Disseminating and Implementing Research-informed Best Practices

A new tool for annotating genetic variant data from large-scale studies enables researchers to improve the complex work of identifying inherited disease-causing variants while following guidelines developed by the American College of Medical Genetics-Association for Molecular Pathology.

Children's Hospital of Philadelphia researchers developed the tool, named Automated Germline Variant Pathogenicity (AutoGVP), in collaboration with the Perelman School of Medicine at the University of Pennsylvania and the National Cancer Institute.

By integrating information about disease-causing variants from the ClinVar database with InterVar software, AutoGVP automatically provides researchers with pathogenicity classifications that follow recommended guidelines as well as avoids the overinterpretation of pathogenicity.

"Our goal was to create a publicly available tool that could evolve with these guidelines while still using many of the critical databases and approaches the research community has come to know," said Sharon Diskin, PhD, a faculty member in CHOP's Department of Biomedical and Health Informatics, and senior author of the Bioinformatics paper.

Dr. Diskin and her colleagues are currently applying AutoGVP to genetic data from pediatric brain tumor patients and larger neuroblastoma cohorts. Much of those samples comes from the Children's Brain Tumor Network, a collaborative, multi-institute research project pioneered by CHOP's Center for Data Driven Discovery and Biomedicine.

Neuroblastoma, a solid tumor that develops in early forms of nerve cells, often manifests with a large heterogeneity of symptoms, severity, and progression. Patients with low and intermediate risk of the disease, for example, have survival rates higher than 90%, while those with high risk have survival rates around 50%.

Because of this diversity, a clear set of guidelines about the disease's risk stratification can empower clinicians to make effective evidence-based decisions. Children's Hospital of Philadelphia's Solid Tumor Section Chief, Rochelle Bagatell, MD, shared her expertise in caring for children with solid tumors to lead the development of the first set of recommendations for treating neuroblastoma.

"There are some children who need minimal therapies, even just observation in some extreme cases, all the way to the most complex multimodality treatments in other cases," Dr. Bagatell said. "In Pediatrics, you don't want to undertreat or overtreat — you really need to right-size it. That's why these nuanced, detailed guidelines are so helpful for clinicians and for families."

The guidelines help clinicians choose the most beneficial treatments and minimize side effects as well as inform teams on how to incorporate multidisciplinary care, such as surgery, radiation, and chemotherapy regimens.

Dr. Bagatell chaired the panel behind the guidelines, which was composed of an alliance of leading cancer centers called the National Comprehensive Cancer Network (NCCN). The NCCN consists of multidisciplinary clinicians from across the country, including oncologists, pathologists, radiologists, radiation oncologists, and surgeons.

An international group of experts led by Children's Hospital of Philadelphia researchers characterized 113 mitochondrial genes causing Leigh syndrome spectrum, a breakthrough that could facilitate improved diagnosis and the development of personalized therapeutic options for the condition occurring in approximately 1 in 40,000 births.

Elizabeth McCormick, MS, CGC

The characterization comes after years of evidence curation and panel review by a group of mitochondria experts in the Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP).

Leigh syndrome spectrum is the most common form of mitochondrial disease in children and is described as a spectrum because it encompasses both Leigh syndrome and Leigh-like syndromes. Patients on the Leigh syndrome spectrum may have overlapping clinical and biochemical features that result from different variants within the same group of genes.

The 113 gene-disease relationships were described in the Annals of Neurology by lead author Elizabeth McCormick, MS, CGC, a Certified Genetic Counselor and Senior Research Coordinator in the Mitochondrial Medicine Frontier Program at CHOP, and her colleagues.

"As we broaden our understanding of Leigh syndrome spectrum, confirming the strength of available evidence to support the relationship between which genes are linked to this disease and how they cause symptoms in patients is critical to making sure we are improving the diagnostic accuracy," McCormick said.

Marni Falk, MD, Executive Director and attending physician in the Mitochondrial Medicine Frontier Program, was also involved in the expert panel and described the work as reflective of the "remarkable dedication of the global mitochondrial disease research community coming together to make sure we are ultimately able to establish the most accurate genetic diagnoses for our patients."

Besides providing clinicians with a framework for making accurate clinical diagnoses, Dr. Falk emphasized that a consensus agreement of the disease-causing genes also will help to inform eligibility guidelines for clinical trials of precision medicine being developed for Leigh syndrome spectrum.

A novel sepsis surveillance tool developed by Children's Hospital of Philadelphia researchers went national with support from the Centers for Disease Control and Prevention and a collaboration with Harvard Pilgrim Health Care Inc., alongside other institutions.

By harnessing data from electronic health records (EHR), the tool tracks the epidemiology of sepsis in children and enables researchers to collect accurate, objective, and reliable data on sepsis outcomes and incidences over time. Measuring the burden of pediatric sepsis has previously proved challenging because sepsis, in which organs malfunction because of a dysregulated response to infection, has non-specific diagnostic criteria.

"One of the challenges with sepsis is that it's complicated," said Frances Balamuth, MD, PhD, attending physician in the Division of Emergency Medicine and Co-director of the Pediatric Sepsis Program. "Diagnostic codes can easily identify patients with pneumonia or cellulitis, for example, but people have shown time and again that diagnostic codes are neither sensitive nor specific for identifying sepsis."

Dr. Balamuth, working with Scott Weiss, MD, now Division Chief of Critical Care Medicine at Nemours Children's Health, and CHOP's data science platform Arcus, described their initial programming and validation of the algorithm in 2017 using data from the CHOP Sepsis Registry and the then-new Arcus Archives. The algorithm was subsequently published in 2020 and recognized by professional societies and federal agencies.

Now, CHOP and its grant co-leaders at Harvard University plan to expand the use of the tool, first by defining an EHR-based pediatric sepsis event (PSE) with a panel of experts and later evaluating the tool's performance in cohorts at CHOP, Children's Hospital Colorado, and Lurie's Children's Hospital of Chicago.

The team's second aim involves applying the validated PSE definition to geographically and demographically diverse datasets using EHR data from hundreds of U.S. hospitals. A final aim involves developing a PSE toolkit that hospitals can use to facilitate local sepsis surveillance.

"I want to see outcomes for pediatric sepsis improve," Dr. Balamuth said. "And for them to improve, we need to be able to count it well and figure out where we're struggling. We hope this project will allow us to identify sepsis patterns in the United States so that we can tailor our future improvement efforts. "

The official journal of the American College of Genetics and Genomics, Genetics in Medicine, named a 2023 review by CHOP and the University of Pennsylvania as the top Editor's Choice article, a testament to CHOP's continued leadership in 22q11.2 deletion syndrome research. CHOP also houses the largest clinical and research program in the world for 22q11.2 deletion syndrome patients.

In the paper, Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome, the researchers reviewed more than 2,300 studies to provide updated recommendations for the optimal care, surveillance, and management of symptoms for children and adolescents with 22q11.2, the most common microdeletion syndrome in humans. The condition can lead to varying physical, cognitive, and behavioral disorders.

Donna McDonald-McGinn, MS, CGC

"This paper was the culmination of incalculable efforts on the part of expert co-authors from around the globe representing more than 20 sub-specialties, under the auspices of the 22q11.2 Society over a period of two years, including amazing colleagues from the 22q and You Center at CHOP and Penn," said the study's senior author, Donna McDonald-McGinn, MS, CGC, Associate Director of the Clinical Genetics Center, and Director of the 22q and You Center.

The recommendations outline the developmental, cognitive, and psychiatric phenotypes that may concern parents of patients throughout childhood and beyond. It also includes considerations for speech-language disorders and prenatal screenings, as well as new data on physical features like scoliosis that may develop due to the deletion.

A web-based genomic dataset analysis platform developed by Children's Hospital of Philadelphia and Children's Hospital Los Angeles will help researchers easily identify likely disease-causing gene variants in patients with suspected mitochondrial disease.

The user-friendly resource described this year in Current Protocols, uniquely supports the special characteristics of primary mitochondrial disease, such as its dual genome nature. Primary mitochondrial diseases are multi-system disorders that may result from gene variants in either the nuclear DNA of cells or in the DNA genomes that exist outside the nucleus within mitochondria (mitochondrial DNA, or mtDNA).

Because hundreds of variants in more than 400 genes across both genomes have been associated with primary mitochondrial diseases, researchers require effective and reliable resources to better understand the underlying genetic diagnoses of these energy deficiency diseases.

In the study, the researchers found that the Mitochondrial Disease Variant Classifier, developed for use with Quick-Mitome, correctly classified more than 98% of variants. It further predicted primary mitochondrial disease-causing variants with 94% precision based on performance benchmarks.

"Quick-Mitome represents a significant effort from the international mitochondrial disease research community to create an automated and user-friendly experience for researchers who want to be able to directly analyze raw genomic datasets in the context of specific medical features of individual primary mitochondrial disease patients," said senior study co-author Marni Falk, MD, Executive Director of the Mitochondrial Medicine Frontier Program at CHOP.