Bench to Bedside

October 2015

Driving Safety Research Accelerates Into Business


If you do not expect pediatric research to have anything to do with improving the bottom line of a parcel delivery service or cable company, then the story of Diagnostic Driving may surprise you.

Diagnostic Driving, a startup company spun out from The Children’s Hospital of Philadelphia Research Institute, has spent the past several months accelerating from an idea based on teen driver safety research into a thoroughly researched, successfully piloted business model for improving the safety of corporate automotive fleets. At the end of October, Venk Kandadai, MPH, co-founder of the company, traveled across the country presenting Diagnostic Driving’s success to date and seeking investments so the company can continue its growth.

The company’s journey is an illustration of what a growing number of CHOP-generated ideas may experience soon under the guidance of the new Office of Entrepreneurship & Innovation.

To trace this company’s road from research to the startup world, let’s hit reverse and see where it began.

Diagnostic Driving emerged from driving safety research led by Flaura K. Winston, MD, PhD, scientific director and founder of the Center for Injury Research and Prevention (CIRP) at CHOP, and co-founder of the new startup company with Kandadai, a project manager and statistician at CIRP. Dr. Winston has led decades of research on driving safety and risk reduction for teenagers and is a national leader in the field.

Earlier this year, Dr. Winston and colleagues at CHOP and the University of Pennsylvania reached a major milestone in their research: They validated a simulated driving assessment software package they had developed to assess driver safety and provide insight to personalized interventions to improve driving. Creating and validating the tool was a five-year process, building on more than a decade of Dr. Winston’s foundational research funded by the National Science Foundation and other sources.

“We had this validated tool to differentiate drivers based on skill and experience,” Dr. Winston said. “We knew we needed to get it out there.”

When the opportunity arose to apply to the DreamIt Health startup business accelerator program this spring, she and Kandadai applied and were accepted.

DreamIt Health, a collaboration between the business accelerator company DreamIt Ventures, Independence Blue Cross, and Penn Medicine, helps launch startup businesses focused on health and healthcare. For the past two years, CHOP-developed teams have participated alongside the independent businesses accepted into DreamIt Health to receive mentoring and training in business development strategy, finance, legal consultation, technology, and market research.

During the four-month incubation, Diagnostic Driving shifted and grew. The team built its first mobile prototype in July and constantly sought and responded to feedback from potential customers.

“It was hard,” Kandadai said. “Even though the research was done for teenagers, we determined that the market size was too small to sell to parents and teens.”

Only 2 percent of parents in Pennsylvania enroll their teenagers in driving schools. These parents did not rate preventing crashes as highly as an insurance discount as their reason for doing so.

“For driving assessment software, there just so happened to be a market in corporate fleets,” Kandadai said — and their research indicates that market is worth $4 billion.

“Corporations spend $60 billion per year on crashes,” Kandadai said during his presentation Monday, Oct. 26, as part of DreamIt Health’s Demo Day. He noted that corporate fleets lack reliable ways to predict and quantify crash risk in their employee populations, and to intervene to improve safety in targeted ways. He outlined the company’s growth and vision to an audience including industry leaders, potential investors, potential customers, and media.

During the incubation period, Kandadai said, Diagnostic Driving was piloted successfully with a Fortune 100 global pharmaceutical company that now has a letter of intent pending for continued use of the program. Diagnostic Driving also has received interest in early adoption from several other large corporations, including a large parcel delivery company and a major cable television company.

Diagnostic Driving is next seeking seed funding from venture capitalists and other investors, as well as contacts at Fortune 500 companies with large automotive fleets.

“Our work is fundamentally about population health,” Dr. Winston said. In that realm, Diagnostic Driving is poised to make a potentially big difference — making the roads safer while reducing the bottom-line cost of insuring drivers at large businesses at the same time.

Entrepreneurship and Innovation at CHOP

Diagnostic Driving is one of the earliest companies to accelerate into business based on ideas developed at CHOP, but it is not alone. Last year, the CHOP-spinoff medical information security company Haystack went through the DreamIt Health incubation process, and it is continuing to grow as an independent company.

All of the CHOP-spinoff companies are independently owned and operated, while CHOP owns equity. CHOP’s involvement also includes logistical support, such as protected time to focus on the entrepreneurial venture that Kandadai noted was particularly helpful in the launch of Diagnostic Driving.

“We have a lot of smart clinicians, researchers, administrative staff, and others who come up with great ideas,” said Patrick FitzGerald, who joined CHOP in the newly created position of vice president for entrepreneurship & innovation in June. “CHOP is a fantastic place to be to develop ideas from a scientific perspective, but people here didn’t necessarily have the outlet to explore their ideas from a business perspective.”

That realization was the impetus for CHOP’s participation in DreamIt Health and for the creation and growth of the Office of Entrepreneurship & Innovation. The office works to create an entrepreneurial spirit throughout the organization, both in the Research Institute and in clinical and administrative domains. It identifies and supports potential spinouts, develops strategic partnerships, and helps people at CHOP to develop early stage ideas including innovative devices, therapies, mobile applications, and software tools. The office has created a centralized hub for managing existing and future entrepreneurial and innovative projects. It will begin holding open office hours biweekly on Fridays beginning Nov. 6 for CHOP employees to discuss their ideas and learn about innovation.

“CHOP has always been a leader in research, a place full of people generating ideas that improve health,” FitzGerald said. “Now what we’re trying to do is build on that strength with the entrepreneurial skill set to bring those ideas to market in a faster and more commercially focused way.”

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New Growth Charts for Down Syndrome a Tall Order


Pediatricians have long known that children with Down syndrome grow differently than typical children, but the last growth charts for children with Down syndrome were developed almost 30 years ago. Since that time, clinical care for children with Down syndrome, especially early in life, has changed enormously, and their life expectancy has increased from 35 years in 1985 to 53 years in 2007.

It was clear to researchers at The Children’s Hospital of Philadelphia and the Centers for Disease Control and Prevention (CDC) that the growth charts available for children with Down syndrome no longer measured up.

In 2009, they launched the Down Syndrome Growing Up Study (DSGS), funded by a four-year, $1.2 million grant from the CDC. The goal was to gather information about contemporary growth patterns of children with Down syndrome so that pediatricians and parents could see where a child’s height and weight stood relative to their genetic potential.

Using highly trained people to do the growth measurements, the study team led by Babette Zemel, PhD, director of the Nutrition and Growth Laboratory at CHOP, followed 637 participants, up to age 20, from January 2010 to July 2013. About 80 percent of the participants were recruited from the Trisomy 21 Program at CHOP and from community locations in the greater Philadelphia area.

“The families and the kids were so enthusiastic and appreciative that we were doing this project,” Dr. Zemel said. “They knew that there was a problem with the growth charts for children with Down Syndrome, and they really wanted to be a part of fixing it. The Trisomy 21 Program, led by Mary Pipan, MD, was superb to work with. ”

While checking a child’s height and weight may seem like an ordinary task, asking hundreds of children with Down syndrome to take their shoes off is far from routine. Down syndrome, a multisystem genetic disorder resulting from an extra copy of chromosome 21, occurs in about one in 700 U.S. births. Medical complications that accompany the condition affect every aspect of children’s daily lives, including eating, sleeping, hearing, talking, moving, and learning.

“Rather than using growth measurements that were acquired in the clinic, which are sometimes done under hurried circumstances, we were able to do it in a research setting so that we could take our time and make sure the children were comfortable and got used to the idea,” Dr. Zemel said. “We had a picture book to show and explain to them how we would take growth measurements so that they could anticipate what we were going to do. We had good participation and very accurate measurements.”

Results from the study appeared online Oct. 26 in Pediatrics. Dr. Zemel’s co-authors were Dr. Pipan, Virginia A. Stallings, MD; Waynitra Hall, MS; Kim Schadt, MSN; all from CHOP; and David S. Freedman, PhD, and Phoebe Thorpe, MD, MPH, both of the CDC.

One of the major study findings is that infants with Down syndrome are growing much better than they were several decades ago. Children under age 3 showed marked improvements in weight gain compared to the 1988 U.S. growth charts for children with Down syndrome. Improvements in height, reflecting taller stature, occurred mainly in males aged 2 to 20, relative to the earlier charts. In general, the DSGS charts were consistent with charts from children with Down syndrome in the United Kingdome, published in 2002.

The DSGS team also created the first-ever body mass index (BMI) charts for children with Down syndrome. The researchers noted that the charts do not represent an ideal distribution of BMI, but only describe BMI distribution among their study participants. They added that further investigations should determine how to use the BMI charts to screen patients for excess body fat and associated health symptoms.

While clinicians and researchers realize that obesity is a problem for children with Down syndrome, especially as they move into their teenage years and beyond, an interesting finding from the study that Dr. Zemel pointed out is that the weight charts for children with Down syndrome did not change much over the past few decades.

“This is quite surprising, given that for the rest of the U.S. population, there has been an increase in the prevalence of obesity,” said Dr. Zemel, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.

Another research project led by Andrea Kelly, MD, at CHOP and Sheela Magge, MD, MSCE, at Children’s National Medical Center is focusing on any health consequences of excess weight in teens with Down syndrome. They will determine if being overweight or obese carries the same cardiometabolic risks as it does for typical children, and they also will assess study participants’ body image and quality of life.

For more information on the DSGS study, visit here.

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Cornering a Cancer-Connected Autoimmune Disease


It is certainly not good news for children to get a double whammy of both cancer and autoimmune disease. Unfortunately, for a small subset of children with neuroblastoma, a common childhood cancer of the peripheral nervous system, an extremely rare autoimmune disorder called Opsoclonus Myoclonus Ataxia Syndrome (OMAS) comes along for the ride. The overactive immune response is believed to be triggered by the cancer.

But there is a twist.

“Patients with neuroblastoma who have OMAS have better outcomes, in terms of their tumor, than patients with neuroblastoma who don’t have OMAS,” said Jessica Panzer, MD, PhD, a pediatric neurologist and attending physician at The Children’s Hospital of Philadelphia who is studying this disease.

That pattern leads Dr. Panzer and other researchers to wonder: Is it possible that OMAS is a case of the body’s immune system finding a successful defense against cancer (but taking it a little too far against healthy cells)? And could we learn safe ways to harness its ability to help more children with neuroblastoma, or even other cancers?

These are among many long-term questions on the distant horizon for researchers who study this little-understood autoimmune disease. First, they need to understand the basics.

Little is known about the underlying biology of OMAS even though the condition has been known for more than 50 years. Only about 3 percent of neuroblastoma patients develop OMAS — accounting for about half of OMAS patients overall. Many clinicians will never encounter a patient with its characteristic jerky eye movements, known as opsoclonus. Because the condition involves immune cells attacking areas of the brain that affect balance and movement, children with OMAS can have chronic challenges with movement, speech, and coordination. Mood and behavioral complications, such as crankiness, are also common.

Dr. Panzer has teamed up with Miriam Rosenberg, PhD, of the Weizmann Institute of Science in Israel, for a new research collaboration to better understand the basic mechanism of what triggers OMAS in children with neuroblastoma. It is a critical first step toward better treatments and new insights into both OMAS and neuroblastoma. They received a grant earlier this year from the Pablove Foundation to begin their work together.

Imaging the Antigen

Dr. Panzer’s part of the project is aimed at finding the antigen — some chemical on the surface of nerve cells — that triggers the autoimmune response in OMAS. She will use serum samples from patients with neuroblastoma and OMAS and expose them to in vitro rodent neuron cells, from the types of healthy brain tissue that are under attack in OMAS.

This is a technique developed by researchers from the University of Pennsylvania and CHOP that previously successfully identified the antibody underlying a severe form of encephalitis. When antibodies or other substances in the serum bind to the surface of the neurons, this technique will light up their union. Comparing the interactions of healthy neurons with the OMAS patients’ serum, to neurons’ interactions with various control samples, Dr. Panzer hopes to find the spots lighting up for a compound that is unique to OMAS patients. Preliminary findings from a pilot study published this summer are pointing her in the right direction.

Secrets in the Sequencing

Meanwhile, Dr. Rosenberg is looking at samples from patients’ tumors to find out what the immune system is doing inside neuroblastoma tumors in children with OMAS. Few people have looked in this comprehensive way before.

“Little is known about the immune profile of neuroblastoma,” Dr. Rosenberg said. “Even less about this rare subset with OMAS. Maybe there is something special in these kids that is helping them to contain the neuroblastoma.”

On the hunt for that possible “something special,” Dr. Rosenberg will look at the tumors’ genomic DNA to identify sequences that match the characteristic mature pattern of the immune system’s T-cell receptors. She also will look at the sequence of the mRNA molecules in the tumor cells to find out which proteins and non-coding RNAs are expressed in those cells.

If there are unique T-cell receptor DNA signatures or differentially expressed genes in the OMAS patients’ tumors, compared to non-OMAS patients’ tumors, then Dr. Rosenberg might be on the trail of the antigen that triggers the autoimmune disease.

Outcomes Uncertain

The researchers hope that by casting a wide net, eventually this research will contribute to an antibody test to identify OMAS clinically without relying solely on symptoms. Such a test also could quantitatively track patients’ progress while in treatment for the disorder —something that is hard to do based on symptoms alone, when that judgment entails monitoring a toddler’s motor coordination. A targeted therapy for OMAS would be an even better long-term outcome, as would potential insight that OMAS research might offer into new cancer treatments.

A long road lies ahead. But, Dr. Panzer said, “You can’t get anywhere down the road without understanding the very first step. That’s where we are.”

To read more about the story behind Dr. Panzer’s collaboration with Dr. Rosenberg, and how both scientists became interested in studying OMAS, read the post on Cornerstone, the CHOP Research Institute blog.

Since 2010, The Pablove Foundation has awarded more than $1,150,000 in Childhood Cancer Research Grants to 16 institutions worldwide. Their researchers are searching for more effective treatment options, and for a better understanding of how childhood cancers behave. To learn more, visit the Pablove Foundation grants page.

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Research Institute’s Bryan Wolf, MD, PhD, New to Pennsylvania Bio Board


The Children’s Hospital of Philadelphia Research Institute is among 2,300 life sciences establishments that call Pennsylvania home. As a newly appointed member of Pennsylvania Bio’s Board of Directors, Bryan Wolf, MD, PhD, Chief Scientific Officer of the Research Institute, will foster supportive relationships within this vibrant community of scientists, biotechnology companies, drug manufacturers, and entrepreneurs.

Pennsylvania Bio is a statewide trade association representing 650 members that aims to ensure the economic vitality of the life sciences industry by promoting collaboration and public policies that support innovation in the pursuit of improving human health. Dr. Wolf, who also is chief scientific officer and executive vice president of The Children’s Hospital of Philadelphia, will help Pennsylvania Bio achieve its mission by contributing his insights from 25 years of working with pediatric health researchers and basic scientists to advance science and then rapidly translate that knowledge to facilitate healthcare decision making.

Prior to becoming CSO of the Research Institute in 2015, Dr. Wolf was chief information officer and senior vice president of CHOP, and he continues to serve in biomedical and health informatics leadership roles. From 2001 to 2008, he was responsible for the research activities, clinical operations, and education in the Department of Pathology and Laboratory Medicine at CHOP as pathologist-in-chief and chair. His research interests focus on diabetes.

“A key role of the Research Institute is to take the discoveries and breakthroughs from the research labs into everyday clinical practice, in order to have the greatest impact on the care of our children,” Dr. Wolf said.

As one of Pennsylvania’s top industries, the life sciences sector employs about 78,300 people directly and is known for its highly skilled workforce. Pennsylvania Bio has honored several leading visionaries in this scientific arena for their groundbreaking research and medical engineering performed at the Research Institute and at University of Pennsylvania’s Perelman School of Medicine.

Robert M. Campbell, MD, received Pennsylvania Bio’s Patient Impact Award this year as the inventor of the vertical expandable prosthetic titanium rib, the first device approved by the FDA to treat thoracic insufficiency syndrome, a rare condition affecting children in which the thorax cannot support regular growth or breathing. In 2014, CHOP received Pennsylvania Bio’s Deal of the Year Award for its successful spinout of gene company Spark Therapeutics, while the University of Pennsylvania and CHOP were jointly given the Patient Impact Award for their groundbreaking cancer immune therapy research.

In addition to Dr. Wolf, Pennsylvania Bio named four other new members to its board of directors: Brian Halak, PhD, of Domain Associates; John Hubbard, PhD, of BioClinica; David Ledbetter, PhD, of Geisinger Health System; and Bruce Shook of Intact Vascular Inc.

“As the trade association for the life sciences in Pennsylvania, including biopharma, medical devices, diagnostics and digital health, these additions to our Board present opportunities for both the industry and health systems to work together to ensure Pennsylvania is a global leader in the life sciences,” stated Pennsylvania Bio President and CEO Christopher P. Molineaux in a press release.

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Drug Trial Shows “Profound” Success Treating Rare Blood Disorders


When the immune system inappropriately destroys blood cells, in a relatively rare group of diseases called autoimmune cytopenias, children may suffer for years with anemia, uncontrolled bleeding, and vulnerability to infections, while their parents struggle to find a diagnosis.

Once diagnosed, even the standard treatment does not necessarily bring patients’ struggles to an end. Some patients cannot tolerate the standard corticosteroid drugs that are used to suppress the immune system, and some develop resistance. Over the long term, corticosteroids also increase the risk of osteoporosis and vulnerability to infection.

Findings from a new multicenter research study may offer hope to these patients. The study, led by hematology researchers at The Children’s Hospital of Philadelphia and published in the journal Blood, demonstrates success that the researchers called “profound” in a treating a small group of children and young adults with cytopenias, and particularly the condition autoimmune lymphoproliferative syndrome (ALPS). All the patients in the trial with ALPS showed a durable, complete response, with normal blood cell counts and rapid improvements.

“Patients with ALPS and similar autoimmune disorders have had few long-term treatment options for managing their disease,” said study leader David T. Teachey, MD, a physician-researcher in hematology and oncology at CHOP. “The immunosuppressive drug we used, sirolimus, is effective and well-tolerated, with very few side effects.”

The current study builds on preliminary results published by Teachey and colleagues in 2009, showing sirolimus successfully treated a small cohort of five children with ALPS. Most were treated at CHOP, which has one of the world’s largest clinical programs for ALPS patients.

“These patients undergo multiple trials of other treatments, some with many side effects, and often without resolution of their symptoms,” said Karen Bride, MD, PhD, a fellow in hematology and oncology at CHOP and first author of the new study. “Sirolimus led to a complete remission in all of the patients with ALPS, which is extraordinary and a real boon for these patients and families.”

In the current study, the first prospective multicenter trial of sirolimus in patients with refractory autoimmune cytopenias, there were 30 participants, ranging in age from 5 to 19 years old. Twelve patients had ALPS, six had other autoimmune cytopenias, and 12 others had secondary cytopenias caused by other underlying autoimmune diseases. All were intolerant of or resistant to corticosteroids.

Of the 12 children with ALPS, 11 had complete responses — normal blood cell counts — from one to three months after receiving sirolimus, with the 12th patient having a complete response after 18 months. Patients also had improvements in spleen and lymph node abnormalities. All 12 patients were able to discontinue steroids and other drugs within one to three months after receiving sirolimus. Over a median follow-up of two years, there were few adverse side effects, primarily mucositis — an inflammation of the mucous membranes.

The majority of the patients with non-ALPS, secondary autoimmune cytopenias (eight out of 12), also had complete responses, although later than for ALPS patients. The six patients with other autoimmune cytopenias had less robust results — one complete response and two partial responses.

“More research remains to be done, but this treatment has produced profound, dramatic results for children, and has improved their quality of life,” s Dr. Teachey said.

Sirolimus, an immunosuppressant also known as rapamycin, has long been used to prevent rejection after a solid organ transplant. Based on the new findings, the study team recommended that doctors should consider using sirolimus early in the management of patients with autoimmune blood disorders that require ongoing treatment. In addition, Dr. Teachey said, further studies should investigate whether sirolimus can be discontinued after patients achieve a complete response.

He added that because many ALPS cases result from underlying gene mutations, future studies also could test whether sirolimus can treat other ALPS-like disorders with mutations in similar genes.

“This type of genomic profiling will hopefully increase our understanding of the underlying pathogenesis of autoimmune cytopenias, which we believe will naturally lead to precision-medicine approaches to this rare set of disorders, and more improved outcomes,” Dr. Bride said.

Collaborators from 15 medical centers contributed to the research; Dr. Teachey and Dr. Bride had study co-authors from four institutions. Funding for this study came from Cures Within Reach, the Partnership for Cures Patient Impact Initiative, as well as from the United States Immunodeficiency Network, through the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Other funders were the Goldman Philanthropic Partnerships, the Rockefeller Brothers Fund, the Barbara Brodsky Foundation and a Foerderer-Murray Award. In addition to his CHOP position, Dr. Teachey is an assistant professor at the Perelman School of Medicine at the University of Pennsylvania.

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On the Trail of a Cancer Predisposition Syndrome


Inside the cells of a developing human embryo is a little piece of “Alice in Wonderland.” While most of our bodies’ genes are expressed from both our mothers’ and fathers’ chromosomes, there is a particular growth-regulating region of chromosome 11 where Dad’s genes make you grow bigger, and Mom’s genes make you small. As in Alice’s adventure, there is potential for some difficult situations to occur when that growth process is not handled with exacting care.

With new grants awarded by the St. Baldrick’s Foundation and the National Cancer Institute, attending physician and geneticist Jennifer M. Kalish, MD, PhD, at The Children’s Hospital of Philadelphia, is going down the rabbit hole to try to set things right. She aims to answer key questions about cancer while helping children with Beckwith-Wiedemann Syndrome (BWS), an overgrowth disorder that can result when epigenetic regulation of growth-regulating regions of chromosome 11 goes awry.

Dr. Kalish’s current research builds on earlier work she conducted as a Young Investigator funded by the Alex’s Lemonade Stand Foundation.

Managing a Mosaic Syndrome

Ary Devlin was born in December 2013, seeming perfectly healthy in every way. But her mother, Alisha, was not so sure.

“I knew something was wrong,” Alisha said. “She never closed her mouth.”

After seeing multiple doctors seeking a cause for Ary’s macroglossia, or enlarged tongue, Ary eventually received a diagnosis of BWS, and Alisha and sought Dr. Kalish’s expertise at CHOP.

Part of Dr. Kalish’s challenge in both studying and treating children with BWS is that the syndrome’s manifestation is widely varied. Some children like Ary have subtle growth differences that are barely detectable, while others have more obvious growth differences.

Common features of BWS include omphaloceles (abdominal wall defects), hemihyperplasia (some body parts being larger than others, such as an enlarged arm or leg), enlarged organs, and increased risk of heptoblastoma (liver cancer) and Wilms tumor (kidney cancer). Treatment generally varies from child to child, as the focus is on managing an individual’s symptoms.

“Most of these changes happen as the embryo is developing,” said Dr. Kalish, who is also an instructor in pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Not every cell in their body has the genetic change, and therefore they end up being mosaic.”

One thing all children with BWS have in common is that their families face uncertainties about the future. Many of these unknowns have persisted because researchers have not yet compiled large-scale data to determine patterns of outcomes.

A Registry to Provide Answers

“One of the frustrating things, especially being at what I think is the greatest hospital in the world, where they know so much about BWS, is hearing, ‘Well, we don’t really have any data about this; there aren’t any studies,’” said Becky Feldman, whose 2-year-old son, Julian, has BWS.

To help other parents get more answers, both Becky and Alisha are advocates for a key piece of Dr. Kalish’s research: A clinical registry of patients with BWS, established at CHOP more than a year ago to build knowledge based on the hospital’s cohort of BWS patients, which is the largest in the country.

The registry is collecting longitudinal data on development and outcomes of interventions. Individuals of all ages with BWS or other forms of growth differences are welcome to participate in the registry, even if not treated at CHOP. Participants share their clinical data and biological samples remaining from clinical testing.

Biological samples are abundant because standard care for BWS includes regular blood tests every six weeks and ultrasounds every three months to catch liver and kidney cancers early if they develop. These screenings continue until ages 4 and 8, respectively, when the children’s risk drops off.

 Finding Cancer Mechanisms

As a physician-scientist, Dr. Kalish is taking her research beyond analysis of clinical data in the registry. She also is conducting basic research using BWS registry participants’ cells to better understand the mechanisms of cancer development. In the lab, she is converting these samples into induced pluripotent stem cells and developing them into the cancer-prone liver and kidney cell types.

By examining the functioning of these cells, she aims to better understand how cancer develops as a consequence of the growth dysregulation on chromosome 11 that causes BWS. She hopes this study will provide insight into nearby alterations believed to play a role in other cancers, too. And because BWS patients’ bodies are mosaic (including both normally developing cells and cells with altered growth-gene expression), she will be able to compare both types of cells from individual patients.

In another part of her study, Dr. Kalish is developing a new mouse model for BWS that demonstrates aspects of the condition’s development that existing models do not.

“By studying a syndrome where you have a confined molecular cause that you know the patients have, you can actually understand many other pathways about how tumors form in other kinds of cancer as well,” said Dr. Kalish.

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CHOP-led Consortium Focuses on Patient-Reported Outcomes


“How tired do you feel?” a doctor asks a child with a chronic disease. Or, “How well are you managing stress?”

The answers to questions like these are even more important, from many patients’ and families’ perspectives, than the particular numerical result of their lab test results.

But the answers are less useful to doctors than they could be. Doctors do not have validated tools to use such patient-reported outcomes to track progress managing a condition over time in the same way they can compare results of blood tests over time. In clinical research, they are unable to compare the answers across patients to ultimately show an experimental drug meaningfully improves fatigue or other patient-reported measures.

“Our vision is that patient-reported outcomes become like lab tests,” said Christopher Forrest, MD, PhD, a pediatrician and researcher at The Children’s Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Soon doctors will use patient-reported outcomes to monitor patients’ clinical care in the same way they use lab tests or X-rays.”

Dr. Forrest and colleagues at CHOP and partner institutions received a new grant from the National Institutes of Health to advance the science of patient-reported outcome measures to one day achieve that vision.

The grant establishes CHOP as the administrative leader and one of four centers awarded as part of the Validation of Pediatric Patient-Reported Outcomes in Chronic Diseases (PEPR) Consortium. The PEPR Consortium will work to improve pediatric health and well-being by capturing the voice and experience of children and their families living with a variety of chronic diseases and conditions.

“There are a lot of outcomes that we can’t get except by child report,” said Katherine Bevans, PhD, who is co-leading the PEPR Consortium research at CHOP with Dr. Forrest. “There’s a long line of research, going back 20 years, that kids are in fact accurate and reliable reporters of their own health.”

Dr. Bevans noted that considering patient-reported outcomes is essential to ensure that clinicians and clinical researchers are achieving their goals of delivering patient- and family-centered care.

The group will test several tools for collecting children’s self-reported outcomes that were previously developed under the Pediatric PROMIS initiative. Under PROMIS, NIH-funded researchers at multiple sites, including a group led by Dr. Forrest at CHOP, developed survey tools for collecting and scoring a variety of patient-reported outcome measures in both pediatric and adult populations.

Development of new tools under PROMIS has ended, and the PEPR consortium will now continue to collect evidence to validate the tools’ effectiveness at measuring clinically meaningful outcomes specifically in populations of children with chronic diseases. They intend to connect children’s scores on PROMIS surveys to clinically meaningful outcomes so doctors and clinical researchers can know when a fluctuation in a survey score represents a meaningful improvement or worsening.

In addition, PEPR Consortium centers will include a focus on improving understanding of environmental influences on pediatric diseases, in keeping with the goals of the National Children’s Study (NCS). PEPR is one of the NIH programs receiving funds diverted from the now-cancelled NCS and tasked with answering some of the study’s important questions about children’s environment and health.

The group led by Dr. Bevans and Dr. Forrest at CHOP will integrate PROMIS survey tools into several existing studies, including a long-term study of chronic kidney disease led at CHOP by nephrology division chief Susan Furth, MD, PhD; a clinical trial for pediatric Crohn’s disease, led at CHOP by Andrew Grossman, MD; and, a clinical study of survivors of cancer treatment at St. Jude Children’s Research Hospital.

“The opportunity with the PEPR grant is to get a much more in-depth view from the patient’s perspective on how concerns that go along with chronic kidney disease including pain, mobility issues, and social functioning, affect their lives,” said Dr. Furth. “Ultimately, when we can target our interventions and include the perspectives of kids and their families, we will focus on the key areas that really make their lives better.”

Dr. Grossman noted, “The PEPR grant will afford the opportunity for us to develop and refine the tools that will allow the patient and parent voice to be inculcated into our assessment of disease activity. In turn, we will better be able to determine the effectiveness of our interventions going forward.”

As the administrative leader of the PEPR Consortium, CHOP also will support resources and technical expertise for projects undertaken by PEPR investigators at the other three centers receiving NIH PEPR awards. These centers will benefit from Dr. Forrest’s work as principal investigator of PEDSnet, a major clinical data research network that includes data from electronic health records and patient-reported data. The infrastructure developed under PEDSnet will offer a data management platform and standardized data formats and sharing for PEPR research data.

At CHOP, Dr. Forrest and Dr. Bevans are further working to build both PEPR and PEDSnet into a new center of emphasis focused on research that informs doctors’ routine treatment decisions. They aim to build a community of clinicians and researchers interested in effectiveness research and patient-reported outcomes. They encourage CHOP researchers and clinicians to contact them to discuss collaborations.

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Infant Brain Imaging Study Finds Early Differences in Autism Symptom Domains


Subtle signs of autism spectrum disorder (ASD) are evident much earlier than previously thought, according to a landmark study conducted by the Infant Brain Imaging Study (IBIS), a large, multisite research collaboration that includes the Center for Autism Research (CAR) at The Children’s Hospital of Philadelphia.

In its eighth year, IBIS receives funding from the National Institutes of Health to support the network’s goal of gathering data to better understand the early development of children with ASD, a highly heritable neurodevelopmental condition that emerges over the first few years of life.

While individuals express ASD in various ways, shared characteristics include difficulties with social interaction and communication, and repetitive behaviors and restricted interests. One in 68 children in the United States has ASD, making it one of the most common pediatric disabilities.

While diagnosis as early as 2 to 3 years of age is possible, the majority of individuals in the U.S. are not diagnosed until 4 years of age or later. When parents or caregivers suspect that a child is showing signs of autism, clinicians often will ask when those signs first began to appear. This can be difficult for parents to recollect, especially since differences in behavioral and social development are often not apparent in very young children — to parents or pediatricians.

The recent IBIS study takes a prospective approach to answer this question, by studying high risk babies starting at 4 to 6 months of age, and following them to at least age 3 years. This allows more accurate pinpoint of the earliest features of autism and a detailed characterization of how it unfolds.

“It still is not clear what is the fundamental essence of autism,” said Robert Schultz, PhD, director of CAR. “Autism is quite varied in its presentation. An important question remains: What features are the first to emerge? The answers can provide a strong clue as to what is at the core of autism.”

The IBIS study is designed to follow babies at risk for autism by virtue of having an already diagnosed older sibling; the estimated recurrence risk of having another child with ASD is approximately 15 percent. The research involves careful study of behavioral manifestations of autism, including cognitive and social skills, as well as study of the development of brain structure and function using MRI. IBIS has published several papers on brain development in the last few years, and as data has now been collected new, larger analyses are now underway. However, the just published paper, focuses on behavior and cognitive manifestations in the first year of life.

For this study, the researchers carefully evaluated 210 infants at high risk for ASD and compared their cognitive development, adaptive skills, and early behavioral features to a group of 98 infants at lower risk for ASD. They performed the assessments at six months, 12 months, and 24 months. When the study results appeared in the Journal of Neurodevelopmental Disorders, it was the first time that researchers had demonstrated some of the earliest manifestations of autism.

“At 12 months of age, we’re finding differences in the symptom domains that define autism — between those who go on to get a diagnosis of autism at 24 months and those who do not,” Dr. Schultz said. “The size of the study provides a level of precision not available previously. It tells us about some of the foundational properties of autism.”

Because the symptoms of autism seem to be clearly emerging in the second half of the first year of life, this helps focus attention of neuroscientist on this period. It also helps further dispel claims of later causes such as vaccinations.

Previously published brain MRI results from the IBIS study indicate structural changes in the white matter fiber tracts which connect key nodes in the social brain network. The first IBIS publications on this suggested hints of structural connectivity changes emerging at 6 months, becoming more clear up through 24 months of age. That is six months to a year before autistic children typically begin to show any outward signs of their condition. Because data collection has continued, the next round of analyses will be better able to clarify what is happening in the brain at these earliest stages of development.

The current paper also found important behavioral predictors of later autism at 6 months of age, but not in measurements of its diagnostic features. At this age, social and other core features of autism were not manifesting; rather, the best predictors of autism were in gross motor skills — an area which increasingly is being highlighted in the research literature as potentially foundational to autism. School age children with autism, for example, exhibit a range of motor atypicalities that when measured carefully, show substantial differences from typically developing youth.

“Taken together, these new data illustrate a pattern of unfolding symptoms in children with ASD, starting in the sensorimotor domain at 6 months [during which children experience the world and gain knowledge through their senses and motor movements] and progressing to the social-communication domain in the second year of life,” the study authors wrote.

It makes sense to Dr. Schultz that motor and visual disruptions would appear early in life for children who develop ASD. How we begin social communication and language as infants relies heavily on how we engage with and interpret other people’s movements and facial expressions, and then our ability to reproduce them, he explained. As infants develop and become more in tune with these processes, they are typically able to interact with their environment in more complex ways.

“For example, most babies at 12 months express a lot of nonverbal language,” Dr. Schultz said. “A child will point when they find something that they’re excited about, they’ll look at you, and want to bring it into their world. These are early markers that kids with autism often don’t have.”

While children with ASD on average have a lower IQ and are at high risk for intellectual disability, Dr. Schultz noted that the study results show both groups had similar overall global neurodevelopmental as infants; by 12 months of age, they began to diverge, and there was a clear downward trajectory for those who go on to have autism. Some have described it as if a curtain has been pulled down, when that period of seemingly normal behavioral development seems to go off course.

“For treatment, if we can understand that decline in early cognitive development, we may be able to change that trajectory,” Dr. Schultz said. Numerous studies have concluded that early diagnosis of ASD, along with prompt, evidence-based intervention, provides the best possible outcome for a child.

The IBIS study team is completing brain imaging of all the study participants in hopes of finding what kind of features in the developing brain might predict these outward manifestations. The Center for Autism Research is currently enrolling infants between 3 to 6 months of age who have an older sibling diagnosed with ASD, in order to further study the earliest signs of ASD.

In the meantime, the recently published findings give parents and clinicians meaningful information that they can use for early detection and screening, particularly for families with a history of ASD. If these parents recognize very early differences in sensorimotor or visual tracking, perhaps the child could be referred to an intensive early intervention that could possibly blunt the expression of ASD over their lifetime.

“Once you have a developmental disability like autism, it changes the way you develop and the way you interact with the world,” Dr. Schultz said. “We are never sure in the full picture of autism, are we seeing the consequences of having autism, or are we seeing the essence of autism?”

The research project was supported by grants from the National Institute of Child Health and Human Development, the National Institute of Mental Health, Autism Speaks, and the Simons Foundation.

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Researchers Debunk Claim that Vaccines Cause Retinal Bleeding in Children


Most of the time, we associate research with laboratories and test tubes, not courtrooms and gavels. Yet, studies that build scientific evidence can influence our legal system in important ways. Clinician researchers at The Children’s Hospital of Philadelphia, for instance, recently conducted a study that could help to disprove an unsupported hypothesis that defense teams sometimes propose in high-stakes child abuse cases.

Retinal hemorrhage, a sign of potential abusive head trauma, is abnormal bleeding from the blood vessels in the retina, the membrane in the back of the eyes. Defense attorneys have suggested that vaccinations could be an alternate cause of retinal hemorrhage in young children. While clinicians at CHOP suspected that this was highly unlikely based on their knowledge of the pathophysiology and clinical patterns of retinal hemorrhage, they conducted a retrospective study in order to settle the question objectively: Do vaccinations cause retinal hemorrhage?

The study team harnessed the electronic medical records of 5,177 pediatric outpatients under the age of 2 who had visited a pediatric ophthalmologist between June 2009 and August 2012 for various eye concerns but otherwise were healthy. All of the children had their eyes dilated during the examinations, allowing the ophthalmologists to see the retina. Out of the 7,675 examinations, the doctors found nine children with retinal hemorrhages, an extraordinarily low prevalence (0.17 percent).

“Very few children had retinal hemorrhage,” said Gil Binenbaum, MD, MSCE, an attending surgeon in the Division of Ophthalmology at CHOP, who led the study. “We looked closely at the records of the nine children who had retinal hemorrhage to see what the potential cause could be, and every one had been seen previously as an inpatient with a diagnosis of abusive head trauma that had been diagnosable based on nonocular findings.”

The study team then analyzed data from a subgroup of 2,210 patients whose vaccination records during the study period were available. About 500 of those children received an eye exam within 21 days of vaccination. If vaccinations caused retinal hemorrhage, then the researchers expected that the incidence of retinal hemorrhage would be quite frequent in the weeks following injection, but this was not the case. The researchers found no association between the timing of vaccinations and retinal hemorrhage in the prior seven, 14, or 21 days.

“We concluded that vaccinations do not cause retinal hemorrhage,” Dr. Binenbaum said, “and it is an unsupported theory that should not be accepted as a plausible idea clinically or in court.”

Beyond the legal ramifications, Dr. Binenbaum said, the study suggests that ophthalmologists who examine children under the age of 2 and detect even mild retinal hemorrhage without an obvious cause, such as recent eye surgery, should think carefully about what the reason might be and consider a child abuse evaluation.

The study results appeared online in JAMA Ophthalmology. Co-authors were from The Scheie Eye Institute and the Perelman School of Medicine at the University of Pennsylvania, where Dr. Binenbaum also is an assistant professor of Ophthalmology.

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