OBJECTIVE: The aim of this project was to create time-aware, individual-level risk score models for adverse drug events related to multiple sclerosis disease-modifying therapy and to provide interpretable explanations for model prediction behavior.
METHODS: We used temporal sequences of observational medical outcomes partnership common data model (OMOP CDM) concepts derived from an electronic health record as model features. Each concept was assigned an embedding representation that was learned from a graph convolution network trained on a knowledge graph (KG) of OMOP concept relationships. Concept embeddings were fed into long short-term memory networks for 1-year adverse event prediction following drug exposure. Finally, we implemented a novel extension of the local interpretable model agnostic explanation (LIME) method, knowledge graph LIME (KG-LIME) to leverage the KG and explain individual predictions of each model.
RESULTS: For a set of 4859 patients, we found that our model was effective at predicting 32 out of 56 adverse event types (P < .05) when compared to demographics and past diagnosis as variables. We also assessed discrimination in the form of area under the curve (AUC = 0.77 ± 0.15) and area under the precision-recall curve (AUC-PR = 0.31 ± 0.27) and assessed calibration in the form of Brier score (BS = 0.04 ± 0.04). Additionally, KG-LIME generated interpretable literature-validated lists of relevant medical concepts used for prediction.
CONCLUSIONS: Many of our risk models demonstrated high calibration and discrimination for adverse event prediction. Furthermore, our novel KG-LIME method was able to utilize the knowledge graph to highlight concepts that were important to prediction. Future work will be required to further explore the temporal window of adverse event occurrence beyond the generic 1-year window used here, particularly for short-term inpatient adverse events and long-term severe adverse events.

Histopathology image-based survival prediction aims to provide a precise assessment of cancer prognosis and can inform personalized treatment decision-making in order to improve patient outcomes. However, existing methods cannot automatically model the complex correlations between numerous morphologically diverse patches in each whole slide image (WSI), thereby preventing them from achieving a more profound understanding and inference of the patient status. To address this, here we propose a novel deep learning framework, termed dual-stream multi-dependency graph neural network (DM-GNN), to enable precise cancer patient survival analysis. Specifically, DM-GNN is structured with the feature updating and global analysis branches to better model each WSI as two graphs based on morphological affinity and global co-activating dependencies. As these two dependencies depict each WSI from distinct but complementary perspectives, the two designed branches of DM-GNN can jointly achieve the multi-view modeling of complex correlations between the patches. Moreover, DM-GNN is also capable of boosting the utilization of dependency information during graph construction by introducing the affinity-guided attention recalibration module as the readout function. This novel module offers increased robustness against feature perturbation, thereby ensuring more reliable and stable predictions. Extensive benchmarking experiments on five TCGA datasets demonstrate that DM-GNN outperforms other state-of-the-art methods and offers interpretable prediction insights based on the morphological depiction of high-attention patches. Overall, DM-GNN represents a powerful and auxiliary tool for personalized cancer prognosis from histopathology images and has great potential to assist clinicians in making personalized treatment decisions and improving patient outcomes.

Machine learning methods have seen increased application to geospatial environmental problems, such as precipitation nowcasting, haze forecasting, and crop yield prediction. However, many of the machine learning methods applied to mosquito population and disease forecasting do not inherently take into account the underlying spatial structure of the given data. In our work, we apply a spatially aware graph neural network model consisting of GraphSAGE layers to forecast the presence of West Nile virus in Illinois, to aid mosquito surveillance and abatement efforts within the state. More generally, we show that graph neural networks applied to irregularly sampled geospatial data can exceed the performance of a range of baseline methods including logistic regression, XGBoost, and fully-connected neural networks.

Recent studies have illuminated the critical role of the human microbiome in maintaining health and influencing the pharmacological responses of drugs. Clinical trials, encompassing approximately 150 drugs, have unveiled interactions with the gastrointestinal microbiome, resulting in the conversion of these drugs into inactive metabolites. It is imperative to explore the field of pharmacomicrobiomics during the early stages of drug discovery, prior to clinical trials. To achieve this, the utilization of machine learning and deep learning models is highly desirable. In this study, we have proposed graph-based neural network models, namely GCN, GAT, and GINCOV models, utilizing the SMILES dataset of drug microbiome. Our primary objective was to classify the susceptibility of drugs to depletion by gut microbiota. Our results indicate that the GINCOV surpassed the other models, achieving impressive performance metrics, with an accuracy of 93% on the test dataset. This proposed Graph Neural Network (GNN) model offers a rapid and efficient method for screening drugs susceptible to gut microbiota depletion and also encourages the improvement of patient-specific dosage responses and formulations.

OBJECTIVE: Alzheimer\'s disease dementia (ADD) is well known to induce alterations in both structural and functional brain connectivity. However, reported changes in connectivity are mostly limited to global/local network features, which have poor specificity for diagnostic purposes. Following recent advances in machine learning, deep neural networks, particularly Graph Neural Network (GNN) based approaches, have found applications in brain research as well. The majority of existing applications of GNNs employ a single network (uni-modal or structure/function unified), despite the widely accepted view that there is a nontrivial interdependence between the brain\'s structural connectivity and the neural activity patterns, which is hypothesized to be disrupted in ADD. This disruption is quantified as a discrepancy score by the proposed \"structure-function discrepancy learning network\" (sfDLN) and its distribution is studied over the spectrum of clinical cognitive decline. The measured discrepancy score is utilized as a diagnostic biomarker and is compared with state-of-the-art diagnostic classifiers.
METHODS: sfDLN is a GNN with a siamese architecture built on the hypothesis that the mismatch between structural and functional connectivity patterns increases over the cognitive decline spectrum, starting from subjective cognitive impairment (SCI), passing through a mid-stage mild cognitive impairment (MCI), and ending up with ADD. The structural brain connectome (sNET) built using diffusion MRI-based tractography and the novel, sparse (lean) functional brain connectome (ℓNET) built using fMRI are input to sfDLN. The siamese sfDLN is trained to extract connectome representations and a discrepancy (dissimilarity) score that complies with the proposed hypothesis and is blindly tested on an MCI group.
RESULTS: The sfDLN generated structure-function discrepancy scores show high disparity between ADD and SCI subjects. Leave-one-out experiments of SCI-ADD classification over a cohort of 42 subjects reach 88% accuracy, surpassing state-of-the-art GNN-based classifiers in the literature. Furthermore, a blind assessment over a cohort of 46 MCI subjects confirmed that it captures the intermediary character of the MCI group. GNNExplainer module employed to investigate the anatomical determinants of the observed discrepancy confirms that sfDLN attends to cortical regions neurologically relevant to ADD.
CONCLUSIONS: In support of our hypothesis, the harmony between the structural and functional organization of the brain degrades with increasing cognitive decline. This discrepancy, shown to be rooted in brain regions neurologically relevant to ADD, can be quantified by sfDLN and outperforms state-of-the-art GNN-based ADD classification methods when used as a biomarker.

Graph neural networks (GNNs) have demonstrated exceptional performance in processing various types of graph data, such as citation networks and social networks, etc. Although many of these GNNs prove their superiority in handling homophilic graphs, they often overlook the other kind of widespread heterophilic graphs, in which adjacent nodes tend to have different classes or dissimilar features. Recent methods attempt to address heterophilic graphs from the graph spatial domain, which try to aggregate more similar nodes or prevent dissimilar nodes with negative weights. However, they may neglect valuable heterophilic information or extract heterophilic information ineffectively, which could cause poor performance of downstream tasks on heterophilic graphs, including node classification and graph classification, etc. Hence, a novel framework named GARN is proposed to effectively extract both homophilic and heterophilic information. First, we analyze the shortcomings of most GNNs in tackling heterophilic graphs from the perspective of graph spectral and spatial theory. Then, motivated by these analyses, a Graph Aggregating-Repelling Convolution (GARC) mechanism is designed with the objective of fusing both low-pass and high-pass graph filters. Technically, it learns positive attention weights as a low-pass filter to aggregate similar adjacent nodes, and learns negative attention weights as a high-pass filter to repel dissimilar adjacent nodes. A learnable integration weight is used to adaptively fuse these two filters and balance the proportion of the learned positive and negative weights, which could control our GARC to evolve into different types of graph filters and prevent it from over-relying on high intra-class similarity. Finally, a framework named GARN is established by simply stacking several layers of GARC to evaluate its graph representation learning ability on both the node classification and image-converted graph classification tasks. Extensive experiments conducted on multiple homophilic and heterophilic graphs and complex real-world image-converted graphs indicate the effectiveness of our proposed framework and mechanism over several representative GNN baselines.

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline.

OBJECTIVE: Heart failure (HF) impacts millions of patients worldwide, yet the variability in treatment responses remains a major challenge for healthcare professionals. The current treatment strategies, largely derived from population based evidence, often fail to consider the unique characteristics of individual patients, resulting in suboptimal outcomes. This study aims to develop computational models that are patient-specific in predicting treatment outcomes, by utilizing a large Electronic Health Records (EHR) database. The goal is to improve drug response predictions by identifying specific HF patient subgroups that are likely to benefit from existing HF medications.
METHODS: A novel, graph-based model capable of predicting treatment responses, combining Graph Neural Network and Transformer was developed. This method differs from conventional approaches by transforming a patient\'s EHR data into a graph structure. By defining patient subgroups based on this representation via K-Means Clustering, we were able to enhance the performance of drug response predictions.
RESULTS: Leveraging EHR data from 11 627 Mayo Clinic HF patients, our model significantly outperformed traditional models in predicting drug response using NT-proBNP as a HF biomarker across five medication categories (best RMSE of 0.0043). Four distinct patient subgroups were identified with differential characteristics and outcomes, demonstrating superior predictive capabilities over existing HF subtypes (best mean RMSE of 0.0032).
CONCLUSIONS: These results highlight the power of graph-based modeling of EHR in improving HF treatment strategies. The stratification of patients sheds light on particular patient segments that could benefit more significantly from tailored response predictions.
CONCLUSIONS: Longitudinal EHR data have the potential to enhance personalized prognostic predictions through the application of graph-based AI techniques.

Noncoding RNA (NcRNA)-protein interactions (NPIs) play fundamentally important roles in carrying out cellular activities. Although various predictors based on molecular features and graphs have been published to boost the identification of NPIs, most of them often ignore the information between known NPIs or exhibit insufficient learning ability from graphs, posing a significant challenge in effectively identifying NPIs. To develop a more reliable and accurate predictor for NPIs, in this article, we propose NPI-DCGNN, an end-to-end NPI predictor based on a dual-channel graph neural network (DCGNN). NPI-DCGNN initially treats the known NPIs as an ncRNA-protein bipartite graph. Subsequently, for each ncRNA-protein pair, NPI-DCGNN extracts two local subgraphs centered around the ncRNA and protein, respectively, from the bipartite graph. After that, it utilizes a dual-channel graph representation learning layer based on GNN to generate high-level feature representations for the ncRNA-protein pair. Finally, it employs a fully connected network and output layer to predict whether an interaction exists between the pair of ncRNA and protein. Experimental results on four experimentally validated datasets demonstrate that NPI-DCGNN outperforms several state-of-the-art NPI predictors. Our case studies on the NPInter database further demonstrate the prediction power of NPI-DCGNN in predicting NPIs. With the availability of the source codes (https://github.com/zhangxin11111/NPI-DCGNN), we anticipate that NPI-DCGNN could facilitate the studies of ncRNA interactome by providing highly reliable NPI candidates for further experimental validation.

Bioactive peptide therapeutics has been a long-standing research topic. Notably, the antimicrobial peptides (AMPs) have been extensively studied for its therapeutic potential. Meanwhile, the demand for annotating other therapeutic peptides, such as antiviral peptides (AVPs) and anticancer peptides (ACPs), also witnessed an increase in recent years. However, we conceive that the structure of peptide chains and the intrinsic information between the amino acids is not fully investigated among the existing protocols. Therefore, we develop a new graph deep learning model, namely TP-LMMSG, which offers lightweight and easy-to-deploy advantages while improving the annotation performance in a generalizable manner. The results indicate that our model can accurately predict the properties of different peptides. The model surpasses the other state-of-the-art models on AMP, AVP and ACP prediction across multiple experimental validated datasets. Moreover, TP-LMMSG also addresses the challenges of time-consuming pre-processing in graph neural network frameworks. With its flexibility in integrating heterogeneous peptide features, our model can provide substantial impacts on the screening and discovery of therapeutic peptides. The source code is available at https://github.com/NanjunChen37/TP_LMMSG.