BioVU and the Synthetic Derivative

Erica Bowton, PhDProgram 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

Joh

n D

oe

4

One

way

has

h

A7C

CF

99D

E65

732

….

scru

bbed

Joh

n D

oe

~2 million records

The Synthetic Derivative: can be

updated5

eligibleJoh

n D

oe

One

way

has

h A7C

CF

99D

E57

32…

.

A7C

CF

99D

E65

732

….

scru

bbed

Extract DNA

A7C

CF

99D

E65

732

….

Joh

n D

oe

~2 million records

The Synthetic Derivative: can be

updated6

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 FormA 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

Jul-07

Jan-08Jul-0

8Jan-09

Jul-09

Jan-10Jul-1

0Jan-11

Jul-11

Jan-12Jul-1

2Jan-13

Jul-13

Jan-14Jul-1

4Jan-15

Jul-15

0

25,000

50,000

75,000

100,000

125,000

150,000

175,000

200,000

225,000

Anticipated pediatric sample accrual

Anticipated adult sample accrual

Pediatric samples accrued

Adult samples accrued

Current accrual as of 2-19-2014:155,090 adult

21,472 pediatric

11

RTS SmaRTStore

Where are BioVU samples stored?

BioVU Operations OversightInstitutional 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 DerivativeA 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 genotypes13

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 recordso ~1 million with detailed longitudinal datao 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 + policyDe-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

Number in SD Number in BioVUCentral Nervous SystemAlzheimer’s 3,429 497Parkinson’s 4,365 778Migraine 15,699 3,299PsychiatricDementia 3,747 1,045Major Depressive Disorder 20,008 3,385ADHD 12,922 1,184Generalized Anxiety Disorder 5,828 1,195Schizophrenia 4,069 495

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: Requests: 104 Approved so far: 86

BioVU Utilization

BioVU Requests BioVU Approvals0

20

40

60

80

100

120 DNA Requests

Data Requests

Current BioVU Studies

21

Heart Dise

ase

Cancer

Other

Neurologica

l Dise

ase

Diabetes

Immune Syste

m Disease

Obesity

Pharmaco

genomics

Obstetri

cs & Gyneco

logy

Lung Dise

ase

Eye Disease

Privacy

0

5

10

15

20

25

BioVU Study Areas

Num

ber

of S

tudi

es

22

USE CASE 1Synthetic Derivative Study

23

11/1/2

007

11/13/2

007

11/25/2

007

12/7/2

007

12/19/2

007

12/31/2

007

1/12/2

008

1/24/2

008

2/5/2

008

2/17/2

008

2/29/2

008

3/12/2

008

3/24/2

008

4/5/2

008

4/17/2

008

4/29/2

008

5/11/2

008

5/23/2

008

6/4/2

008

6/16/2

008

6/28/2

008

7/10/2

008

7/22/2

008

8/3/2

008

8/15/2

008

8/27/2

008

9/8/2

00815

20

25

30

35

40

Ability to analyze quantitative, longitudinal repeated measures

BMI

Normal Range

Zyprexa Prescription

USE CASE 1Synthetic Derivative Study

USE CASE 1Synthetic Derivative Study

24

25

USE CASE 1Synthetic Derivative Study

26

USE CASE 1Synthetic Derivative Study

27

0

100

200

300

400

500

600

700

800

900

0 13.3 26.2 40.9 73.4 300+

BMI

USE CASE 1Synthetic Derivative Study

28

USE CASE 2Existing Genetic Data

29

USE CASE 2Existing Genetic Data

30

USE CASE 2Existing Genetic Data

USE CASE 2Existing Genetic Data

31

32

USE CASE 2Existing Genetic Data

33

USE CASE 2Existing Genetic Data

USE CASE 3New Genotyping/Sequencing

34

USE CASE 3New Genotyping/Sequencing

35

36

USE CASE 3New Genotyping/Sequencing

37

USE CASE 3New Genotyping/Sequencing

Investigator query

cases

controls

+

Data use agreement

One

way

has

hUSE CASE 3New Genotyping/Sequencing

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

One

way

has

h

Investigator query

cases

controls

+

Data use agreement

Data analysis

Sample retrieval

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

B6

99

tre

563

msd

..

scru

bbed

F5

rt7

83

mb

nc

ds

…

scru

bbed

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

F5r

t783

mb

ncd

s….

B69

9tre

563m

sd…

.

Genotyping, genotype-phenotype relations

cases

controls

+Investigator

query

cases

controls

+

Data use agreement

One

way

has

h

BioVU

VANTAGEVanderbilt Technologies for Advanced Genomics

VANGARDVanderbilt 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

1-2 months

BioVU Project Life Cycle

For ALL BioVU Studies…

42

Resources:1. BioVU Project Management: BioVU@vanderbilt.edu

2. Programming services: IDASC CORE

3. Genomic technologies: VANTAGE CORE

4. Data analysis services: VANGARD CORE

https://starbrite.vanderbilt.edu/biovu/

43

END

0.5 5

Validating EMR phenotype algorithms

0.5 50.5 5.01.0

Odds Ratio

rs2200733 Chr. 4q25

rs10033464 Chr. 4q25

rs11805303 IL23R

rs17234657 Chr. 5

rs1000113 Chr. 5

rs17221417 NOD2

rs2542151 PTPN22

rs3135388 DRB1*1501

rs2104286 IL2RA

rs6897932 IL7RA

rs6457617 Chr. 6

rs6679677 RSBN1

rs2476601 PTPN22

rs4506565 TCF7L2

rs12255372 TCF7L2

rs12243326 TCF7L2

rs10811661 CDKN2B

rs8050136 FTO

rs5219 KCNJ11

rs5215 KCNJ11

rs4402960 IGF2BP2

Atrial fibrillation

Crohn's disease

Multiple sclerosis

Rheumatoid arthritis

Type 2 diabetes

diseasegene / region

marker

2.0

Ritchie et al, 2010

observedpublished