Experts Look to Big Data to Identify New Therapeutic Targets for CVD

Recent technological advancements — including portable ECGs, wearable health monitors and printable tattoo biosensors — have made complex data more available than ever, according to Eric Schadt, PhD, of the Icahn School of Medicine at Mount Sinai, New York, N.Y. These data, he said, will be instrumental in the development of molecular profiling technologies to create a more holistic view of the health of individuals

During a keynote address at TCT 2014, Schadt discussed the challenges of using integrated data to improve health at both the individual and population level.

“We are living in a big data universe,” Schadt said. “Can we leverage the digital universe of information that can be generated about individuals and populations of individuals to make better predictions about how we can diagnose and treat patients?”

According to Schadt, it can be done by integrating data on components like DNA, RNA, metabolites and proteins to better understand the networks they comprise. These networks, Schadt said, drive biological processes that cause disease; if we better understand these complex networks, we will better understand the best treatment approach.

Application in research  

To give the audience an idea of how this is possible, Schadt cited a 2012 paper published in Nature in which he and colleagues analyzed 163 genetic loci for inflammatory bowel disease (IBD) in the context of molecular networks. By projecting these loci onto the network, the researchers were able to identify biological processes in sub-networks and determine the role of specific genes in the course of disease. Once sub-networks are identified, computer simulations can then be performed to better understand which specific genes are important. At times, “key modulators” — genes that change the network to a disease state or healthy state — are identified, he explained.

From there, therapeutic targets can be explored, Schadt said; they can be used to map marketed drugs, natural products or environmental interventions like diet and exercise in order to identify appropriate treatment approaches. In the Nature article, he and colleagues determined the antiseizure drug topiramate is as effective as prednisolone for the treatment of IBD in rats.

Potential in CVD  

Schadt is currently working with Valentin Fuster, MD, also of Mount Sinai, to apply this integrative approach to CVD using the STARNET Biobank. The group has access to tissue samples — including artery wall, atherosclerotic lesion, subcutaneous fat, liver and skeletal muscle — obtained from over 1,000 patients undergoing open thoracic cardiac surgery. Roughly half of these patients had CVD, and the other half underwent the procedure for other reasons, creating a control group from the CVD standpoint, Schadt said. Like the study in IBD, researchers can now integrate these data into workflows to identify molecular networks in an effort to better understand CVD. Thus far, Schadt and colleagues have identified networks consisting of genes that have been shown to increase the risk for CVD, including PCSK9 and ABCG5. Pipelines are also in place to perform higher throughput validation of these networks, he said.

“At the end of the day, what we’re hoping to do is use this information — the networks that we form here — and start mapping individuals through the perturbations in their DNA [and] the perturbations in their environment, and start locking onto which sub-networks in the vast network of the complexity of life are underlying their particular form of disease, their particular form of CVD,” Schadt said. “Once we know those molecular mechanisms at play, we can map those to therapeutics or behavior modifications. … That ultimately is the goal of this work in the future: We can guide one’s health course by better monitoring the health of the individual both at the molecular and physiological level to achieve this kind of benefit.”

Disclosures:

• Schadt reports serving on the science advisory board for Ayasdi, Berg Pharmaceuticals, Ingenuity, NuMedii, Pacific Biosciences and Whole Biome. He also reports research collaborations with Eli Lilly and Janssen Pharmaceuticals.