Youth Mental Health, Predicting CKD Progression, Improved Rare Disease Diagnosis

 

In this week's research news roundup, we congratulate David Teachey, MD, on a prestigious Childrens Oncology Group committee chair appointment. In addition, we highlight collaborative study findings on psychosocial risk factors in adolescents, the implications of the first single cell atlas of the human kidney on predicting chronic kidney disease progression, a driving skills assessment as a standard of preventive care screening, and a new method to improve rare disease diagnosis.

David Teachey, MD, Appointed Chair of Children's Oncology Group ALL Disease Committee

David Teachey, MD, has been appointed Chair of the Acute Lymphoblastic Leukemia (ALL) Disease Committee in the Children's Oncology Group (COG), the world's largest organization devoted exclusively to childhood and adolescent cancer research.

The COG unites more than 10,000 experts in childhood cancer at more than 200 leading children's hospitals, universities, and cancer centers across North America, Australia, and New Zealand.

"I look forward to collaborating with experts across COG institutions to initiate new clinical trials and support innovative therapies for children with ALL," said Dr. Teachey, attending physician and Distinguished Endowed Chair in the Department of Pediatrics at Children's Hospital of Philadelphia. He also co-leads the Immune Dysregulation Frontier Program at CHOP and is a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

ALL is the most common cancer in children. Six international phase 2 and phase 3 COG trials for children and young adults with ALL are open, and more are in development to test new therapies. Dr. Teachey will oversee these trials that enroll more than 2,000 children with ALL each year, including about 70% of children and adolescents diagnosed with ALL in the United States.

In parallel, COG researchers have identified new targets for treatment, made novel insights into the disease biology of ALL, and tested the activity of new treatments in preclinical models in many labs, including those at CHOP and throughout North America.

Read more about Dr. Teachey's appointment in this CHOP news release.

Researchers Examine Neighborhoods, Psychosocial Risk Factors, and Mental Health

A new study from the Department of Biomedical and Health Informatics and the Center for Violence Prevention at CHOP analyzed associations between psychosocial risk factors and mental health symptoms reported by adolescents, and the influence of objective neighborhood characteristics.

The researchers incorporated seven years of behavioral health screening data collected from 13,837 ED visits by patients between the ages of 14 and 18. Researchers matched that screening data with neighborhood stress levels, determined by gun violence incidents during the same seven-year period (2013-2020) and the Child Opportunity Index 2015.

The study results showed that the odds of mental health symptoms increased by the total number of psychosocial risk factors, particularly in low-stress neighborhoods. The researchers recognized that living in disadvantaged neighborhoods and coping with chronic stress, such as food insecurity and housing instability, could possibly overshadow adolescents' psychosocial risk factors associated with depression and suicide risk.

The study team suggested that their findings reinforce the importance of a universal approach to adolescent mental health screening, regardless of their neighborhood characteristics.

Among the contributors to the study were first author Jungwon Min, PhD, MS, principal biostatistician in DBHi; Joel A. Fein, MD, MPH, co-director, Center for Violence Prevention; and Aditi Vasan, MD, MSHP, faculty member at PolicyLab and research scholar at the Center for Violence Prevention.

Additional CHOP co-authors included Vicky Tam, MA, principal data scientist in DBHi; Heather Griffis, PhD, senior director of the Informatics Services; Polina Krass, MD, MSHP, a research scholar at the Center for Violence Prevention and fellow in the Division of Pediatric Emergency Medicine; and Stephanie Doupnik MD, MSHP, previously on faculty at PolicyLab at CHOP, and current division director of Pediatric Hospital Medicine at Vanderbilt University Medical Center.

Their findings were published in the Journal of Adolescent Health.

Single Cell Kidney Atlas that Sheds Light on CKD Progression

Researchers at CHOP and Penn revealed an extensive single-cell atlas of the human kidney that captures the complexity of healthy and diseased kidneys and can help in predicting chronic kidney disease (CKD) progression earlier in its course. The findings were published in Nature Genetics.

"CKD is rare in children, but for those affected, it can be a very serious life-altering condition," said Jonathan Levinsohn, MD, PhD, co-first author and a pediatric nephrology fellow in the Division of Nephrology at CHOP. "It is also clear that while CKD most commonly affects older individuals, the risk for developing the disease starts to accrue much earlier, starting during gestation and childhood."

The study team analyzed more than 700,000 cells from 81 kidney samples in patients from ages 24 to 90. Using machine learning to develop the high-resolution atlas, the researchers integrated multi-omics data to map cellular and spatial information, identify tissue microenvironments, and develop predictive models for kidney disease progression. Among their key findings was a gene signature in the fibrotic microenvironment called FME-GS that can classify kidney samples and predict future kidney function decline.

Senior study author Katalin Susztak, MD, PhD, co-leads the Penn-CHOP Kidney Innovation Center, a research collaboration focused on transforming patient care through early detection, prevention, and treatment of kidney disease across the lifespan. Susztak, who is a professor of Medicine at Penn, said the findings present the first roadmap of the human kidneys that includes the analysis of spatial relationship of the cells, creating a powerful tool for prognosis that outperforms histopathological analysis.

Learn more in this CHOP news release.

Implementation of Virtual Driving Assessment in Primary Care Continues to Grow

CHOP researchers and clinicians published findings from the first two years of implementation of a validated Virtual Driving Assessment (VDA) that provide a potential blueprint for how individual primary care sites or other healthcare systems could integrate the VDA into routine adolescent care.

The VDA measures driving skills in common serious crash scenarios that cannot be evaluated with on-road testing, while also providing personalized feedback to families on driving skills that still need improvement.

"More than 75% of teens who completed the assessment at their primary care preventive visit would recommend it to their friends and would like to take it again," said Maura Powell, MPH, MBE, manager of the Possibilities Project. "And with some practice sites seeing nearly 30% of teens opting to take the assessment, we think the demand for this tool will continue to grow."

CHOP's Clinical Futures and the Possibilities Project (CHOP's Primary care Implementation Program) began implementing VDA across the CHOP Primary Care network in May 2021, thanks to a gift from NJM Insurance Group. They supported integration of the VDA into primary care visits with multiple approaches. For example, they sent reminder texts to eligible families ahead of scheduled visits and raised awareness of the VDA with posters designed with teen input that were displayed in participating practices.

During the first two years of implementation, 24,657 adolescents visited CHOP for preventive care, with 33,037 completing the VDA as part of the visit.

The study was published in the Annals of Family Medicine. Read more in this CHOP press release.

Researchers Develop Method to Re-characterize Variants Implicated in Alagille Syndrome

CHOP and Penn researchers collaborated to provide a more accurate diagnosis for Alagille syndrome by developing a high-throughput assay to reduce uncertainty when classifying Jagged1 (JAG1) missense variants.

The predominant cause of Alagille syndrome is variants in the JAG1 gene, which helps make a protein that controls how cells grow and develop into different types of tissues and organs. Missense variants, which alter proteins' amino-acid sequence, can be benign or pathogenic. Up to 85% of reported JAG1 missense variants have uncertain or conflicting classifications.

The researchers focused on the exons where these missense variants were most likely to occur and parsed out variants that could be compared to ones known to be responsible for disease, according to the study's first author Melissa Gilbert, PhD, manager of translational research in the Division of Genomic Diagnostics at CHOP, and research assistant professor of Pathology and Laboratory Medicine at Penn Medicine.

Starting from a library of 2,832 JAG1 nucleotide variants, the researchers used the high-throughput assay and data analysis to narrow down 26 JAG1 gene variants as likely pathogenic or causing Alagille syndrome.

"We hope that this dataset can provide genetic counselors and clinicians with an enhanced ability to classify these variants when they are first detected in patients with Alagille syndrome and reduce the uncertainty and anxiety faced by families and patients," said Nancy Spinner, PhD, senior study author and chief of the Division of Genomic Diagnostics.

The findings were published in the American Journal of Human Genetics.

Learn more in this CHOP news release.

Antibiotic Use in Extremely Low Birth Weight Infants Decreased Over Time

CHOP researchers found that the total amount of antibiotics prescribed to extremely low birth weight (ELBW) infants admitted to neonatal intensive care units (NICUs) decreased over time.

The authors speculated that antibiotic stewardship initiatives aimed at optimizing antibiotic use among these vulnerable patients were likely key drivers of the change. The findings were published in the Archives of Disease in Childhood Fetal and Neonatal Edition.

"Our findings show that stewardship aimed at antibiotic duration is working and must continue," said Dustin D. Flannery, DO, MSCE, an attending physician at CHOP and CHOP Newborn Care at Pennsylvania Hospital, and a core faculty member in Clinical Futures. "It is also imperative that we cultivate new and different ways to risk stratify extremely low birth weight infants who are at risk of infection, to continue to optimize the use of these drugs."

The study team used a comprehensive administrative database of patients admitted to academic and community hospitals across the US, to assess trends in antibiotic rates across a large cohort of ELBW infants over 13 years (2009 to 2021). The researchers found that of 37,000 infants admitted to 402 NICUs, there was no significant change in the number of infants exposed to antibiotics during this period, but they also observed a reduction of one-third in the duration of antibiotic use per 1,000 patient days.

Learn more in this CHOP news release.

ICYMI

Catch up on our headlines from our July 19 In The News:

• Surgery to Repair Patellar Sleeve Fractures Helps Restore Range of Motion
• CHOP Designated as Center of Excellence for Telomere Biology Disorders
• Study Reveals Some Youths May Takes Opioids Months After Surgery
• Foerderer Grants to Fund 11 Innovative, Internal Projects
• Antioxidants May Reduce Mitochondrial Damage From SARS-CoV-2 Virus
• Penn Health-Tech Awards Accelerator Grants to Six CHOP Teams
• Study Underscores Role of Caregiver Support in LGBTQ+ Youth Mental Health

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