Diversity and molecular network patterns of symptom phenotypes

Symptom phenotypes have continuously been an important clinical entity for clinical diagnosis and management. However, non-specificity of symptom phenotypes for clinical diagnosis is one of the major challenges that need be addressed to advance symptom science and precision health. Network medicine has delivered a successful approach for understanding the underlying mechanisms of complex disease phenotypes, which will also be a useful tool for symptom science. Here, we extracted symptom co-occurrences from clinical textbooks to construct phenotype network of symptoms with clinical co-occurrence and incorporated high-quality symptom-gene associations and protein-protein interactions to explore the molecular network patterns of symptom phenotypes. Furthermore, we adopted established network diversity measure in network medicine to quantify both the phenotypic diversity (i.e., non-specificity) and molecular diversity of symptom phenotypes. The results showed that the clinical diversity of symptom phenotypes could partially be explained by their underlying molecular network diversity (PCC = 0.49, P-value = 2.14E-08). For example, non-specific symptoms, such as chill, vomiting, and amnesia, have both high phenotypic and molecular network diversities. Moreover, we further validated and confirmed the approach of symptom clusters to reduce the non-specificity of symptom phenotypes. Network diversity proposes a useful approach to evaluate the non-specificity of symptom phenotypes and would help elucidate the underlying molecular network mechanisms of symptom phenotypes and thus promotes the advance of symptom science for precision health.