Utilizing graph machine learning within drug discovery and development.

Graph machine learning (GML) is receiving growing interest within the pharmaceutical and biotechnology industries for its ability to model biomolecular structures, the functional relationships between them, and integrate multi-omic datasets - amongst other data types. Herein, we present a multidisciplinary academic-industrial review of the topic within the context of drug discovery and development. After introducing key terms and modelling approaches, we move chronologically through the drug development pipeline to identify and summarize work incorporating: target identification, design of small molecules and biologics, and drug repurposing. Whilst the field is still emerging, key milestones including repurposed drugs entering in vivo studies, suggest GML will become a modelling framework of choice within biomedical machine learning.

Graph Machine Learning for Improved Imputation of Missing Tropospheric Ozone Data.

Gaps in the measurement series of atmospheric pollutants can impede the reliable assessment of their impacts and trends. We propose a new method for missing data imputation of the air pollutant tropospheric ozone by using the graph machine learning algorithm "correct and smooth". This algorithm uses auxiliary data that characterize the measurement location and, in addition, ozone observations at neighboring sites to improve the imputations of simple statistical and machine learning models. We apply our method to data from 278 stations of the year 2011 of the German Environment Agency (Umweltbundesamt - UBA) monitoring network. The preliminary version of these data exhibits three gap patterns: shorter gaps in the range of hours, longer gaps of up to several months in length, and gaps occurring at multiple stations at once. For short gaps of up to 5 h, linear interpolation is most accurate. Longer gaps at single stations are most effectively imputed by a random forest in connection with the correct and smooth. For longer gaps at multiple stations, the correct and smooth algorithm improved the random forest despite a lack of data in the neighborhood of the missing values. We therefore suggest a hybrid of linear interpolation and graph machine learning for the imputation of tropospheric ozone time series.

Deciphering gp120 sequence variation and structural dynamics in HIV neutralization phenotype by molecular dynamics simulations and graph machine learning.

Human immunodeficiency virus (HIV) exploits the sequence variation and structural dynamics of the envelope glycoprotein gp120 to evade the immune attack of neutralization antibodies, contributing to various HIV neutralization phenotypes. Although the HIV neutralization phenotype has been experimentally characterized, the roles of rapid sequence variability and significant structural dynamics of gp120 are not well understood. Here, 45 prefusion gp120 from different HIV strains belong to three tiers of sensitive, moderate, and resistant neutralization phenotype are structurally modeled by homology modeling and then investigated by molecular dynamics (MD) simulations and graph machine learning (ML). Our results show that the structural deviations, population distribution, and conformational flexibility of gp120 are related to the HIV neutralization phenotype. Per-residue dynamics indicate the local regions especially in the second structural elements with high-flexibility, may be responsible for the HIV neutralization phenotype. Moreover, a graph ML model with the attention mechanism was trained to explore inherent representation related to the classification of the HIV neutralization phenotype, further distinguishing the strong related gp120 sequence variation together with structural dynamics in the HIV neutralization phenotype. Our study not only deciphers gp120 sequence variation and structural dynamics in the HIV neutralization phenotype but also explores complex relationships between the sequence, structure, and dynamics of protein by combining MD simulations and ML.

Interacting brains revisited: A cross-brain network neuroscience perspective.

Elucidating the neural basis of social behavior is a long-standing challenge in neuroscience. Such endeavors are driven by attempts to extend the isolated perspective on the human brain by considering interacting persons' brain activities, but a theoretical and computational framework for this purpose is still in its infancy. Here, we posit a comprehensive framework based on bipartite graphs for interbrain networks and address whether they provide meaningful insights into the neural underpinnings of social interactions. First, we show that the nodal density of such graphs exhibits nonrandom properties. While the current hyperscanning analyses mostly rely on global metrics, we encode the regions' roles via matrix decomposition to obtain an interpretable network representation yielding both global and local insights. With Bayesian modeling, we reveal how synchrony patterns seeded in specific brain regions contribute to global effects. Beyond inferential inquiries, we demonstrate that graph representations can be used to predict individual social characteristics, outperforming functional connectivity estimators for this purpose. In the future, this may provide a means of characterizing individual variations in social behavior or identifying biomarkers for social interaction and disorders.

Knowledge Graphs in Pharmacovigilance: A Scoping Review.

PURPOSE: To critically assess the role and added value of knowledge graphs in pharmacovigilance, focusing on their ability to predict adverse drug reactions. METHODS: A systematic scoping review was conducted in which detailed information, including objectives, technology, data sources, methodology, and performance metrics, were extracted from a set of peer-reviewed publications reporting the use of knowledge graphs to support pharmacovigilance signal detection. FINDINGS: The review, which included 47 peer-reviewed articles, found knowledge graphs were utilized for detecting/predicting single-drug adverse reactions and drug-drug interactions, with variable reported performance and sparse comparisons to legacy methods. IMPLICATIONS: Research to date suggests that knowledge graphs have the potential to augment predictive signal detection in pharmacovigilance, but further research using more reliable reference sets of adverse drug reactions and comparison with legacy pharmacovigilance methods are needed to more clearly define best practices and to establish their place in holistic pharmacovigilance systems.

Disease Prediction Using Graph Machine Learning Based on Electronic Health Data: A Review of Approaches and Trends.

Graph machine-learning (ML) methods have recently attracted great attention and have made significant progress in graph applications. To date, most graph ML approaches have been evaluated on social networks, but they have not been comprehensively reviewed in the health informatics domain. Herein, a review of graph ML methods and their applications in the disease prediction domain based on electronic health data is presented in this study from two levels: node classification and link prediction. Commonly used graph ML approaches for these two levels are shallow embedding and graph neural networks (GNN). This study performs comprehensive research to identify articles that applied or proposed graph ML models on disease prediction using electronic health data. We considered journals and conferences from four digital library databases (i.e., PubMed, Scopus, ACM digital library, and IEEEXplore). Based on the identified articles, we review the present status of and trends in graph ML approaches for disease prediction using electronic health data. Even though GNN-based models have achieved outstanding results compared with the traditional ML methods in a wide range of disease prediction tasks, they still confront interpretability and dynamic graph challenges. Though the disease prediction field using ML techniques is still emerging, GNN-based models have the potential to be an excellent approach for disease prediction, which can be used in medical diagnosis, treatment, and the prognosis of diseases.

Applying precision medicine principles to the management of multimorbidity: the utility of comorbidity networks, graph machine learning, and knowledge graphs.

The current management of patients with multimorbidity is suboptimal, with either a single-disease approach to care or treatment guideline adaptations that result in poor adherence due to their complexity. Although this has resulted in calls for more holistic and personalized approaches to prescribing, progress toward these goals has remained slow. With the rapid advancement of machine learning (ML) methods, promising approaches now also exist to accelerate the advance of precision medicine in multimorbidity. These include analyzing disease comorbidity networks, using knowledge graphs that integrate knowledge from different medical domains, and applying network analysis and graph ML. Multimorbidity disease networks have been used to improve disease diagnosis, treatment recommendations, and patient prognosis. Knowledge graphs that combine different medical entities connected by multiple relationship types integrate data from different sources, allowing for complex interactions and creating a continuous flow of information. Network analysis and graph ML can then extract the topology and structure of networks and reveal hidden properties, including disease phenotypes, network hubs, and pathways; predict drugs for repurposing; and determine safe and more holistic treatments. In this article, we describe the basic concepts of creating bipartite and unipartite disease and patient networks and review the use of knowledge graphs, graph algorithms, graph embedding methods, and graph ML within the context of multimorbidity. Specifically, we provide an overview of the application of graph theory for studying multimorbidity, the methods employed to extract knowledge from graphs, and examples of the application of disease networks for determining the structure and pathways of multimorbidity, identifying disease phenotypes, predicting health outcomes, and selecting safe and effective treatments. In today's modern data-hungry, ML-focused world, such network-based techniques are likely to be at the forefront of developing robust clinical decision support tools for safer and more holistic approaches to treating older patients with multimorbidity.

Novel graph-based machine-learning technique for viral infectious diseases: application to influenza and hepatitis diseases.

BACKGROUND: Most infectious diseases are caused by viruses, fungi, bacteria and parasites. Their ability to easily infect humans and trigger large-scale epidemics makes them a public health concern. Methods for early detection of these diseases have been developed; however, they are hindered by the absence of a unified, interoperable and reusable model. This study seeks to create a holistic and real-time model for swift, preliminary detection of infectious diseases using symptoms and additional clinical data. MATERIALS AND METHODS: In this study, we present a medical knowledge graph (MKG) that leverages multiple data sources to analyse connections between different nodes. Medical ontologies were used to enhance the MKG. We applied various graph algorithms to extract key features. The performance of multiple machine-learning (ML) techniques for influenza and hepatitis detection was assessed, selecting multi-layer perceptron (MLP) and random forest (RF) models due to their superior outcomes. The hyperparameters of both graph-based ML models were automatically fine-tuned. RESULTS: Both the graph-based MLP and RF models showcased the least loss and error rates, along with the most specific, accurate recall, precision and F1 scores. Their Matthews correlation coefficients were also optimal. When compared with existing ML techniques and findings from the literature, these graph-based ML models manifested superior detection accuracy. CONCLUSIONS: The graph-based MLP and RF models effectively diagnosed influenza and hepatitis, respectively. This underlines the potential of graph data science in enhancing ML model performance and uncovering concealed relationships in the MKG.

Bridging the Gap of AutoGraph Between Academia and Industry: Analyzing AutoGraph Challenge at KDD Cup 2020.

Graph structured data is ubiquitous in daily life and scientific areas and has attracted increasing attention. Graph Neural Networks (GNNs) have been proved to be effective in modeling graph structured data and many variants of GNN architectures have been proposed. However, much human effort is often needed to tune the architecture depending on different datasets. Researchers naturally adopt Automated Machine Learning on Graph Learning, aiming to reduce human effort and achieve generally top-performing GNNs, but their methods focus more on the architecture search. To understand GNN practitioners' automated solutions, we organized AutoGraph Challenge at KDD Cup 2020, emphasizing automated graph neural networks for node classification. We received top solutions, especially from industrial technology companies like Meituan, Alibaba, and Twitter, which are already open sourced on GitHub. After detailed comparisons with solutions from academia, we quantify the gaps between academia and industry on modeling scope, effectiveness, and efficiency, and show that (1) academic AutoML for Graph solutions focus on GNN architecture search while industrial solutions, especially the winning ones in the KDD Cup, tend to obtain an overall solution (2) with only neural architecture search, academic solutions achieve on average 97.3% accuracy of industrial solutions (3) academic solutions are cheap to obtain with several GPU hours while industrial solutions take a few months' labors. Academic solutions also contain much fewer parameters.

An Epidemiological Neural Network Exploiting Dynamic Graph Structured Data Applied to the COVID-19 Outbreak.

With the recent COVID-19 outbreak, we have assisted to the development of new epidemic models or the application of existing methodologies to predict the virus spread and to analyze how the different lock-down strategies can effectively influence the epidemic diffusion. In this paper, we propose a novel machine learning based framework able to estimate the parameters of any epidemiological model, such as contact rates and recovery rates, based on static and dynamic features of places. In particular, we model mobility data through a graph series whose spatial and temporal features are investigated by combining Graph Convolutional Neural Networks (GCNs) and Long short-term memories (LSTMs) in order to infer the parameters of SIR and SIRD models. We evaluate the proposed approach using data related to the COVID-19 dynamics in Italy and we compare the forecasts of the trained model with available data about the epidemic spread.

Knowledge graphs and their applications in drug discovery.

INTRODUCTION: Knowledge graphs have proven to be promising systems of information storage and retrieval. Due to the recent explosion of heterogeneous multimodal data sources generated in the biomedical domain, and an industry shift toward a systems biology approach, knowledge graphs have emerged as attractive methods of data storage and hypothesis generation. AREAS COVERED: In this review, the author summarizes the applications of knowledge graphs in drug discovery. They evaluate their utility; differentiating between academic exercises in graph theory, and useful tools to derive novel insights, highlighting target identification and drug repurposing as two areas showing particular promise. They provide a case study on COVID-19, summarizing the research that used knowledge graphs to identify repurposable drug candidates. They describe the dangers of degree and literature bias, and discuss mitigation strategies. EXPERT OPINION: Whilst knowledge graphs and graph-based machine learning have certainly shown promise, they remain relatively immature technologies. Many popular link prediction algorithms fail to address strong biases in biomedical data, and only highlight biological associations, failing to model causal relationships in complex dynamic biological systems. These problems need to be addressed before knowledge graphs reach their true potential in drug discovery.