A Systems Approach to Refine Disease Taxonomy by Integrating Phenotypic and Molecular Networks

The International Classification of Diseases (ICD) relies on clinical features and lags behind the current understanding of the molecular specificity of disease pathobiology, necessitating approaches that incorporate growing biomedical data for classifying diseases to meet the needs of precision medicine. Our analysis revealed that the heterogeneous molecular diversity of disease chapters and the blurred boundary between disease categories in ICD should be further investigated. Here, we propose a new classification of diseases (NCD) by developing an algorithm that predicts the additional categories of a disease by integrating multiple networks consisting of disease phenotypes and their molecular profiles. With statistical validations from phenotype-genotype associations and interactome networks, we demonstrate that NCD improves disease specificity owing to its overlapping categories and polyhierarchical structure. Furthermore, NCD captures the molecular diversity of diseases and defines clearer boundaries in terms of both phenotypic similarity and molecular associations, establishing a rational strategy to reform disease taxonomy. •The International Classification of Diseases (ICD) lags behind the current molecular characteristics of disease.•We quantified the limitations (specificity and blurred boundary) of ICD with integrated phenotypic and molecular profiles.•An integrative disease network integrating phenotypic and genotypic profiles proposes a refined disease category framework. Disease taxonomy is one of the foundations of medical science and healthcare solutions. The most widely used disease taxonomy in clinical settings is the International Classification of Diseases (ICD), a system established >100years ago and maintained by the World Health Organization to track disease incidence. It is well recognized that ICD, which is based on clinical observations, largely lags behind the molecular achievements of this medical big data era. We quantified the limitations of ICD using integrated phenotypic and molecular profiles and proposed a refined disease taxonomy with possible applications for precision medicine.