Roberts Individualized Medical Genetics Center Breaking Down Silos to Share Data

By Nancy McCann

With more than 3,600 patient encounters since opening in 2014, the Roberts Individualized Medical Genetics Center (RIMGC) has become a destination for families from around the world in search of diagnostic answers. 

As the first pediatric individualized genomic program in the country, led by physician-scientist Ian Krantz, MD, and senior genetic counselor Livija Medne, MS, LCGC, its mission, in part, is to facilitate access to state-of-the-art individualized genetic testing and management for children and families. It also provides interpretative and educational support to clinicians pursuing this testing for their patients. These unique services rely on the expertise of RIMGC’s team of physicians, genetic counselors, research coordinators, bioinformaticians, laboratory technicians, and administrators. 

With genetics at the genesis of many childhood health problems, the RIMGC also is committed to advancing research efforts at CHOP to gain new insights into how genes relate to health problems, to facilitate gene discoveries, to aid in the development of novel therapeutics, and ultimately to improve patient care. 

The RIMGC works to establish exquisitely detailed codified clinical information (phenotypes) and family histories (pedigrees) and collaborates closely with the Division of Genomic Diagnostics (DGD), and its manager of translational research, Melissa Gilbert, PhD, to correlate these phenotypes with genomic test results. This clinical and genomic data is linked to DNA samples and cell lines stored in CHOP’s biorepository that have been collected from patients and their family members who have enrolled in the research program. 

As part of these efforts the RIMGC, in collaboration with Bimal Desai, MD, MBI, FAAP, and his team, have built an Epic-embedded Human Phenotype Ontology (HPO) tool called PheNominal that is available to all CHOP clinicians and investigators. All of this phenotypic data, genomic data, and allied biospecimens is now accessible to all CHOP investigators through the RIMGC’s new large genetic database and portal, advancing CHOP’s mission and commitment to the future of genetic and individualized medicine. 

“A lot of initiatives are going into making all of this rich and valuable data that’s being generated on both a clinical and research level available to investigators and their collaborators here at CHOP and beyond our walls,” said Dr. Krantz, who is also a professor of Pediatrics and Genetics in the Perelman School of Medicine at the University of Pennsylvania.

Through a broad Institutional Review Board (IRB) approved protocol allowing for the collection, banking, and sharing of data and biospecimens in an identified or de-identified way, the RIMGC aims to create an open data and sample resource to streamline discovery. The database currently includes data from approximately 1,750 enrolled patients and families. Through the portal, all CHOP clinicians and researchers can easily perform searches by patient phenotype, genotype, or sample availability. 

“We’ve developed this portal with a user friendly interface where someone can log in and see all of the available data initially in a de-identified way and identify cohorts of interest,” said Tiffiney Hartman, PhD, genetic counselor and director of Research within the RIMGC. 

For example, if a cardiologist is interested in genetic contributors to cardiomyopathy and wants to see how many patients are in the portal with cardiomyopathy who have had a genomic sequencing done and a sample in the biorepository, the cardiologist can find that out and then request the data and/or samples, Dr. Krantz explained. The hope is that this resource will help researchers at CHOP and collaborating institutions, now, and in the future, by providing easier access to data and samples and the support necessary for research and testing new treatments. 

Accelerating Discovery Through Genomics Research Innovation Network

One of the goals for the repository and database built by RIMGC’s bioinformatician, Batsal Devkota, PhD, is for it to be shared with similar data and sample repositories at Boston Children’s and Cincinnati Children’s Hospitals as part of the Genomics Research Innovation Network (GRIN). The goal of GRIN is to facilitate the gathering of large patient cohorts necessary for all aspects of genetic studies, particularly rare diseases, but also for common traits. From the pediatric perspective, this kind of collaboration is especially important, Dr. Krantz said. 

“If you are a family of child with a rare diagnosis, and CHOP is interested in studying the underlying cause, it could take 10 or 20 years to get enough patients and enough data collected to make any progress or breakthroughs” Dr. Krantz said. “But by participating in GRIN, where a much larger cohort is available, we could significantly break down that timeline to years or less instead of decades.”

GRIN, a collaboration between CHOP, Boston Children’s Hospital, and Cincinnati Children’s Hospital Medical Center, was initiated in 2015 by each hospital’s CEOs and departmental and scientific leadership to foster a culture of collaboration and data sharing in order to accelerate genomic discovery and improve clinical outcomes. It aims to produce the world’s leading cohort of pediatric subjects representing the full spectrum of diseases and conditions, with availability of clinical, genomic, and sample metadata. 

GRIN was just awarded a multi-year grant by the National Institutes of Health worth more than $8.5 million to further establish a collaborative genomics information commons and expand its network to include the University of Pittsburgh Medical Center and Washington University in St. Louis. 

“Genomics is impacting all aspects of healthcare and research in pediatrics,” Dr. Krantz stated in a press release. “In order to optimize the utility of this information for breakthroughs in care and discovering new cures, we need a new model to share data collaboratively across institutions. GRIN has stepped up to do this, and this award is a validation of this approach to transforming precision medicine.” 

Dr. Krantz co-authored a paper describing GRIN in the journal Genetics in Medicine, along with GRIN co-founders Kenneth D. Mandl, MD, MPH, of Boston Children’s and Tracy Glauser, MD, of Cincinnati Children’s. In addition to detailing the origins and structure of the network, that paper also reports outcomes in three proof-of-concept pilot studies: severe childhood epilepsy, early childhood obesity, and growth disorders and short stature. A CHOP team published the epilepsy findings earlier this year.

Center for Rare Diagnoses and New Grants

Another way the RIMGC’s research initiatives have expanded is with the creation of the Center for Rare Diagnoses, headed up by Sarah Raible, MS, LCGC. The Center for Rare Diagnoses, a clinical core embedded in the RIMGC, provides a medical and research home for families and children who have rare diagnoses such as Cornelia de Lange syndrome (CdLS).

The RIMGC received funding through the NIH Gabriella Miller Kids First Initiative to support the genomic sequencing of 400 children with CdLS related diagnoses who are strongly suspected of having an underlying genetic alteration to explain their clinical features, but whose previous genetic testing was negative. An additional new NIH grant was awarded to support analysis of this data set. 

The goal of the Kids First program is “to develop a large-scale data resource to help researchers uncover new insights into the biology of childhood cancer and structural birth defects, including the discovery of shared genetic pathways between these disorders. These new pathways may help researchers discover novel treatments.” The Gabriella Miller Kid’s First Data Resource Center is hosted at CHOP and is supported through a grant held by Adam Resnick, PhD, and Deanne Taylor, PhD. 

Leveraging this CdLS data, the researchers want to understand the mutational mechanisms in critical developmental genes that lead to structural birth defects when present in the germ line (the parent’s egg or sperm cells) and result in cancer when mutated somatically (acquired mutations that occur at some time during a person’s life and are present only in certain cells). 

Industry-sponsored Trials

The RIMGC is also participating in several clinical trials, including NICUSeq, a multi-institution clinical trial sponsored by a global leader in genomic sequencing technology. With this study, the RIMGC researchers are evaluating the clinical utility of rapid (two week compared to standard two month turn-around time) whole genome sequencing testing in acutely ill infants suspected of having a genetic condition in CHOP’s neonatal intensive care unit. 

“We are determining the potential clinical advantage of getting genomic results back earlier rather than later,” Dr. Krantz said. “We just finished enrollment and data entry, and we’re in the process of data analysis — which we believe will lead to a major publication that will help shape clinical practice in genomic medicine.”

Through the RIMGC and DGD, CHOP is embarking on another multi-institution industry-sponsored study called the Pediatric Outpatient Genomic Sequencing Observational Study (POGOS). This clinical trial of over 300 CHOP patients will compare the utility of upfront genome sequencing versus standard-of-care genetic testing in the pediatric outpatient setting. Results will help inform ways to expedite patient diagnosis, end the diagnostic odyssey, allow for more rapid implementation of targeted interventions, and advance individualized medicine. Initial enrollment is planned for January 2020. 

“The unique clinical capabilities of the RIMGC coupled with an established comprehensive IRB protocol and robust research infrastructure makes us excellent partners for these broader clinical studies examining critical issues in genomic sequencing integration into pediatric care” Dr. Krantz said.