Doctor of Big Data

From the Summer 2016 edition of Vanderbilt Medicine Magazine

Photo by Daniel Dubois
Photo by Daniel Dubois

 

For several months in 2014, Josh Denny, M.D., a 37-year-old father of three young children, and an internist with a busy practice, quietly worked on a project in his office on Nashville’s West End Avenue, that he could not discuss with his family, friends or co-workers.

“I did tell my wife, but I’m not sure I was supposed to,” he confessed with a grin.

During that time he researched, wrote, edited and re-wrote draft papers for an important “client” in Washington, D.C., who was committed to spending $215 million of the country’s fiscal 2016 budget on the project. Important work, in other words.

On Jan. 20, 2015, the entire country was let in on the secret when President Barack Obama announced his Precision Medicine Initiative (PMI) at the State of the Union Address. Denny watched from his couch at home.

“There was a small team—that I was fortunate to be a part of—that created a series of draft papers for what would become known as PMI before the President announced it at his State of the Union address. No one knew what I was working on. It was kind of cool,” Denny recalls. “I couldn’t tell anybody. If the President is going to announce it at the State of the Union, you can’t tell a soul. When the President wants to control the message, you have to be really quiet.

“I did tell a few family members to watch the State of the Union that year—and then told them afterward why.”

“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type — that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?”

Obama used these words to frame his announcement of PMI. Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person—and PMI seeks to dramatically accelerate the medical discovery to bring precision medicine to every patient.

Of the $215 million announced to support PMI, $130 million would be dedicated to beginning the process of building a group of 1 million or more research participants who will volunteer to share their biological, environmental, lifestyle and behavioral information and tissue samples with qualified researchers in a way that protects participant privacy.

Shortly after the State of the Union address, Denny, associate professor of Biomedical Informatics and Medicine, was tapped by the National Institutes of Health (NIH) to help guide planning for PMI and was one of 19 experts in precision medicine and large-scale clinical research chosen for the newly formed NIH Working Group devoted to the initiative.

“Establishing a 1 million person cohort is an audacious endeavor,” said NIH Director Francis Collins, M.D., Ph.D., in an NIH press release. “But the results from studying such a large group of Americans will build the scientific evidence necessary for moving precision medicine from concept to reality.

“I’m confident that we’ve pulled together the best of the best in this working group to put us on the right path forward. And we look forward to broad input from a wide cross-section of stakeholders as this process moves forward.”

 

No Time to Waste

The group had just five months to submit a plan for implementing Obama’s PMI. Denny relocated to Rockville, Maryland, during the summer of 2015 to work on it, living in an apartment just a few Metro stops from the NIH in Bethesda.

Working long hours, Denny would sometimes ponder the reasons he is drawn to precision medicine. Could it have helped his four aunts and uncles, each of whom had succumbed to cystic fibrosis before he was born?

“That is a personal story that is ever present in our family that is motivational as well,” he said.

There are 1,900 mutations that can cause cystic fibrosis (CF), which has no cure. Recently FDA-approved CFTR modulator therapies offer some hope by correcting the function of the defective protein made by the CF gene. So far, they are effective only in people with specific mutations, but it is an example of the possibilities of precision medicine.

What if there was a way to predict how all patients respond to all medications for all diseases? This is the question that Denny hopes to answer, and his drive to do so dates back to his medical school days.

“Once we started going on the wards as med students, I was struck by all the data we were collecting, how regimented health care could be and how little evidence we have for a lot of the things that could be known. I was energized by the opportunity to learn something from everything we do. That desire motivates a lot of what I do. Every opportunity to engage a patient is an opportunity to learn, both individually and by scale. I think Vanderbilt’s been a leader in that,” said Denny who helped engineer the de-identified electronic health records linked to more than 215,000 genetic samples stored in BioVU, Vanderbilt’s massive DNA repository.

In Bethesda, working with a group of like-minded big data enthusiasts from top-20 academic medical centers and the private sector, Denny drafted the report and coordinated deliberations, while Dan Masys, M.D., former chair of Vanderbilt’s Department of Biomedical Informatics, provided extensive consultation.

On Sept 17, 2015, their report—The Precision Medicine Initiative Cohort Program—Building a Research Foundation for 21st Century Medicine—was announced by Collins. The report helped define what can be learned from a study of this scale and scope, and considered issues related to the study design, and what success would look like five and 10 years out.

 

The New Framingham

On Feb. 25, federal officials with the White House and the NIH announced that VUMC will lead the Direct Volunteers Pilot Studies under the first grant to be awarded in the federal Precision Medicine Initiative Cohort Program.

“This award speaks to Vanderbilt’s investments not only in genomics and pharmacogenomics, but also in community engagement and in the people and informatics tools needed to create, analyze and make available to the community very large datasets,” said Dan Roden, M.D., Senior Vice President for Personalized Medicine, and an originator of BioVU.

Denny was named principal investigator of the grant and will oversee the effort to create a set of technologies and experiments that will inform the successful approach for the research cohort of 1 million volunteers. Collaborators include experts from Verily (formerly Google Life Sciences) as well as the University of Michigan and the Broad Institute of MIT and Harvard.

“The Precision Medicine Initiative is a grand experiment on a scale that has never been tested before. We’ll pilot how to authentically engage individuals to participate in the program and build the initial informatics and Web infrastructures to support it,” said Denny, comparing it to the Framingham Heart Study of the 1950s, which recruited men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, whom would be analyzed for common patterns related to cardiovascular disease development.

“PMI is the Framingham for the next generation—a project that could last 50 years or more. Framingham started with 5,000 people; we are starting with 1 million, so we have to be a lot more efficient with how we collect data and engage people. Modern technology should help that.”

As part of the Direct Volunteers Pilot Studies, VUMC will create a prototype website that engages a diverse array of potential volunteers, and develop an interface for obtaining consent, basic enrollment and health information. This information, when combined with genetic and other molecular data, will provide a broad platform that can be used for discoveries that will help advance the science of preventive care, as well as new treatments, and potentially cures for diseases.

And they will do this before the end of the year.

“President Obama wants this to happen under his watch, so it will,” Denny said.