachapproach, provide a survey of the solutions proposed for dilemma resolution. Finally, we provide a comparative summary and discuss directions in which further research is needed.
Benchmarking Fish Dataset and Evaluation Metric in Keypoint Detection - Towards Precise Fish Morphological Assessment in Aquaculture Breeding
PDF ↗Accurate phenotypic analysis in aquaculture breeding necessitates the quantification of subtle morphological phenotypes. Existing datasets suffer from limitations such as small scale, limited species coverage, and inadequate annotation of keypoints for measuring refined and complex morphological phenotypes of fish body parts. To address this gap, we introduce FishPhenoKey, a comprehensive dataset comprising 23,331 high-resolution images spanning six fish species. Notably, FishPhenoKey includes 22 phenotype-oriented annotations, enabling the capture of intricate morphological phenotypes. Motivated by the nuanced evaluation of these subtle morphologies, we also propose a new evaluation metric, Percentage of Measured Phenotypes (PMP). It is designed to assess the accuracy of individual keypoint positions and is highly sensitive to the phenotype measured using the corresponding keypoints. To enhance keypoint detection accuracy, we further propose a novel loss, Anatomically-Calibrated Regularization (ACR), that can be integrated into keypoint detection models, leveraging biological insights to refine keypoint localization. Our contributions set a new benchmark in fish phenotype analysis, addressing the challenges of precise morphological quantification and opening new avenues for research in sustainable aquaculture and genetic studies. Our dataset and code are available at https://github.com/WeizhenLiuBioinform/FishPhenotype-Detect.
ZeroDDI: A Zero-Shot Drug-Drug Interaction Event Prediction Method with Semantic Enhanced Learning and Dual-modal Uniform Alignment
PDF ↗Drug-drug interactions (DDIs) can result in various pharmacological changes, which can be categorized into different classes known as DDI events (DDIEs). In recent years, previously unobserved/unseen DDIEs have been emerging, posing a new classification task when unseen classes have no labelled instances in the training stage, which is formulated as a zero-shot DDIE prediction (ZS-DDIE) task. However, existing computational methods are not directly applicable to ZS-DDIE, which has two primary challenges: obtaining suitable DDIE representations and handling the class imbalance issue. To overcome these challenges, we propose a novel method named ZeroDDI for the ZS-DDIE task. Specifically, we design a biological semantic enhanced DDIE representation learning module, which emphasizes the key biological semantics and distills discriminative molecular substructure-related semantics for DDIE representation learning. Furthermore, we propose a dual-modal uniform alignment strategy to distribute drug pair representations and DDIE semantic representations uniformly in unit sphere and align the matched ones, which can mitigate the issue of class imbalance. Extensive experiments showed that ZeroDDI surpasses the baselines and indicate that it is a promising tool for detecting unseen DDIEs. Our code has been released in https://github.com/wzy-Sarah/ZeroDDI.
SCTrans: Multi-scale scRNA-seq Sub-vector Completion Transformer for Gene-selective Cell Type Annotation
PDF ↗Cell type annotation is pivotal to single-cell RNA sequencing data (scRNA-seq)-based biological and medical analysis, e.g., identifying biomarkers, exploring cellular heterogeneity, and understanding disease mechanisms. The previous annotation methods typically learn a nonlinear mapping to infer cell type from gene expression vectors, and thus fall short in discovering and associating salient genes with specific cell types. To address this issue, we propose a multi-scale scRNA-seq Sub-vector Completion Transformer, and our model is referred to as SCTrans. Considering that the expressiveness of gene sub-vectors is richer than that of individual genes, we perform multi-scale partitioning on gene vectors followed by masked sub-vector completion, conditioned on unmasked ones. Toward this end, the multi-scale sub-vectors are tokenized, and the intrinsic contextual relationships are modeled via self-attention computation and conditional contrastive regularization imposed on an encoding transformer. By performing mutual learning between the encoder and an additional lightweight counterpart, the salient tokens can be distinguished from the others. As a result, we can perform gene-selective cell type annotation, which contributes to our superior performance over state-of-the-art annotation methods.
Deep Spiking Neural Networks (SNNs), as an advanced form of SNNs characterized by their multi-layered structure, have recently achieved significant breakthroughs in performance across various domains. The biological plausibility and energy efficiency of SNNs naturally align with the requisites of edge computing (EC) scenarios, thereby prompting increased interest among researchers to explore the migration of these deep SNN models onto edge devices such as sensors and smartphones. However, the progress of migration work has been notably challenging due to the influence of the substantial increase in model parameters and the demanding computational requirements in practical applications. In this work, we propose a deep SNN splitting framework named EC-SNN to run the intricate SNN models on edge devices. We first partition the full SNN models into smaller sub-models to allocate their model parameters on multiple edge devices. Then, we provide a channel-wise pruning method to reduce the size of each sub-model, thereby further reducing the computational load. We design extensive experiments on six datasets (i.e., four non-neuromorphic and two neuromorphic datasets) to substantiate that our approach can significantly diminish the inference execution latency on edge devices and reduce the overall energy consumption per deployed device with an average reduction of 60.7% and 27.7% respectively while keeping the effectiveness of the accuracy.
Spiking Neural Networks (SNNs), as the third generation of neural networks, have gained prominence for their biological plausibility and computational efficiency, especially in processing diverse datasets. The integration of attention mechanisms, inspired by advancements in neural network architectures, has led to the development of Spiking Transformers. These have shown promise in enhancing SNNs' capabilities, particularly in the realms of both static and neuromorphic datasets. Despite their progress, a discernible gap exists in these systems, specifically in the Spiking Self Attention (SSA) mechanism's effectiveness in leveraging the temporal processing potential of SNNs. To address this, we introduce the Temporal Interaction Module (TIM), a novel, convolution-based enhancement designed to augment the temporal data processing abilities within SNN architectures. TIM's integration into existing SNN frameworks is seamless and efficient, requiring minimal additional parameters while significantly boosting their temporal information handling capabilities. Through rigorous experimentation, TIM has demonstrated its effectiveness in exploiting temporal information, leading to state-of-the-art performance across various neuromorphic datasets. The code is available at https://github.com/BrainCog-X/Brain-Cog/tree/main/examples/TIM.
The Moran process is a classic stochastic process that models the rise and takeover of novel traits in network-structured populations. In biological terms, a set of mutants, each with fitness m ∈ (0, ∞) invade a population of residents with fitness 1. Each agent reproduces at a rate proportional to its fitness and each offspring replaces a random network neighbor. The process ends when the mutants either fixate (take over the whole population) or go extinct. The fixation probability measures the success of the invasion. To account for environmental heterogeneity, we study a generalization of the Standard process, called the Heterogeneous Moran process. Here, the fitness of each agent is determined both by its type (resident/mutant) and the node it occupies. We study the natural optimization problem of seed selection: given a budget k, which k agents should initiate the mutant invasion to maximize the fixation probability? We show that the problem is strongly inapproximable: it is NP-hard to distinguish between maximum fixation probability 0 and 1. We then focus on mutant-biased networks, where each node exhibits at least as large mutant fitness as resident fitness. We show that the problem remains NP-hard, but the fixation probability becomes submodular, and thus the optimization problem admits a greedy (1 − 1/e)-approximation. An experimental evaluation of the greedy algorithm along with various heuristics on real-world data sets corroborates our results.
Leverage the Explainability of Transformer Models to Improve the DNA 5-Methylcytosine Identification (Student Abstract)
PDF ↗DNA methylation is an epigenetic mechanism for regulating gene expression, and it plays an important role in many biological processes. While methylation sites can be identified using laboratory techniques, much work is being done on developing computational approaches using machine learning. Here, we present a deep-learning algorithm for determining the 5-methylcytosine status of a DNA sequence. We propose an ensemble framework that treats the self-attention score as an explicit feature that is added to the encoder layer generated by fine-tuned language models. We evaluate the performance of the model under different data distribution scenarios.
Transcription factors (TFs) play a fundamental role in gene regulation by selectively binding to specific DNA sequences. Understanding the nature and behavior of these TFs is essential for insights into gene regulation dynamics. In this study, we introduce a robust multi-task learning framework specifically tailored to harness both TF-specific annotations and TF-related domain annotations, thereby enhancing the accuracy of TF predictions. Notably, we incorporate cutting-edge language models that have recently garnered attention for their outstanding performance across various fields, particularly in biological computations like protein sequence modeling. Comparative experimental analysis with existing models, DeepTFactor and TFpredict, reveals that our multi-task learning framework achieves an accuracy exceeding 92% across four evaluation metrics on the TF prediction task, surpassing both competitors. Our work marks a significant leap in the domain of TF prediction, enriching our comprehension of gene regulatory mechanisms and paving the way for the discovery of novel regulatory motifs.
The identification of sensory cues associated with potential opportunities and dangers is frequently complicated by unrelated events that separate useful cues by long delays. As a result, it remains a challenging task for state-of-the-art spiking neural networks (SNNs) to establish long-term temporal dependency between distant cues. To address this challenge, we propose a novel biologically inspired Two-Compartment Leaky Integrate-and-Fire spiking neuron model, dubbed TC-LIF. The proposed model incorporates carefully designed somatic and dendritic compartments that are tailored to facilitate learning long-term temporal dependencies. Furthermore, the theoretical analysis is provided to validate the effectiveness of TC-LIF in propagating error gradients over an extended temporal duration. Our experimental results, on a diverse range of temporal classification tasks, demonstrate superior temporal classification capability, rapid training convergence, and high energy efficiency of the proposed TC-LIF model. Therefore, this work opens up a myriad of opportunities for solving challenging temporal processing tasks on emerging neuromorphic computing systems. Our code is publicly available at https://github.com/ZhangShimin1/TC-LIF.
Efficient computation or approximation of Levenshtein distance, a widely-used metric for evaluating sequence similarity, has attracted significant attention with the emergence of DNA storage and other biological applications. Sequence embedding, which maps Levenshtein distance to a conventional distance between embedding vectors, has emerged as a promising solution. In this paper, a novel neural network-based sequence embedding technique using Poisson regression is proposed. We first provide a theoretical analysis of the impact of embedding dimension on model performance and present a criterion for selecting an appropriate embedding dimension. Under this embedding dimension, the Poisson regression is introduced by assuming the Levenshtein distance between sequences of fixed length following a Poisson distribution, which naturally aligns with the definition of Levenshtein distance. Moreover, from the perspective of the distribution of embedding distances, Poisson regression approximates the negative log likelihood of the chi-squared distribution and offers advancements in removing the skewness. Through comprehensive experiments on real DNA storage data, we demonstrate the superior performance of the proposed method compared to state-of-the-art approaches.
The de novo generation of hit-like molecules that show bioactivity and drug-likeness is an important task in computer-aided drug discovery. Although artificial intelligence can generate molecules with desired chemical properties, most previous studies have ignored the influence of disease-related cellular environments. This study proposes a novel deep generative model called GxVAEs to generate hit-like molecules from gene expression profiles by leveraging two joint variational autoencoders (VAEs). The first VAE, ProfileVAE, extracts latent features from gene expression profiles. The extracted features serve as the conditions that guide the second VAE, which is called MolVAE, in generating hit-like molecules. GxVAEs bridge the gap between molecular generation and the cellular environment in a biological system, and produce molecules that are biologically meaningful in the context of specific diseases. Experiments and case studies on the generation of therapeutic molecules show that GxVAEs outperforms current state-of-the-art baselines and yield hit-like molecules with potential bioactivity and drug-like properties. We were able to successfully generate the potential molecular structures with therapeutic effects for various diseases from patients’ disease profiles.
Protein structure-based property prediction has emerged as a promising approach for various biological tasks, such as protein function prediction and sub-cellular location estimation. The existing methods highly rely on experimental protein structure data and fail in scenarios where these data are unavailable. Predicted protein structures from AI tools (e.g., AlphaFold2) were utilized as alternatives. However, we observed that current practices, which simply employ accurately predicted structures during inference, suffer from notable degradation in prediction accuracy. While similar phenomena have been extensively studied in general fields (e.g., Computer Vision) as model robustness, their impact on protein property prediction remains unexplored. In this paper, we first investigate the reason behind the performance decrease when utilizing predicted structures, attributing it to the structure embedding bias from the perspective of structure representation learning. To study this problem, we identify a Protein 3D Graph Structure Learning Problem for Robust Protein Property Prediction (PGSL-RP3), collect benchmark datasets, and present a protein Structure embedding Alignment Optimization framework (SAO) to mitigate the problem of structure embedding bias between the predicted and experimental protein structures. Extensive experiments have shown that our framework is model-agnostic and effective in improving the property prediction of both predicted structures and experimental structures.
Backpropagation (BP), the standard learning algorithm for artificial neural networks, is often considered biologically implausible. In contrast, the standard learning algorithm for predictive coding (PC) models in neuroscience, known as the inference learning algorithm (IL), is a promising, bio-plausible alternative. However, several challenges and questions hinder IL's application to real-world problems. For example, IL is computationally demanding, and without memory-intensive optimizers like Adam, IL may converge to poor local minima. Moreover, although IL can reduce loss more quickly than BP, the reasons for these speedups or their robustness remains unclear. In this paper, we tackle these challenges by 1) altering the standard implementation of PC circuits to substantially reduce computation, 2) developing a novel optimizer that improves the convergence of IL without increasing memory usage, and 3) establishing theoretical results that help elucidate the conditions under which IL is sensitive to second and higher-order information.