Project Summary

This project seeks to:

Improve early screening of toxic stress.
Develop a new measure to identify stress-related health risks.

Background

The very best health outcomes can be achieved by identifying infants at greatest risk for Adverse Childhood Experiences (ACEs) and toxic stress and then intervening early to reduce the chronic stress response. ACEs can cause body and brain disturbances associated with poor health and educational outcomes across a person’s lifespan. Developmental delays are often the first detectable consequence of ACEs. However, in California nearly 40% of children are not screened with any developmental tool. There are significant racial/ethnic disparities among those who are screened. For some infants and toddlers, ACE-associated health conditions may not be caught during developmental or other clinical screens, making it difficult to fully understand and respond to the impact of ACEs.

The CHLA team aims to improve early screening by combining questionnaires and assessments of child-caregiver interactions with innovative laboratory tests that detect disruptions in metabolic health, a key indicator of toxic stress.

Project Goals

Improve toxic stress screening through a powerful biomarker: Mitochondrial Allostatic Load
This graphic describes the project goals. The goals are to identify infants at risk for toxic stress by screening for an elevated metabolic biomarker known as mitochondrial allostatic load, determine if there is a relationship between toxic stress and cognitive development, and design improved screening tools based on these findings.

The CHLA team is addressing these challenges by improving the power of toxic stress screening with a biomarker that reliably reveals early life stress: mitochondrial allostatic load (MAL). CHLA and its community partners, including Kaiser Permanente of Southern California and Ventura County Medical Center, are recruiting and retaining 300+ mother-infant pairs, seen at six and twelve months to:

  1. Measure maternal health and well-being and infant development with currently available evaluation tools.
  2. Determine child ACEs score with the pediatric ACEs questionnaire (PEARLS).
  3. Monitor infant attention circuits using eye movement.
  4. Collect physical samples (via cheek swab) to measure mitochondrial allostatic load.

The combined strategy brings precision to identifying infants and toddlers who are both at greatest risk for developmental harm from toxic stress and who are less likely to have been identified by screening questionnaires. A multi-pronged approach provides opportunities for early detection of stress in infants, which means interventions can be more scalable, affordable, and ultimately most effective. The immediate impact for the study participants is the connection with family-centered, evidence-based infant mental health services at CHLA. The lessons learned from this project’s approach of combining biological measures with existing tools will inform future efforts to integrate precision medicine techniques into current clinical practice.

Biomarkers (short for biological markers) are indicators that can be measured to determine information about the state of a living thing and include molecules in your blood, proteins, antibodies, genes, etc. Exposure to ACEs and toxic stress can change biomarker levels, especially those related to neurologic, endocrine, metabolic, and immune systems. These disrupted biomarkers might be the earliest signs that an individual is at risk of developing toxic stress physiology and other health conditions.

Predictive biomarkers can be used to identify people who may be more susceptible to a certain health outcome before it happens, or who might respond the best to a particular course of treatment. A well-known predictive biomarker is the BRCA1/BRCA2 gene mutation, which increases risk of developing breast and ovarian cancer. Diagnostic biomarkers can be used to diagnose health conditions and diseases and provide indications for treatment plans based on which biomarkers are deficient, or above normal levels, in your body.

Mitochondria are the energy generators in cells. Long- and short-term stress can change the structure and function of mitochondria, and cause damage to a mitochondria’s DNA. These stress-induced changes, also known as Mitochondrial Allostatic Load, can interfere with the ability of the body to respond appropriately to stress, which may contribute to disease.

Team Leaders

Pat Levitt, PhD

Children’s Hospital Los Angeles

Dr. Pat Levitt is the Chief Scientific Officer, Vice President and Director, The Saban Research Institute, Simms/Mann Chair in Developmental Neurogenetics of the Children’s Hospital Los Angeles, W.M. Keck Provost Professor in Neurogenetics at USC.

His research program includes basic studies that probe the ways in which circuitries that controls learning, emotional and social behavior develop, using advanced technologies in genetics, cell biology and behavior. Clinical research investigates children with autism spectrum disorder who have co-occurring gastrointestinal and other conditions. Studies of infant resilience to adversity focus on the brain-based and metabolic changes that may have short and long-term impacts on mental and physical health. He has published over 275 scientific papers.

Dr. Levitt received his B.A. in Biology at the University of Chicago, a Ph.D. in Neuroscience at University of California, San Diego and a postdoctoral fellow at Yale University.

Xiaowu Gai, PhD

Children’s Hospital Los Angeles

Xiaowu Gai, PhD serves as the Director of Bioinformatics in the Center for Personalized Medicine in the Department of Pathology and Laboratory Medicine at Children's Hospital Los Angeles (CHLA). He is a Professor of Clinical Pathology at the Keck School of Medicine at the University of Southern California. Dr. Gai's research interests are aimed at understanding human genetic variation at the molecular genetic level and how it is related to human diseases, using bioinformatics and genomics methodologies. Prior to joining CHLA, Dr. Gai was the Director of Bioinformatics and Associate Director of the Ocular Genomics Institute in the Department of Ophthalmology at Harvard Medical School & Massachusetts Eye and Ear Infirmary, Boston.

Dr. Gai received his MS in Genetics from the Institute of Genetics at the Chinese Academy of Sciences, Beijing, and his PhD in Genetics at Iowa State University.

Alexander Judkins, MD, FCAP, FRCP (Edin)

Children’s Hospital Los Angeles

Alexander R. Judkins, MD, FCAP, FRCP (Edin), is Pathologist-in-Chief at Children’s Hospital Los Angeles (CHLA), and Professor (Clinical Scholar) and Vice Chair of Pathology at the Keck School of Medicine of the University of Southern California (KSOM). Dr. Judkins is internationally recognized as an expert in the diagnosis of pediatric brain tumors and for his development of pediatric brain tumor biomarkers. He also leads CHLA’s precision medicine initiative as the Executive Director of the Center for Personalized Medicine (CPM). He received a bachelor’s degree (1991) from State University of New York Geneseo and his medical degree (1996) from the University of Rochester School of Medicine. He completed his post-graduate medical training at the University of Pennsylvania where he was a faculty member in the Perelman School of Medicine and served as Chief of Neuropathology at Children’s Hospital of Philadelphia (CHOP) before joining CHLA in 2010. Dr. Judkins is board certified in anatomic pathology, neuropathology, and forensic pathology.

Jenny Kingsley, MD

Children’s Hospital Los Angeles

Dr. Jenny Kingsley, MD, MA is an attending physician and Associate Professor of Clinical Pediatrics in the Keck School of Medicine at the University of Southern California. She serves in the Pediatric Intensive Care Unit (PICU) at Children’s Hospital Los Angeles and as faculty in the Center for Bioethics. She obtained her MD at the University of Washington Medical School, completed her residency in pediatrics at the Monroe Carell Jr Children's Hospital at Vanderbilt University, and completed fellowships in Pediatric Critical Care Medicine and Clinical Bioethics at Seattle Children’s Hospital. Additionally, she obtained an MA in Bioethics and Medical Humanities at the University of Washington.

Suzanne Roberts, MD

Children’s Hospital Los Angeles

Suzanne Roberts, MD is an attending physician and clinical associate professor of pediatrics (Clinician Educator) at the Keck School of Medicine at the University of Southern California (USC). Her clinical interests include children with special health care needs, spina bifida, and children in foster care. Dr. Roberts is interested in the role of the pediatrician in mitigating toxic stress response from early life adversity.

Dr. Roberts obtained an MD at the Keck School of Medicine at USC, an internship in pediatrics at Harbor UCLA Medical Center, and chief residency in pediatrics at Harbor UCLA Medical Center.

Sonya Negriff, MD

Kaiser Permanente Southern California Research Center

Sonya Negriff, PhD is a research scientist in the Division of Behavioral Research, Department of Research & Evaluation at Kaiser Permanente Southern California. She trained as a developmental psychologist with expertise in the effects of child maltreatment on physical and mental health. Dr. Negriff uses a biopsychosocial approach to examine the pathways linking child maltreatment to negative outcomes. Dr. Negriff’s research has focused on analyzing the biological (e.g., stress reactivity, pubertal timing, epigenetics, neuroimaging) and social (e.g., social support, social media use) mechanisms that increase vulnerability to mental health problems for children and adolescents with early trauma experiences.

Dr. Negriff received an MA and PhD in Developmental Psychology at the University of Southern California and completed a postdoctoral fellowship at Cincinnati Children’s Hospital Medical Center.

Marian Williams, MD

Children’s Hospital Los Angeles

Marian Williams, PhD is an Associate Professor of Clinical Pediatrics in the Keck School of Medicine, the Program Area Lead for the Early Childhood Mental Health Program at Children's Hospital Los Angeles UCEDD (University Center for Excellence in Developmental Disabilities), the Autism Training Coordinator for the LEND (Leadership Education in Neurodevelopmental Disabilities) program, and Director for the Stein Tikun Olam Infant-Family Mental Health Program.

Partners, Collaborators, and Supporters

  • Fiesta Educativa, Inc.
    • Irene Martinez
  • Kaiser Permanente of Southern California
    • Sonya Negriff, PhD
  • Karsh Family Social Service Center
    • Frances Nova, MSW
  • Maternal Mental Health Now
  • Para Los Niños
    • Natalie Garcia
  • St. Anne’s Family Services
    • Victoria Meira, MA
  • University of Southern California
    • Suzanne Roberts, MD
  • Ventura County Medical Center
    • Christopher Landon, MD

For More Information

David Reiner, PhD
David Reiner is a Science Officer within the California Initiative to Advance Precision Medicine.