Lizhi Liu1, Hiroshi Mamitsuka2,3, Shanfeng Zhu4,5,6. 1. School of Computer Science, Fudan University, Shanghai, 200433, China. 2. Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto Prefecture, Japan. 3. Department of Computer Science, Aalto University, Espoo, Finland. 4. Institute of Science and Technology for Brain-Inspired Intelligence and Shanghai Institute of Artificial Intelligence Algorithms, Fudan University, Shanghai, 200433, China. 5. Ministry of Education, Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), China. 6. Shanghai Key Lab of Intelligent Information Processing, Fudan University, Shanghai, 200433, China.
Abstract
MOTIVATION: Exploring the relationship between human proteins and abnormal phenotypes is of great importance in the prevention, diagnosis and treatment of diseases. The human phenotype ontology (HPO) is a standardized vocabulary that describes the phenotype abnormalities encountered in human diseases. However, the current HPO annotations of proteins are not complete. Thus, it is important to identify missing protein-phenotype associations. RESULTS: We propose HPOFiller, a graph convolutional network (GCN)-based approach, for predicting missing HPO annotations. HPOFiller has two key GCN components for capturing embeddings from complex network structures: 1) S-GCN for both protein-protein interaction (PPI) network and HPO semantic similarity network to utilize network weights; 2) Bi-GCN for the protein-phenotype bipartite graph to conduct message passing between proteins and phenotypes. The core idea of HPOFiller is to repeat run these two GCN modules consecutively over the three networks, to refine the embeddings. Empirical results of extremely stringent evaluation avoiding potential information leakage including cross-validation and temporal validation demonstrates that HPOFiller significantly outperforms all other state-of-the-art methods. In particular, the ablation study shows that batch normalization contributes the most to the performance. The further examination offers literature evidence for highly ranked predictions. Finally using known disease-HPO term associations, HPOFiller could suggest promising, unknown disease-gene associations, presenting possible genetic causes of human disorders. AVAILABILITY: https://github.com/liulizhi1996/HPOFiller. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
MOTIVATION: Exploring the relationship between human proteins and abnormal phenotypes is of great importance in the prevention, diagnosis and treatment of diseases. The human phenotype ontology (HPO) is a standardized vocabulary that describes the phenotype abnormalities encountered in human diseases. However, the current HPO annotations of proteins are not complete. Thus, it is important to identify missing protein-phenotype associations. RESULTS: We propose HPOFiller, a graph convolutional network (GCN)-based approach, for predicting missing HPO annotations. HPOFiller has two key GCN components for capturing embeddings from complex network structures: 1) S-GCN for both protein-protein interaction (PPI) network and HPO semantic similarity network to utilize network weights; 2) Bi-GCN for the protein-phenotype bipartite graph to conduct message passing between proteins and phenotypes. The core idea of HPOFiller is to repeat run these two GCN modules consecutively over the three networks, to refine the embeddings. Empirical results of extremely stringent evaluation avoiding potential information leakage including cross-validation and temporal validation demonstrates that HPOFiller significantly outperforms all other state-of-the-art methods. In particular, the ablation study shows that batch normalization contributes the most to the performance. The further examination offers literature evidence for highly ranked predictions. Finally using known disease-HPO term associations, HPOFiller could suggest promising, unknown disease-gene associations, presenting possible genetic causes of human disorders. AVAILABILITY: https://github.com/liulizhi1996/HPOFiller. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.