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Artificial neural network (ANN) is the main tool to dig data and was inspired by the human brain and nervous system. Several studies clarified its application in medicine. However, none has applied ANN to predict the efficacy of folic acid treatment to Hyperhomocysteinemia (HHcy). The efficacy has been proved to associate with both genetic and environmental factors while previous studies just focused on the latter one. The explained variance genetic risk score (EV-GRS) had better power and could represent the effect of genetic architectures. Our aim was to add EV-GRS into environmental factors to establish ANN to predict the efficacy of folic acid therapy to HHcy. We performed the prospective cohort research enrolling 638 HHcy patients. The multilayer perception algorithm was applied to construct ANN. To evaluate the effect of ANN, we also established logistic regression (LR) model to compare with ANN. According to our results, EV-GRS was statistically associated with the efficacy no matter analyzed as a continuous variable (OR = 3.301, 95%CI 1.954–5.576, P < 0.001) or category variable (OR = 3.870, 95%CI 2.092–7.159, P < 0.001). In our ANN model, the accuracy was 84.78%, the Youden's index was 0.7073 and the AUC was 0.938. These indexes above indicated higher power. When compared with LR, the AUC, accuracy, and Youden's index of the ANN model (84.78%, 0.938, 0.7073) were all slightly higher than the LR model (83.33% 0.910, 0.6687). Therefore, clinical application of the ANN model may be able to better predict the folic acid efficacy to HHcy than the traditional LR model. When testing two models in the validation set, we got the same conclusion. This study appears to be the first one to establish the ANN model which added EV-GRS into environmental factors to predict the efficacy of folic acid to HHcy. This model would be able to offer clinicians a new method to make decisions and individual therapeutic plans. [ABSTRACT FROM AUTHOR]