Genotype imputation plays a key role in genome-wide association studies and polygenic risk score analyses by expanding the portion of the genome that can be analyzed for phenotypic associations, at a fraction of the cost of sequencing. Imputation services allow researchers to leverage large reference panels (without direct access to protect participant privacy) while also eliminating the need to build and manage the complex computational infrastructure required for imputation pipelines.

The largest and most diverse panel in the world

Our imputation service features a diverse reference panel of genomes from over 515,000 participants from the All of Us Research Program and AnVIL Center for Common Disease Genomics, including more than 250,000 genomes from non-European inferred genetic ancestries. 

Figure 1.  The All of Us + AnVIL reference panel contains more than 515,00 total genomes from the following computed genetic ancestries: 254,416 European (49%), 101,982 African (20%), 90,553 Americas (18%), 13,226 East Asian (3%), 9,710 South Asian (2%), 1,065 Middle Eastern (0.2%), and 44,627 remaining individuals (9%). 

The All of Us + AnVIL reference panel is the largest and most ancestrally diverse reference panel currently available, enabling researchers to enhance their datasets with greater accuracy. When imputing 42 arrays representing an ancestrally diverse set of samples against their whole genome sequences, we found high confidence (R² of 0.7) in both imputed SNPs and indels, even at very low allele frequencies in most ancestries. You can read more about our reference panel in our documentation.

Figure 2. Mean R² values for imputed SNPs (top) and indels (bottom) across all chromosomes compared to their respective 30X whole genomes for 42 samples from diverse ancestries (African, African-American, Admixed American, East Asian, Non-Finnish European, South Asian). The X axis is allele frequency, and the Y axis is the mean R². 

Secure and scalable infrastructure

Behind the scenes, the imputation service leverages the Terra platform. This means you can expect the same level of security and privacy, including the ability to impute controlled access data that requires NIST-800-53 Rev5 FedRAMP Moderate compliance. You can learn more about Terra’s security at https://terra.bio/terra-security/.

Because our service runs on the cloud, you can expect to get your results fast without having to wait in a queue of users. Early testing revealed that submitting 2,500 samples to the service returns results the next day.

Get Started

The beta release of the service offers imputation of array data via a command-line tool called terralab. When a user signs up during the beta release, they may be eligible for credits, allowing them to submit up to 2,500 samples at no cost, thanks to funding from the National Institutes of Health. 

Discover how to utilize our service by visiting our documentation page at https://broadscientificservices.zendesk.com/hc/en-us.

What to expect over the next year

Soon, we plan to release a point-and-click web user interface, as well as support for imputing cloud-hosted data. 

With the rapid growth of genomic projects, we are preparing to meet increasing demand. After the beta period, we will transition to a paid model designed to support large-scale studies, expanded pre- and post-analysis options, and the release of imputation pipelines for low-pass genomes. 

Acknowledgments 

This work was made possible by National Institutes of Health (NIH) awards: (1) OT2OD035404, “All of Us Data and Research Center (DRC);” (2) OT2OD03821, “Broad-Color: The Genome Center for the Future of All of Us;” (3) OT2OD002750, “The Broad-LMM-Color Genome Center for All of Us,” funded by the NIH Office of the Director; and (4) U24HG010262, “AnVIL: A National Resource for Genomic Data Analysis and Visualization,” funded by the National Human Genome Research Institute.

We gratefully acknowledge All of Us and Centers for Common Disease Genomics participants for their contributions, without whom this research would not have been possible. We also thank the National Institutes of Health’s All of Us Research Program and NHGRI AnVIL for making available the participant data for the reference panel.

The post Introducing the All of Us + AnVIL Imputation Service appeared first on Terra.

Dockstore has been evolving rapidly thanks to support from NHGRI AnVIL and NHLBI BioData Catalyst, two NIH initiatives centered on hosting petabytes of data in the cloud for researchers to analyze securely and collaboratively, using interconnected platforms that include Dockstore and Terra. As the platform’s capabilities expand, we’re seeing growing numbers of tool developers and organizations contributing content to Dockstore, as well as an influx of researchers who are new to working in the cloud and are looking for workflows that are available “out of the box”.

This kind of growth highlights two key requirements of any repository of community-contributed content: we need to ensure that contributors can manage their content conveniently, and that researchers are able to find the right content for their needs. Today I want to highlight some of the improvements we’ve recently made in this space, which we hope will help meet the needs of our expanding user community and lay solid foundations for sustainable growth over time.

New ways to organize and search for workflows

Over the past year, we’ve introduced two new features that content contributors can use to organize their workflows, called Organizations and Collections. The Organizations feature is meant for grouping workflows produced by a particular team, institution or consortium. At the next level down, the Collections feature is intended to help group content by topic or use case. For example, if you look up workflows published by the Broad Institute, you’ll see that the Broad’s workflows are further grouped into Collections that reflect different functional areas and projects. 

Screenshot of the Broad Institute’s Organization page on Dockstore showing 2 of the 7 Collections currently maintained by Broad teams.

Both Organizations and Collections are controlled by verified members of the organizations in question; creating a new organization involves making a request to the Dockstore curation team, who will verify the affiliation of the requestor, which helps ensure that users can trust the provenance of the workflows they find in the repository. Organizations have three membership levels (Admin, Maintainer, Member) with varying permissions to allow administrators to maintain all current members of their organization while also being able to moderate changes by only giving certain members editing privileges. There are currently 31 verified organizations that publish their workflows in Dockstore!

In a similar vein, content contributors can now link their ORCID profile to their Dockstore account, which makes it easier for anyone interested in their content to look up their qualifications and published work. Currently, ORCIDs are displayed as part of the user thumbnails shown in the list of an organization’s members, and in the list of users who have “starred” an organization or a specific workflow. 

The process of linking your ORCID profile is straightforward; see this documentation article for instructions. Keep an eye on this feature as we plan to enhance our integration with ORCID to offer more ways to share your workflow contributions with the research community. 

Integrating development, deployment and publication

From a functional standpoint, we also want to make it easy for contributors to keep their content up to date with minimal manual intervention. To that end, we recently published a Github App that enables developers who use Github to set up their code repository to automatically sync with Dockstore. The process involves doing a one-time registration step per repository or organization, described here, and adding a short .yml configuration file to your Github repository, listing the workflow(s) that should be synced. Note that this can be used to register workflows in Dockstore in the first place, bypassing the “normal” manual workflow registration process. 

When your content on Dockstore is ready for an official release, you can create an immutable “snapshot” version of your workflow and request a Digital Object Identifier (DOI) for it through Zenodo, so that others can cite it in their own work. 

Screenshot of an example workflow’s version management page showing the snapshot creation and DOI request action links. 

You can find detailed instructions on creating the snapshot and DOI in the Dockstore documentation. 

A video playlist to learn more about how to use Dockstore to the fullest

Finally, if you’re just getting started and all this sounds lovely, but you’re not sure how to get started with Dockstore, check out our new video series on YouTube. It was originally a full end-to-end online workshop that we recorded, which had the advantage of covering all the topics you’re likely to want to learn as a newcomer with the platform in a well-ordered progression, but at a runtime of over 2 hours it was daunting and impractical for most viewers. So we cut it up into a playlist of short digestible segments that maintains the original continuity yet is a lot easier to tackle by increments, and also allows you to jump to specific topics much more conveniently.

I hope this will help you take full advantage of Dockstore’s latest improvements, and I look forward to following up on this to announce other enhancements to the platform that are currently in progress. 

Resources

For a short review of how to import a workflow from Dockstore starting from within a Terra workspace, see this video, starting at 2:11.

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