Bench to Bedside

September 2017

Teaming Up to Quantify Youth Concussions

From the clinic to the lab to the playing field, tag-team science is the key to a new research initiative that will tackle the accuracy of youth concussion diagnoses head-on. With a $4.5 million grant from the National Institute of Neurological Disorders and Stroke, researchers from Children’s Hospital of Philadelphia and the University of Pennsylvania will lead a five-year venture to design evidence-based, diagnostic assessment tools for the clinic and the sidelines, as well as create the foundation for better headgear and other protective equipment.

The goal: Enhance the accuracy of sports-related concussion diagnoses that can provide prognoses of the time-to-recovery and safe return-to-play for youth athletes.

The game plan: Combine bioengineering and sports medicine expertise under the leadership of three passionate scientists: Kristy Arbogast, PhD, co-scientific director of the Center for Injury Research and Prevention; Christina Master, MD, primary care sports medicine specialist and co-director of the Concussion Care for Kids: Minds Matter Program; and Susan Margulies, PhD, Robert D. Bent Professor of Bioengineering at the University of Pennsylvania’s School of Engineering.

“I’m a parent of two athletes, and concussions are something that’s talked about on the sidelines,” Dr. Arbogast said. “Parents are concerned. What we’re hoping to do is provide some evidence-base that is specific to kids and contribute to the scientific foundation of what clinicians do in the clinic. We have to get past the current diagnostic approach of relying on subjective symptoms to be able to begin to understand the burden of these injuries long-term.”

While the heft of previous concussion research looks at college-aged and professional athletes, the CHOP and Penn team will widen their scope to study a high school population, for whom there is little available data on injury criteria and thresholds.

Moving Away From Subjective Symptoms

Clinicians currently rely on subjective symptomatology to diagnose youth concussions. From physical symptoms like headaches and fatigue to cognitive ones like mental fog, self-reported indicators don’t always provide the clearest of metrics.

“The child has to recognize the symptoms in themselves, report them to someone, and then many of the symptoms are either subjective or non-specific,” Dr. Arbogast said. “Symptoms like headaches and fatigue are common in adolescence and could be attributed to other causes besides concussion.”

To complicate the matter, Dr. Arbogast said that adolescents might conceal their symptoms or the severity of what they feel. Previous research has found that fewer than 50 percent of high school football players reported their concussions, perhaps because they don’t believe or don’t know that their symptoms might indicate a concussion, or because they would like to keep playing on a sports team.

“The motivation for an athlete might be that he or she wants to be cleared to go back to the big game so they don’t lose their starting spot,” Dr. Arbogast said. “That can lead to challenges for clinicians.”

If the research team can identify a suite of objective metrics that clinicians will use when diagnosing or treating a concussion, then they can begin to improve the accuracy and precision by which they identify concussed youth and monitor their recovery.

Quantifying Concussions in the Clinic

Because concussions are an injury of function rather than one of structure (meaning that they are measured by impaired function rather than a clearly broken body part), the team will use objective metrics that measure a child’s brain function, in order to build a suite of quantitative assessment tools.

Currently, outpatient clinicians assess children with qualitative assessments of balance (such as walking straight, backwards, or with their eyes closed). While these are useful, Dr. Master believes that it is time to develop more precise criteria for those kinds of assessments.

“We’re hoping to get away from qualitative,” Dr. Master said. “With objective metrics of diagnosis, we can sort out the injured from not injured cohort, and monitor their path through recovery.”

Enrolling participants from CHOP’s Concussion Care for Kids: Minds Matter program, the researchers will measure and track the objective metrics of balance, neurosensory processing (such as eye tracking), and cerebral blood flow in adolescents ages 14 to 18 with a diagnosed concussion, then compare those metrics to healthy controls.

All of these metrics measure brain function in different ways: If a child’s brain isn’t functioning well, they won’t have stable balance or controlled eye movements. Preliminary evidence also suggests that cerebral blood flow can decrease during concussion. The resulting data will facilitate the development of guidelines that can help clinicians determine how long a child will take to recover, or when a young athlete can return to play.

“What we’re hoping to do is use technology to better understand concussions and translate that into less expensive and more accessible techniques that could eventually be implemented in the clinic,” Dr. Master said. “Not everyone is fortunate enough to be right next to a children’s hospital with options for advanced imaging, so we’re really trying to develop objective but less expensive, portable, and user-friendly tools.”

From the Lab to the Field

Not content to stop there, Drs. Arbogast, Master, and Margulies will lead two other study components that run parallel to their collection of objective metrics.

With a head-impact sensor study, the researchers plan to track the magnitude and direction of head impacts of youth on the sports field. Equipped with head-impact sensors, the high school athletes will go about their play while the researchers take pre-and post-season objective clinical metrics data and analyze head impacts from the sensors. The head impact sensor component of the study will enroll research participants from suburban Philadelphia’s The Shipley School.

The data gleaned from those metrics will then help to inform a study using a porcine animal model of traumatic brain injury (TBI). Animal studies have long been used to study traumatic brain injury (with the University of Pennsylvania being one of the pioneers of such methods); for this study, they have adapted their porcine model of moderate and severe TBI to focus on concussion.

By studying both humans and animals rather than simply one or the other, the researchers can replicate the head rotations observed of adolescents on the playing field in the animal model. This translation gives them the control, range, and scope to study the very specific mechanisms of a concussion. For example, previous research has shown that tolerance to an injury can depend on the way the head moves, but with athletes in real time on the playing field, the researchers can’t control how their head might be hit. With animals in the lab, however, the researchers can carefully control direction and magnitude to truly understand concussion tolerance.

Another benefit of using pigs, Dr. Arbogast said, is the fact that their brains are initially in an uninjured state. Unlike adolescents, who naturally bring some injury history including the potential for previous concussions and TBI, the animals used in this study have an uninjured brain.

“While you always have to think how animal research translates to humans, it might not be perfect, but it does give us control over some of the parameters we think are important,” Dr. Arbogast said.

The Dream Team

The biggest strength of the study lies in its collaborative nature: It was essential to combine a bioengineering perspective with that of a sports medicine clinician, in order to best address the complicated research questions at hand, according to Dr. Arbogast. While Dr. Arbogast is a bioengineer focused on injury prevention and Dr. Margulies works as a lab-based bioengineer, Dr. Master brings the perspective of a sports medicine clinician as well as a primary care pediatrician. Together, the team can take a holistic and thorough view of concussion treatment.

“We had all been meeting broadly about concussions to brainstorm, and we realized that we were of like-mind,” said Dr. Arbogast of the team’s dynamic energy. “The research questions being addressed by this project can only be answered by interconnected study across the clinic, the lab, and on the field.  Each component informs the other’s research in important ways.”

Besides that, there is another exciting component to the team’s energy, according to Dr. Arbogast. “We think it’s exciting that this study is being led by three accomplished female scientists,” Dr. Arbogast said. “We’re really proud of this and hope that our working together to lead this aspect of concussion research can provide a model for other young women in the field.”

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Promoting Equity in the ED: Why We Need to Understand Implicit Racial Bias

Tiffani Johnson, MD, a physician in the department of Emergency Medicine at Children’s Hospital of Philadelphia and PolicyLab member, is driving clinical practice one step closer toward equity for children, regardless of their race.

To better understand the factors that contribute to disparities in care, Dr. Johnson’s most recent research unravels the unconscious biases that, despite the best of intentions, can affect how a physician in the emergency department (ED) might treat a child of a particular race or ethnicity. Known as implicit racial bias, these unconscious attitudes can unknowingly surface when doctors default to heuristic thinking under pressure.

“Children are one of the most vulnerable populations. I think we like to think that they’re immune to disparities and discrimination, but this research shows that unfortunately, they aren’t,” Dr. Johnson said. “Most pediatricians have egalitarian attitudes and really want to treat everyone the same, but these implicit biases can live below the level of our consciousness and impact the care we provide.”

With her team at PolicyLab, Dr. Johnson’s powerful research spotlights a field of research previously focused on adults outside the healthcare setting and one which can begin to drive mindful change.

How Does Implicit Racial Bias Work?

If we think of the mind like an iceberg, a small portion of its mass remains visible above the water – clear as day and easily accounted for. This is where our conscious mind lives. Our brains, however, consist of more than what we can self-report or see. Below the waterline, a large part of the iceberg lies submerged, and this is where our unconscious biases exist.

In certain pressure-filled situations, (like a crowded pediatric emergency department at 2 a.m.), these biases can emerge to intuitively affect how physicians behave and make decisions. For physicians, they can impact everything from how providers communicate with patients, to differences in treatment, to a family’s satisfaction with their ED visit, and their decision to adhere to the treatment recommendation.

Implicit racial bias, however, does not equal racism – and this is one point Dr. Johnson hopes to make clear to potentially concerned parents. Implicit racial bias goes unnoticed in our consciousness, and parents and providers alike bring some form of it to the table.

“The goal isn’t to point fingers and ask someone what their biases are, but to understand how biases impact care and then try to reduce that impact,” Dr. Johnson said.

Exploring Implicit Racial Bias

In the first phase of her research, Dr. Johnson documented how heavy cognitive loads affect the way that ED physicians might treat a variety of different patients. In a study published in Academic Emergency Medicine, Dr. Johnson and her colleagues gave residents in the ED an implicit association test (IAT) before and after their shifts. An IAT test is a powerful tool for revealing how our minds associate certain images and words as good or bad, preferable or non-preferable.

Often taken online, the test prompts its participants to categorize a series of words and pictures that appear on the screen by clicking one button or another on their keyboard. In a Race Attitude IAT, participants must match pictures of faces – black and white in varying turns – with positive words like “love,” “laughter,” and “pleasure,” or negative words like “horrible,” “hurt,” and “evil.”  Because participants are asked to complete the task as fast as they can, they often default to mental shortcuts and intuition, providing researchers with a valuable insight into the mental associations existing below their consciousness.

After giving the residents the Adult Race IAT, the researchers found that when the ED was more crowded or residents had taken care of more patients, residents exhibited more pro-white/anti-black bias at the end of their shift.

“It makes sense that when you’re making lots of decisions, you’re tired and stressed out, so you’re more likely to rely on your heuristics, which can include bias and stereotyping,” Dr. Johnson said.

As a pediatrician, Dr. Johnson’s next goal was to examine the implicit racial attitudes that providers have toward children. She enlisted the Child Race IAT, initially designed for children to determine when they develop racial bias. Instead of black and white adult faces, the IAT showed those of children. Dr. Johnson gave it to residents in the pediatric ED.

The results proved eye-opening: 91 percent of residents had a pro-white bias toward children – a very similar level to the 85 percent of residents who had pro-white/anti-black bias toward adults in Dr. Johnson’s earlier study, with no significant difference in IAT scores.

“[The IAT] had pictures of these cute little brown kids and these cute little white kids, and I thought residents would have no bias on the Child Race IAT,” Dr. Johnson said. “I was wrong.”

In a clinical setting, implicit bias may play out in a physician’s perception and management of patients who are presenting with painful conditions such as fractures, sickle cell disease, or appendicitis. Using this example, Dr. Johnson wondered whether unconscious attitudes become activated when caring for African American patients – so that physicians don’t assess a patient’s pain, don’t believe when they report it, or even jump to perceptions about drug-seeking behavior that result in inadequate management of that pain. Studies have shown that ED physicians often cite drug misuse as one reason they do not prescribe analgesics – despite the fact that no evidence exists showing minorities are more likely to abuse prescription drugs.

Implicit bias may also emerge when physicians communicate with parents. Unlike primary care pediatricians (to whom families become familiar with after routine visits), parents meet doctors in the ED for the first time – and often under stressful circumstances. Without an established doctor-patient relationship, patients and parents may be more prone to mistrust, while doctors may rely on bias and stereotyping. This may affect how physicians communicate and how patients and their parents follow treatment recommendations.

Identifying Interventions

The good news, however, is that unconscious attitudes are not fixed like the DNA we carry throughout our lifetimes. Though our biases can be influenced by what we are exposed to in the media, the households and neighborhoods we grow up in, and the people we interact with at work or play, they are far from fixed.

“We’re all exposed to lots of things on a daily basis that subconsciously prime us and impact our unconscious attitudes,” Dr. Johnson said. “There’s actually a growing body of evidence, however, that shows our biases are malleable.”

While more work must be done to understand implicit bias and how it specifically impacts pediatric care, a few strategies can reduce the impact of these unconscious attitudes. Studies conducted outside the healthcare setting suggest that mindfulness meditation is one method that has helped to reduce implicit racial bias. Researchers from Central Michigan University gave participants an IAT test for age and racial bias after listening to either mindfulness or a control audio track and found that mindfulness may have resulted in a decrease in both age and racial bias.

Emergency departments may also actively implement strategies to prevent overcrowding and ease a resident’s patient load. In a PolicyLab blog post, Dr. Johnson outlines several suggestions, including some that the ED team at CHOP already incorporate: Hospitals can open an after-hours clinic or place a team of providers in the ED waiting room to get a jumpstart on care until a room is available. On top of that, specific guidelines for clinical effectiveness can reduce variability in care, while a little self-care (such as staying hydrated and eating healthy) may go a long way in helping physicians cope with ED stress.

Finally, precision medicine may help to reduce the impact of implicit bias on care. By individualizing care to each child, precision medicine becomes a tool to reduce clinical uncertainty on the part of providers, thereby helping to reduce disparities in care.

“The less uncertainty, then the less likely we are to rely on our heuristics that can include bias and stereotyping,” Dr. Johnson said. “Precision medicine is an important opportunity to give the proper treatment to the right patient at the right time, and we’re making decisions based on our interactions with individuals and not necessarily group-based stereotypes.”

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A Problem Solver, Dimitri Monos, PhD, Receives Distinguished Scientist Award

Puzzles always captivated Dimitri Monos, PhD, as a young child in Greece. If you gave him a geometry problem, it would instantaneously “capture his brain.” Today, this passion for problem solving fuels the tremendous time and energy that Dr. Monos devotes to tackling some of the greatest challenges in immunogenetics — a dynamic field of science and medicine that explores the connections between the immune system and genetics.

“For me, this work is another extension of having fun,” said Dr. Monos, director of the Immunogenetics Laboratory in the department of Pathology and Laboratory Medicine that provides integral services to all of the transplantation programs at Children’s Hospital of Philadelphia, along with supporting other clinical and research efforts. “Our whole lab has this culture. They are passionate and interested in this type of work. They are motivated. They take initiatives.”

Those same qualities are among the many reasons why Dr. Monos received the prestigious 2017 Distinguished Scientist Award from the American Society of Histocompatibility and Immunogenetics (ASHI), an international society of professionals dedicated to advancing the science, education, and application of immunogenetics and transplant immunology. The annual award recognizes ASHI members who have made extraordinary scientific contributions in their field, which may also have broad clinical applications to autoimmune diseases, cancer, vaccine development, and pharmacogenomics.

A Fascinating Region of the Human Genome 

Dr. Monos is an expert on histocompatibility molecules called human leukocyte antigens (HLA) and the genes that encode them, known as the major histocompatibility complex (MHC). HLA genes are tremendously diverse, or polymorphic. This is good news for people because the HLA polymorphisms give our immune system an advantage to fight off a wide variety of foreign invaders such as infectious diseases. But because there are so many versions of HLA genes, called alleles, it has been extremely challenging for researchers to characterize all of them.

Identifying key HLA alleles is critical for the success of bone marrow, blood stem cell, and solid organ transplantation. The closer the genetic match between the donor’s and recipient’s HLA genes, the less likely that the transplanted donor cells will trigger an immune response by the recipient’s body to destroy the foreign tissue. To help prevent this reaction, Dr. Monos’ lab performs precise HLA typing to ensure that antigens between the donor and recipient are as similar as possible.

Dr. Monos became fascinated by these complex HLA molecules after he earned his doctorate in biochemistry/immunology from Georgetown University in Washington, D.C., and in 1982 began working for the nearby National Institutes of Health in Bethesda, MD. He recognized that the extent of the range of polymorphisms was much greater than what scientists had previously considered. Currently, about 16,000 HLA polymorphisms are known.

“The expected range of these polymorphisms is in the millions, so pursuing their identification is extremely exciting,” Dr. Monos said.

After completing his fellowship training in immunology at the Hospital of the University of Pennsylvania (HUP), Dr. Monos moved to Harvard University in Cambridge, Mass., to work on an NIH grant. He returned to HUP’s Immunogenetics Laboratory in 1990, became a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, and then in 1996 established CHOP’s Immunogenetics Laboratory as its first director. So far, Dr. Monos has contributed to the publication of more than 100 scientific papers.

Next-generation Sequencing: A Game Changer

Over the course of his career, a continuous evolution of technologies has refined the way scientists define HLA polymorphisms. Everyone in Dr. Monos’ lab is open-minded, looks for new ideas, and is adaptable moment to moment, so when next-generation sequencing came along in the mid-2000s, the team quickly embraced it as a game changer.

“I immediately made the connection that this technology potentially could address the HLA typing problem entirely, giving us information about the whole gene, all polymorphisms, even for regions outside the gene that can be of regulatory nature,” Dr. Monos said. “The field was open to a thorough and accurate characterization of these genes.”

And that is exactly what Dr. Monos and his colleagues did, publishing their findings in a 2010 paper titled, “Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing.” They demonstrated how this single test could provide the highest resolution possible by covering the full HLA genomic region.

But Dr. Monos and his team didn’t stop there. The Immunogenetics Laboratory at CHOP was the first clinical lab to offer a new protocol for using HLA genotyping at the allele level based on a next-generating sequencing platform that was faster, more precise, and cost less than existing testing procedures. The test may improve transplantation outcomes through an enhanced assessment of donor compatibility, and it expedites the donor selection process. CHOP licensed the new method in June 2014, and it is distributed commercially throughout the world.

Allison Gasiewski is a technical specialist in Dr. Monos’ lab who performs clinical testing, communicates with the transplant programs, and improves procedures and products. When she entered the field 15 years ago, Gasiewski couldn’t have predicted that it would be possible for the transformation in how HLA typing is performed to happen so quickly.

“The way we used to do testing now seems ancient,” Gasiewski said. “It’s quite amazing. The field has changed so much. We have much better results, and we can make decisions for matching of organs much more confidently… I love that the work we do directly benefits our patients’ care. It’s rewarding.”

HLA Sequencing and Disease Association Studies

Dr. Monos’ staff is constantly experimenting with ways to fine-tune the protocol and creative applications for the technology. They collaborate with physicians who are interested in a wide spectrum of HLA-related issues beyond the sphere of transplantation, including experts from CHOP’s clinical divisions of Oncology, Hematology, Nephrology, Cardiology, Gastroenterology, Rheumatology, Neurology, Immunology and Infectious Diseases.

“We’ve found that with this HLA typing via next-generation sequencing, we are in a position to aid the physicians in many different ways that we wouldn’t have imagined,” Dr. Monos said.

For example, the technology helped to give new insights into the mechanisms underlying a condition called acquired aplastic anemia. Research suggests that this is an autoimmune disease in which your immune system’s T cells attack your own blood cells. In order to evade the T cells, the blood cells change their HLA genes as part of a process called clonal hematopoiesis. HLA-typing using next-generation sequencing allowed researchers to recognize the clonal signature of acquired aplastic anemia and identify clone emergence, which may assist in earlier diagnosis of the disease.

Plethora of Data Reveals New Research Directions

During his Distinguished Scientist Award lecture at ASHI’s annual meeting held in San Francisco in September, Dr. Monos discussed how next-generation sequencing technology also provides an advanced tool that reveals uncharted directions in MHC research. The HLA gene family sits in a genomic region that has four million bases and is loaded with other immunologic genes. Dr. Monos and colleagues — some helping him from as far away as his homeland in Greece — are taking a systematic look to understand the content of this region in detail, which is associated with at least 100 known unique disease phenotypes.

In a paper published in May, Dr. Monos and his study team reported on a single intronic microRNA, a genomic element that regulates post-transcriptional gene silencing, that is encoded by a HLA gene and controls the expression of nearly 200 transcripts involved with immune response. Their findings suggest a new role for HLA genes that could influence numerous metabolic pathways.

“Imagine if each one of the thousands of microRNAs in the MHC controls hundreds of transcripts and therefore control an extremely large number of processes in the cell,” Dr. Monos said. “If we take advantage of these new sequencing tools, maybe they will help in the deconvolution of these relationships.”

It’s an entirely new puzzle that Dr. Monos is eager to unravel.

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Center for Applied Genomics Moving Research Toward Clinical Applications

It was like the Wild West when next generation sequencing entered the genomics landscape a dozen years ago, and Avni Santani, PhD, jumped into the excitement as a postdoctoral fellow at Children’s Hospital of Philadelphia. On the horizon, she saw the transformative power of the technology that now enables scientists to interrogate entire genomes in a span of hours or days. Reining in the full potential of these advancements to improve clinical care is a vital part of Dr. Santani’s new role as director of Clinical Laboratories, Strategic Partnerships and Innovation at the Center for Applied Genomics (CAG) at CHOP.

“When I read the publication on the first next generation sequencing instrument, I thought, ‘Wow, this is going to change our world.’” Dr. Santani said. “But I could not have predicted how disruptive this technology has been for the genomics community. For years, in the clinical laboratory, we were used to standardized protocols using sequencing technology like Sanger that were honed and optimized for 20 plus years. There was practically no R&D back then for a molecular genetics laboratory. Now, we have state-of-the-art instruments and technology, but they are in a constant state of improvement, and the informatics tools to analyze and interpret vast amounts of data are still being developed or optimized.”

For the last decade, the genomics community collaboratively has been figuring out which technologies were working, and how can they can get the data they produce to do what they want it to do. Today, they have within sight an affordable whole genome test. As next generation sequencing has quickly become more sophisticated, faster, and less expensive, CAG has been blazing the trail toward applying this genomic technology paired with reliable informatics to facilitate rare pediatric disease diagnosis, prevention, and management.

“This is a pivotal time to be involved in clinical genomics,” Dr. Santani said. “We face new challenges every day, yet at the same time we are making more gene discoveries than ever before and identifying novel treatments for our patients.”

For example, CHOP researchers and CAG analysts recently identified a loss-of-function mutation in the KIF15 gene that is associated with Braddock-Carey Syndrome, a rare disease characterized by craniofacial malformations and low levels of platelets in the blood. In another international multi-center collaboration, CAG led a study team that used whole-exome sequencing to identify variants in the TBCK gene that occurred in 13 individuals (from nine unrelated families) who all had intellectual disability and decreased muscle tone; many also had seizures and changes in the white matter of their brains.

Detecting these disease-causing glitches helps families arrive at a definitive diagnosis, often after pursuing many years of physician visits and medical testing. Knowing the underlying genetic problems can inform their future medical care and help them to understand if other family members are at risk of developing the same condition.

Achieving CLIA Certification

In order to perform clinical grade sequencing and genotyping on patient samples and use these insights to better inform healthcare choices, CAG needed to meet Clinical Laboratory Improvement Amendments (CLIA) certification requirements mandated by the Centers for Medicare & Medicaid Services. That was Dr. Santani’s first hurdle to cross when she accepted her new position with CAG. Dr. Santani also is a director in the division of Genomics Diagnostics in the department of Pathology at CHOP and is an assistant professor of Clinical Pathology at the Perelman School of Medicine at the University of Pennsylvania.

CLIA oversight of laboratories and personnel has a strong emphasis on developing a quality management program — quality control, quality assurance, and quality improvement practices. The goal of the certification process and required bi-annual proficiency testing is to make certain that a laboratory team carefully considers the integrity and accuracy of complex lab procedures; ensures the sensitivity, specificity, and reproducibility of their data; and promotes the safety of patients and research participants. In short, they must continuously adhere to high standards in all aspects of their work and be able to prove it every step of the way.

Dr. Santani and CAG’s staff developed a rigorous and systematic program to continuously monitor quality for CAG’s pediatrics genomics biobank, which includes samples from more than 400,000 people, and all sequencing and genotyping activities. After a detailed onsite inspection from the U.S. Department of Health, CAG received CLIA certification in December 2016.

“This reflects a major accomplishment from the entire team at CAG who worked tirelessly for many months to achieve this milestone,” Dr. Santani said. “The CAG team is excellent and dedicated to the pursuit of quality in every step of the pathway from specimen collection to data analysis.”

A Perfect Match for Collaboration

Hakon Hakonarson, MD, PhD, director of CAG and professor of Pediatrics at Penn, couldn’t agree more. With CLIA certification under its belt along with more than a decade of experience in biobanking and in the generation and management of genomic data, CAG is in a unique position as the only CLIA-certified high throughput sequencing and SNP-array facility that operates within a world-renowned pediatric research institution that has such integrative assets, Dr. Hakonarson said. CAG has the ability to process and deliver results on several thousand specimens a month with the infrastructure and secure cloud-based storage it has in place to handle the vast amount of data that is collected.

“All of what we do is focused on how we can make our discoveries work toward better diagnostics and improved therapies that we can bring to the pediatric clinic,” Dr. Hakonarson said. “CLIA status opens up numerous opportunities for a big research lab like ours to accomplish this.”

Partners and collaborators within CHOP and in other academic, biotechnology, and pharmaceutical organizations worldwide can rely on CAG to support large clinical research studies and clinical trials. Suppose a pharmaceutical company would like to conduct a biomarker trial. The pharma team could choose to establish an entire laboratory and data processing center on their own, which would be an intensive undertaking. Or they could work with CAG’s specialists who already have established the appropriate technical and regulatory framework to streamline these type of projects, all of which are backed up by CHOP’s biobanking efforts.

CAG extended one of those successful genomics collaborations in February with Aevi Genomics Medicine. The company has access to certain data from the CAG biobank to pinpoint genetic mutations underlying specific rare and orphan diseases, and it plans to utilize this information to identify development candidates for advancement into therapeutic and diagnostic products for sick children, according to a press release announcing terms of the agreement.

‘Our Ultimate Goal is to Improve the Health of Our Patients’

CAG also offers an individualized, “one stop” approach for the CHOP-Penn research community. They’ve teamed up with over 60 internal investigators in various ways, such as providing input on grant applications or helping them to generate data through collaboration and access to the CAG biobank for their studies. CAG experts often sit down with study teams to determine the best ways to design, optimize, and validate assays that will help them arrive at the answers they’re looking for — and just as importantly — have confidence when results come back negative, Dr. Santani said.

“The question that most people don’t ask is: What happens when you sequence a whole genome, and you don’t find a pathogenic variant?” Dr. Santani said. “Because analysis of genome data is so complex, there is always the underlying concern about quality and how well was the analysis performed. This is a challenge for the entire genomics community. The inter-disciplinary team at CAG is very experienced both in generation of sequencing data and also in the analysis and management of data. We are familiar with the complexities of our informatics infrastructure, which has been established to meet high quality standards. So, when the results on a whole genome analysis are negative, one can be assured that we have leveraged the strengths of the available informatics tools, and no stone has been left unturned in looking for that pathogenic variant.”

The CAG team applies this same rugged determination as it explores new methods to genome sequencing and analysis. They have created several tools that are implemented by research and clinical laboratories throughout the world. One is an algorithm (Penn CNV) that scientists use to analyze copy number changes that are detected in the genome. That platform has received more than 1,200 citations reflecting its use in the community. Also, genome annotation software developed at CAG (ANNOVAR) helps to map genes and their functions in the coding and non-coding regions of a genome. It has more than 3,000 citations.

“Sequencing technology and informatics tools are changing at a blindingly rapid pace, and clinical researchers are unable to keep up, let alone make informed decisions to improve patient care,” said Dr. Santani, who holds board certifications in Clinical Molecular Genetics and Clinical Cytogenetics. “Our team of 70-plus scientists at CAG are at the perfect nexus to use their expertise to evaluate and develop new technologies, collaborate with researchers and biotech companies, establish the clinical utility of genomic information, and advance medicine. It’s an intellectually rich environment where the focus is on resolving the critical challenges that genomics presents to us almost on a daily basis. Our ultimate goal is to improve the health of our patients by diagnosing patients earlier than we can do today and to also find new treatments to better manage these conditions.”

New Frontiers as Genomics Goes Mainstream

One of those challenges involves coupling genomic data with patients’ electronic medical records (EMRs). CAG is part of a consortium called the Electronic Medical Records and Genomics (eMERGE) network that is now in its third phase. One of the project’s aims, Dr. Hakonarson explained, is to identify and validate actionable genetic variants that impact patients’ health, such as genetic variations that may cause individuals to have adverse reactions to certain drugs, and then integrate that information into EMRs. An overarching question that the investigators are trying to answer is how patients’ knowledge of their genomic results generated by eMERGE and other CAG-related efforts affect their medical, ethical, and financial decision-making.

Genetic carrier screening is one example of how genomics has arrived at the intersection of mainstream clinical applications. Finding variants can be very informative for couples who are at childbearing age, Dr. Hakonarson said. Perhaps they are parents of a child with a rare pediatric genetic disorder and want to find out their risk of conceiving another child with the same disease. Or maybe a couple is planning to start a family and already know that one partner’s ancestral background predisposes them to harboring a certain genetic condition; they may want to confirm if the other partner has the exact same gene variant that could increase the chance that their baby would be affected.

“A child has six billion base pairs — three billion from the father and three billion from the mother that reside in the pair of 23 chromosomes each of our cells harbors,” Dr. Hakonarson said. “Among the millions of base pairs that vary among individuals, one variant may be totally critical to whether a child is healthy or has a major medical condition. It’s incredible. Our CAG analysts are focused on finding that one pathogenic variant after looking at billions of base pairs.”

As interest grows from a consumer standpoint for genetic carrier screening services and the costs become less prohibitive, Dr. Hakonarson anticipates that CAG’s new CLIA status will attract future third-party opportunities, in which CAG would perform the complicated genomic work of isolating the DNA, processing the sequencing data and annotating the information based on all of the variants generated. CAG would provide the third party requesting the information for their clients about the results, and then genetic counselors could help interpret the findings, convey them to their concerned families, and help them understand their genetic risks.

“And we will always ask for the opportunity to use the samples and information we gather in a de-identified way for research,” Dr. Hakonarson said. “This will allow for our biobank to grow much faster and allow for far more productive research to be done, a win-win situation for all.”

As genomics research moves closer to clinical application, the CAG team is ready to tackle these new frontiers to discover and resolve the underlying genetic causes of children’s most complex and extremely rare diseases.

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Consortiums Improve Proficiency in Bladder Exstrophy Care in U.S. and Overseas

Watching 2-year-old Gianni Garrow scramble up and down the physician’s chair in the urology exam room, it’s difficult to imagine that he was born with his bladder exposed on the outside of his body. Six surgeries later, he no longer points to his belly as his “boo-boo” place — instead, he shows off his scraped knees, the hallmarks of toddlerhood.

The Garrow family traveled four hours from their New York home to visit the Urology team at Children’s Hospital of Philadelphia who are part of a unique multi-institutional consortium to increase their experience and proficiency in the care of bladder exstrophy, a rare, complex abnormality that occurs early in fetal development. The infant’s hips are splayed, and the abdominal wall doesn’t fuse properly, leaving an open bladder that protrudes through this defect.

Other parts of the infant’s “plumbing system” may not form or function correctly, including the opening of the urethra (epispadias) and the sphincter muscles that work together with the bladder to hold and release urine. In Gianni’s case, he developed inguinal hernias associated with bladder exstrophy that also needed to be repaired.

The Multi-Institutional Bladder Exstrophy Consortium (MIBEC), which formally launched in 2013, includes CHOP, Boston Children’s Hospital, and Children’s Hospital of Wisconsin. When an infant with bladder exstrophy is ready for surgery, the participating urology surgeons visit each other’s operating rooms to observe, provide helpful commentary, and record all of the procedures with high-definition video. The MIBEC program’s research goals are to evaluate both short and long-term outcomes of bladder exstrophy patients, including quality of life, continence, and body image.

The MIBEC team published study results in the June issue of the Journal of Pediatric Urology that describe how this real-time, collaborative teaching approach benefited a cohort of 27 patients who underwent complete primary repair of exstrophy (CPRE) from 2013 to 2015. With CPRE, the bladder closure, epispadias repair, and bladder neck reconstruction occur during the same surgery.

“This represents the most complex surgical correction that we get challenged to do in pediatric urology,” said Douglas Canning, MD, chief of the division of Urology at CHOP. “We all get better when we have more experience tackling such a complicated problem.”

Experience Needed to Enhance Surgeons’ Knowledge of Rare Condition

Only about 100 babies a year in the U.S. are born with bladder exstrophy, so each patient case that the MIBEC team encounters is a valuable opportunity to refine their CPRE technique and expertise. Many of these families gathered at CHOP’s campus in early June for the International Exstrophy Conference hosted in partnership with the Association for the Bladder Exstrophy Community (A-BE-C). Over the weekend, they shared their experiences of living with bladder exstrophy and heard updates about MIBEC’s progress.

Waiting for completion of the 12-hour-long surgery is stressful for parents and caregivers, and it’s just as exhausting for the surgical team. Every nuance of the CPRE procedure is under scrutiny so that the MIBEC surgeons can standardize critical steps, timing, and technical details.

For instance, Dr. Canning, who also is a professor of Urology in Surgery at Perelman School of Medicine at the University of Pennsylvania, recalled a “revelation” that occurred during one surgery he was performing that led to improved safety and consistency during a particular stage of the procedure. A Wisconsin colleague noticed that the blood supply to the infant’s penis became compromised when they attempted to pull the pubic bones together. The team made adjustments and subsequently modified the operation’s algorithm and monitoring techniques to avoid penile injuries.

Following the surgeries, the MIBEC team stays in close touch with the infants’ parents and caregivers. While Gianni was recovering at home after his operation in the fall of 2015, his parents would measure his urine output and take him for ultrasounds every few days. They sent the results to Dana Weiss, MD, an attending pediatric urologist at CHOP, who recognized that Gianni wasn’t voiding enough on his own. His bladder would fill up, but the urine would shoot back up through his ureters into his kidneys, putting him at risk for urinary tract infections. To solve this complication, Gianni had another surgery six months ago to re-implant his ureters.

“He’s been great ever since,” said his mother, Lisa Lafrazza-Garrow. “Looking at him, you would never know that he has had six surgeries so far. He likes anything to do with throwing balls, riding his bike outside, going to the playground. And he loves doughnuts.”

Because the CPRE operation usually is performed in the U.S. on babies who are only weeks to months old, the urologists must wait until children like Gianni reach their fourth or fifth birthdays to see who is truly able to hold their urine and who cannot. The urinary continence rate of children who underwent CPRE is currently about 20 to 25 percent, and the surgeons expect the continence to improve as the children age.

In the meantime, the MIBEC team will continue to track the children’s continence rates, review and compare video clips, and gather research data that will help them to improve patient outcomes. One project underway involves taking samples of the infants’ microbiome — the community of bacteria that is growing on their bladder plate — and analyzing them to better understand how to lower post-surgery infection rates, which stand at 60 percent.

“As families are learning about this work, our three institutions are getting more referrals,” Dr. Canning said. “The families want to come to a place that is studying this carefully and invested in solving this critical problem … It is expensive to do, but the payoff is in the little children who now are given a better chance of voiding normally.”

More Fertile Learning Opportunities Internationally

Across the world in India, this model for sustained collaboration has taken shape over the last decade as the International Bladder Exstrophy Consortium. It is based on a long-term commitment from visiting U.S. surgeons and a competent, skilled host team who are dedicated to reducing the burden of disease in this part of the world, which has about five times the number of live births with bladder exstrophy than in the U.S.

Aseem Shukla, MD, director of Minimally Invasive Surgery, division of Urology at CHOP, showed the International Exstrophy Conference audience photos from Civil Hospital in Ahmedabad, India, where they take care of every child for free. A group of clinicians from CHOP, Cincinnati Children’s Hospital, and Sidra Medical and Research Center in Qatar travel there once a year in January and stay for two weeks to complete as many bladder exstrophy closures as they have time to accomplish. They also meet with about 80 families for consultations and rigorous follow-up care.

“Not only are we doing our very best for these children,” Dr. Shukla said, “we also are learning an amazing amount of information on an accelerated time curve. Even in a busy U.S. hospital, we might see five to 10 bladder exstrophy closures a year. In India, we see 15 in a week. This is fertile ground for interchange and sharing of best practices.”

Dr. Shukla, who also is associate professor of Surgery in Urology at Penn, and colleagues reported the team’s outcomes for 75 of those patients in a scientific abstract that won a clinical research prize at the Societies for Pediatric Urology Annual Meeting held in May. Based on their findings, the study team concluded that the collaborators successfully performed reconstruction in older children (mean age was 3 years for the CPRE procedure), and about 25 percent of these patients are showing some level of urinary continence.

As word has spread about the center for bladder exstrophy at Civil Hospital, families come from all over the Indian state of Gujarat, which has a population of 60 million people, to get help. Many comprise the lowest socio-economic strata in India, so they are tremendously compromised when a child is born with bladder exstrophy.

Dr. Shukla shared the story of a boy born with bladder exstrophy in central India who was asked to leave his joint family hut because of the overwhelming smell of urine. He also was dismissed from several schools because he left wet spots everywhere. The ostracized 14-year-old met the team of visiting surgeons, and they decided to repair his bladder exstrophy, even though he was much older than the majority of patients they had treated.

“Afterward, he did exceedingly well,” Dr. Shukla said. “He now experiences a couple hours of continence at a time. For him, the village was transformed. He is back in school getting an education. The family has a picture of the surgical team on their wall that neighbors come and bow to, as if a divine intervention had happened in their lives. These are the impacts we can make with the work we do.”

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Healing Head and Heart: CICU Nursing Research Addresses New Moms’ Stress

Three months after giving birth, a new mother held her baby for the very first time. Born with a congenital heart defect, her child had been rushed to the Cardiac Intensive Care Unit for surgery soon after delivery. Like most newborns in the CICU, the infant’s post-operative condition complicated everything from the first breastfeeding session to the simplest skin-to-skin intimacy. Strict safety protocols ensured that the newborn remained stable, while lines, tubes, and wires hooked him to complex machinery.

This mother’s wish, however, had been granted by the band of nurses who appeared by her bedside during their developmental care rounds at Children’s Hospital of Philadelphia. Befitting their nickname of the “warm-and-fuzzies,” which was given to them by one of the new mothers, the nurses talked less of medicine and more about motherly matters:

What would she like to tell them about her baby? Would she like to learn how to developmentally play with him or her? When was the last time she had held her child? Would she like to, now?

Questions like these can create a world of possibilities for new mothers and their critically ill infants – one that includes improved mental and physical wellness, as well as the ability to cultivate a healthy post-hospital home. These questions form the foundation of developmental care – a paradigm introduced to the CICU at CHOP over seven years ago, and a fertile research field that continues to strengthen with the work of nurse scientists.

One such scientist, Amy Jo Lisanti, PhD, RN, CCNS, CCRN-K, a clinical nurse specialist at CHOP – and one of the “warm-and-fuzzies” – is building on stories shared by parents during developmental rounds to discover how nurses can best address a new mother’s anxiety when they learn that their child has congenital heart disease (CHD). In her most recent study, published in the American Journal of Critical Care, Lisanti identified some of the strongest factors that contribute to such distress.

“There was 30 years of literature on the stress of parents in pediatric and neonatal intensive care units but nothing on the CICU,” Lisanti said. “Based on my clinical experience talking with these parents, sensing their stress, and seeing that they wanted to discuss their anxiety in developmental rounds, it was clear: We really need to come up with ways to understand what is feeding into parents’ stress so we as nurses can do something about it.”

Encouraged by her mentor, Barbara Medoff-Cooper, PhD, RN, FAAN, Ruth M. Colket Professor in Pediatric Nursing at CHOP, Lisanti used demographic data and reports from 62 mothers from three CICUs in the U.S., in order to address the gap in knowledge. These mothers’ babies had entered the CICU within one month of their birth for complex congenital heart disease surgery. Their reports provided Lisanti with the documented scientific evidence she needed to begin to drive more change in CICU nursing practice.

Why Do New Mothers Feel Stressed in the CICU?

Mothers ranked their newborn’s appearance and behavior as the highest perceived stressor when their baby has CHD, according to Lisanti’s results. The babies often appear paralyzed and unresponsive after surgery due to anesthesia or narcotics, leaving parents to worry that their infant is in pain.

“The parent meets their child in the CICU, and their baby could have a breathing tube, chest tubes, incisions, heart lines, and so on,” Lisanti said.

Coming in as the second highest perceived stressor was an experience known as parental role alteration. Lisanti defines parental role alteration as a parent’s sense that they have lost their role as “mom” or “dad” in a heartbreaking disconnection from reality. That disconnection often begins when babies must be taken to the CICU soon after birth.

“Mothers want to pick up their baby, comfort their baby, protect their baby from pain and harm, clothe them, feed them,” Lisanti said. “The CICU environment takes most of this away. As the baby undergoes cardiac surgery and subsequent recovery, it becomes very difficult for mothers to participate in normal infant-care activities. It can feel like the nurse is caring for the baby, while mom can’t do anything to protect her baby during that time.”

Furthermore, when Lisanti examined stress response in mothers, as measured by maternal state anxiety, mothers scored extremely high. She also found that parental role alteration and trait anxiety (an individual mother’s tendency to become anxious) predicted 26 percent of the variance in state anxiety scores.

Incorporating Intimacy Into CICU Care

To address maternal anxiety and parental role alteration in particular, Lisanti said nurses can begin with encouraging a new mother to hold her critically ill newborn with an established protocol.

“Developmental care is about providing all the pieces for parents to get more involved,” Dr. Medoff-Cooper said. “Getting parents to hold the babies is one of the things that Amy has been very concerned about. She developed a holding protocol so we can get parents to hold babies sooner.”

From helping mothers feed their babies to encouraging them while pumping breast milk, and other “innate natural things,” mothers can feel more active and attached. Nurses can further enhance parental role at the bedside by helping mothers read and respond to their baby’s cues.

“For moms, the concern is that they sometimes see all the cues as potentially signaling their baby is in pain,” Lisanti said. “But we can say, ‘Oh look, your baby just showed us that she needs her diaper changed. Let’s do that together.’ The more we can incorporate the parents into the care of the baby, the better.”

While there is always room for improvement, Lisanti believes that CHOP nurses already incorporate many of the interventions in their day-to-day care, contrary to practice 10 years ago.

“The culture used to be, ‘Don’t touch the baby,’ and parents couldn’t come to the bedside during medical rounds,” Lisanti said. “Even though we were family-centered, I don’t think we were as family-centered as we are now.”

Change began when Lisanti, Dr. Medoff-Cooper, and several other nurses at CHOP began to push for a paradigm shift in care that included developmental rounds in the CICU. The nurse scientists also began to discuss the subject of developmental care specific to the CICU in scientific papers. Today, they remain the only nurse researchers discussing the subject in the literature.

Helping New Moms Beyond Hospital Walls

Lisanti’s work in the CICU forms one portion of a larger five-year randomized clinical trial, led by Dr. Medoff-Cooper, that monitors new mothers and families on their return home from the delivery room. The study’s goal is to determine whether additional contact beyond hospital walls might improve both infant and parent outcomes.

Officially titled the Transitional Telehealth Home Care Study (also known as REACH), the trial is funded by the National Institute for Nursing Research and utilizes daily text messages and virtual home visits via Skype or Facebook to check in with the families on factors that include stress, weight gain, quality of life, and others. With reams of data already collected, Dr. Medoff-Cooper looks to complete the study later this year.

Like Lisanti’s study, the REACH study hinges on the idea that to support critically ill babies, we must first support their mothers’ mental and physical health.

“If we do not support families, it interferes with their parenting ability,” Dr. Medoff-Cooper said. “It interferes with their ability to hear what is being told to them, and to manage their kids in the best possible way. You have to set the stage to have a better environment for the families so that when they do go home, and the children have long-term critical illnesses such as our cardiac kids, we’re doing a better job of helping parents be better parents.”

While addressing a mother’s anxiety in the CICU may seem relatively new to scientific literature, these instincts and actions are nothing novel to Lisanti, Dr. Medoff-Cooper, and their fellow nurses. Whether it is asking a mother about her personal concerns to treating a family as a whole, it comes quite naturally to the nature of nursing – and nursing research.

“Nursing research is about finding ways to improve care through evidence, just the same as medicine,” Dr. Medoff-Cooper said. “But the way we give care is different. We’re not changing drugs. We’re changing the way we care for the kids.”

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Myelin Biorepository Fuels Understanding of Leukodystrophies

A decade after seeing her patients (and oftentimes beyond that), Adeline Vanderver, MD, program director of the Leukodystrophy Center of Excellence at Children’s Hospital of Philadelphia, still calls up families when she discovers something new about their child’s leukodystrophy. Like most pediatricians who treat rare disease, Dr. Vanderver knows that many families seek knowledge about their child’s condition whether or not he or she has passed away. They would like to learn what went wrong inside their child’s body and help other children and families who struggle through a similar pain.

Now, a 10-year biobank project that first began at D.C.’s Children’s National Medical Center in 2003 and moved to its new headquarters at CHOP in 2016, will allow Dr. Vanderver and her team at the Leukodystrophy Center to do this with even more acuity. Through the Myelin Disorder Biorepository Project (MDBP), researchers at CHOP will collect the blood, tissue, cells, and myelin from children with various types of leukodystrophies in order to diagnose unclassified forms of the condition, understand the underlying mechanisms of known types, and test new therapies.

With an estimated one in every 7,000 babies inheriting the progressive disorder, the biobank has the potential to change the lives of clinicians, parents, and patients – beginning with providing a clearer picture of the genetic disorder itself.

What are Leukodystrophies?

Children with different forms of leukodystrophies have one common characteristic: the presence of damaged myelin, also known as “white matter,” in their brain and spinal cord. Because the central nervous system (CNS) operates as our control center, directing nerve tissues throughout the entire body, this impairment can disrupt every aspect of a child’s mental and physical development.

“White matter works as insulation to convey the information that the brain is trying to send to the body, like speech, movement, and everything else that our brains contribute to our lives,” Dr. Vanderver said. “When you have leukodystrophy and that myelin is broken, you’re not able to convey all that information.”

Because leukodystrophies are a degenerative condition, symptoms can also emerge or worsen late into adolescence or adulthood as the myelin damage spreads. Despite such an extensive impact, leukodystrophies remain difficult for clinicians to diagnose. Many different types of leukodystrophies exist, with a different gene abnormality underlying each form. Researchers currently know of 30 types of leukodystrophy, and Dr. Vanderver guesses that there are many more. Through the biorepository, she hopes to drive what she describes as the “broken train” of leukodystrophy research forward – an analogy she uses to describe the disorder with her patient’s parents.

“Think of train tracks that aren’t working properly,” Dr. Vanderver said. “There are train cars that are running on those tracks, and some leukodystrophies are at the front of the train.”

These, she said, are the forms of the disorder that researchers know the most about, including the gene responsible for the damaged myelin and its effect on the child’s CNS. For these types of leukodystrophies, developing new therapies and testing their impact is a top priority.

Next, there are leukodystrophies in the middle of the train.

“For these forms, we might know what the gene is, but we don’t understand what the broken gene does to the myelin, and we certainly don’t have therapies,” Dr. Vanderver said.

Finally, there are the leukodystrophies at the back of the train: the ones that need the most fuel and perhaps the most help. Researchers don’t know the cause of these leukodystrophies at all.

“My hope is that through this biorepository project, we can bring the whole train forward so that ultimately, leukodystrophies are easier to diagnose, understand, and care for,” Dr. Vanderver said.

Fueling Research

Currently, the biorepository stores the DNA and RNA from more than 1,200 families. According to Dr. Vanderver, the genomic data has already helped researchers make significant progress.

“The biorepository has contributed in a direct and indirect way to uncovering the findings of about a dozen leukodystrophies,” Dr. Vanderver said. “And at this point now, we’re actually achieving diagnosis in about 80 percent of cases.”

Next-generation sequencing (NGS) technologies that utilize patient samples drive these breakthroughs. Through whole exome sequencing and whole genome sequencing, researchers can identify genetic variations of leukodystrophies by piecing together an individual child’s genetic code. Previously, clinicians were able to identify leukodystrophies by observing white matter abnormalities in a child’s CNS through neuroimaging, but even then, more than half of these conditions still don’t have a definitive diagnosis, referred to vaguely as “leukodystrophies of unknown etiology.”

Adding to this, it can be difficult for patients to receive a diagnosis: The diagnostic odyssey averages about eight years long, with $8,000 in test expenses per patient. Through the MDBP and other ongoing studies, Dr. Vanderver hopes to assess the further usefulness of NGS, which may yield faster and more cost-effective approaches. The technology has already shown promise in modernizing medical research into rare diseases, since an estimated 80 percent of rare diseases have a genetic origin. In an ongoing study called LeukoSEQ, Dr. Vanderver and her team will use NGS to help diagnose a group of patients who have suspected leukodystrophies (according to clinical symptoms observed through MRI imaging) but no particular genetic diagnosis.

In addition to genomic-level data, banked tissues, cells, and blood samples will help the team understand and establish the mechanisms of existing and unclassified leukodystrophies, as well as track current care and natural history of the disease.

“We continue to work on diagnosis, but the next step has been understanding the mechanisms of disease and working on therapies,” Dr. Vanderver said.

Molecular data gives the team the ability to recreate and understand how a gene variant wreaks havoc in a child’s body. Researchers can make induced pluripotent stem (iPS) cells, or stem cells re-programmed with the ability to produce any kind of cell or tissue in the human body, to model and investigate a given leukodystrophy. On top of that, Dr. Vanderver’s team can also make neurons and dendrites (in order to see what happens with the broken gene at a cellular level) as well as develop biomarkers to test the impact of novel therapies.

A Patient’s Role

So far, Dr. Vanderver has witnessed an astonishing level of enthusiasm from families and patients who are willing to donate samples. She equates the effect to what happens during a snowstorm.

“When you’re in a situation where things are challenging, people really do band together to try to recruit others,” Dr. Vanderver said. “Families are amazingly altruistic, and they understand that oftentimes, they’re giving samples that may never help their individual child.”

By the time researchers understand what causes the disease and how to treat it, too much time may have passed for the donation to have an impact on their own baby or child. Nevertheless, families still want to help.

“It seems so unfair to have this enemy that you don’t even know what it’s doing,” Dr. Vanderver said

As a result, families consent to participate and provide the team with clinical records, DNA, and blood samples for both child and parent, but their participation doesn’t just stop at donating samples. The registry has allowed Dr. Vanderver to put families in contact with one another, to have them attend family meetings and join together.

“Its goal really is to provide a network,” Dr. Vanderver said.

Naturally, that network also includes the collaboration of other researchers outside of the Vanderver lab and across different disciplines.

“If researchers have families that they think should be participating, it’s a huge gift to help us connect those dots,” Dr. Vanderver said. “There are more than 30 myelin disorders and no way that my lab can do all the work. The big goal of the registry is to share samples and information so that we can, in essence, advance the whole train forward better.”

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Loud and Clear: Qualitative Methods Research Affinity Group Gives Research a Voice

Scientific research can be so much more than just the facts. A new research affinity group at Children’s Hospital of Philadelphia launched this summer to help investigators use qualitative research methods and techniques to reach a deeper understanding of patient and family attitudes, beliefs, and preferences that will give their quantitative research findings a “human voice.”

If you think of a picture in a coloring book, quantitative research would be the drawing’s solid outlines, and qualitative research would be the shaded colors. Together, the two methodologies can help to create a fuller picture of a research problem and possible interventions or solutions.

Over the last decade, healthcare professionals have recognized the value of both kinds of research. Quantitative research findings are based on numerical data and statistics to demonstrate whether a particular intervention successfully reached a designated outcome. Qualitative research aims to describe the implications of these measurements and how or why the outcomes were achieved.

In pediatric research, a mixed-methods research approach can be particularly valuable because parents’ or caregivers’ viewpoints can be poles apart from a child’s or adolescent’s perspective, not to mention the goals of providers and a hospital system.

“Qualitative research opens opportunities to understand the impact of health and wellness and disease from different perspectives,” said Cynthia Mollen, MD, MSCE, who is leading the new Qualitative Methods Research Affinity Group. “Learning directly from a population about what their needs and goals are can really impact how we care for them.”

Dr. Mollen, an emergency medicine attending physician and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, used a qualitative research approach when she and colleagues conducted an in-depth interview study about an emergency department-based intervention to improve access to emergency contraception among sexually active teens. The researchers did in-depth interviews with a group of adolescent girls to better understand their attitudes toward information delivery in the ED setting. They learned that the research participants thought using ED visits would be an important opportunity to learn more about pregnancy prevention, but that interventions should target patients coming to the ED with specific chief complaints.

“What was interesting to us, is the study team was thinking that it would be a good idea to provide this type of service to all teens who came to the ED,” Dr. Mollen said. “But what we heard from that group was that they would really be more interested in learning about sexual and reproductive healthcare issues if they were in the emergency room for a complaint that was related to a potential issue that was similar. So that really pivoted our thinking around what kind of intervention we would want to develop moving forward.”

These are the type of “lessons learned” that the Qualitative Methods Research Affinity Group aims to share when they bring together researchers interested in using qualitative research techniques in their work. They will collaborate to provide resources to help facilitate their projects, such as introducing them to qualitative methods software. And they plan to invite speakers who are experts in qualitative methods so that the group can gain new insights and perspectives.

Dr. Mollen also wants to draw upon the expertise that already exists at CHOP by hosting a “Works in Progress” series. Research teams who have experience using qualitative methods will guide others on how to get started, ways to perform data analysis, or ethical issues that they’ve encountered.

“For a long time, qualitative initiatives have popped up and grown in separate pockets across the Research Institute,” Dr. Mollen said. “This groups aims to connect researchers together so that we can learn from each other and build creative and rewarding collaborative relationships.”

One of many resources that the new Research Affinity Group aims to highlight in order to enrich the qualitative work carried out by CHOP researchers is the Family Partners Program. Under the umbrella of CHOP’s department of Patient and Family Experience, research family partners can offer authentic insights about what it’s like to live with an illness or disease that can inform many aspects of qualitative study planning, development, and execution.

“What they do inherently is a qualitative technique, in that they provide in-depth descriptions of what their experiences have been, and the Research Affinity Group could certainly use their help in so many ways,” Dr. Mollen said.

For example, they can assist in determining which health outcomes matter most to patients and families, narrowing down patient groups to select for a study, and deciding on the best ways to phrase research questions.

The creation of this new Research Affinity Group comes at a time of heightened demand for qualitative approaches in research. Funding agencies, such as the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Patient-Centered Outcomes Research Institute, have recognized the value of engaging patients and stakeholders into studies and are increasingly asking for investigators to integrate qualitative methods into their proposals.

“There is so much interest in qualitative methods, and we definitely want to be engaging people who want to learn more about it and, within an environment of finite resources, do the best work that they can do,” Dr. Mollen said.

If you want to join the Qualitative Methods Research Affinity Group, contact its coordinator, Katie Kellom. A kickoff event will be held Nov. 16, 11:30 a.m. to 1 p.m., on the first floor of the Roberts Center for Pediatric Research.

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