Discovery Over a NGLY1 deficiency Knowledge Graph
•
2 likes•401 views
This document discusses using a knowledge graph and machine learning techniques to generate hypotheses for clinical therapies for NGLY1 deficiency, a rare genetic disease. It describes biocuration efforts to capture the pathophysiology and phenotypic spectrum of NGLY1 deficiency and add this information to a knowledge graph. The document proposes using the updated knowledge graph with an edge prediction algorithm called Rephetio to identify potential drug repurposing candidates for treating NGLY1 deficiency.
More Related Content
What's hot
What's hot (20)
Similar to Discovery Over a NGLY1 deficiency Knowledge Graph
Similar to Discovery Over a NGLY1 deficiency Knowledge Graph (20)
More from Núria Queralt Rosinach
More from Núria Queralt Rosinach (6)
Recently uploaded
Recently uploaded (20)
Discovery Over a NGLY1 deficiency Knowledge Graph
- 1. Discovery over a NGLY1 deficiency Knowledge Graph Núria Queralt Rosinach The Su Lab @ Scripps, CA BioHackathon 2017 Symposium, Tokyo-Morioka
- 2. Knowledge Discovery From DisGeNET-RDF to knowledge discovery over knowledge graphs Drug repurposing Rare diseases as a challenge Clinical Economical Social
- 3. NGLY1 Deficiency Autosomal recessive genetic disease (Congenital Disorders of DeGlycosilation) First report in 2012 NGLY1 gene: the cells of the body cannot synthesize the enzyme N-Glycanase 1 Nonsense mutations Extremely rare: clinical and molecular data for <100 patients Clinical phenotypes: heterogeneity and not fully characterized NO treatment, NO understanding, LACK of data Alacrima Movement disorders Developmental delay Liver disease
- 4. NGLY1 NGLY1 gene Encodes N-glycanase 1 Well conserved in eukaryotes Known function: enzymatic activity Cleaves N-Glyco from protein parts on misfolded N-Glycoproteins Endoplasmic Reticulum Associated Degradation (ERAD) pathway Wide organ/tissue expression Associated to neurological and mithocondrial diseases
- 5. Goals 1) Generate hypotheses on clinical therapies for NGLY1 deficiency 3) Treatments to cure or improve the quality of life 2) Drug repurposed candidates
- 6. Approach NGLY1-oriented knowledge graph Apply graph mining tools for discovery NGLY1 deficiency Drugs EVIDENCE- BASED HYPOTHESES
- 8. Hetionet v1.0: hetnet for drug repurposing 1552 small molecules 137 complex diseases 755 treatments (supervised) 47,031 nodes, 11 types 2,250,197 edges, 24 types 29 public resources Studies over the last half century Heterogeneous Network Credit: D. Himmelstein http://slides.com/dhimmel/thesis-
- 10. DISEASEDISEASEVARIANTVARIANT DISEASEDISEASEGENEGENE Animal models Text mining LHGDN BEFREE GAD CTD RGD MGD UniPro t CTD Curated Orpha net HPO ClinVar GWAS Catalo g PsyGe NET • 13 sources• 13 sources • Linked Open Data• Linked Open Data http://www.disgenet.org/ support@disgenet.org twitter: @DisGeNET V5.0
- 11. Edge Prediction doi: 10.1109/ASONAM.2011.112 PathPredict To predict if two objects will build a relationship Based on heterogeneous networks Metapaths as topological features Interpretability of the mechanism behind the relationship predicted
- 12. Heterogeneous Network Edge Prediction (HNEP) Hetnet → Metapaths → DWPC → Supervised model
- 13. Heterogeneous Network Edge Prediction (HNEP) Extraction of topological features from the network Metapath: encodes a relationship with a biological interpretation Logistic Regression
- 14. Rephetio Predictions Interpretability Himmelstein, Systematic integration of biomedical knowledge prioritizes drugs for repurposing DOI: https://doi.org/10.1101/087619
- 15. RD-Rephetio Add NGLY1 content – Biocuration Add Rare Disease (RD) content – Orphanet, DrugCentral
- 16. Biocuration
- 17. Biocuration To capture the pathophysiology
- 18. NGLY1 Deficiency edges to: SYMPTOMS NGLY1 GO annotation ERAD pathway PPI ERAD pathway NGLY1 Deficiency NGLY1 Disease/Phenotypes Gene/Proteins GO_CellComponent GO_BiologicalProcess GO_MolecularFunction Pathway Taxon
- 19. Biocuration To capture the phenotypic spectrum
- 20. Biocuration NGLY1 phenotype annotation ~100 phenotypes ~50 new HPO terms
- 21. Biocuration Enns et al. (2014) Lam et al. (2017)
- 22. Drug repurposing for NGLY1 Drugs Deep Phenotyping Anchor NGLY1 deficiency: DOID:0060728 Added Rare Diseases (Orphanet) Added Rare Disease to Gold Standard (DrugCentral) Phenome Genome
- 23. Rephetio pros/cons Pros Interpretability Cons Scalability Computational cost Based on connectivity similarity
- 24. BioHackathon 2016 Availability: https://github.com/bio-ontology-research-group/walking-rdf-and-owl
- 25. Proposal for BH17 Add edges Text mining Ontologies Latest edge prediction algorithm Biocuration Testing Framework RD-Rephetio
- 26. Join me!
- 28. Questions?
- 29. Proposal for BH17 Add edges Text mining Ontologies Latest edge prediction algorithm Biocuration Testing Framework RD-Rephetio Contact: nuria#slack