Systematic Phenotypic Characterisation of Skeletal Dysplasias with the Human Phenotype Ontology

Presentation given at the 2017 Meeting of the International Skeletal Dysplasia Society in Bruges, Belgium.

Transcript

1. Systematic Phenotypic Characterisation of Skeletal Dysplasias with the Human Phenotype Ontology Andreas Zankl MD FMH FRACP Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney Department of Clinical Genetics, The Children’s Hospital at Westmead Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research
3. PubMed grows by >1 publication per minute
6. Femoral bowing Bowed femurs
7. The Human Phenotype Ontology HP:0004998 Bowed Femurs HP:0004998 Femoral Bowing
8. The Human Phenotype Ontology (HPO) • a standardised vocabulary to describe phenotypic abnormalities in human disease • based on OMIM’s clinical synopsis • curated by a team of volunteers • over 10’000 entries • the de facto standard for rare disease phenotype annotation
9. The Human Phenotype Ontology HP:0004998 gebogen femurs HP:0004998 bowed femurs
10. The Human Phenotype Ontology HP:0004998 ⼤腿⾻を曲げた HP:0004998 bowed femurs
11. The HPO can link related concepts Joint Dislocations (HP:0002772) Lower Extremity Joint Dislocations (HP:0030311) Upper Extremity Joint Dislocations (HP:0030310) Knee Dislocations (HP:0004976) Hip Dislocations (HP:0001375)
12. Knee Dislocation (HP:0004976) I know, its a type of Joint Dislocation (HP:0002772)
13. Semantic similarity matching Short Stature Hip dislocations Short Stature Knee dislocations
15. Cross-species similarity matching Hand anomalies (HP:0005858) Paw abnormalities (MP:0004271)
16. The Exomiser
17. So how well does this work for skeletal dysplasias?
18. So how well does this work for skeletal dysplasias? • Does HPO have the right vocabulary?
19. So how well does this work for skeletal dysplasias? • Does HPO have the right vocabulary? • Does HPO assign the right terms?
20. Spranger -> HPO • Concise description of clinical and radiographic features for 275 skeletal dysplasias • Can we match those to HPO terms?
21. HPO -> Spranger • The HPO Consortium provides HPO terms (annotations) for most skeletal dysplasias • How do these compare to the descriptions in the Spranger book?
22. Step 1: split Spranger description into individual terms 1. Short trunk with prominent abdomen. 2. Flat midface, micrognathia, often cleft palate. 3. absent ossification of the sacrum. … • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum.
23. Step 1: split Spranger description into individual terms 1. Short trunk with prominent abdomen. 2. Flat midface, micrognathia, often cleft palate. 3. absent ossification of the sacrum. … • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum.
24. Step 2: find matching HPO terms through text mining - - midface retrusion (HP:0011800) micrognathia (HP:0000347) cleft palate (HP:0000175) - • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum.
25. Step 2: find matching HPO terms through text mining - - midface retrusion (HP:0011800) micrognathia (HP:0000347) cleft palate (HP:0000175) - • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum.
26. short thorax (HP:0010306) abdominal distention (HP:0003270) malar flattening (HP:0000272) micrognathia (HP:0000347) cleft palate (HP:0000175) - frontal bossing (HP:0002007) postaxial polydactyly (HP:0001162) • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum. • - • - Step 3: manually match HPO’s annotation to Spranger
27. short thorax (HP:0010306) abdominal distention (HP:0003270) malar flattening (HP:0000272) micrognathia (HP:0000347) cleft palate (HP:0000175) - frontal bossing (HP:0002007) postaxial polydactyly (HP:0001162) • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum. • - • - Step 3: manually match HPO’s annotation to Spranger
28. short thorax (HP:0010306) abdominal distention (HP:0003270) malar flattening (HP:0000272) micrognathia (HP:0000347) cleft palate (HP:0000175) - frontal bossing (HP:0002007) postaxial polydactyly (HP:0001162) • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum. • - • - Step 3: manually match HPO’s annotation to Spranger
29. short thorax (HP:0010306) abdominal distention (HP:0003270) malar flattening (HP:0000272) micrognathia (HP:0000347) cleft palate (HP:0000175) - frontal bossing (HP:0002007) postaxial polydactyly (HP:0001162) • short trunk • prominent abdomen • flat midface • micrognathia • cleft palate • absent ossification of the sacrum. • - • - Step 3: manually match HPO’s annotation to Spranger
30. Results 5477 Spranger Annotations 6351 HPO Annotations
31. Results • 44% of Spranger annotations could be matched to HPO • 54% of clinical annotations matched to HPO • 34% of radiographic annotations matched to HPO • 38% of HPO annotations matched to Spranger
32. Limitations • Automatic HPO term recognition is imperfect • Manual matching error-prone • Not every Spranger term might be worth matching
33. Limitations • Automatic HPO term recognition is imperfect • Manual matching error-prone • Not every Spranger term might be worth matching … but it’s a start!
34. Spranger HPO ISDS Let’s create the ISDS HPO Annotation List!
36. Achondroplasia OMIM 123456 • Macrocephaly (HP:00012355) • Rhizomelia (HP:00034674) • Hyperlordosis (HP:0126798) the next Edition…?
37. Acknowledgements Marcus Lau Tudor Groza Nelson Ma Tim Gibson Edward Selig Lok Fung