BioVU and the Synthetic Derivative Erica Bowton, PhD Program Manager, Personalized Medicine

Personalized Medicine

What is BioVU? The move towards personalized medicine requires very large sample sets for discovery and validation BioVU: biobank intended to support a broad view of biology and enable personalized medicine Contains de-identified DNA extracted from leftover blood after clinically-indicated testing of Vanderbilt patients who have not opted out Linked to Synthetic Derivative: de-identified EMR

John Doe 4

One way hash A7CCF99DE65732…. scrubbed John Doe ~2 million records The Synthetic Derivative : can be updated 5

eligible John Doe One way hash A7CCF99DE5732…. A7CCF99DE65732…. scrubbed Extract DNA A7CCF99DE65732…. John Doe ~2 million records The Synthetic Derivative : can be updated 6

7 Accepted samples must:  Be of good quality  Have sufficient amount of blood  Be from a patient who has signed the BioVU form  Be from a patient who has not opted out How BioVU Samples are Accepted

8 The BioVU Form A component of the Consent for Treatment process

9 Awareness Generation Posters in phlebotomy areas in English and Spanish Brochures freely available to VUMC clinics in English and Spanish BioVU hotline available for questions and opt-out

10 BioVU Sample Accrual: 176,448 Current accrual as of : 155,090 adult 21,472 pediatric

11 RTS SmaRTStore Where are BioVU samples stored?

BioVU Operations Oversight Institutional Review Board BioVU General Counsel Med Ctr Ethics Vice Chancellor (Chair) Ethics/ELSI (2) Ctr Human Genetics Research (2) Clinical genetic testing lab (1) Genetics/Genetic Medicine (6) Pediatric genetics (1) Clin. Pharmacology(PI) * Includes (or exclusively) external membership ** (n)= number of members representing this discipline/area. Several members are represented in more than one area Patient advocacy (2) University counsel (1) Biostatistics (3) Cancer center (3) Operations Oversight Board** Community Advisory Board* Ethics Advisory Board* = oversight Vice Chancellor’s Office = input, advisory Program staff BioVU Protocol Review Committee

Resources for EMR-based research at VUMC 13 The Synthetic Derivative A de-identified and continuously-updated image of the EMR (2 M records) BioVU DNA samples available: >175,000 Plasma collection underway Redeposited genotypes Subjects with GWAS data: >12,000 Subjects with any genotyping: >60,000 > 8,000,000,000 genotypes 13

The Synthetic Derivative Rich, multi-source database of de-identified clinical and demographic data A Derivative of the EMR - information content reduced by ‘scrubbing’ identifiers Systematically shifted event dates User Interface tool that can be used for access and analysis Services are available to help deliver results for non-standard queries (temporal queries, controls matching, etc) Contains ~2.1 million records o ~1 million with detailed longitudinal data o averaging 100,000 bytes in size o an average of 27 codes per record Records updated over time and are current through 8/31/13

Narratives, such as:  Clinical Notes  Discharge Summaries  History and Physicals  Problem Lists  Surgical Reports  Progress Notes  Letters Diagnostic Codes, Procedural Codes Forms (intake, assessment) Reports (pathology, ECGs, echocardiograms) Clinical Communications Lab Values and Vital Signs Medication Orders TraceMaster (ECGs) Tumor Registry Synthetic Derivative Data Types

Technology + policy De-identification Derivation of 128-character identifier (RUI) from the MRN generated by Secure Hash Algorithm (SHA-512) HIPAA identifiers removed using combination of custom techniques and established de-identification software Date Shift Our algorithm shifts the dates within a record by a time period (up to 364 days backwards) that is consistent within each record, but differs across records Restricted access & continuous oversight Access restricted to VU; not a public resource IRB approval for study (non-human) Data Use Agreement Audit logs of all searches and data exports

Data Use Agreement No attempt at re-identification Inform BioVU staff if a record is identifiable Research confined to that which is described Genotypes to be re-deposited back to BioVU

Phenotyping Approach Algorithm Development Identify phenotype of interest Case & control algorithm development and refinement Manual review; assess precision Deploy in BioVU ≥95% <95%

Disease Cohorts 19

20 Pre-Review BioVU Committee Review  Expedited Review  Genotyping data requests  Reviewed by BioVU Chair  Full Review  DNA sample access requests  Reviewed and scored by Primary and Secondary reviewers BioVU Projects: 104  Requests: 104  Approved so far: 86 BioVU Utilization

Current BioVU Studies 21

22 USE CASE 1 Synthetic Derivative Study

23 Ability to analyze quantitative, longitudinal repeated measures BMI Normal Range Zyprexa Prescription USE CASE 1 Synthetic Derivative Study

24

25 USE CASE 1 Synthetic Derivative Study

26 USE CASE 1 Synthetic Derivative Study

BMI USE CASE 1 Synthetic Derivative Study

28 USE CASE 2 Existing Genetic Data

29 USE CASE 2 Existing Genetic Data

30 USE CASE 2 Existing Genetic Data

31

32 USE CASE 2 Existing Genetic Data

33 USE CASE 2 Existing Genetic Data

USE CASE 3 New Genotyping/Sequencing 34

USE CASE 3 New Genotyping/Sequencing 35

36 USE CASE 3 New Genotyping/Sequencing

37 USE CASE 3 New Genotyping/Sequencing

Investigator query cases controls + Data use agreement One way hash USE CASE 3 New Genotyping/Sequencing

One way hash Investigator query cases controls + Data use agreement Data analysis

Sample retrieval Genotyping, genotype- phenotype relations cases controls + Investigator query cases controls + Data use agreement One way hash

BioVUVANTAGE Vanderbilt Technologies for Advanced Genomics VANGARD Vanderbilt Technologies for Advanced Genomics Analysis and Research Design Access approvals/application Cohort identification Clinical data extraction Programming support Study design Agreements Genotyping/sequencing approaches Assay design SNP selection Sample pulling and plating Genomic data analysis and research design Biostatistical/bioinformatic support 2-3 months 1-2 months BioVU Project Life Cycle

For ALL BioVU Studies… 42 Resources: 1. BioVU Project Management: 2. Programming services: IDASC CORE 3. Genomic technologies: VANTAGE CORE 4. Data analysis services: VANGARD CORE

END 43

Validating EMR phenotype algorithms Odds Ratio rs Chr. 4q25 rs Chr. 4q25 rs IL23R rs Chr. 5 rs Chr. 5 rs NOD2 rs PTPN22 rs DRB1*1501 rs IL2RA rs IL7RA rs Chr. 6 rs RSBN1 rs PTPN22 rs TCF7L2 rs TCF7L2 rs TCF7L2 rs CDKN2B rs FTO rs5219KCNJ11 rs5215KCNJ11 rs IGF2BP2 Atrial fibrillation Crohn's disease Multiple sclerosis Rheumatoid arthritis Type 2 diabetes disease gene / region marker 2.0 Ritchie et al, 2010 observedpublished