The past, present, and future of IPF research at the DCRI

January 15, 2019 – The DCRI has been on the forefront of research into the chronic and fatal lung disease.

Little is known about the cause of idiopathic pulmonary fibrosis (IPF), a devastating disease that is characterized by progressive scarring of the lung tissue that affects a person’s ability to breathe and leads to death within three to five years of onset.  However, a team of respiratory medicine researchers at the DCRI is working to advance understanding of the deadly disease across the translational and clinical research spectrum.

The DCRI has been making strides in IPF research since 2005, when it became the coordinating center for IPFnet, a network of 26 clinical sites that was designed to conduct multiple clinical trials in the IPF space. Kevin Anstrom, PhD, director of biostatistics for the DCRI, was the principal investigator for IPFnet’s data coordinating center until 2014 and designed the clinical trials conducted within the network.

“IPFnet as a whole really changed the field and benefited everyone, including patients,” Anstrom said. “It not only cleared the way for other treatments to be introduced to market, but it also removed toxic therapies and gave patients more choice for their treatment.”

IPFnet helped set the stage for further research, Anstrom said; for example, many of the same clinical sites and investigators involved in IPFnet are now involved in the DCRI’s ongoing IPF-PRO registry.

Gaining Perspective

The IPF-PRO registry, which began in 2014 when the DCRI partnered with Boehringer-Ingelheim, follows patients with IPF for at least three years. Scott Palmer, MD, MHS, (pictured left) director of respiratory research at the DCRI and principal investigator for IPF-PRO, works on the registry along with the other members of the IPF-PRO team, which includes Laurie Snyder, MD, MHS; Jamie Todd, MD; Megan Neely, PhD; Eric Yow, MS; Emily Obrien, PhD; and Rosalia Blanco.

The IPF-PRO registry recently hit a milestone when it reached its goal of enrolling 1,000 patients. Although work with the registry continues, it has already resulted in 28 papers, abstracts, or presentations. As patients are followed out to longer time points, the study will provide increased ability to identify clinical factors and biomarkers that predict disease progression. In addition, the study captures information regarding the impact of the disease upon patient quality of life and will help clinicians and patients better understand the full impact of the disease and its treatment on patient-centered outcomes.

The team has also received funding to begin work on the second phase of the project. Concurrently with IPF-PRO, DCRI researchers will launch a parallel study called Interstitial Lung Disease-PROspective Outcomes (ILD-PRO), which will enroll non-IPF patients with interstitial lung disease (ILD). Boehringer-Ingelheim will also fund the new study and has committed $15 million, which will carry the study through 2025.

The study will focus on non-IPF patients, whose diseases are not considered “idiopathic” because a cause for the fibrosis has been identified. Even though they do not have IPF, some non-IPF ILD patients develop a progressive phenotype that mirrors IPF, Palmer said.

ILD-PRO will enroll these newly progressive patients and study patient data in much the same way as IPF-PRO in an attempt to understand the impact on patients’ quality of life, predictors of survival, and disease progression. All of the 47 active clinical sites that participate in IPF-PRO will also participate in ILD-PRO.

“It’s building upon what we already did (with IPF-PRO) and leveraging the collegial relationships we have with everybody involved,” Palmer said. “The beauty of having these two parallel studies is investigators can compare and contrast clinical factors and biological factors across interstitial lung disease, between IPF and what’s classified as non-IPF ILD to understand their underlying similarities and differences.”

A Genetic Link

The IPF-PRO registry also includes a biorepository of blood samples collected from patients, including DNA, RNA, serum, and plasma. This material, which was collected at patient enrollment and then at approximately six month intervals, will allow researchers to better understand biomarkers of IPF and how they are linked to IPF progression, said Jamie Todd, MD, co-chair of the IPF-PRO biomarkers committee.

“Right now, there are no FDA-approved biomarkers that could help clinicians with diagnosis and prognosis for IPF, so we are currently in a discovery phase with an ultimate goal of identifying some of those biomarkers,” Todd said. “In addition, because there are two relatively new treatments that have come onto the market since 2014, we may be able to identify biomarkers that indicate response to treatment.”

Because the team needed a control group to compare to the IPF population, it partnered with another study called the MURDOCK Study to identify a group of people who did not have lung disease.

Now, Todd said, the team is not only able to make comparisons among individuals with IPF, but can also understand what differences appear between a healthy person and a person with the disease. They have already found at least 40 proteins that significantly differ between the IPF population and the healthy population. Protein analyses within the IPF population could also help inform whether certain proteins correlate to disease severity and progression.

With the launch of ILD-PRO, the team will be following the same process to build a new biorepository with the ILD patient samples. Once the ILD repository is built, Todd hopes to compare the material to both the IPF and healthy repositories and conduct similar analyses. If biomarkers can help to understand disease mechanisms, she said, they can also assist in developing better treatments.

Todd (pictured right) also sees other potential uses for the genetic material, such as applying novel genome sequencing technology.

“Before IPF-PRO, there was no large, multicenter IPF biorepository in the United States,” Todd said. “This biorepository distinguishes IPF-PRO from other ongoing IPF registries in the U.S. and abroad. Now that the infrastructure exists, there are many opportunities for us to do some high-end, translational science in partnership with BI and our IPF-PRO site investigators.”

Changing the Game

In addition to the studies, the DCRI is also running NHLBI-funded clinical trials in the IPF space.

Anstrom is currently working on a trial he designed, CleanUP IPF.

The trial, which will enroll 500 patients and become the largest randomized study in the IPF space, seeks to determine whether two antibiotics, co-trimoxazole and doxycycline, help improve IPF outcomes. Both drugs will be tested against standard care.

“This type of high-dose treatment of antibiotics isn’t targeted at the fibrosis; rather, it’s used to prevent infections that could create other problems for IPF patients,” Anstrom said. “Previous literature suggests this approach has been helpful in cancer and other diseases. It would be valuable if it could also be applied to IPF because these therapies are affordable. The two treatments currently on the market are expensive, and there is no evidence that they reduce mortality.”

Each of these studies will benefit from the years of IPF research conducted by the DCRI. This community of researchers, Palmer said, has helped advance the state of IPF science. Another important component, he said, is that the DCRI’s clinical faculty on the IPF studies are physician investigators who treat people with IPF.

“I’m a physician, so I see patients with IPF every week, take care of them, and recognize the tremendous unmet needs associated with the disease,” Palmer said. “IPF research is a wonderful example of the strengths of the collaborative team at the DCRI. Our projects span from outcome registries to trials and include clinical and biostatistics faculty as primary investigators. We have built a network of really well-aligned investigators who care about IPF and about doing multi-center clinical research to move the field forward.”

Former commissioners call for FDA to become independent federal agency

January 9, 2019 – In a commentary published in Health Affairs, seven former FDA Commissioners call for the FDA to evolve into an independent federal agency in order to better support its core missions, foster efficiency, and remove administrative roadblocks.

A commentary authored by seven former Commissioners of the U.S. Food and Drug Administration (FDA), including the DCRI’s Robert Califf (pictured) and Mark McClellan from the Duke Margolis Center for Health Policy, calls for a series of steps that would transition the FDA from beneath the umbrella of the Department of Health and Human Services and establish it as an independent federal agency. Published in the January issue of Health Affairs, the article makes the case that such changes are needed to better leverage science and technology in support of public health and safety while also fostering therapeutic and technological innovation and transparent decision-making.

Citing the agency’s track record and its very full plate — the FDA’s oversight currently encompasses trillions of dollars’ worth of medical products, drugs, food, cosmetics, and more — the authors predict that the FDA’s reconfiguration as an autonomous entity will enable it to better fulfill its increasingly multifarious and challenging efforts to “promote and protect” the health of the American public.

The authors were convened by the Health, Medicine, and Society Program of the Aspen Institute, an international nonprofit think tank that brought the former commissioners together to probe the issue of the FDA’s organizational relationships and decision-making authority within the larger architecture of the Department of Health and Human Services. Drawing upon decades of collective experience spanning both Republican and Democratic administrations, the former commissioners have chalked out an interim pathway to independence through a series of recommendations to HHS. The authors acknowledged the magnitude of the legislative and logistical efforts their recommendations would require, but noted that they deem the change necessary to further strengthen and fortify the FDA to fulfill its mission in coming years.

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.”