TRANSFORM-HF team pioneers new type of clinical trial

January 2, 2019 – One of the first DCRI studies of its kind could become a model for the future.

Heart failure patients have a tendency to accumulate excess fluid in the body, which can lead to debilitating symptoms such as shortness of breath and swelling. Loop diuretic medication, aims to prevent accumulation of this fluid and is the cornerstone treatment for heart failure signs and symptoms. With more than six million Americans affected by heart failure, and about one million hospitalized every year, a new DCRI study called TRANSFORM-HF will directly compare two well-known diuretics – furosemide and torsemide – to determine which is the most effective.

At the same time, the trial’s innovative design could change the way medical research is developed and managed for years to come. Investigators hope that TRANSFORM-HF, which began this summer, will live up to its name – that its innovative approach will transform the clinical trial experience for researchers, site staff, and patients.

“This is one of the first contemporary heart failure studies to significantly streamline the trial process in many important ways,” said Robert Mentz, MD, (pictured) co-principal investigator on the study. “It’s designed to have a lighter touch than most heart failure trials and reduce the burden on everyone involved. We’re striving to surpass traditional rates of site activation and patient enrollment.”

TRANSFORM-HF is being led by the DCRI team and Eric Velazquez at Yale University as well as the National Heart, Lung, and Blood Institute, which recently awarded both institutions grants for the Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC). The primary endpoint is all-cause mortality. Secondary endpoints include patient-reported quality of life and hospitalizations.

The trial was designed to improve the clinical research experience for site coordinators and patients at enrolling hospitals. The study has a projected enrollment of 6,000 patients at approximately 50 sites in the U.S. over the next three years. Enrollment criteria are very broad so that those with both low ejection fraction (weak hearts) and normal ejection fraction (stiff hearts) may enroll. Patients are randomized to either furosemide or torsemide as the study drug, but medication dose and frequency are determined by the patient’s usual medical team.

To date, no large, definitive clinical trial has determined which loop diuretic— furosemide or torsemide—is best, and neither American College of Cardiology nor American Heart Association HF guidelines provides a specific recommendation.

“With slow enrollment across many recent heart failure trials, we’ve been in a particularly challenging time for this kind of research,” Mentz said. “So a key aim was to make TRANSFORM-HF as streamlined as possible for site staff as well as patients, many of whom are elderly and might not otherwise enroll because of the burden of participating in a traditional trial.”

TRANSFORM-HF also aims to streamline data collection and enroll a broad representative population of heart failure patients.

During TRANSFORM-HF, heart failure patients admitted to the hospital are enrolled and randomized equally between the two diuretics before discharge, and then continued on that diuretic as part of their daily care after they return home. While most trials require patients to come to the clinic for extra visits, patients in TRANSFORM-HF follow up per usual care with their normal care teams—there are no extra visits.

Instead, study follow-up is coordinated by the DCRI call center, with patients receiving a 15-minute phone call 30 days into the study and then every six months for up to 36 months, asking scripted questions about medication use, quality of life, and hospitalizations. This “televisit” process saves patients the time, effort, and expense of the extra clinic visits usually required from conventional studies. Hospital records and the National Death Index also will be used to gather follow-up information.

“We knew that if questions were to be answered, TRANSFORM-HF needed to be a really large study in addition to being simple, decentralized, and patient-centered,” said Kevin Anstrom, PhD, co-principal investigator at the trial’s DCC. “There was no way we could do this study with the traditional model.”

“We worked closely with sites on the trial design and the processes to enroll patients and collect patient data,” said Eric Eisenstein, DBA, another co-principal investigator at the DCC. “And because the trial is essentially embedded in the patient’s usual care with their healthcare providers, nothing changes for them –we’re not impacting how they’re otherwise treated. Fewer moving parts lowers trial costs and makes it much easier for everyone in the study.”

According to Eisenstein, investigators also wanted to focus on minimizing the amount of data collected throughout the trial, by, for example, limiting the detail of case report forms. They wanted to optimize the process without sacrificing data quality or the study’s scientific validity, he said.

Because investigators are not “dealing with an investigative product where we don’t know the side effects, this kind of comparative study lends itself well to a streamlined model,” said Mary Creed, MSN, associate director of DCRI’s clinical operations.

“That said, we still have the challenge of keeping the study foremost in patients’ minds and helping to prevent dropout, particularly without the in-person site visits. But simple strategies such as wallet cards in English and Spanish and refrigerator magnets should be helpful.”

TRANSFORM-HF is an exception to traditional HF trials where so few patients qualify, according to DCRI Fellow Stephen Greene, MD.

“Most heart failure trials have many exclusion and inclusion criteria, so only a small percentage of patients seen in general practice qualify,” he said. “TRANSFORM-HF is different – the vast majority of patients seen in everyday practice are going to be eligible. This will help the enrollment rate, and importantly, will also generate trial results that will apply to the at-large heart failure community.”

“Loop diuretics are such an incredibly common heart failure therapy that we really need to know if there is a best one to use,” said Greene. “We owe it to the scientific community, and to our patients, to know the best loop diuretic for heart failure patients.”

Other DCRI contributors on TRANSFORM-HF include Ingrid Jones, Sharon Settles, Varsha Gajjar, Wendy Johnson, Joshua D. Lance, Vivian Thompson, Tina Harding, Amanda Harrington, Kristi Prather, Carol Pereira, Rochelle Suffern, and Shelby Morgan.

Exposure to cannabis alters the genetic profile of sperm

December 19, 2018 – Whether genetic changes can be reversed or are passed on to children is still unknown.

As legal access to marijuana continues expanding across the U.S., more scientists are studying the effects of its active ingredient, tetrahydrocannabinol (THC), in teens, adults and pregnant women.

New research from DCRI and Duke investigators suggests men in their child-bearing years should also consider how THC could impact their sperm and possibly the children they conceive during periods when they’ve been using the drug.

Much like previous research that has shown tobacco smoke, pesticides, flame retardants and even obesity can alter sperm, the Duke research shows THC also affects epigenetics, triggering structural and regulatory changes in the DNA of users’ sperm.

Experiments in rats and a study with 24 men found that THC appears to target genes in two major cellular pathways and alters DNA methylation, a process essential to normal development.

The researchers do not yet know whether DNA changes triggered by THC are passed to users’ children and what effects that could have. Their findings were published online Dec. 19 in the journal Epigenetics.

“What we have found is that the effects of cannabis use on males and their reproductive health are not completely null, in that there’s something about cannabis use that affects the genetic profile in sperm,” said the DCRI’s Scott Kollins, PhD, senior author of the study.

“We don’t yet know what that means, but the fact that more and more young males of child-bearing age have legal access to cannabis is something we should be thinking about,” Kollins said.

National research has shown a steady decline in the perceived risk of regular marijuana use. This, combined with the demand and wide availability of marijuana bred specifically to yield higher THC content, make this research especially timely, Kollins said.

The study defined regular users as those who smoked marijuana at least weekly for the previous six months. Their sperm were compared to those who had not used marijuana in the past six months and not more than 10 times in their lifetimes.

The higher the concentration of THC in the men’s urine, the more pronounced the genetic changes to their sperm were, the authors found.

THC appeared to impact hundreds of different genes in rats and humans, but many of the genes did have something in common — they were associated with two of the same major cellular pathways, said lead author Susan K. Murphy, PhD, associate professor and chief of the Division of Reproductive Sciences in obstetrics and gynecology at Duke.

One of the pathways is involved in helping bodily organs reach their full size; the other pathway involves a large number of genes that regulate growth during development. Both pathways can become dysregulated in some cancers.

“In terms of what it means for the developing child, we just don’t know,” Murphy said. It’s unknown whether sperm affected by THC could be healthy enough to even fertilize an egg and continue its development into an embryo, she said.

The study was a starting point on the epigenetic effects of THC on sperm and is limited by the relatively small number of men involved in the trial, Murphy said. The findings in men also could be confounded by other factors affecting their health, such as their nutrition, sleep, alcohol use and other lifestyle habits.

The Duke team plans to continue its research with larger groups. They intend to study whether changes in sperm are reversed when men stop using marijuana. They also hope to test the umbilical cord blood of babies born to fathers with THC-altered sperm to determine what, if any epigenetic changes, are carried forward to the child.

“We know that there are effects of cannabis use on the regulatory mechanisms in sperm DNA, but we don’t know whether they can be transmitted to the next generation,” Murphy said.

“In the absence of a larger, definitive study, the best advice would be to assume these changes are going to be there,” Murphy said. “We don’t know whether they are going to be permanent. I would say as a precaution, stop using cannabis for at least six months before trying to conceive.”

In addition to Kollins and Murphy, study authors include Nilda Itchon-Ramos, Zachary Visco, Zhiqing Huang, Carole Grenier, Rose Schrott, Kelly Acharya, Marie-Helene Boudreau, Thomas M. Price, Douglas J. Raburn, David L. Corcoran, Joseph E. Lucas, John T. Mitchell, F. Joseph McClernon, Marty Cauley, Brandon J. Hall, and Edward D. Levin.

The research was supported by a grant from the John Templeton Foundation.

Early physical therapy could reduce opioid dependence for pain patients

December 14, 2018 – New research points to evidence that a nonpharmacological treatment option could reduce opioid use in patients with musculoskeletal pain.

Early physical therapy could lead to fewer pain patients becoming dependent on opioids, according to new research co-authored by the DCRI’s Steven George, PhD.

George worked with Stanford University’s Eric Sun, PhD, MD, and other DCRI faculty members, including Chad Cook and Adam Goode, to analyze a proprietary database that pulls from insurance claims and other data recorded during routine patient visits. The team, whose research was published today in JAMA Network Open, reports that when patients with low back, shoulder, knee, or neck pain sought physical therapy early, their subsequent opioid use for the following year was reduced by approximately 10 percent.

Stephen George cropped photoGeorge, the DCRI’s director of musculoskeletal research, said he initially became interested in the association between physical therapy and opioid use because of the patients he saw in his clinical practice as a physical therapist, which suggested that nonpharmacological treatments for back pain patients could have protective effects against long-term opioid use.

The most recent study expanded beyond previous research in back pain to determine whether the protective effect would also apply to patients with neck, knee, and/or shoulder pain.

“Because the CDC guidelines and the American College of Physicians guidelines are pushing toward early non-drug options for patients, this was an opportunity for us to look at a real-world data set to see what one of the non-drug options looked like across the four most common musculoskeletal pain conditions,” George said.

There is no standard definition for what constitutes early physical therapy, George said, but the new study focused on patients who received physical therapy within 90 days of their index date. The study also only included patients who were opioid naïve, meaning that they had not used opioids within a year before their index date. The researchers examined data from almost 89,000 patients with back, neck, knee, or shoulder pain between 2007 and 2015.

In all four pain categories, patients who received early physical therapy were found to use opioids for a shorter length of time than those who did not. In a sensitivity analysis, the researchers found that early physical therapy may be most likely to limit chronic opioid use in patients with back or knee pain. When patients did continue to use opioids, those who received early physical therapy took a smaller amount of opioids in terms of dosages.

The exception for dosage was patients with neck pain, as results for this group were not statistically significant. George said there could be several reasons why the neck pain group did not show the same results as the other pain groups. Neck conditions could be more resistant to physical therapy, or could initially be prescribed higher dosages of opioids.

Although research suggests that early physical therapy is potentially beneficial, there are still time delays and barriers for patients looking to access this type of treatment. For example, many insurance providers still require patients to see a primary care provider first and get a referral to a physical therapist — and while seeing a physician can be beneficial for many reasons, it does delay physical therapy, George said.  High co-payments can also be a barrier — often, the co-payment for a one-month opioid prescription is less than the co-payment for a single session with a chiropractor or physical therapist.

George acknowledges that to further expand use of nonpharmacological treatments, health care systems will need to change established delivery patterns. “Because the system is set up to deliver prescriptions, it’s a lot easier for it to do that than deliver nonpharmacological interventions,” he said. “However, the opioid crisis has led to awareness that the system needs to improve in delivering on these interventions if we are going to successfully reduce unnecessary exposure to opioids for pain relief.”

Sharing knowledge: An inside look at the DCRI’s publication process

December 18, 2018 – Contributions and collaboration underpin the path from protocol to print.

In the most recent fiscal year, DCRI faculty and staff published 1,204 articles in more than 400 peer-reviewed journals, including more than 200 high-impact journals. Since 1996, more than 14,000 DCRI publications have been cited in more than 618,000 scientific articles. These publications are the primary vehicle for the DCRI’s mission—to share knowledge that improves patient care around the world.

Each article represents not only the answer to a scientific question, but the culmination of a process that involves many people beyond those listed as authors. Without the work of these often overlooked contributors, the organization’s mission would go unfulfilled.

Project leaders are essential to the journey of a publication from idea to implementation. As the individuals responsible for developing study protocols and coordinating with other teams, they are the linchpin of every successful study. Mary Ann Sellers, MSN, PMP, is a project leader in the Government Trials and Networks group.

“I like to equate the project management aspect of the job to making sure all the tributaries flow into the river,” Sellers said. “There are a lot of separate pieces and stakeholders, but they all come together to give input toward the whole.”

Another key group in any study are the biostatisticians. These include both lead trial statisticians, who oversee the primary analysis, and statisticians who work with the trial team to perform secondary analyses. These statisticians are co-authors of the manuscripts and often write or edit the methods and results sections.

Lisa Wruck, PhD, MSPH, the director for the DCRI’s Center for Predictive Medicine, oversees a team of about 20 statisticians. They work hand in hand with a study’s principal investigators to ensure that a study’s results are interpreted correctly in the final manuscript.

“Usually once we send an investigator a report, that triggers more brainstorming, so they’ll come back with additional requests or things they’d like to see,” Wruck said. “It’s a very iterative process.”

Scientific articles are often collaborations not just across the DCRI or Duke but across the globe. In fiscal year 2018, DCRI manuscripts included more than 5,300 co-authors from approximately 1,800 institutions in 69 countries. A full overview of DCRI’s 2018 publication numbers can be viewed here. Managing the development of such articles often falls to DCRI’s medical communications team.

“Our team of experienced, skilled editors work closely with faculty to provide editorial support for manuscripts, abstracts, and presentations,” said Elizabeth Cook, head of medical communications and scientific publications at the DCRI. “The editors are also a valuable resource for best practices in medical publishing and are knowledgeable about current recommendations from the International Committee of Medical Journal Editors and publications guidelines.”

“Publications project managers serve as the hub for all activities related to the secondary manuscripts and presentations,” Cook said. “We act as the liaisons between the sponsor, publications committee members, statisticians, and authors, and we work closely with all stakeholders to ensure that the publication and presentation processes run smoothly and on time.”

John Alexander, MD, MHS, faculty director for cardiology, estimates he has been working with the DCRI’s medical communications team for 10 to 15 years.

“It has been very beneficial to establish a working relationship with the medical communications team because I’ve gotten to work with the same editors, and they know my writing style, my priorities, and edit my papers while still maintaining my voice,” Alexander said.

“Editors act as another source of connection in the already very collaborative work we engage in daily, and it’s really valuable to have someone help me keep track of it all,” he said. “We try to publish manuscripts in concurrence with presentations we are making, and the editors also communicate with the journals and help coordinate publication, often on a tight timeline.”

DCRI to lead new study of treatments for patients with diabetes and heart disease

December 13, 2018 – The COORDINATE-Diabates trial will analyze how different interventions affect guideline-recommended therapies among caregivers and patients.

The DCRI is leading a new clinical study to optimize care for people with type 2 diabetes and cardiovascular disease through evaluation of a multidisciplinary approach at cardiology clinics across the U.S. The research program, COORDINATE-Diabetes (COOrdinating CaRDIology CliNics RAndomized Trial of Interventions to Improve OutcomEs), will be funded by Boehringer Ingelheim and Eli Lilly and Company.

“The public health impact of type 2 diabetes and cardiovascular disease in the U.S. is immense,” said the DCRI’s Christopher Granger, MD, lead researcher for COORDINATE-Diabetes. “While highly effective evidence-based treatments have been developed, these treatments are not consistently used, and thus preventable death and disability are occurring. Our goal with COORDINATE-Diabetes is to better understand the effectiveness of specific interventions at cardiology clinics to achieve best practices for improving patient health.”

People with diabetes are up to four times more likely to develop cardiovascular disease than those without diabetes, and cardiovascular disease ranks as their leading cause of death and disability despite available treatments. To help improve these striking statistics, COORDINATE-Diabetes will examine the impact of multifaceted interventions involving guideline-based therapies among cardiologists, endocrinologists, primary care providers and patients, including the recommendations outlined in the American Diabetes Association (ADA) 2018 Standards of Medical Care in Diabetes and the American College of Cardiology (ACC) Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in adults with type 2 diabetes and atherosclerotic cardiovascular disease.

The trial will include 46 cardiology clinics in the U.S. and aims to enroll 30 patients at each site. The clinics will be randomized to a basic education arm (in which patients will be treated by clinicians who receive only basic information about guideline-based therapy) or an intensive intervention arm (that focuses on coordinating care between cardiologists and endocrinologists to develop and implement an integrated, multidisciplinary care pathway). The care teams at the intervention sites will be encouraged to communicate with patients’ primary care physicians to facilitate a well-rounded, multidisciplinary approach to patient care. The trial will measure the impact of the intervention on the sites’ use of guideline-recommended therapies after 12 months.

“We are pleased to support evidence-based research to understand how to best manage risks and optimize care for patients with type 2 diabetes and cardiovascular disease in a real-world, clinical setting,” said Thomas Seck, MD, senior vice president, Medicine and Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Although there are treatments with proven cardiovascular benefits recommended by the ADA and other organizations, many healthcare providers are not prescribing them to all their patients who may benefit. We look forward to learning more about how healthcare providers can work together to improve adherence to these treatment guidelines in the quest to reduce patients’ cardiovascular risk.”

The trial will also leverage the power of electronic health record data from a consortium of health systems across the U.S. that have curated their data to support research and improve outcomes. Researchers will begin enrolling clinics and patients for the study in 2019 with the goal of sharing the main results by 2021.

“Few rigorous studies have tested the effectiveness of a multidisciplinary approach to improving care among this vulnerable patient population,” noted Sherry Martin, MD, vice president, Medical Affairs, Lilly. “Given the serious cardiovascular complications associated with type 2 diabetes, it is important for cardiologists and endocrinologists to work collaboratively to help improve care for people with type 2 diabetes and cardiovascular disease.”

Age is the biggest risk for heart disease, but lifestyle and meds have impact

December 11, 2018 – Understanding what modifications can work will help improve adherence to guidelines, researchers say.

Of all the risk factors for heart disease, age is the strongest predictor of potential trouble.

While no one can stop the march of time, making healthy lifestyle choices or adhering to medication regimens for conditions such as high cholesterol, hypertension or diabetes can substantially reduce the risk of heart disease.

Michael Pencina

Understanding which risk factors modifications are actually effective, and by how much, is increasingly important for doctors and patients to understand in light of new blood pressure and cholesterol guidelines that drive medical care.

In a study published online Dec. 7 in the journal Circulation, a research team led by the DCRI provided a statistical analysis that answers the question of what works to lower heart disease risk, and by how much.

“Guidelines of who to treat for cardiovascular disease depend on risk, so we need to accurately estimate that risk,” said lead author Michael Pencina, PhD, vice dean for Data Science and Information Technology at the Duke School of Medicine and member of DCRI.

“Although taken individually, each modifiable risk factors contributes only modestly to the heart disease risk model performance,” Pencina said. “But our analysis indicate that eliminating or controlling these factors can lead to substantial reductions in serious cardio-vascular events.”

Pencina and colleagues analyzed key modifiable heart disease risk factors, including lipids/cholesterol, systolic blood pressure, diabetes and smoking. Each of those factors was assessed for associations with major heart events such as myocardial infarction, angina or cardiac arrhythmia.

Using pooled participant-level data from four National Heart, Lung and Blood Institute studies that included more than 22,000 people aged 45-85, the researchers found that:

  • Age, sex, and race account for about 80 percent of the predictive power of cardiovascular risk models, with age being the main predictor.
  • Adding either systolic blood pressure, high cholesterol, diabetes, or smoking to a model with other risk factors only minimally increases the ability of the model to determine who will suffer heart disease events.
  • Lowering blood pressure to current recommendations (systolic measurement of less than 130) and lowering low-density lipoprotein cholesterol by 30 percent could reduce the 10-year coronary heart disease risk by as much as a third.

Pencina said there are two ways to achieve lower blood pressure and cholesterol: Never acquire the adverse conditions by maintaining a healthy weight and exercising, or manage them with appropriate lifestyle modifications and medications. The better of the two approaches is, not surprisingly, not developing risk factors.

“Our models suggest that when making individual treatment decisions, clinicians and patients should consider not only the 10-year risk of coronary heart disease, but also the expected benefit from the intervention,” Pencina said. “We are moving from models that focus either on the causes or the risks, to a model that combines both and focuses on potential risk reduction.”

In addition to Pencina, study authors include Ann Marie Navar, Daniel Wojdyla, Robert J. Sanchez, Irfan Khan, Joseph Elassal, Ralph B. D’Agostino, Eric D. Peterson and Allan D. Sniderman.

DCRI researcher receives 2018 Carolinas Collaborative Grant

December 5, 2018 – Melissa Daubert, MD, will collaborate with researchers at UNC-Chapel Hill to study how to optimize cardiovascular care in women with hypertensive disorders of pregnancy.

The DCRI’s Melissa Daubert, MD, has received one of four 2018 Carolinas Collaborative Grant awards to examine the postpartum care received by pregnant women with hypertensive disorders.

“From retrospective studies, we know that hypertensive disorders during pregnancy put women at higher risk for cardiovascular events later in life,” Daubert said. “If we screen for these early markers for future disease and treat them appropriately, we have the potential to change the trajectory for these patients.”

The $50,000 grant, administered by the North Carolina Translational and Clinical Sciences Institute, calls for applicants to collaborate with researchers from other institutions to use resources from the Carolinas Collaborative. The Collaborative harmonizes electronic health record data across Duke, the University of North Carolina at Chapel Hill, the Medical University of South Carolina, and Wake Forest University.

Daubert, the principal investigator, will work with co-investigators in cardiology and obstetrics-gynecology at Duke (the DCRI’s Tracy Wang, MD, and Thomas Price, MD) and UNC-Chapel Hill (Rachel Urrutia, MD, MS, and Paula Miller, MD). The team will study women with hypertensive disorders of pregnancy who received treatment from Duke and UNC between January 2007 and June 2018. Preliminary results show that over 10,000 women have experienced a hypertensive disorder of pregnancy, which is about 14 percent of all pregnancies that received care at Duke and UNC-Chapel Hill during this time period.

“The national average for the proportion of pregnancies in which the mother has a hypertensive disorder is 10 percent, so these complications are particularly prevalent in our region,” Daubert said. “That makes this study especially important to figure out how best to care for this high-risk population of women and devise interventions to reduce their future cardiovascular risk.”

In North Carolina, many patients transition between Duke and the University of North Carolina Health Care Systems for their primary and specialty care needs. The collaborative nature of the study is also important, Daubert said, because if the research team looked at records from only one institution, there would be a high likelihood of missing follow-up care or treatment for women who saw providers at both Duke and UNC. Because the Carolinas Collaborative has coded electronic health records so that they can be viewed simultaneously across institutions, she said, it was the perfect opportunity to answer this research question.

Guidelines from the American Heart Association advise that women who have hypertensive disorders during pregnancy should be screened six to 12 months after giving birth. Daubert and her team will look at how consistently this screening is being carried out, as well as which types of providers are conducting the screening. They will also compare outcomes of women who received screenings and women who did not.

“While there is growing awareness that these hypertensive disorders increase risks down the road, this correlation is still often unrecognized by patients and providers,” Daubert said. “There is also a misconception that the cardiovascular events will occur decades later, but in reality, up to 45 percent of women who have hypertensive disorders during pregnancy will develop overt hypertension that needs treatment within five years of giving birth.”

Daubert said her team will also be considering how providers in different specialty areas can have the most impact, as well as how care for these patients should be distributed.

“Not only will this lay the groundwork for future studies, but it will also help us identify gaps in care and determine where therapeutics interventions could be implemented in clinical practice,” she said.

The project also recently received a $20,000 DCRI Innovation Award.

DCRI faculty make “highly cited” list again

November 28, 2018 – Ten DCRI faculty members are listed in a new ranking of the world’s most influential researchers.

Once again, several DCRI faculty members are included in the 2018 Highly Cited Researchers list compiled by Clarivate Analytics and Web of Science.

A high citation rate is an indication that a researcher’s work is influential in their field. In both 2016 and 2017, Duke was the fifth-highest cited U.S. institution.

The DCRI researchers listed on this year’s list are Robert Califf, Lesley Curtis, Pamela Douglas, Christopher Granger, Richard S.E. Keefe, L. Kristin Newby, E. Magnus Ohman, Manesh Patel, Michael Pencina, and Eric Peterson. Pencina, the school of medicine’s vice dean for data science and information technology, appears on the list in two separate categories. Several of this year’s researchers also appeared on previous year’s lists.

This year’s list of 6,078 names recognizes world-class researchers for their production of multiple highly cited papers that rank in the top one percent by citations for their field and over the past decade (2006 to 2016), based on Web of Science data. Clarivate’s website allows users to explore the data further.

“The Highly Cited Researchers 2018 list helps to identify the researchers who are having the greatest impact on the research community as measured by the rate at which their work is being cited by others and that contributes so greatly to extending the frontier and gaining knowledge and innovations for society,” said Annette Thomas, CEO of the Scientific and Academic Research group at Clarivate Analytics.

The DCRI’s Sheng Luo on the benefit of biostatistics

November 27, 2018 – DCRI biostatisticians play a key role in many of the organization’s projects.

When the Duke Department of Anesthesiology recently re-applied for a research grant from the National Institutes of Health (NIH), it invited DCRI’s Sheng Luo, PhD, to contribute his biostatistical expertise. The NIH grant would be for a study related to chronic pelvic pain affecting reproductive-aged women.

Sheng LuoThe trial was a multi-site, randomized, double-blinded trial to compare the efficacy of individualized treatments in alleviating pain and improving outcomes for patients suffering from vestibulodynia (VBD). Investigators hoped the study’s findings would help patients, their partners, and their clinicians make more informed decisions about pain management related to VBD. The study design was longitudinal, with patients followed over a period of time and returning for follow-up visits.

“Because data will be collected at each visit,” Luo said, “it was especially important to add a statistical section in the proposal on how we analyze that kind of longitudinal data and what model the study will use. We want to plan for many variables and outcomes of interest.”

A major challenge in all clinical studies is patient enrollment and retention, and especially the probability of patient dropout, according to Luo.

“We want to be ready to handle that with the right statistical analysis plan,” he said. “A study could see as much as a 10 to 20 percent dropout rate, greatly reducing the chances of statistically and clinically significant results. So we use a whole set of criteria to assess how to increase sample size from the beginning to compensate for dropout.”

In general, he said, when preparing a grant application, “it’s ideal to have a statistician join the conversation as early as possible to tackle a wide range of challenges and issues. When properly designed, the study’s data should have sufficient power to show that therapies do or do not work. This is what we looked at with the VBD study.”

DCRI biostatisticians also help predict whether investigators can meet study targets on time, according to Luo, and if patients will be randomized and blinded properly. “The NIH is very concerned about these issues, which can create huge red flags. When studies are properly designed with enough patients and power to produce usable results, time and money will have been well-spent.”

Working with data related to living organisms, DCRI biostatisticians both crunch numbers and help design studies where enough data and the right kind of information are collected. Along the way, they analyze, evaluate, and interpret results while accounting for biases, and missing data, and other relevant issues.

Luo said that including biostatisticians as part of a study team during the grant application process can help boost the chances for a winning proposal. Thanks in part to Luo’s contributions, this fall the Department of Anesthesiology received the five-year NIH grant for its VBD study. Luo also credited Kevin Anstrom, the DCRI’s Director of Biostatistics, for his assistance in applying for the grant.

“Whether a clinical trial is for government or industry,” Luo said, “biostatistics should always play a major role. We’re glad to be brought into the process as early as possible to provide investigators with feedback on the protocol. The sooner the better, really.”

AHA 2018: Plasma proteins may be biomarkers for cardiovascular disease risk in persons living with HIV

November 12, 2018 – A DCRI substudy identified proteins that may differentiate diastolic dysfunction in HIV patients from non-HIV individuals.

As antiretroviral therapy has transformed HIV from a potentially fatal disease to a chronic one, persons living with HIV (PLHIV) may develop more cardiovascular risk factors and CV-related morbidity and mortality, even with viral suppression, than those not infected by HIV.

“Antiretrovirals have shifted the epidemiology of heart failure in HIV from systolic to diastolic dysfunction (DD), putting PLHIV at a higher risk for cardiovascular disease,” said the DCRI’s Svati Shah, MD, MHS. “The question has been what are the mechanisms?”

On Monday at the American Heart Association’s Scientific Sessions 2018 in Chicago, Shah presented her research on proteomics that identify inflammatory, lipid, and cell proliferative pathways in diastolic dysfunction in HIV. Her presentation was a substudy of the CHART (Characterizing Heart Function on Antiretroviral Therapy) clinical trial that recently enrolled 195 healthy PLHIV through the National Heart, Lung, and Blood Institute’s Heart Failure Network.

“With a goal of looking deeply at these patients, we used proteomic profiling technologies to test CHART blood samples and locate the novel biomarkers and potential mechanisms underlying DD in PLHIV,” Shah said. “Both cardiac fibrosis and inflammation have been proposed as key mechanisms in PLHIV underlying cardiovascular disease and heart failure with preserved ejection fraction (HFpEF), but those mechanisms had not been well understood.”

After assaying 977 unique protein biomarkers, Shah and her colleagues determined that cardiac fibrotic pathways (as represented by extracellular matrix proteins) rather than inflammatory pathways were the strong differentiators of DD in PLHIV. “We believe these biomarkers can help identify those PLHIV who have DD and are at risk of developing HFpEF or diastolic heart failure.”

Shah’s team also used STRING bioinformatics tools to analyze which pathways may be “overrepresented” in the data. The extra cellular matrix, which is the core component of cardiac fibrosis, was overrepresented in the significant proteins, Shah said.

“This reinforces other findings that it is not just one protein but several proteins in that pathway that are significant in the development of DD in PLHIV,” she said. “The beauty of these relatively new technologies is the ability to measure so many proteins in very small amounts of blood. It’s like a liquid biopsy, and with such high specificity that we can be confident of what we are measuring.”

“Basically, we are measuring the stiffness of the heart, which is, at a simple level, what DD is,” Shah said. “These proteins essentially show us how cells talk to each other and how they become stiff and cause cardiovascular disease. Going forward, we plan to compare these results to a non-HIV infected group and to perform longitudinal assessments.”

Shah said this may be the first time anyone has been able to look at this many plasma proteins at one time.

“We may also be the first to use high throughput large-scale proteomic profiling to get this comprehensive and unbiased view of the diverse biological pathways underlying DD in PLHIV,” she said.

In addition to Shah, DCRI contributors included Lydia Coulter Kwee, Steven McNulty, and Adrian Hernandez.