Integrative and translational analysis of the phenome

467 views

Published on

Integrative and translational analysis of the phenome

  1. 1. Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary Integrative and translational analysis of the phenome Robert Hoehndorf Department of Physiology, Development and Neuroscience University of Cambridge 26 September 2012
  2. 2. H um an2004 Ge no m e Pr2005 oj KO ec M t P2006 EU C O M2007 M2008 1, 00 0 Ge2009 no Ge m n om es e2010 10 k2011 IM PC2012 EN CO D E
  3. 3. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryTranslational research National Cancer Institute: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce [disease] incidence, morbidity, and mortality.
  4. 4. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesAlmost 4,000 genetic diseases in OMIM have an unknown molecular basis.
  5. 5. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesOrphaNet 5,917 orphan diseases 2,543 genes linked to 2,544 diseases 2,700 diseases indexed with clinical signs
  6. 6. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesAnimal models have been shown to be highly successful in studying human disease
  7. 7. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryApproach Can we use phenotypes of mutant animal organisms to find candidate genes for orphan diseases?
  8. 8. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryApproach Can we use phenotypes of mutant animal organisms to find candidate genes for orphan diseases? 1 make animal and human phenotypes comparable 2 systematically analyze the phenome for possible causative mutations 3 evaluate using real biomedical data
  9. 9. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesPATO and the EQ method enable the integration of phenotype ontologies across species. use of Entity-Quality definitions homologous anatomical structures integration based on species-independent ontologies Gene Ontology ChEBI, Protein ontology, Celltype ontology
  10. 10. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesIntegration of phenotypes enables direct comparison between species Proximal fibular overgrowth Abnormal fibula morphology (HPO): (MP): E: Proximal epiphysis of E: fibula (MA) fibula (FMA) Q: morphology (abnormal) Q: hypertrophic UBERON: fibula (MA) orthologous to Fibula (FMA) FMA: Proximal epiphysis of fibula part-of Fibula PATO: hypertrophic is-a morphology Proximal fibular overgrowth is-a Abnormal fibula morphology
  11. 11. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesExperimental data can be integrated through ontologies and explored using automatedreasoning. integration of phenotype ontologies yeast, fly, slime mold, worm, fish, mouse, rat, human ontology-based integration of phenotypes mutant phenotypes for yeast, fly, slime mold, worm, fish, mouse, rat human disease phenotypes from OMIM and OrphaNet OWL ontology with more than 500,000 classes OWL reasoner reveals connections between phenotypes
  12. 12. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesSemantic similarity over phenotype ontologies measures phenotypic similarity. semantic similarity: metric based on information contained in the axioms of an ontology pairwise comparison of disease and animal phenotypes IC (x) x∈Cl(P)∩Cl(D) sim(P, D) = IC (y ) y ∈Cl(P)∪Cl(D)
  13. 13. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesSimilarity-based comparison Evaluation against known gene–disease associations: OMIM MGI OrphaNet
  14. 14. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesOMIM phenotypes AUC (OMIM): 0.78 AUC (MGI): 0.87
  15. 15. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesOrphaNet phenotypes AUC (OrphaNet): 0.73 AUC (OMIM): 0.76 AUC (MGI): 0.80
  16. 16. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryGenetic diseasesOntology-based integration and analysis can reveal disease genes for orphan diseases. Adam19 and Fgf15 in mice are strong candidates for Tetralogy of Fallot Gene disease associations for orphan diseases Slc34a1 (MGI:1345284) and Fanconi renotubular syndrome 1 (OMIM:134600) Disease pathways Cytokine-cytokine receptor interaction pathway (ko04060) is significantly correlated with Tetralogy of Fallot (p = 5 · 10−7 , Wilcoxon signed-rank test)
  17. 17. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe SyndromeSigns and symptoms skeletal: kyphosis, hypertensible joints, cubitus valgus muscular: hypotonia, muscle hypotrophy, amyotrophy behavior: abnormal gait, amimia visual: cataract, strabismus reproductive: hypogonadism, hypogenitalism, abnormal ovaries, hypoplastic testis, reduced fertility
  18. 18. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe Syndromehttp://phenomebrowser.net
  19. 19. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe SyndromeHIP1 knockout mice
  20. 20. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe SyndromeHIP1 mouse phenotypes Bassoe Syndrome: Mouse phenotypes: kyphosis, hypertensible kyphosis, abnormal spine curvature, joints, cubitus valgus lordosis amyotrophy, hypotonia, abnormal muscle morphology muscle hypotrophy abnormal gait, amimia abnormal gait, hypoactivity, tremors cataract, strabismus nuclear cataracts, microphthalmia testicular atrophy, hypogonadism, testicular atrophy, male infertility hypogenitalism, abnormal ovaries, reduced fertility
  21. 21. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe SyndromeHIP1 mouse phenotypes Bassoe Syndrome: Mouse phenotypes: kyphosis, hypertensible kyphosis, abnormal spine curvature, joints, cubitus valgus lordosis amyotrophy, hypotonia, abnormal muscle morphology, muscle muscle hypotrophy hypotrophy, muscle wasting abnormal gait, amimia abnormal gait, hypoactivity, tremors, failure to thrive, ataxia cataract, strabismus nuclear cataracts, microphthalmia testicular atrophy, hypogonadism, testicular atrophy, male infertility, hypogenitalism, ovarian abnormalities, testicular abnormal ovaries, degeneration, increased apoptosis of reduced fertility postmeiotic spermatids, oligospermia
  22. 22. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryBassoe Syndrome Computational analysis of mouse phenotypes provides a strong indication that HIP1 may be involved in Bassoe syndrome.
  23. 23. Genetic diseasesROC analysis quantifies the performance of the approach.
  24. 24. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryQuestion Is there a similarity between a knock-out/knock-down of a gene (through targeted mutation) and the inhibition/negative regulation of a gene (through a drug action)?
  25. 25. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryPhenomeNET compares phenotypes across species
  26. 26. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryStatistical testing to rank drug–disease pairs one-sided Wilcoxon signed rank test result: ranking of drugs for each disease based on p-value
  27. 27. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryPhenotype-based comparison can provide some informationabout drug indications PhenomeDrug improved 1 0.9 0.8 0.7 AUC (CTD): 0.61 True Positive Rate 0.6 AUC (FDA): 0.67 0.5 0.4 0.3 0.2 0.1 x original latest 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 False Positive Rate
  28. 28. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryFuture: phenotype-based drug repurposing similarity between inhibition (drug action) and knock-out/knock-down (mutation) effects indications targets combination with interaction networks D inhibits G1 and G1 positively regulated G2 ⇒ D inhibits G2 . drug pathways pharmacodynamics pharmacokinetics physiological pathways
  29. 29. Pharmacogenomics databases
  30. 30. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryAims: queries and integrated analysis integrate and query knowledge in pharmacogenomics identify aberrant pathways and patho-physiology underlying disease identify drug pathways (pharmacokinetics and pharmacodynamics) personalized treatment and dosage guidelines
  31. 31. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryApproach to data integration in pharmacogenomics integration of databases containing drug, gene, genotype, disease and pathway information DrugBank: drugs and drugs targets PharmGKB: genotype and drug response Pathway Interaction Database: biological pathways CTD: toxicogenomics information (chemical–gene–disease)
  32. 32. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryQueries What drugs can be used to treat parasitic infectious diseases (DOID:1398)? Chloroquine Arthemeter ...
  33. 33. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryQueries What drugs are effective for diseases affecting the joints (FMA:7490)? Folic acid (for arthritis) Chloroquine (for Chikungunya virus) ...
  34. 34. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryQueries What genotypes are related to diseases affecting the joints (FMA:7490)? RSID:rs70991108 (with arthritis) RSID:rs1207421 (Osteoarthritis, Knee) ...
  35. 35. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryQueries What genotypes are related to response to steroids (CHEBI:35341)? RSID:rs45566039 (with estrogen) RSID:rs1042713 (with budesonide) ...
  36. 36. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryDisease and drug pathwaysOntology enrichment analysis can identify over-represented ontology classes. ontology-based, statistical approach to identify drug and disease pathways use graph structure of ontology to identify statistically over- and under-represented ontology classes aims: identify over-represented disease classes (in disease ontology) for genes in a pathway (disease pathways) identify over-represented chemical classes (from chemical ontology) for genes in a pathway (drug pathways)
  37. 37. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryDisease and drug pathwaysOntoFUNC enables enrichment analyses over OWL ontologies. OntoFUNC: http://ontofunc.googlecode.com based on FUNC (http://func.eva.mpg.de) supports hypergeometric test Wilcoxon rank test binomial test McDonaldKreitman (2x2 contingency) test correction for multiple testing (FWER, FDR)
  38. 38. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryDisease and drug pathwaysOntoFUNC identifies disease classes that are enriched in pathways. hypergeometric test over Disease Ontology genes participating in pathway P vs. all other genes carcinosarcoma (DOID:4236) and Zidovudine Pathway (PharmGKB:PA165859361) (p < 10−10 ). mood disorder (DOID:3324) and Zidovudine Pathway (PharmGKB:PA165859361) (p < 0.01). (All results at http://pharmgkb-owl.googlecode.com)
  39. 39. Species Inferred p-value Fish 1717 0.240 Yeast 14047 0.162 Fly 1633 0.041 Worm 9221 0.003 Mouse 15693 7 · 10−5 D. dario D. melanogaster S. cerevisiae 1 1 1 0.9 0.9 0.9 0.8 0.8 0.8 0.7 0.7 0.7True Positive Rate True Positive Rate True Positive Rate 0.6 0.6 0.6 0.5 0.5 0.5 0.4 0.4 0.4 0.3 0.3 0.3 0.2 0.2 0.2 0.1 original 0.1 original 0.1 original new new new x x x 0 0 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 False Positive Rate False Positive Rate False Positive Rate M. musculus C. elegans 1 1 0.9 0.9 0.8 0.8 0.7 0.7 True Positive Rate True Positive Rate 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 original 0.1 original new new x x 0 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 False Positive Rate False Positive Rate
  40. 40. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummarySummaryOntologies can be used to enable integrative biology. 1 integration of ontologies 2 integration of data through ontologies 3 ontology-based data analysis semantic similarity statistical tests graph-/network-based algorithms 4 quantitative evaluation on real biological data
  41. 41. Introduction Animal and disease phenotypes Pharmacogenomics Pathways SummaryAcknowledgements George Gkoutos Pierre Grenon Paul Schofield Midori Harris Michel Dumontier Pascal Hitzler Heinrich Herre Simon Jupp Janet Kelso Frank Loebe Dietrich Kay Pruefer Rebholz-Schuhmann Gabrielle Rustici Dan Cook Stefan Schulz John Gennari Robert Stevens Anika Oellrich Sarala Wimalaratne Nico Adams ... Bernard de Bono
  42. 42. Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary Thank you! http://phenomebrowser.net

×