1. Vanderbilt’s DNA Databank:
BioVU

2. Personalized Medicine
Integration of genomic information into clinical decision making
Personalized disease treatment and also preventative therapies

3. Personalized Medicine
A SNP is a single base-pair mutation that occurs at a specific site in the DNA sequence - occurs in at least 1% of the population
SNPs are responsible for over 80% of the variation between two individuals; they are ideal for establishing correlations between genotype and phenotype
As some SNPs predispose individuals to have a certain disease or trait or react to a drug in a different way, they will be highly useful in diagnostics and drug development

4. 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
Current sample number: 116,551
105,910 adult samples
10,641 pediatric samples

6. The “synthetic derivative”
Extract DNA
John Doe
A7CCF99DE65732….
eligible
A7CCF99DE5732….
One way hash
A7CCF99DE65732….
scrubbed
John Doe
The “synthetic derivative”
(SD): can be updated

7. Synthetic Derivative vs. BioVU
A7CDE6532 ….
scrubbed
A7CDE6532 ….
scrubbed
A7CDE6532…. +
Synthetic Derivative BioVU
~1.9 million ~116,000

8. The Synthetic Derivative
A Derivative of the EMR - information content reduced by ‘scrubbing’ identifiers
Systematically shifted event dates
Contains ~1.9 million records
~1 million with detailed longitudinal data
averaging 100,000 bytes in size
an average of 27 codes per record
Records updated over time and are current through 9/31/09
Can be searched restricting to records for which DNA is available

9. Synthetic Derivative Data Types
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)

10. BioVU Program Review

11. Sample accrual

12. BioVU Sample Management
Samples are stored in a robotic sample storage system that allows for fully automated high speed sample picking. Currently genotyping on BioVU samples is being done in the DNA Resources Core here at Vanderbilt.
RTS SmaRTStore

13. Validation in BioVU Sample handling algorithms Ancestry
Gender match
1/384 gender mismatches
Ancestry
Characterize sample ancestry, assess usefulness of ‘race’ as defined in EMR
Provide a panel of ancestry informative markers that define ancestry
No significant difference between the concordance of self-report or observer-report with genetic ancestry
Demonstration project – American Journal of Human Genetics
Can known associations between genetic variants and common diseases be identified in the EMR?

14. The “demonstration project”
Genotype “high-value” SNPs in the first 8,000 samples accrued.
including SNPs associated by replicated genome-wide experiments with common diseases & traits
Atrial fibrillation
Crohn’s disease
Multiple Sclerosis
Rheumatoid arthritis
Type II Diabetes
Develop Natural Language Processing methods to identify cases and controls
Are genotype-phenotype relations replicated?

15. First results 0.5 1.0 2.0 5.0 Odds Ratio gene / disease marker region
Chr. 4q25
Atrial fibrillation rs
Chr. 4q25 rs
IL23R rs
Chr. 5
Crohn's disease rs
Chr. 5 rs
NOD2 rs
PTPN22 rs
DRB1*1501
Multiple sclerosis rs
IL2RA rs
IL7RA rs
Chr. 6
Rheumatoid arthritis rs
RSBN1 rs
PTPN22 rs
TCF7L2 rs
TCF7L2 rs
TCF7L2 rs
CDKN2B
Type 2 diabetes rs
FTO
rs5219
KCNJ11
rs5215
KCNJ11 rs
IGF2BP2
0.5
1.0
2.0
5.0
Odds Ratio

16. First results 0.5 1.0 2.0 5.0 Odds Ratio gene / disease marker region
Chr. 4q25
Atrial fibrillation rs
Chr. 4q25 rs
IL23R rs
Chr. 5
Crohn's disease rs
Chr. 5 rs
NOD2 rs
PTPN22 rs
DRB1*1501
Multiple sclerosis rs
IL2RA rs
IL7RA rs
Chr. 6
Rheumatoid arthritis rs
RSBN1 rs
PTPN22 rs
TCF7L2 rs
TCF7L2 rs
TCF7L2 rs
CDKN2B
Type 2 diabetes rs
FTO
rs5219
KCNJ11
rs5215
KCNJ11 rs
IGF2BP2
0.5
1.0
2.0
5.0
Odds Ratio

17. Types of projects
Discovery or validation of genotype-phenotype relations for disease susceptibility or drug responses
Discovery of new disease/susceptibility genes  resequence in patients (obesity, Cushing's, susceptibility to infection, insomnia, pre-term birth)
Access samples without disease X, or “normals” of specified ancestry, or old normals
Phenome-wide association study (PheWAS): in development

18. Research Use Cases Retrospective chart reviews Rapid preliminary
data for
grant
submissions
Feasibility assessment
Hypothesis
generation

19. Examples of ICD-9 codes for rare diseases Example Rare Disease
Number in SD
Number in BioVU
Microcephalus
1,070 85
Pica
115 22
Septicemic Plague 21
Pick’s Disease 45 8
Acromegaly and Gigantism
571
123
Ehlers-Danlos Syndrome
285 34
Narcolepsy without Cataplexy
438 76
Spina Bifida
1968
238
Stiff-Man Syndrome 82 17
Tourette Syndrome
667
Bell’s Palsy
2534
402
Bulimia Nervosa
919 88
Cushing’s
1443
298
Peyronies Disease
694
157
Wilson’s Disease
140 49
Meningioma
1444
355
Wegener’s
363
141

20. Data use agreement + IRB Approval
Investigator query
Data use agreement + IRB Approval
cases
controls + 20

21. Data use agreement + IRB Approval
Investigator query
Data use agreement + IRB Approval
Manual Review
cases
controls + 21

22. Data use agreement + IRB Approval
cases
controls +
Investigator query
Data use agreement + IRB Approval
Sample retrieval
cases
controls + 22

23. + + cases Investigator query controls Sample retrieval cases controls
Genotyping, genotype-phenotype relations
Investigator query
Data use agreement + IRB Approval
Sample retrieval
cases
controls + 23

24. Data Use Agreement

25. Genotyping Data Accrual

26. Coronary Artery Disease
Nationally Prevalent Diseases in the African American Population
Disease
BioVU Count
Hypertension
1095
Type 2 Diabetes
714
Coronary Artery Disease
273
Kidney Disease
252
Asthma
210
Pneumonia
193
Stroke
133
Lupus 48
Lung cancer 21
Genotype data on 1786 AA subjects

27. BioVU Home page. Description of resource
BioVU Home page. Description of resource. On the left, you can click for application instructions, status of your application, information about support for BioVU projects, and Record Counter to determine approximate number of records that meet specific criteria (useful for sample size estimations and power calculations when developing BioVU projects/proposals). Tools for assistance with grant language and also statistical analysis plan for BioVU proposals. Click “Genotyping Data” button for more information about current sample counts and genotyping data (page that comes up is on next slide).

28. BioVU Home page. Description of resource
BioVU Home page. Description of resource. On the left, you can click for application instructions, status of your application, information about support for BioVU projects, and Record Counter to determine approximate number of records that meet specific criteria (useful for sample size estimations and power calculations when developing BioVU projects/proposals). Tools for assistance with grant language and also statistical analysis plan for BioVU proposals. Click “Genotyping Data” button for more information about current sample counts and genotyping data (page that comes up is on next slide).

32. Record Counter is on the BioVU homepage.

33. This is the screen when you log into Record Counter.

34. You can query by ICD-9 code, for example MS.

36. You can also query for medications as shown here.

37. It will instruct you to enter the medication as shown here with avonex as an example.

38. You can search for multiple medications as well.

39. For example, if you want to query the records for MS cases with interferon treatment, you can add the medications to the same Criteria Group as shown here for 3 different interferon medications. This results in a query for MS cases with either avonex, betaseron, OR rebif. This will pull MS records with an occurrence of any of the 3 medications. If you wanted to query for MS cases on all 3 medications, you would need to add each medication to a SEPARATE Criteria Group. This is just using “and” / “or” logic. If you want to query only cases with DNA samples in BioVU, you have to click “Limit by DNA availability”. When you have all your criteria entered, click “Execute Query”.

40. This will give you a readout of total number of cases in BioVU that meet your criteria with demographic breakdown.

42. This will give you a readout of total number of cases in BioVU that meet your criteria with demographic breakdown.

43. BioVU Home page. Description of resource
BioVU Home page. Description of resource. On the left, you can click for application instructions, status of your application, information about support for BioVU projects, and Record Counter to determine approximate number of records that meet specific criteria (useful for sample size estimations and power calculations when developing BioVU projects/proposals). Tools for assistance with grant language and also statistical analysis plan for BioVU proposals. Click “Genotyping Data” button for more information about current sample counts and genotyping data (page that comes up is on next slide).

44. This will give you a readout of total number of cases in BioVU that meet your criteria with demographic breakdown.

47. When you click on “Application Instructions”, an explanation of the 5 different application options will appear. This depends on whether investigator will be requesting genotyping or not and also whether the investigator intends to apply for VICTR funding to support their BioVU project. The first option is just for SD users (the process will now be electronic).

48. An example of the web-based application process (this particular example is for an investigator who wants to request genotyping as well as apply for VICTR funding). Investigators will need IRB approval for their project, a 5 page research proposal, and a biosketch. They will also need to sign a Data Use Agreement. Once all of these are completed, they will complete the electronic application (in REDCap) where they will download all of their documents and complete application information. The link to VICTR resource request is also there (this process will not change – they will apply for VICTR funding as usual, however their application will not be processed until Shraddha receives the go ahead that the BioVU proposal has been approved).

52. For assistance with BioVU project development or application submission, there are office hours, information clinics, and studios. Investigators may also apply for VICTR funding.

53. BioVU Application Process
Investigator(s) completes
VICTR Resource Request
Funding request reviewed
by VICTR SRC
BioVU Application Process
Proposal reviewed by
BioVU Review Committee
BioVU program office contacts
investigators with any necessary
revisions if applicable
Proposal Approved/
Access granted
Investigator resubmits
proposal if necessary
Total Time:
Data Requests: 4-6 weeks
DNA Access: 8-12 weeks
Funding Decision
Proposal Review Process:

54. BioVU Genotyping Process
Genotyped data analyzed
by investigator
Investigator selects cases
and controls from
Synthetic Derivative
Investigator signals BioVU program
to initiate sample selection
BioVU notifies DNA resources core
that samples are ready for
selection and picking
Samples are provided to
appropriate lab and are genotyped
Investigator and BioVU program
receive genotype data
BioVU Genotyping Process:

55. BioVU Requests
37 Total Requests
24 Approvals

56. FAQ “answers” SD access: “non-human subjects” IRB review (days)
Current access costs: $4/sample
Genotyping:
Investigator-funded
Consider VICTR as a funding source
Genotyping/sequencing performed in VUMC Core Facilities
Justification must be provided for outside genotyping, including quality control plans
Genotype “redeposit” part of the data use agreement
Anticipate 16,000 BioVU subjects will have GWAS-type genotyping data by fall 2011

57. Contact: Erica Bowton PhD
Questions?
Contact: Erica Bowton PhD
BioVU Program Manager