1. Rockefeller Phenotyping Initiative Translational Key Function Committee 8/3/2010 Laboratory of Blood and Vascular Biology Laboratory of Human Genetics and Hematology Laboratory of Genome Maintenance Informatics Core The Rockefeller University

2. The Case for Deep Phenotyping “Our capacity to undertake [genome-wide] projects will probably not be the limiting step in elucidating the genetic basis of common diseases. Instead, we may be held back by our inability to specify precisely the phenotypes… in those individuals whose genomes we investigate.” Nat. Gen. 2003, 34: 15-21

3. “We continue to depend primarily on standard disease diagnoses, which are both incomplete and imprecise, as representations of human phenotypes.” Nat. Gen. 2003, 34: 15-21 The Case for Deep Phenotyping

4. “Furthermore, phenotyping is still rooted in clinical traditions, which vary greatly between medical specialties and between different locales; it does not yet have the systematization or throughput to match the worldwide genotyping studies that are envisioned.” Nat. Gen. 2003, 34: 15-21 The Case for Deep Phenotyping

5. Prototype Projects Bleeding History Phenotyping System International Fanconi Anemia Registry

6. Rockefeller University Bleeding History Phenotyping System Aim: to provide a common set of tools and unified database for the collection, curation, and dissemination of standardized bleeding phenotypes Bleeding History Questionnaires Laboratory data entry Query and visualization software http://ds9.rockefeller.edu/RUBHPSR/

7. Bleeding History Ontology http://bioportal.bioontology.org/visualize/38563

8. Single Reports DemographicsGraph Aggregate Reports Phenotype Recording Instruments (PRIs) Data query and representation Bleeding History Ontology Questionnaire PRI(s) Laboratory PRI MySQL Database

9. Phenotype Recording Instrument

11. Laboratory Data Entry Instrument

12. Single Report

13. Aggregate Report

14. Master Database Available for Analysis By All Authorized Investigators Groups Uploading Their De-Identified Data Into Master Database and Downloading the Cumulative Data Master Database New York City TokyoChicagoParis

15. Bleeding History Phenotyping Project Phenotyping healthy individuals Phenotyping individuals with bleeding disorders Deriving bleeding “scores” to maximize diagnostic and prognostic discrimination Streamlining questionnaires for primary care physicians and in the developing world Database mergers Natural language processing Mobile Web development

16. International Fanconi Anemia Registry (IFAR) Established in 1982 to study a large number of patients exhibiting the full spectrum of diverse features of FA. Data-rich starting point: – 28 year compendium of demographic, cytogenetic, medical history, hematologic, genealogic, treatment and transplantation data from over 1400 patients

17. Fanconi Anemia Mutation Database Established in 1998 as a cooperative effort to accelerate the availability of information on mutations in these important cancer- predisposing genes

18. The problem: An inability to grasp the complete picture Diverse data sources unlinked Current IFAR database stored in rigid, inflexible legacy system Lack of a complete description of the knowledge base and data relationships Inability to merge genotype and phenotype/demographic information Desire to expand the range and specificity of phenotype data Desire to include new information (i.e. next gen. sequencing) as data becomes available

19. Ontology- based Filtering Graph Consolidated IFAR database Data query and representation Enhanced International Fanconi Anemia Registry Fanconi Anemia Ontology Original IFAR database Mutation database Novel phenotyping instrument

20. Fanconi Anemia Ontology

21. Ontology-Based Filtering

22. Additional Data Visualizations

23. Conclusions The Rockefeller Phenotyping Inititative seeks to develop novel methods for collecting and characterizing phenotypes, with the goal of improving the ability to identify genotype- phenotype correlations As part of the Rockefeller CTSA renewal, we have offered to undertake one additional phenotyping project per year on behalf of the CTSAs

24. Acknowledgements This work is supported in part by CTSA grants 1U54RR023419-01, 5UL1RR024143-04 and ARRA Supplement grant 3UL1RR024143-04S2 from the National Institutes of Health.