Childhood cancers, infectious diseases, genetic diseases, and many other contemporary biomedical and health problems are full of challenges. But an astounding glut of data created in the course of trying to solve those problems may itself be one of the most dominant challenges in 21st century.

Analyzing patients’ biological samples with newer sequencing tools results in huge amounts of data about genes and genomes, RNAs, and proteins — and making sense of that sequencing data requires a huge amount of computational power. At the same time, organizational structures divide how clinical and research data can be shared and used to gain collaborative insights. Fortunately, innovators at Children’s Hospital of Philadelphia are deftly navigating these emerging roadblocks to success with the next phase of pediatric discoveries. CHOP experts are pursuing multiple leading-edge ways of harnessing and sharing big data to improve children’s health and lives in the realms of bioinformatics and clinical informatics.

A population health project spearheaded by two CHOP clinical informatics fellows is one such example. The Population Health Risk Assessment Support Engine (PHRASE Health) is an electronic portal built to integrate into any electronic health record (EHR) system that allows for a two-way flow of data between clinicians and public health agencies. Such a flow could be especially useful in the event of evolving public health situations, such as the outbreak of Zika virus. Public health officials can provide timely updates about evolving disease and patient risk factors through the system, while clinicians consume these recommendations in the EHR and utilize one-click reporting of disease cases back to the public health department.

In December 2015, PHRASE creators Marc Tobias, MD, and Naveen Muthu, MD, of CHOP’s Department of Biomedical and Health Informatics (DBHi), received first prize in the “Closing the Data Divide” Virtual Challenge, jointly sponsored by the de Beaumont Foundation and the Practical Playbook. In July 2016, PHRASE was named a Phase 1 winner of the Provider User Experience Challenge by the U.S. Department of Health and Human Services’ Office of the National Coordinator for Health Information Technology.

While PHRASE represents an approach to harness and empower medical data for population health (and vice-versa), another CHOP-led effort launched this year shows how collaborative approaches to data can strengthen and speed discovery of new biomedical approaches to pediatric disease. The Center for Data-Driven Discovery in Biomedicine (D3b) was established in December 2015 as a way to break down silos that keep data separate and limit its usefulness for discoveries in pediatric cancer and other pediatric diseases. By building platforms that empower patient participation in research, make data more open, and encourage sharing and collaboration, D3b aims to accelerate discoveries that would not be possible when individual researchers and institutions keep data to themselves. Led by CHOP’s Research Institute and DBHi, D3b builds on related, successful examples of CHOP-led multi-institutional research and clinical trial consortia, including the Children’s Brain Tumor Tissue Consortium (CBTTC) and the Pacific Pediatric Neuro-Oncology Consortium (PNOC).

One of D3b’s first major initiatives is the launch of its open-access pediatric genomic data cloud, CAVATICA, announced in October 2016 as a private commitment in conjunction with the national Cancer Moonshot. CAVATICA gives clinicians and scientists access to big data about diverse pediatric diseases that is empowered for secure, collaborative analysis through scalable cloud computing — meaning that the users of the service do not need to bring their own high-powered computers in order to perform complex analyses of vast quantities of data. Researchers worldwide will be able to access this information and work together to fully empower and share novel ideas and approaches for new biological targets for precise, less toxic clinical treatments on behalf of children.

“Data and patients are the organizing principle of how we do what we do,” said Adam Resnick, PhD, scientific chair of the CBTTC and PNOC and co-director of D3b with Neurosurgery Division Chief Phillip “Jay” Storm, MD. “Data can be immortalized forever, and that’s a legacy that patients and families leave behind when they choose to contribute to and participate in research in the face of serious and sometimes lethal diseases. It is our responsibility as partners in research to honor that legacy to support rapid discovery of new treatments and new cures for childhood diseases through partnership and collaboration.”

Read more about PHRASE Health and about the launch of D3b in Bench to Bedside.

A chair equipped with a high-tech helmet is a new hot seat of innovation in research on autism spectrum disorder (ASD). Studies at Children’s Hospital of Philadelphia that use noninvasive magnetoencephalography (MEG) brain imaging are allowing researchers to understand more about ASD and other neurological conditions. Compared to other types of brain-imaging methods, MEG enables researchers to look deeper inside the brain, to better visualize brain functions in conjunction with structural brain images to gain new insights, and to engage high-need patient populations who have been underserved in research.

“When neural activity is happening, it produces electrical and magnetic fields,” said J. Christopher Edgar, PhD, a clinical neuropsychologist and brain imaging researcher in the department of Radiology at CHOP and associate professor of Radiology at the Perelman School of Medicine at the University of Pennsylvania. “We use this machine to measure the magnetic field. We do that to look at brain function.”

In recent years, Dr. Edgar and Timothy Roberts, PhD, vice chair of research and director of the Lurie Family Foundation’s MEG Imaging Center in Radiology at CHOP and professor of Radiology at Penn, and their colleagues in Radiology and CHOP’s Center for Autism Research (CAR), have used MEG to identify neural differences that correlate with the level of clinical impairment of individuals on the autism spectrum, particularly in the realm of language ability. Those subtle functional neural differences can now be used as biomarkers to detect whether an interventional approach has a measurable impact on the brain in some individuals, even if a behavioral impact is difficult to measure — and several ongoing studies are headed in that direction. And MEG is also allowing the team to ask more basic questions about the physiology of ASD.

One such question, according to Dr. Roberts: “Is the autism spectrum continuous or discrete in terms of these brain markers?” In a study he co-leads with Dr. Edgar and CAR clinical psychologist Emily Kuschner, PhD, he is able to address that question by enrolling nonverbal and minimally verbal individuals on the autism spectrum who are otherwise rarely included in brain-imaging research, and who therefore cannot be assumed to benefit from most such studies’ findings.

This is made possible by an innovative study design that takes advantage of some of MEG’s distinct benefits compared to other brain-imaging techniques: It measures brain responses that automatically occur without intentional action by the participant, such as auditory nerve signaling when hearing sounds or resting-state brain rhythms that occur without any action. And MEG scanning does not require participants to stay completely motionless for extended periods of time. This approach, called MEG-PLAN (MEG Protocol for Limited Ability Neuroimaging), also incorporates unique behavioral design elements to tailor the experience for this population, taking the standard effort at autism-friendliness in research to a new, more personalized level.

The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) and part of CHOP’s Intellectual and Developmental Disabilities Research Center.

With other MEG studies, researchers at CHOP are taking a deeper look at structural and functional aspects of brain differences in ASD which may be the critical missing step in developing new and better therapies. For example, in MEG studies funded by the National Institute of Neurological Disorders and Stroke and National Institute of Mental Health of the NIH, Dr. Edgar is using MEG to obtain measures of activity throughout the entire brain, rather than just on the surface of the head — starting with the thalamus, a deep brain structure that may be the source of a fundamental brain rhythm that coordinates brain activity more broadly.

In children and teens with and without ASD, he aims to examine the association between the structure of the thalamus, pathways from the thalamus to the brain surface, and brain activity. He will also measure changes in these brain structural and activity measures in participants over time to see if differences in brain development can distinguish youth on the autism spectrum from their typically developing peers. If Dr. Edgar’s findings bear out the hypothesis that the thalamus is associated with these fundamental brain-rhythm abnormalities in ASD, they could indicate a need for new treatment strategies that target related pathways.

Read more about MEG-PLAN and MEG studies of thalamus-related brain rhythms in Bench to Bedside.

Precision medicine is the gleaming new hope for defeating disease. These newer treatments targeted to the underlying molecular causes of cancer, in particular, have shown exciting promise. But the ways new drugs are tested are perhaps still too blunt.

“We’re setting ourselves up for failure,” said Yael Mossé, MD, a pediatric oncologist at Children’s Hospital of Philadelphia and associate professor at the Perelman School of Medicine at the University of Pennsylvania, describing traditional clinical trials for pediatric cancer. Most trials of new drugs enroll patients with relapsed or refractory disease for whom no curative options remain — regardless of whether there is any reason to think that the investigational drug will act on the molecular cause of the patient’s cancer. And they test just one drug at a time.

Dr. Mossé is leading an innovative new trial for neuroblastoma that dynamically and quickly translates findings from the lab into new, personalized treatments for children with relapsed or refractory neuroblastoma. Usually appearing as a solid tumor in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy.

Neuroblastoma is “a microcosm of the childhood cancer problem,” Dr. Mossé said.

This group of tumors of the peripheral nervous system has one name and generally looks similar under the microscope. Yet, by working with patients, researchers have learned time and again that the disease is extremely heterogeneous, due in large part to the many different underlying genetic and molecular causes of disease, which can both interact to affect treatment responsiveness and change over time in cases where the cancer relapses after treatment.

Dr. Mossé’s new study is the first prospective clinical trial in children with cancer that, by design, addresses the cancer’s hidden biological diversity — one disease by name, many diseases at the molecular level. Known as the NExt-generation Personalized NEuroblastoma THErapy (NEPENTHE) trial, it is moving forward with a new $1.5 million grant from Alex’s Lemonade Stand Foundation (ALSF), announced in December 2015. Earlier support for this trial was provided by the Band of Parents and Arms Wide Open, Solving Kids’ Cancer Foundation, and the Open Hands Overflowing Hearts Foundation. The NEPENTHE trial, which opened to patient accrual in August 2016, is a collaborative effort, enlisting the expertise of co-investigator and internationally prominent CHOP neuroblastoma researcher John Maris, MD, and numerous other specialists throughout CHOP and other institutions.

“The novelty of this trial could be viewed on numerous levels,” Dr. Mossé said. “It’s based on rigorous preclinical data, understanding the molecular drivers that are important in this disease. It’s combining multiple novel drugs, not just one at a time. And it’s bringing that to the clinic and assigning patients to therapy based on what their tumor genetics are teaching us at the time that they meet us with relapsed or refractory cancer.”

Dr. Mossé hopes that ultimately investigators can use NEPENTHE as a model for future precision medicine clinical trials — dynamically linking clinical needs to preclinical insights — that could apply more broadly to other childhood cancers.

Read more in Bench to Bedside.

Sometimes the most innovative thing a scientist can do is to venture outside of research. For a rapidly growing cohort of investigators and clinicians at Children’s Hospital of Philadelphia, doors are opening to new entrepreneurial ventures that take their ideas from the lab and clinic and disseminate them to save and improve lives in the wider world through commercialization.

“The big issue for me is that this is actually going to have a life beyond scientific papers and impact lives,” said Flaura Winston, MD, PhD, founder and scientific director of the Center for Injury Research and Prevention (CIRP) at CHOP and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Winston anticipates having this impact through Diagnostic Driving Inc., a spinoff company of which she is co-founder and chief scientific advisor. It is one of three companies to accelerate into business based on ideas developed at CHOP in the last year with help from the Office of Entrepreneurship & Innovation (OEI), which was established in May 2015.

Diagnostic Driving is built on more than two decades of foundational research on motor vehicle crashes, a leading cause of death and disability in the U.S. This research, conducted by Dr. Winston and her colleagues, was funded by the National Science Foundation, the National Institutes of Health, the Commonwealth of Pennsylvania, and other sources, and culminated in a five-year process of creating and validating a Simulated Driving Assessment software package. The software reliably identifies dangerous drivers and leverages these data to mitigate risk and coach drivers to be safer on the road.

“For driving assessment software, there just so happened to be an initial market in corporate fleets,” said Venk Kandadai, MPH, co-founder and CEO of Diagnostic Driving, who initially worked with Dr. Winston as a project manager and a data scientist at CIRP.

The pair gained this insight through participation in the business accelerator Dreamit Health in 2015. They conducted market research, finding that the corporate fleet market is worth $4 billion, of an estimated $60 billion per year that these companies spend on automotive crashes; they built a mobile prototype of their software; and they piloted the software with a Fortune 100 corporation. The team sees other markets emerging, including with U.S. states around driver licensing procedures.

“By commercializing this software we can intervene to prevent disability, lost work, and cost for employers and society,” said Dr. Winston, who also chairs the Scientific Advisory Committee for OEI. “Through hard and diligent work, Venk is transforming what is strong science but not really practical into something that is very practical and can have utility far and wide. That is incredibly gratifying.”

OEI and other CHOP offices continuously offered logistical support to the fledgling company prior to its launch, in the form of protected time for Kandadai to focus on the entrepreneurial venture while he was still a CHOP employee, support with IRB and conflict-management processes to ensure ethical and transparent approaches to business activities, and more. After the startup’s official launch as an independently owned and operated company, CHOP owns equity in the company. These are among the many ways OEI works to create an entrepreneurial spirit throughout CHOP, both in the Research Institute and in clinical and administrative domains. It identifies and supports promising ideas that can be nurtured and developed into licensable assets, new clinical services, and spinouts; develops strategic partnerships; and helps people at CHOP to develop early stage ideas including innovative devices, therapies, mobile applications, and software tools.  

OEI’s SPRINT program, begun in late 2015, provides in-house business incubation for a wide variety of entrepreneurial ideas generated within the CHOP community. A few examples emerging from CHOP research include the PHRASE Health software to connect public health data and patients’ electronic health records in clinical settings and a beverage to reduce the risk of diabetes.

“CHOP has always been a leader in research, a place full of people generating ideas that improve health,” said Patrick FitzGerald, vice president for entrepreneurship & innovation. “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.”

Read more about Diagnostic Driving in Bench to Bedside.