A Novel Directed Acyclic Graph (DAG) Framework for Integrative Causal Analysis for the Pathogenesis of Idiopathic Scoliosis
Department of Orthopedics, Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China
| Abstract: | Background: Idiopathic scoliosis (IS) presented as one of the most common types in adolescent’s and remains a multifactorial disorder with mysterious and poorly understood etiopathogenesis, which posing challenges for early diagnosis and targeted therapy, while directed acyclic graphs (DAGs) offer a transformative method to this disorder. Objectives: This study introduces an innovative DAG based systems biology approach to systematically map causal interactions among genetic, epigenetic, biomechanical, and neuroendocrine factors driving IS progression. Method: By synthesizing evidence from twin studies, epigenomics, mechanobiology, and clinical endocrinology, we construct the first integrated DAG model of IS pathogenesis, validated through a comprehensive review of studies from PubMed, Scopus, Web of Science, and Google Scholar. Results: The analysis identifies three key mechanistic pathways: 1. A genetic-epigenetic cascade involving DNA methylation dysregulation in growth plate chondrocytes, 2. A neuroendocrine-biomechanical feedback loop mediated by leptin hypothalamic pituitary gonadal axis crosstalk, and 3. A Platelet-Derived Growth Factor driven vicious cycle in vertebral microvasculature. Conclusion: The model demonstrates strong predictive power for idiopathic scoliosis. Furthermore, highlight its translational potential through a DAG-guided therapeutic decision and enabling personalized interventions based on the dominant pathogenic pathways. This framework bridges molecular mechanisms with clinical phenotypes and offering a paradigm shift in IS research and patient care. |
| Keywords: | Idiopathic Scoliosis; Directed Acyclic Graphs; Systems Medicine; Epigenetic Biomarkers; Causal Inference |
| DOI: | 10.57237/j.cmf.2025.03.001 |
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Received: 22 September 2025
Accepted: 3 December 2025
Published Online: 24 December 2025
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