GTE: a graph learning framework for prediction of T-cell receptors and epitopes binding specificity.

The interaction between T-cell receptors (TCRs) and peptides (epitopes) presented by major histocompatibility complex molecules (MHC) is fundamental to the immune response. Accurate prediction of TCR-epitope interactions is crucial for advancing the understanding of various diseases and their prevention and treatment. Existing methods primarily rely on sequence-based approaches, overlooking the inherent topology structure of TCR-epitope interaction networks. In this study, we present $GTE$, a novel heterogeneous Graph neural network model based on inductive learning to capture the topological structure between TCRs and Epitopes. Furthermore, we address the challenge of constructing negative samples within the graph by proposing a dynamic edge update strategy, enhancing model learning with the nonbinding TCR-epitope pairs. Additionally, to overcome data imbalance, we adapt the Deep AUC Maximization strategy to the graph domain. Extensive experiments are conducted on four public datasets to demonstrate the superiority of exploring underlying topological structures in predicting TCR-epitope interactions, illustrating the benefits of delving into complex molecular networks. The implementation code and data are available at https://github.com/uta-smile/GTE.

MARS: a motif-based autoregressive model for retrosynthesis prediction.

MOTIVATION: Retrosynthesis is a critical task in drug discovery, aimed at finding a viable pathway for synthesizing a given target molecule. Many existing approaches frame this task as a graph-generating problem. Specifically, these methods first identify the reaction center, and break a targeted molecule accordingly to generate the synthons. Reactants are generated by either adding atoms sequentially to synthon graphs or by directly adding appropriate leaving groups. However, both of these strategies have limitations. Adding atoms results in a long prediction sequence that increases the complexity of generation, while adding leaving groups only considers those in the training set, which leads to poor generalization. RESULTS: In this paper, we propose a novel end-to-end graph generation model for retrosynthesis prediction, which sequentially identifies the reaction center, generates the synthons, and adds motifs to the synthons to generate reactants. Given that chemically meaningful motifs fall between the size of atoms and leaving groups, our model achieves lower prediction complexity than adding atoms and demonstrates superior performance than adding leaving groups. We evaluate our proposed model on a benchmark dataset and show that it significantly outperforms previous state-of-the-art models. Furthermore, we conduct ablation studies to investigate the contribution of each component of our proposed model to the overall performance on benchmark datasets. Experiment results demonstrate the effectiveness of our model in predicting retrosynthesis pathways and suggest its potential as a valuable tool in drug discovery. AVAILABILITY AND IMPLEMENTATION: All code and data are available at https://github.com/szu-ljh2020/MARS.

MolAICal: a soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm.

Deep learning is an important branch of artificial intelligence that has been successfully applied into medicine and two-dimensional ligand design. The three-dimensional (3D) ligand generation in the 3D pocket of protein target is an interesting and challenging issue for drug design by deep learning. Here, the MolAICal software is introduced to supply a way for generating 3D drugs in the 3D pocket of protein targets by combining with merits of deep learning model and classical algorithm. The MolAICal software mainly contains two modules for 3D drug design. In the first module of MolAICal, it employs the genetic algorithm, deep learning model trained by FDA-approved drug fragments and Vinardo score fitting on the basis of PDBbind database for drug design. In the second module, it uses deep learning generative model trained by drug-like molecules of ZINC database and molecular docking invoked by Autodock Vina automatically. Besides, the Lipinski's rule of five, Pan-assay interference compounds (PAINS), synthetic accessibility (SA) and other user-defined rules are introduced for filtering out unwanted ligands in MolAICal. To show the drug design modules of MolAICal, the membrane protein glucagon receptor and non-membrane protein SARS-CoV-2 main protease are chosen as the investigative drug targets. The results show MolAICal can generate the various and novel ligands with good binding scores and appropriate XLOGP values. We believe that MolAICal can use the advantages of deep learning model and classical programming for designing 3D drugs in protein pocket. MolAICal is freely for any nonprofit purpose and accessible at https://molaical.github.io.

Multi-level attention graph neural network based on co-expression gene modules for disease diagnosis and prognosis.

MOTIVATION: Advanced deep learning techniques have been widely applied in disease diagnosis and prognosis with clinical omics, especially gene expression data. In the regulation of biological processes and disease progression, genes often work interactively rather than individually. Therefore, investigating gene association information and co-functional gene modules can facilitate disease state prediction. RESULTS: To explore the gene modules and inter-gene relational information contained in the omics data, we propose a novel multi-level attention graph neural network (MLA-GNN) for disease diagnosis and prognosis. Specifically, we format omics data into co-expression graphs via weighted correlation network analysis, and then construct multi-level graph features, finally fuse them through a well-designed multi-level graph feature fully fusion module to conduct predictions. For model interpretation, a novel full-gradient graph saliency mechanism is developed to identify the disease-relevant genes. MLA-GNN achieves state-of-the-art performance on transcriptomic data from TCGA-LGG/TCGA-GBM and proteomic data from coronavirus disease 2019 (COVID-19)/non-COVID-19 patient sera. More importantly, the relevant genes selected by our model are interpretable and are consistent with the clinical understanding. AVAILABILITYAND IMPLEMENTATION: The codes are available at https://github.com/TencentAILabHealthcare/MLA-GNN.

Cross-dependent graph neural networks for molecular property prediction.

MOTIVATION: The crux of molecular property prediction is to generate meaningful representations of the molecules. One promising route is to exploit the molecular graph structure through graph neural networks (GNNs). Both atoms and bonds significantly affect the chemical properties of a molecule, so an expressive model ought to exploit both node (atom) and edge (bond) information simultaneously. Inspired by this observation, we explore the multi-view modeling with GNN (MVGNN) to form a novel paralleled framework, which considers both atoms and bonds equally important when learning molecular representations. In specific, one view is atom-central and the other view is bond-central, then the two views are circulated via specifically designed components to enable more accurate predictions. To further enhance the expressive power of MVGNN, we propose a cross-dependent message-passing scheme to enhance information communication of different views. The overall framework is termed as CD-MVGNN. RESULTS: We theoretically justify the expressiveness of the proposed model in terms of distinguishing non-isomorphism graphs. Extensive experiments demonstrate that CD-MVGNN achieves remarkably superior performance over the state-of-the-art models on various challenging benchmarks. Meanwhile, visualization results of the node importance are consistent with prior knowledge, which confirms the interpretability power of CD-MVGNN. AVAILABILITY AND IMPLEMENTATION: The code and data underlying this work are available in GitHub at https://github.com/uta-smile/CD-MVGNN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Recent Advances in Toxicity Prediction: Applications of Deep Graph Learning.

The development of new drugs is time-consuming and expensive, and as such, accurately predicting the potential toxicity of a drug candidate is crucial in ensuring its safety and efficacy. Recently, deep graph learning has become prevalent in this field due to its computational power and cost efficiency. Many novel deep graph learning methods aid toxicity prediction and further prompt drug development. This review aims to connect fundamental knowledge with burgeoning deep graph learning methods. We first summarize the essential components of deep graph learning models for toxicity prediction, including molecular descriptors, molecular representations, evaluation metrics, validation methods, and data sets. Furthermore, based on various graph-related representations of molecules, we introduce several representative studies and methods for toxicity prediction from the perspective of GNN architectures and graph pretrained models. Compared to other types of models, deep graph models not only advance in higher accuracy and efficiency but also provide more intuitive insights, which is significant in the development of model interpretation and generalization ability. The graph pretrained models are emerging as they can extract prominent features from large-scale unlabeled molecular graph data and improve the performance of downstream toxicity prediction tasks. We hope this survey can serve as a handbook for individuals interested in exploring deep graph learning for toxicity prediction.

When homologous sequences meet structural decoys: Accurate contact prediction by tFold in CASP14-(tFold for CASP14 contact prediction).

In this paper, we report our tFold framework's performance on the inter-residue contact prediction task in the 14th Critical Assessment of protein Structure Prediction (CASP14). Our tFold framework seamlessly combines both homologous sequences and structural decoys under an ultra-deep network architecture. Squeeze-excitation and axial attention mechanisms are employed to effectively capture inter-residue interactions. In CASP14, our best predictor achieves 41.78% in the averaged top-L precision for long-range contacts for all the 22 free-modeling (FM) targets, and ranked 1st among all the 60 participating teams. The tFold web server is now freely available at: https://drug.ai.tencent.com/console/en/tfold.

Improving Ki67 assessment concordance by the use of an artificial intelligence-empowered microscope: a multi-institutional ring study.

AIMS: The nuclear proliferation biomarker Ki67 plays potential prognostic and predictive roles in breast cancer treatment. However, the lack of interpathologist consistency in Ki67 assessment limits the clinical use of Ki67. The aim of this article was to report a solution utilising an artificial intelligence (AI)-empowered microscope to improve Ki67 scoring concordance. METHODS AND RESULTS: We developed an AI-empowered microscope in which the conventional microscope was equipped with AI algorithms, and AI results were provided to pathologists in real time through augmented reality. We recruited 30 pathologists with various experience levels from five institutes to assess the Ki67 labelling index on 100 Ki67-stained slides from invasive breast cancer patients. In the first round, pathologists conducted visual assessment on a conventional microscope; in the second round, they were assisted with reference cards; and in the third round, they were assisted with an AI-empowered microscope. Experienced pathologists had better reproducibility and accuracy [intraclass correlation coefficient (ICC) = 0.864, mean error = 8.25%] than inexperienced pathologists (ICC = 0.807, mean error = 11.0%) in visual assessment. Moreover, with reference cards, inexperienced pathologists (ICC = 0.836, mean error = 10.7%) and experienced pathologists (ICC = 0.875, mean error = 7.56%) improved their reproducibility and accuracy. Finally, both experienced pathologists (ICC = 0.937, mean error = 4.36%) and inexperienced pathologists (ICC = 0.923, mean error = 4.71%) improved the reproducibility and accuracy significantly with the AI-empowered microscope. CONCLUSION: The AI-empowered microscope allows seamless integration of the AI solution into the clinical workflow, and helps pathologists to obtain higher consistency and accuracy for Ki67 assessment.

Deep Graph Learning with Property Augmentation for Predicting Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a crucial factor in determining the qualification of potential drugs. However, the DILI property is excessively difficult to obtain due to the complex testing process. Consequently, an in silico screening in the early stage of drug discovery would help to reduce the total development cost by filtering those drug candidates with a high risk to cause DILI. To serve the screening goal, we apply several computational techniques to predict the DILI property, including traditional machine learning methods and graph-based deep learning techniques. While deep learning models require large training data to tune huge model parameters, the DILI data set only contains a few hundred annotated molecules. To alleviate the data scarcity problem, we propose a property augmentation strategy to include massive training data with other property information. Extensive experiments demonstrate that our proposed method significantly outperforms all existing baselines on the DILI data set by obtaining a 81.4% accuracy using cross-validation with random splitting, 78.7% using leave-one-out cross-validation, and 76.5% using cross-validation with scaffold splitting.

TENDER: Tensor non-local deconvolution enabled radiation reduction in CT perfusion.

Stroke is the leading cause of long-term disability and the second leading cause of mortality in the world, and exerts an enormous burden on the public health. Computed Tomography (CT) remains one of the most widely used imaging modality for acute stroke diagnosis. However when coupled with CT perfusion, the excessive radiation exposure in repetitive imaging to assess treatment response and prognosis has raised significant public concerns regarding its potential hazards to both short- and long-term health outcomes. Tensor total variation has been proposed to reduce the necessary radiation dose in CT perfusion without comprising the image quality by fusing the information of the local anatomical structure with the temporal blood flow model. However the local search in the TTV framework fails to leverage the non-local information in the spatio-temporal data. In this paper, we propose TENDER, an efficient framework of non-local tensor deconvolution to maintain the accuracy of the hemodynamic parameters and the diagnostic reliability in low radiation dose CT perfusion. The tensor total variation is extended using non-local spatio-temporal cubics for regularization, and an efficient algorithm is proposed to reduce the time complexity with speedy similarity computation. Evaluations on clinical data of patients subjects with cerebrovascular disease and normal subjects demonstrate the advantage of non-local tensor deconvolution for reducing radiation dose in CT perfusion.

Geometric deep learning methods and applications in 3D structure-based drug design.

3D structure-based drug design (SBDD) is considered a challenging and rational way for innovative drug discovery. Geometric deep learning is a promising approach that solves the accurate model training of 3D SBDD through building neural network models to learn non-Euclidean data, such as 3D molecular graphs and manifold data. Here, we summarize geometric deep learning methods and applications that contain 3D molecular representations, equivariant graph neural networks (EGNNs), and six generative model methods [diffusion model, flow-based model, generative adversarial networks (GANs), variational autoencoder (VAE), autoregressive models, and energy-based models]. Our review provides insights into geometric deep learning methods and advanced applications of 3D SBDD that will be of relevance for the drug discovery community.

Toward Robust Self-Training Paradigm for Molecular Prediction Tasks.

Molecular prediction tasks normally demand a series of professional experiments to label the target molecule, which suffers from the limited labeled data problem. One of the semisupervised learning paradigms, known as self-training, utilizes both labeled and unlabeled data. Specifically, a teacher model is trained using labeled data and produces pseudo labels for unlabeled data. These labeled and pseudo-labeled data are then jointly used to train a student model. However, the pseudo labels generated from the teacher model are generally not sufficiently accurate. Thus, we propose a robust self-training strategy by exploring robust loss function to handle such noisy labels in two paradigms, that is, generic and adaptive. We have conducted experiments on three molecular biology prediction tasks with four backbone models to gradually evaluate the performance of the proposed robust self-training strategy. The results demonstrate that the proposed method enhances prediction performance across all tasks, notably within molecular regression tasks, where there has been an average enhancement of 41.5%. Furthermore, the visualization analysis confirms the superiority of our method. Our proposed robust self-training is a simple yet effective strategy that efficiently improves molecular biology prediction performance. It tackles the labeled data insufficient issue in molecular biology by taking advantage of both labeled and unlabeled data. Moreover, it can be easily embedded with any prediction task, which serves as a universal approach for the bioinformatics community.

Learning With Noisy Labels Over Imbalanced Subpopulations.

Learning with noisy labels (LNL) has attracted significant attention from the research community. Many recent LNL methods rely on the assumption that clean samples tend to have a "small loss." However, this assumption often fails to generalize to some real-world cases with imbalanced subpopulations, that is, training subpopulations that vary in sample size or recognition difficulty. Therefore, recent LNL methods face the risk of misclassifying those "informative" samples (e.g., hard samples or samples in the tail subpopulations) into noisy samples, leading to poor generalization performance. To address this issue, we propose a novel LNL method to deal with noisy labels and imbalanced subpopulations simultaneously. It first leverages sample correlation to estimate samples' clean probabilities for label correction and then utilizes corrected labels for distributionally robust optimization (DRO) to further improve the robustness. Specifically, in contrast to previous works using classification loss as the selection criterion, we introduce a feature-based metric that takes the sample correlation into account for estimating samples' clean probabilities. Then, we refurbish the noisy labels using the estimated clean probabilities and the pseudo-labels from the model's predictions. With refurbished labels, we use DRO to train the model to be robust to subpopulation imbalance. Extensive experiments on a wide range of benchmarks demonstrate that our technique can consistently improve state-of-the-art (SOTA) robust learning paradigms against noisy labels, especially when encountering imbalanced subpopulations. We provide our code in https://github.com/chenmc1996/LNL-IS.

Solving the non-submodular network collapse problems via Decision Transformer.

Given a graph G, the network collapse problem (NCP) selects a vertex subset S of minimum cardinality from G such that the difference in the values of a given measure function f(G)-f(G∖S) is greater than a predefined collapse threshold. Many graph analytic applications can be formulated as NCPs with different measure functions, which often pose a significant challenge due to their NP-hard nature. As a result, traditional greedy algorithms, which select the vertex with the highest reward at each step, may not effectively find the optimal solution. In addition, existing learning-based algorithms do not have the ability to model the sequence of actions taken during the decision-making process, making it difficult to capture the combinatorial effect of selected vertices on the final solution. This limits the performance of learning-based approaches in non-submodular NCPs. To address these limitations, we propose a unified framework called DT-NC, which adapts the Decision Transformer to the Network Collapse problems. DT-NC takes into account the historical actions taken during the decision-making process and effectively captures the combinatorial effect of selected vertices. The ability of DT-NC to model the dependency among selected vertices allows it to address the difficulties caused by the non-submodular property of measure functions in some NCPs effectively. Through extensive experiments on various NCPs and graphs of different sizes, we demonstrate that DT-NC outperforms the state-of-the-art methods and exhibits excellent transferability and generalizability.

HiCervix: An Extensive Hierarchical Dataset and Benchmark for Cervical Cytology Classification.

Cervical cytology is a critical screening strategy for early detection of pre-cancerous and cancerous cervical lesions. The challenge lies in accurately classifying various cervical cytology cell types. Existing automated cervical cytology methods are primarily trained on databases covering a narrow range of coarse-grained cell types, which fail to provide a comprehensive and detailed performance analysis that accurately represents real-world cytopathology conditions. To overcome these limitations, we introduce HiCervix, the most extensive, multi-center cervical cytology dataset currently available to the public. HiCervix includes 40,229 cervical cells from 4,496 whole slide images, categorized into 29 annotated classes. These classes are organized within a three-level hierarchical tree to capture fine-grained subtype information. To exploit the semantic correlation inherent in this hierarchical tree, we propose HierSwin, a hierarchical vision transformer-based classification network. HierSwin serves as a benchmark for detailed feature learning in both coarse-level and fine-level cervical cancer classification tasks. In our comprehensive experiments, HierSwin demonstrated remarkable performance, achieving 92.08% accuracy for coarse-level classification and 82.93% accuracy averaged across all three levels. When compared to board-certified cytopathologists, HierSwin achieved high classification performance (0.8293 versus 0.7359 averaged accuracy), highlighting its potential for clinical applications. This newly released HiCervix dataset, along with our benchmark HierSwin method, is poised to make a substantial impact on the advancement of deep learning algorithms for rapid cervical cancer screening and greatly improve cancer prevention and patient outcomes in real-world clinical settings.

Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data.

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

NuSegDA: Domain adaptation for nuclei segmentation.

The accurate segmentation of nuclei is crucial for cancer diagnosis and further clinical treatments. To successfully train a nuclei segmentation network in a fully-supervised manner for a particular type of organ or cancer, we need the dataset with ground-truth annotations. However, such well-annotated nuclei segmentation datasets are highly rare, and manually labeling an unannotated dataset is an expensive, time-consuming, and tedious process. Consequently, we require to discover a way for training the nuclei segmentation network with unlabeled dataset. In this paper, we propose a model named NuSegUDA for nuclei segmentation on the unlabeled dataset (target domain). It is achieved by applying Unsupervised Domain Adaptation (UDA) technique with the help of another labeled dataset (source domain) that may come from different type of organ, cancer, or source. We apply UDA technique at both of feature space and output space. We additionally utilize a reconstruction network and incorporate adversarial learning into it so that the source-domain images can be accurately translated to the target-domain for further training of the segmentation network. We validate our proposed NuSegUDA on two public nuclei segmentation datasets, and obtain significant improvement as compared with the baseline methods. Extensive experiments also verify the contribution of newly proposed image reconstruction adversarial loss, and target-translated source supervised loss to the performance boost of NuSegUDA. Finally, considering the scenario when we have a small number of annotations available from the target domain, we extend our work and propose NuSegSSDA, a Semi-Supervised Domain Adaptation (SSDA) based approach.

Structure-Aware DropEdge Toward Deep Graph Convolutional Networks.

It has been discovered that graph convolutional networks (GCNs) encounter a remarkable drop in performance when multiple layers are piled up. The main factor that accounts for why deep GCNs fail lies in oversmoothing, which isolates the network output from the input with the increase of network depth, weakening expressivity and trainability. In this article, we start by investigating refined measures upon DropEdge-an existing simple yet effective technique to relieve oversmoothing. We term our method as DropEdge ++ for its two structure-aware samplers in contrast to DropEdge: layer-dependent (LD) sampler and feature-dependent (FD) sampler. Regarding the LD sampler, we interestingly find that increasingly sampling edges from the bottom layer yields superior performance than the decreasing counterpart as well as DropEdge. We theoretically reveal this phenomenon with mean-edge-number (MEN), a metric closely related to oversmoothing. For the FD sampler, we associate the edge sampling probability with the feature similarity of node pairs and prove that it further correlates the convergence subspace of the output layer with the input features. Extensive experiments on several node classification benchmarks, including both full-and semi-supervised tasks, illustrate the efficacy of DropEdge ++ and its compatibility with a variety of backbones by achieving generally better performance over DropEdge and the no-drop version.

Spatiotemporal denoising of low-dose cardiac CT image sequences using RecycleGAN.

Electrocardiogram (ECG)-gated multi-phase computed tomography angiography (MP-CTA) is frequently used for diagnosis of coronary artery disease. Radiation dose may become a potential concern as the scan needs to cover a wide range of cardiac phases during a heart cycle. A common method to reduce radiation is to limit the full-dose acquisition to a predefined range of phases while reducing the radiation dose for the rest. Our goal in this study is to develop a spatiotemporal deep learning method to enhance the quality of low-dose CTA images at phases acquired at reduced radiation dose. Recently, we demonstrated that a deep learning method, Cycle-Consistent generative adversarial networks (CycleGAN), could effectively denoise low-dose CT images through spatial image translation without labeled image pairs in both low-dose and full-dose image domains. As CycleGAN does not utilize the temporal information in its denoising mechanism, we propose to use RecycleGAN, which could translate a series of images ordered in time from the low-dose domain to the full-dose domain through an additional recurrent network. To evaluate RecycleGAN, we use the XCAT phantom program, a highly realistic simulation tool based on real patient data, to generate MP-CTA image sequences for 18 patients (14 for training, 2 for validation and 2 for test). Our simulation results show that RecycleGAN can achieve better denoising performance than CycleGAN based on both visual inspection and quantitative metrics. We further demonstrate the superior denoising performance of RecycleGAN using clinical MP-CTA images from 50 patients.

Molecule Sequence Generation with Rebalanced Variational Autoencoder Loss.

Molecule generation is the procedure to generate initial novel molecule proposals for molecule design. Molecules are first projected into continuous vectors in chemical latent space, and then, these embedding vectors are decoded into molecules under the variational autoencoder (VAE) framework. The continuous latent space of VAE can be utilized to generate novel molecules with desired chemical properties and further optimize the desired chemical properties of molecules. However, there is a posterior collapse problem with the conventional recurrent neural network-based VAEs for the molecule sequence generation, which deteriorates the generation performance. We investigate the posterior collapse problem and find that the underestimated reconstruction loss is the main factor in the posterior collapse problem in molecule sequence generation. To support our conclusion, we present both analytical and experimental evidence. What is more, we propose an efficient and effective solution to fix the problem and prevent posterior collapse. As a result, our method achieves competitive reconstruction accuracy and validity score on the benchmark data sets.