1. TOPMed Analysis Workshop Genetic Analysis Center Biostatistics Department University of Washington TOPMed Data Coordinating Center
August 7-9, 2017
Introduction to TOPMed and Data Sharing
Cathy Laurie

2. 4/21/2019

3. 4/21/2019

4. Consent Types

5. To access the web site:
Sign and return non-disclosure agreement –from TOPMed DCC –

6. *~50 Participating Studies currently in TOPMed (not shown)

7. TOPMed WGS Overview Study Sequencing Center IRC Michigan NCBI DCC UW
DNA samples
Sequencing Center
sequence data
IRC
Michigan
joint genotype call sets
harmonized sequence data
NCBI
Study Coordinating Center
DCC UW
phenotypes
dbGaP
SRA*
harmonized phenotypes
phenotypes
phenotypes,
genotypes,
sequence data
Working Group
COPD
Working Group
atherosclerosis
Working Group
asthma
Study A analysis team
Study B analysis team
Scientific Community
etc...
etc...
Cross study publications
Study-focused publications
Personalized Medicine
*SRA is being replaced with an NIH cloud as repository for aligned sequence data

8. Data Organization on dbGaP
Parent study accessions*
Phenotype data
Prior SNP array and other non-TOPMed genotype data
Some have ‘omics data
Most are currently released (available to general scientific community)
TOPMed accessions*
Exchange Area – accessible only by authorized TOPMed investigators
Whole genome sequence data and genotype call sets
Some have phenotype data
Some have files contributed by Working Groups for sharing
Released accessions
Phase 1 studies currently being released (~18k, samples)
Include SRA/BAM, VCF, annotation and phenotype files
*click to find accession numbers

9. TOPMed Exchange Area Organization and Current Content
Common Exchange Area
Cross-study genotype call set
Genotype call sets (cross-study)
Variant & sample annotation
Study-specific Exchange Areas
Study A
Study B
Study C
Study-specific TOPMed EA content:
Sample files – sample-subject mapping, subject consent, sample attributes, pedigrees
Study-specific phenotype files - submitted specifically for TOPMed (many studies already have their phenotypes in a released parent study accession that is publicly available)
Harmonized phenotype files – some from DCC and others contributed by Working Group members
BAM/SRA files
Misc files (e.g. prior SNP array data for some studies)

10. Joint call sets from IRC
Sequence Data
Joint call sets from IRC
Freeze 4 (current version) - alignment to build 37; includes all samples from phase 1 studies (except SAFS), ~18k samples
Next freeze (August 2017)– alignment to build 38; to include all phase 1 samples and a large fraction of phase 2 samples

11. Phenotype Data Study-specific phenotypes
Parent study accessions – some have thousands of phenotypes; see website document for tips on how to find what you need in released accessions
TOPMed accessions – most current data are in Exchange Area; phase 1 study releases can be searched like other released accessions
Cross-study harmonized phenotypes
DCC is performing harmonization for a limited set of traits based on data in released dbGaP accession; currently this includes blood cell counts and basic demographics; the harmonized data are in the study-specific Exchange Areas
Working Groups are exchanging files through the Exchange Areas for their own harmonization efforts

12. Other -Omics Data
Many studies have some prior (i.e. non-TOPMed) –omics data
See survey results
Heterogeneous platforms
Much of this is not currently available on dbGaP
TOPMed Omics Pilot – MESA – currently underway
RNASeq
Metabolomics
Array-based methylation
Proteomics
TOPMed plans for additional –Omics data generation and analysis
PAR : Omics Phenotypes of Heart, Lung, and Blood Disorders (X01)
RFA-HL : Integrative Computational Biology for Analysis of NHLBI TOPMed Data (R01)

13. Access & Use Permissions for Data from TOPMed Exchange Areas
Accessing Data
Only 6 Individuals per study are eligible to apply for access (named by PI)
Data Access Requests (DARs) are submitted to dbGaP using TOPMed-generic application
Successful applicants may share data with others at their institution
A group of applicants with coordinated DARs may share data in a cloud environment
Using Data
Data may NOT be used for any purpose without an APPROVED paper proposal
Exception: a study investigator may use his/her own study’s data as they wish
Paper proposals originate in the TOPMed Working Groups
IMPORTANT: Access to TOPMed Exchange Area data does NOT confer permission to use it in analysis

14. Data Access Mechanisms for Exchange Areas
Each study PI and his/her nominees from other institutions apply to dbGaP for access to multiple TOPMed studies (6 total per study)
NHLBI DAC reviews and approves/disapproves applications
Data are downloaded by each approved investigator to their own institution’s IT system
Analysts gain access to cross-study data through the PI/nominee of the study through which they are affiliated
Currently, several PIs/nominees have approved access
See section “Data sharing”

15. Cross-study genotype call set
How data sharing via the Exchange Area works
Study A: phenotypes
Study B: phenotypes
Study C: phenotypes
dbGaP Exchange Areas
Cross-study genotype call set
Local Study Storage
Study B
Cross-study
Association analysis
Local Study Computers
Uploaders
Downloader
Uploading requires study registration
Downloading requires Data Access Request approved by NHLBI DAC

16. Other Data-Sharing Mechanisms
Sharing Exchange Area data in a Cloud Environment requires coordinated dbGaP applications and a Cloud management plan
Study investigators may share their own study’s TOPMed data outside of dbGaP
Data Transfer Agreements are generally required
DCC’s focus is dbGaP sharing, so not able to help with these kinds of arrangements

17. Principles of Data Sharing & Publication in TOPMed
PIs and other investigators who obtain dbGaP approval to download TOPMed data are responsible for how it is used – i.e. making sure that consents and Data Use Limitations are respected by everyone with whom they share the data (generally only within an institution)
Investigators obtain access to data through the PI or other senior investigator of the study with which they are affiliated
Investigators may begin analyzing TOPMed data only after they have an approved paper proposal
Paper proposals must be approved by a TOPMed Working Group prior to submission
Each paper proposal must specify what studies’ data they intend to use and form a collaboration with investigators from that study. PI approval of data use is required prior to submitting the proposal.
The person submitting the proposal must also select specific study-consent groups as they become available and sign off on their agreement to abide by the Data Use Limitations

18. Paper Proposal Process
Steps for TOPMed paper proposal development and approval:
Develop proposal  within a TOPMed Working Group (WG), including selection of studies to be analyzed. Approval by this WG is required before proceeding.
Discuss data access mechanisms with leaders of the TOPMed study with which you are affiliated
Request initial approval from PIs for use of data from selected studies. Approval (or failure to respond within 2 weeks) is required before proceeding.
Submit the paper proposal for scientific review using the online form; this will be reviewed by the TOPMed Publications Committee.
Submit data set selection for review ; this will be reviewed by the PIs of the selected data sets.

19. Date set selection sample
Excerpt from
Each data set corresponds to a single dbGaP consent group within one TOPMed component or main study that has completed TOPMed dbGaP registration
By selecting a data set, the proposer agrees to its displayed Data Use Limitations (DUL)

20. Check your paper proposal to see for which consent groups you have approval. Your manuscript will not be approved for publication if it uses data sets not listed here as approved!

21. Links to resources Guide for Working Groups
Data Sharing through the TOPMed Exchange Areas
Paper Proposal Instructions
Many other pages on the TOPMed web site
Questions: Contact the DCC program coordinators and they will answer or route your query to the appropriate person

22. Extras

23. Paper proposal submission for scientific review

24. Agree to Data Use Limitations (DULs)
After you select your data sets on this page, you will be asked to agree to the Data Use Limitations (DULs)

25. Your dashboard https://www.nhlbiwgs.org/paperproposals/dashboard
Your paper proposals will appear here. You can also use this to access the data set selection page.