Multivariable Clinical-Genetic Model for Predicting Dyskinesia in Early-Onset Parkinson's Disease

Abstract

Background: Levodopa-induced dyskinesias (LIDs) is one of important motor complications, which negatively affect the quality of life of patients with Parkinson disease (PD).Objects: This study aims to establish clinical-genetic models of LIDs prediction and explore clinical and genetic predictors of LIDs in early-onset PD (EOPD). Methods: A prospective cohort design including 279 EOPD patients were followed-up about 9.2 years. Clinical and genetic data were investigated. LIDs prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curve. A multivariable logistic regression model was conducted to discriminate the independent predictive factors of LIDs incident. An independent cohort including 144 EOPD was used as the validation group to confirm the developed prediction models. Results: The incidence of LIDs in EOPD at the first 5 years of duration and at the first 5 years after receiving dopamine replacement therapy (DRT) were 15.4% and 29.7%, respectively. In two clinical-genetic models, adding genotypes from 11 candidate variants significantly increased LIDs predictability compared to prediction based on clinical variables only (p<0.005), which were confirmed in the validation group. Importantly, the AUCs of clinical or clinical-genetic model for predicting LIDs incident were not significantly different when patients carrying seven PD causative genes were excluded or not. In addition, LEDD, DRD3 rs6280, SLC6A3 rs460000 and COMT rs4680 , were the strongest independent predictive factors. Conclusion: LIDs incident was common in the early stage of EOPD, established clinical-genetic models and identified independent predictive factors have good application prospects to LIDs prediction and DRT management. Funding: This study was supported the National Key Research and Development Program of China (grant no. 2016YFC0901504 and 2018YFC1312001), the National Natural Science Fund of China (Grant No. 81571247) and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYJC18038, Grant No. ZYJC18003 and Grant No. 2019HXFH046). Declaration of Interest: None to declare Ethical Approval: This study was approved by the ethics committee of West China Hospital, Sichuan University.