iCDA-CGR: Identification of circRNA-disease associations based on Chaos Game Representation

Found in recent research, tumor cell invasion, proliferation, or other biological processes are controlled by circular RNA. Understanding the association between circRNAs and diseases is an important way to explore the pathogenesis of complex diseases and promote disease-targeted therapy. Most methods, such as k-mer and PSSM, based on the analysis of high-throughput expression data have the tendency to think functionally similar nucleic acid lack direct linear homology regardless of positional information and only quantify nonlinear sequence relationships. However, in many complex diseases, the sequence nonlinear relationship between the pathogenic nucleic acid and ordinary nucleic acid is not much different. Therefore, the analysis of positional information expression can help to predict the complex associations between circRNA and disease. To fill up this gap, we propose a new method, named iCDA-CGR, to predict the circRNA-disease associations. In particular, we introduce circRNA sequence information and quantifies the sequence nonlinear relationship of circRNA by Chaos Game Representation (CGR) technology based on the biological sequence position information for the first time in the circRNA-disease prediction model. In the cross-validation experiment, our method achieved 0.8533 AUC, which was significantly higher than other existing methods. In the validation of independent data sets including circ2Disease, circRNADisease and CRDD, the prediction accuracy of iCDA-CGR reached 95.18%, 90.64% and 95.89%. Moreover, in the case studies, 19 of the top 30 circRNA-disease associations predicted by iCDA-CGR on circRDisease dataset were confirmed by newly published literature. These results demonstrated that iCDA-CGR has outstanding robustness and stability, and can provide highly credible candidates for biological experiments.

Author summary Understanding the association between circRNAs and diseases is an important step to explore the pathogenesis of complex diseases and promote disease-targeted therapy. Computational methods contribute to discovering the potential disease-related circRNAs. Based on the analysis of the location information expression of biological sequences, the model of iCDA-CGR is proposed to predict the circRNA-disease associations by integrates multi-source information, including circRNA sequence information, gene-circRNA associations information, circRNA-disease associations information and the disease semantic information. In particular, the location information of circRNA sequences was first introduced into the circRNA-disease associations prediction model. The promising results on cross-validation and independent data sets demonstrated the effectiveness of the proposed model. We further implemented case studies, and 19 of the top 30 predicted scores of the proposed model were confirmed by recent experimental reports. The results show that iCDA-CGR model can effectively predict the potential circRNA-disease associations and provide highly reliable candidates for biological experiments, thus helping to further understand the complex disease mechanism.