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.