Data Access: Where are the data?

When the Parent study has a dbGaP accession that preceded the existence of the TOPMed program, phenotypic data are in the Parent accession. Otherwise, the phenotypic data are in the TOPMed accession. A number of phenotypes have been harmonized across the TOPMed program.

Unphased genotype calls from TOPMed WGS are available in the TOPMed accession as Variant Call Format (VCF) files. Studies may have multiple sets of VCF files corresponding to the various TOPMed data freezes. The VCF files contain variant-level quality metrics and a support vector machine (SVM) quality filter. The table below summarizes TOPMed WGS characteristics by freeze.

Read alignment data (WGS):  A limited number of TOPMed Phase 1 Compressed Reference-oriented Alignment Map files (CRAMs) aligned to build 37 are available directly through the dbGaP Sequence Read Archive (SRA). These are accessible via their corresponding TOPMed accessions with dbGaP approval . All other CRAMs, including build 38 alignments for all TOPMed WGS samples, are hosted in NHLBI cloud buckets and accessed using Fusera software.

• Instructions for controlled access to TOPMed sequence data on the cloud
• Further documentation on dbGaP cloud access

TOPMed is generating a rich resource of multi-omics data that will include approximately 40,000 samples undergoing RNA-sequencing, 37,000 samples from metabolomics profiling, 57,000 samples from DNA methylation, and 4,000 samples from proteomics assaying. These projected totals include all stages of progress, from DNA/RNA that are currently being extracted, that are undergoing sequencing/profiling, or that have completed sequencing/profiling pipelines. Omics data will be released to the scientific community via NIH-designated repositories (dbGaP and BioData Catalyst).

• Non-WGS omics pipelines and flowcharts are available on the Methods webpage (scroll down)
• Omics progress 

The NHLBI established the Clinical Data Science IRB (CDS-IRB) to provide a useful resource for the research community by offering—at no cost—central review of secondary research proposals utilizing NHLBI datasets for which IRB approval is required.

As a central IRB for research protocols that propose secondary analyses of existing clinical data, the CDS-IRB will address the growing complexity of research and non-traditional uses of biomedical data. Broad utilization of the CDS-IRB will also provide an opportunity for the NHLBI to systematically understand the evolution and range of requests to conduct secondary analyses, recognize emerging trends, and explore ways to enhance data stewardship with the research community.

The Informatics Research Center’s (IRC) joint calling process produces a multi-study VCF file for each chromosome, each of which is split into study-specific components. For studies with multiple consent groups, these components are further divided by consent groups and deposited in the study’s TOPMed accession. The same variants occur in all VCF components of a given call set. To construct a multi-study VCF file for analysis, a user must apply for access to each study-consent group and reassemble the components. Note some TOPMed accessions will have VCF files for more than one data freeze. Therefore, users must take care to select VCF files from the same freeze for their multi-study reassembly. Tools for combining VCF files include vcftools and bcftools.

The Parent studies contributing to TOPMed have many phenotypic measures in common, thereby providing opportunities for cross-study analyses to gain power in detecting genetic effects. However, these studies’ designs differ in how their phenotypic data were collected, and in how their data are annotated and structured. Creating harmonized phenotypic data sets for cross-study analyses is therefore a challenging and largely manual process. Users will need to carefully evaluate the source phenotypes and accompanying documentation before attempting to harmonize across studies. The TOPMed phenotype harmonization efforts are described under TOPMed harmonized phenotypes for the scientific community, along with a phenotype tagging project that can assist members of the scientific community in finding related phenotype variables to perform their own harmonization.

The TOPMed ACC centrally assigns each molecular sample in the TOPMed program a unique sample identifier (e.g., for DNA, “NWD” followed by 6 digits), which is used in all files containing TOPMed sequence, genotype, or other molecular data. Subject (aka participant or individual) identifiers are assigned by study investigators and are not guaranteed to be unique across all studies. The subject identifiers are associated with individual-level phenotypic data and, in most cases, are consistent between the TOPMed and Parent accessions for a given study. Mappings between sample and subject identifiers, as well as subject ID aliases, are given in standard dbGaP files labeled as subject-sample mapping and subject consent files.