Profiles in research: John W. Cole, M.D.
Before going to medical school, John W. Cole, M.D., M.S., was an electrical engineer troubleshooting computer circuits.
He does similar work today in the human brain. As a vascular neurologist, Dr. Cole tries to disarm blood clots that cause strokes. His aim is to save stroke patients’ lives and prevent stroke-related disability.
While many stroke patients who come in soon after stroke symptoms start have good prognosis, those who wait to be treated or don’t recognize stroke symptoms often suffer from long-term disability or death.
However, there’s another aspect to Dr. Cole’s job that he considers just as important as treating stroke patients, namely stroke prevention. “Part of my drive is to figure out ways to prevent stroke because it’s such a devastating illness,” said Dr. Cole, an associate professor of neurology at the Maryland Stroke Center, Baltimore VA Medical Center and University of Maryland School of Medicine.
Through a grant from the American Heart Association’s (AHA) Institute for Precision Cardiovascular Medicine, he conducts research through the AHA Precision Medicine Platform to better understand how having certain genetic variants might make some people more prone to stroke.
“Genetics play a role in stroke for sure,” Dr. Cole said. “The question is how do genetic variants interplay with each individual? Is it based on their risk factor profile, which can include smoking or high blood pressure, that certain genetic causes have a higher effect?”
One of the large datasets that Dr. Cole and colleagues are using to conduct their research is one they’ve compiled of 1,000 young stroke patients—younger than 49. For comparison, that dataset includes a similar group of 1,000 people who have not had stroke.
“If you’re young and have a stroke, there is probably a greater propensity for genetic drivers,” he said.
Dr. Cole’s most recent grant from the Institute focuses on a stroke type caused by small vessel disease, which accounts for 20% to 25% of strokes and is a leading cause of disability.
Using the power of precision medicine, Dr. Cole and colleagues ran genetic panels on all 2,000 people in the young dataset, looking at genetic variants throughout each individual’s genome.
“We’re looking to see if there’s a higher incidence of certain genetic variants in stroke cases and have been able to tease out some genetic risks using our young-onset stroke model, which we’re presenting early next year at the AHA’s International Stroke Conference ,” Dr. Cole said. “The next step is to determine how these genetic variants increase risk. This could be due to an interplay between standard risk factors such as hypertension or diabetes, or through inflammation or increased clotting, or pathways we have yet to consider.”
His ultimate goal is to tailor-make prevention strategies based on an individual’s genetics to reduce stroke risk.
AHA’s Institute is helping foster Dr. Cole’s and other researchers’ work by pooling large datasets and making them accessible.
“One of the key things you have to do, especially in genetics’ research, is once you’ve found something you need to be able to replicate it,” Dr. Cole said. The AHA’s Precision Medicine Platform also facilitates such replication studies. Once replicated, researchers’ discoveries can be put into practice—in the case of Dr. Cole’s research to prevent stroke.
Profiles in research: Stacey Knight, Ph.D.
Intermountain Medical Center, in Salt Lake City, has a goldmine of patients’ clinical health records data collected during the last 20 years. With sophisticated research tools available through the AHA Institute for Precision Cardiovascular Medicine, Intermountain researchers are mining the data to turn it into meaningful heart health discoveries.
Stacey Knight, Ph.D, a cardiovascular and genetic epidemiologist at the Intermountain Medical Center Heart Institute, said the medical center added genealogy (family history) records to match its 1.6 million patient database. Linking clinical to genealogy information will help researchers better understand not only what’s going on health-wise in individual patients, but also how family relationships as distant as nine generations apart might impact disease risk.
“Our project takes those two very large datasets and use the American Heart Association’s Precision Cardiovascular Medicine platform to accelerate findings of cardiovascular disease-related genetic causes,” Dr. Knight said.
The researchers also have access to DNA information for about 10,000 of the people in the dataset. DNA can reveal how shared genes for gene variants in one’s pedigree plays out in a person’s risk for cardiovascular disease.
Finding clues to a person’s disease risk using genetic, DNA and clinical data used to be like searching for a needle in a haystack. Traditional statistical analysis doesn’t work. Instead today’s researchers use technology to do simulations to find what might be fueling disease risk.
There are about a billion such simulations in this research, Dr. Knight said. Combing through the data in the past might have taken years on a single computer. But with the AHA’s platform--using multiple computers across a cloud--the search should take only weeks.
An example that’s already beginning to emerge is a pedigree with a high-risk for an irregular heartbeat called atrial fibrillation, or AFib. This particular pedigree of related people is five times more likely to have AFib than the general patient population.
“They tend to also have early-onset A-fib. At least eight of the pedigrees have AFib starting in their 50s,” she said.
In another pedigree, Dr. Knight and colleagues have found individuals with stable coronary artery disease, meaning they have severe three-vessel coronary artery disease but aren’t getting heart attacks at the rate one might expect.
“We’re searching for what’s protecting them from advancing to having a heart attack,” Dr. Knight said.
Yet another thing that’s remarkable about doing sophisticated research with large data sets on the American Heart Association’s precision medicine platform is that other researchers will be able to study the data, asking their own questions and searching for answers. “We’re hoping to set this up so that other researchers could come in and find a pedigree that they might find interesting. They could use the DNA in that pedigree, do genotyping and then use the same analysis pipeline that we’ve set up,” Dr. Knight said.
The AHA has made it possible for a non-academic hospital to do the kind of research that once only well-funded academic centers could.
“Our focus isn’t cloud computing, and I’m not at a university,” Dr. Knight said. “This allows us to take the data that we do have and use resources that we don’t have to pay to maintain.”
The cost associated with setting up a project like this would be enormous for most hospitals. Instead, researchers can use the American Heart Association’s platform, which offers a secure setting in which only the information is available—not data needed to identify patients.
The reality is research of this magnitude could reveal why some people and their ancestors do or don’t get different types of diseases. Armed with the knowledge, doctors would be positioned to address known risks with medications or lifestyle modifications. With the help of futuristic gene altering technologies, they might even be able to change a person’s genetic profile to prevent disease, according to Dr. Knight.
Profiles in research: Anand Rohatgi, M.D., M.S.C.S.
Researchers have established low-density lipoprotein cholesterol’s (LDL-C) important role in heart disease. By lowering the so-called bad cholesterol with lifestyle modifications and cholesterol-lowering drugs, people can reduce their cardiovascular disease risk.
That’s vital information in the fight against cardiovascular disease, but it’s only one piece of the puzzle.
The problem is cardiovascular disease remains the leading cause of death among men and women, according to Anand Rohatgi, M.D., M.S.C.S., associate professor of cardiology, UT Southwest Medical Center, Dallas, Texas.
What scientists haven’t yet figured out is high-density lipoprotein cholesterol’s (HDL-C) role in heart health. Studies suggest the “good” cholesterol might have the power to remove cholesterol from arteries and plaques, which is called reverse cholesterol transport, according to Dr. Rohatgi.
“But we don’t really have any therapies that target that and work that way. HDL hasn’t gotten a lot of attention because it has been unclear how to measure it and how to define what it does,” Dr. Rohatgi said.
The AHA Institute for Precision Cardiovascular Medicine has provided Dr. Rohatgi and colleagues with not only the financial resources to do his work, but also large frameworks of patient data and sophisticated research tools needed to find out what HDL-C can do and, eventually, how to harness it to remove bad cholesterol. That wasn’t possible with research methods of the past, he said.
“HDL is complex. It’s not just a carrier of cholesterol. It has proteins on it and a lot of other particles that allow it to do what it does,” Dr. Rohatgi said. “With today’s advanced research tools, we can use a person’s genetics to figure out if they have mutations that make their HDL better or worse in terms of moving cholesterol. We can use a technique called deep phenotyping to measure specific cholesterol entities that are on the HDL particles or work with the HDL particles.”
Through the Institute, Dr. Rohatgi has access to important health information from more than 15,000 adults.
“Using these large cohorts of people with available specimens and the deep phenotyping approach, we’ll better understand HDL’s precise function not just for the population as a whole but for specific individuals,” he said. “Our goals are use genetics, lipid metabolites, specific proteins and to combine them to get a very precise, unique signature for each person in terms of that person’s ability to remove cholesterol from plaques.”
The researchers will look at how the HDL-C signature might be different among people according to gender or ethnicity. Among the next steps in the research will be to figure out whether a person’s HDL-C profile better predicts an individual’s heart disease and stroke risk than what’s available today.
“Hopefully, we’ll be able to use this knowledge to promote development of new therapies that can target removing cholesterol effectively and decrease heart disease,” Dr. Rohatgi said.
Profiles in research: Guido J. Falcone M.D., Sc.D., M.P.H.
Spontaneous intracerebral hemorrhage happens when a weakened vessel ruptures in the brain. It’s the most devastating stroke type. Nearly one-third of intracerebral hemorrhage patients die in the hospital and only one-third regain functional independence.
A neurologist also trained as a genetic epidemiologist, Guido J. Falcone M.D., Sc.D., M.P.H., has made it his goal to not only uncover common genetic mutations in intracerebral hemorrhage patients, but also better understand how the risk of this disease differs among ethnicities. The foundation of his research is today’s largest collection of genetic studies of intracerebral hemorrhage.
“The world of genomics and genetics has changed. It used to be that we thought DNA was a static thing and a mutation was a rare occurrence, and that people who had a mutation had a disease,” said Dr. Falcone, assistant professor of neurology at Yale School of Medicine.
Today, scientists know otherwise. Mutations aren’t rare and people who have them might be at higher disease risk but not ever get the disease. “What we know now is that if you look at the general healthy population, there are about 50 million common variations in our genome, also called common genetic variants. My research focuses on understanding how these common genetic mutations influence the occurrence, severity and recurrence of stroke—particularly intracerebral stroke,” Dr. Falcone said.
He aims to establish an association between one or more of these common mutations and intracerebral hemorrhage.
“That can tell us two things: by looking at the protein that is coded by the gene that contains the mutation, we can identify new biological mechanisms underlying the occurrence of intracerebral hemorrhage. And we can also use this genetic information to find new pathways to treat this type of stroke,” according to Dr. Falcone. “Once we identify one of these mutations, we can look at a combination of these mutations and try to gauge a person’s risk even before that person has the disease. That’s the world of precision medicine.”
Dr. Falcone has no plans to do his research in a vacuum. His goal, in fact, is to democratize the data, creating an open-source pipeline that make the information and tools to process it freely available investigators so they, too, can do research.
Dr. Falcone’s datasets of genomics and intracerebral hemorrhage are vital to stroke research also because they include different ethnicities. “Most genetic research so far has been done in whites. The data we’ll be working with contains almost equal portions of whites, blacks and Hispanics,” according to Dr. Falcone. “That’s important because we cannot assume that connections between mutations and disease identified for whites apply to other races.”
In fact, researchers already know the risk for intracerebral hemorrhage is not equal across races. The stroke type is more common among African Americans. The most important risk factor for intracerebral hemorrhage is hypertension, and this racial/ethnic group have a higher prevalence of hypertension.
This research could revolutionize the field of minorities’ research in intracerebral hemorrhage genetics by collecting, harmonizing and publicly sharing the largest trans-ethnic collection of genetic studies looking at this devastating disease to date, according to Dr. Falcone.
Profiles in research: Juan Zhao, Ph.D.
Juan Zhao, Ph.D., has in the last decade honed her skills in machine learning and deep learning. She graduated with a Ph.D. in computer science from the University Chinese Academy of Sciences in Beijing, China, and spent the subsequent years using that knowledge to analyze vast amounts of internet data to, among other things, prevent cybercrime.
While the work tapped her skills in data and information analysis, she wanted to pursue research on a more human level, using human data to solve real-world problems. Now she’s realizing that dream as a postdoctoral fellow in the Center for Precision Medicine at Vanderbilt University Medical Center where she puts her skills to use in biomedical informatics Specifically, Dr. Zhao is leveraging the massive amounts of healthcare data at Vanderbilt University Medical Center to improve stroke and cardiovascular disease prediction. Through a grant from the American Heart Association (AHA) Institute for Precision Cardiovascular Medicine, she's using the AHA Precision Medicine Platform to quickly and efficiently identify which features beyond traditional stroke risk factors might impact a person’s stroke risk.
That’s important because stroke is a leading cause of death and disability worldwide. The American Heart Association and other groups have developed models to predict stroke risk based on known risk factors, such as hypertension, age, diabetes, smoking, and atrial fibrillation. But research suggests these risk factors explain only about 15% to 60% of strokes.
"Looking beyond conventional factors is essential for accurate stroke prevention, especially given that stroke is preventable, and its first sign may be fatal," according to Dr. Zhao.
Health record data could help Dr. Zhao and colleagues detect things that increase stroke risk that are not considered traditional risk factors, such as a patient’s genetics, laboratory test results, medication use, medical history, and more. The data also allows researchers to look at more than just a snapshot of the patient, but rather the patient’s health during longer time periods.
"We are looking at how to incorporate such knowledge into existing risk prediction models," she said.
Dr. Zhao and colleagues are harnessing the powers of machine learning and deep learning on Vanderbilt’s longitudinal electronic health records and genetic data including more than 2.8 million patients to better predict 10-year stroke risk. Better ability to predict stroke could reduce the risk of death and high financial costs from stroke-related disability.
The idea, according to Dr. Zhao, is to arm people and their doctors with a more accurate prediction of stroke risk so that doctors can optimize treatment, and people can make lifestyle changes before stroke occurs.
The AHA Institute’s Precision Medicine Platform is helping her to translate the massive health data into real-life stroke prediction for individual patients. "The Institute’s platform has fantastic features that allowed us to quickly develop algorithms and share the algorithms with other researchers conveniently," Dr. Zhao said. "I came to Vanderbilt for medical informatics to work with large medical data that comes from the real world, realizing the work could benefit people. This motivated me to do this kind of research and continue my career here. It’s really exciting."
For more information on the American Heart Association’s Institute for Precision Cardiovascular Medicine grants, please go to: www.heart.org/en/professional/institute/grants