The Future of Precision Medicine

Collaboration, Integration, Participationprecision medicine initiative

Today the White House hosted the Precision Medicine Initiative (PMI) Summit, celebrating the first year since the President’s announcement of the Precision Medicine Initiative. The entire team at DNAnexus shares President Obama’s sense of excitement as we reflect upon what’s been accomplished; even as we roll our up sleeves and get busy doing the hard work the lies ahead. John Holdren, Director of the White House Office of Science and Technology kicked off the event announcing the progress of a few remarkable initiatives 1) the NIH advancing cancer clinical trials through the development of large research cohorts, 2) the Million Veteran Program which has enrolled 150,000 vets to date and is now open to active duty women and men, and 3) the precisionFDA community platform for NGS assay evaluation and regulatory science, which just launched its first “Consistency Challenge”.

There were a number of inspirational stories from patients and families recalling their own struggle with disease and how precision medicine aided in diagnosis and treatment. It is so rewarding to see real-life examples of how genomic sequencing is being used to diagnose genetic disorders in the clinic and advance treatment and, ultimately, help patients lead healthy and happy lives.

What resonated most for us from the White House PMI panel was the President’s remarks on the healthcare system. Although it is a system labeled for “health care”, it is actually a “disease care” system. The U.S. healthcare system has been designed based on patient passivity; patients wait until they are sick and then it’s the doctor’s job to treat the disease/condition. Instead, we need to transform the healthcare industry to play a more active role in health and get health information into the hands of consumers. This will allow patients to remain healthy and keep disease from manifesting in the first place.

In order to make the President’s PMI a reality, we need to make anonymized patient data available to researchers and to merge information from different studies in order to advance medical research. We believe in a secure and unified platform; one that connects thousands of scientists around the world. True scientific breakthroughs are possible when researchers are able to collaborate openly, securely, and transparently around petabyte-sized datasets.

It’s been a remarkable twelve months for DNAnexus. , We’ve had the opportunity to contribute to a range of efforts expected to advance the science of precision medicine and accelerate its translation into tangible clinical benefits. Examples include:

Looking ahead, we believe that the realization of precision medicine’s promise requires the intelligent integration of genetic data with electronic health record data and a range of other data types. Successfully doing this requires the technology to effortlessly collaborate around large volumes of data in a secure and compliant fashion – which DNAnexus provides. But meaningful progress also requires the commitment to share relevant data, which we believe is developing, especially as (a) stakeholders increasingly recognize the scientific advantages of collaboration as opposed to a history of secrecy and data silos; (b) stakeholders begin to appreciate the ease and security of cloud computing in this process; (c) patients appropriately demand and belatedly receive more ownership of their own (damn!) data, and can easily elect to contribute that data to scientific research.

We’ve been privileged to be so deeply involved in the mission of precision medicine, and are excited by the opportunities to drive this work forward. As a business, and as a U.S. business, we are excited to see President Obama’s vision for precision medicine and improved health care align with our own.

precisionFDA: Why It Matters

Screen Shot 2015-12-15 at 9.32.57 AMI hadn’t intended to write about precisionFDA going live – this post by Dr. Taha Kass-Hout and Elaine Johanson of the FDA provides a terrific summary, and this post by Angela Anderson of DNAnexus offers valuable additional context. However, I found myself today so excited by this project and what it represents that I can’t resist offering a few additional thoughts about what makes this initiative so special.

First, it addresses an important problem in the field: the analytic validity of NGS tests. The ready availability of relatively inexpensive sequencing has enabled us to contemplate diagnostic sequencing at a scale that would have been difficult to imagine even a decade ago. At the same time, the drive to apply sequencing in different clinical contexts raises a critically important question: do I trust this test? A key starting point for clinical interpretation of DNA data is to agree on the sequence itself. If your procedure and analysis reports that a particular sequence in a DNA sample is “GATCGATC” and my procedure and analysis of the same DNA says the sequence is “GATTGATC,” then we’ve got a problem. precisionFDA will allow users to compare approaches, figure out what’s working, and determine where refinements might be needed.

Second, precisionFDA represents a novel and forward-thinking approach to regulation. Rather than envisioning governmental regulators as the folks who will define and then impose a specific set of performance standards, precisionFDA instead sees the government as providing the platform that will enable the NGS community to evolve the standards on their own — organically and transparently.

Finally, the ability to design, refine, and deploy this platform in such a rapid and agile fashion reflects in part the value of well-conceptualized public-private partnerships, in this case between the FDA and DNAnexus. By intentionally leveraging the skills and capabilities of a company like ours, the FDA was able to implement and realize their exciting and ambitious vision.

The ultimate success of the precisionFDA platform will of course depend upon how well it serves the community it is intended to support. However, it’s hard to think of a more auspicious beginning, and my hope would be that success here will encourage more leaders to evaluate the potential of public/private partnerships to deploy platforms that leverage the power of a distributed innovation community to address important shared challenges.

FDA Advancing Innovation Through Deep Collaboration

Today, the FDA announced the beta release of precisionFDA, a community platform for NGS assay evaluation and regulatory science exploration. They are now accepting applications to the precisionFDA community, you can learn more and request access here.

Over the years, genetic testing has become increasingly useful in the diagnosis and treatment of disease in a few areas, including cancer, birth defects and rare diseases. However, for the majority of the population, precision medicine is still far from becoming a reality. FDA’s Center for Devices and Radiological Health and the agency’s Chief Health Informatics Officer, Dr. Taha Kass-Hout, embarked on a bold, new initiative for realizing precision medicine, by establishing precisionFDA. You can read more about their endeavor here.

Currently, most diagnostic tests follow a “one test-one disease paradigm” for evaluating analytical performance. However, diagnostic tests employing next-generation sequencing (NGS) technology can scan up to the entire genome, producing a massive amount of data and are capable of potentially detecting multiple conditions in a single test. The FDA realized that due to the advances in NGS-based technology, a new approach would be required for evaluating the accuracy of a test.

PrecisionFDA was established to help advance the regulatory science needed to assess the accuracy of genome tests and software. By providing a secure cloud-based platform that is open and transparent to the genomics community, researchers and test developers can explore NGS methodologies in order to spur innovation needed to develop necessary standards.

PrecisionFDA is a research sandbox that provides the genomics community with a web portal where they can experiment, share data and tools, collaborate, and define standards for evaluating analytical pipelines. Requirements for the precisionFDA platform were based on suggestions received through a public forum as well as use cases the FDA has gathered throughout the years.

Here are some key features of precisionFDA:

  • FILES – Upload your own files on cloud storage or generate files through running apps. You can publish reference data or any other files, or browse other members’ contributions.
  • APPS – Run mapping & variation calling pipelines or other Linux-based software apps on the cloud. Contribute your own software and scripts and let others explore them.
  • COMPARISONS – Quantify the similarity between two sets of genomic variants (VCF files). Compare your own test set (for a given biospecimen) to establish benchmark sets.
  • NOTES – Write and publish rich notes describing your work. Attach any files, comparisons or apps to your notes. Read what others are reporting and reproduce their workflows.

The concept of comparing two sets of variants (VCF files) is central to the exploration of regulatory science, and to the evaluation of NGS assays. The problem of comparing VCF files constitutes an active area of research. The precisionFDA building crew is represented in the Global Alliance for Genomics and Health (GA4GH) Benchmarking Task Team, which is expected (within the next year) to provide recommendations and/or software solutions for comparing VCFs and for counting, classifying, and reporting results. In the meantime, precisionFDA offers an initial VCF comparison framework, put together in consultation with NIST.

Check out the precisionFDA documentation for some great ideas for using comparisons, including assessing reproducibility and accuracy of NGS tests and bioinformatics variation calling pipelines.

PrecisionFDA follows a robust, audited set of policies, processes, and controls for security and compliance. When your data is in your private area, it is indeed private. It’s not visible to the FDA, members of the precisionFDA community, or any other entity. The platform provides users with access controls for their artifacts (files, apps, jobs, app assets, comparisons, and notes), so that they can either remain private, or published to the precisionFDA community.

Lastly, precisionFDA would be nothing without the support and engagement from its community members. As of today, early adopters have already contributed many valuable tools and reference datasets to the platform, and there are many more in the works! Here is a preview of what you can find on precisionFDA today:

  • NA12878 benchmark calls made by NIST (Genome in a Bottle v2.19)
  • NA12878 benchmark calls made by Illumina (Platinum Genome v8.0.1 and an updated kmer-filtered v7.1.0)
  • HuRef (J. Craig Venter) benchmark calls made by Roche/Bina
  • NA12878 exome test calls made by the Broad Institute
  • NA12878 whole-genome sequencing and test calls made by the Garvan Institute (using the Illumina HiSeq X Ten)
  • Software assets and apps for simulation and evaluation using VarSim, added by Roche
  • An app for local ancestry analysis with RFMIX, added by Stanford

Additional early members of the precisionFDA community:

  • 23andMe
  • Baylor College of Medicine
  • Counsyl
  • Emory Genetics Laboratory
  • GeneDX
  • Human Longevity Institute
  • Intel
  • Natera
  • NIST/GIAB
  • Personalis
  • SeraCare

Above everything else, precisionFDA is a community, where people can collaborate, communicate, and even argue for the future of precision medicine. We are privileged to have been selected as the contractor for this pilot, and look forward to our collaboration with the FDA as the platform and community evolves. At this time, the precisionFDA platform includes features such as App Forking, Item Tracking, and Notes, which ignite collaboration, content expansion, and workflow validation and reproduction.

The Notes section, in particular, lets participants write and publish rich notes describing their thoughts and their work; for example, they can discuss how they used files, comparisons, and apps—which they can also attach to the note—to prove a certain point or to document a procedure. Community members can read what others have reported and access their attachments to take a closer look at that work or even reproduce it on their own.

We believe this new level of collaboration and reporting, together with everything else that precisionFDA has to offer, will define new frontiers for people to showcase to the FDA and to the rest of the community how to address the challenges of precision medicine in the 21st century.