Identification of child risk and resilience to early life stress - adverse childhood experiences (aces) from early life adversity (ELA) impact approximately 15% of the U.S. Population

The National Institute of Child Health and Human Development awarded Children's Hospital Los Angeles $732,995 on September 1, 2026, to identify child risk and resilience factors in response to early life adversity and adverse childhood experiences under the Child Health and Human Development Extramural Research program (CFDA 93.865).

The research develops scalable biological measures to augment existing questionnaire screening for early identification of toxic stress response in children exposed to early life adversity. The study examines mitochondrial genomic measures and oxidative stress markers derived from buccal swabs collected from a mother-child cohort expected to reach 340 dyads. Three different mitochondrial genomic measures combined with oxidative stress samples provide a readout of mitochondrial allostatic load to capture biological adaptation and resilience to early life adversity, representing an important component in assessing toxic stress risk beyond current pediatric ACES and PEARLS questionnaire screening tools.

Performance occurs in Los Angeles, California, with a period of performance extending from September 1, 2026, through May 31, 2031.

ELA results in allostatic load, the cumulative burden of toxic stress. Toxic stress is the child's physiological response to adversity and a precursor to biological dysfunction that can negatively impact neurodevelopmental outcomes leading to poor lifespan health. There is consensus amongst experts in the field that while there is a large body of literature linking ELA, toxic stress response, and poor health, there are currently no agreed upon guidelines for diagnosing a toxic stress response or implementing interventions. Child (pediatric aces and related life events screener - pearls) and caregiver (aces) questionnaire screening in pediatric settings is one strategy applied for early identification. However, child pearls scores have unknown longitudinal predictability. Here, studies on a large mother-child cohort that will soon reach 340 dyads are proposed to develop scalable biological measures to augment questionnaires, improving early identification of a toxic stress response. Mitochondria are multi-functional organelles involved in energy metabolism, stress responses and transcriptional regulation and are targets of the physiological response to ELA. We hypothesize that children exposed to ELA will exhibit an early protective mitochondrial adaptation, which in less adaptive children ultimately produces oxidative stress. This leads to allostatic load, the forerunner of the toxic stress response. Three different mitochondrial genomic measures from a simple buccal swab at each age for child and mother, along with samples from which measures of oxidative stress are obtained, provide a unique combined readout of mitochondrial allostatic load (MAL). Our study captures biological adaptation (resilience) to ELA, an important component in assessing toxic stress risk, by measuring child novelty-induced respiratory sinus arrhythmia (RSA), an adaptive parasympathetic response. We will follow dyads longitudinally from 6-48 months, which includes later ages when neurodevelopmental disturbances due to toxic stress manifest. The current 300+ dyads are from the greater LOS angeles area with a current 98% retention rate. Approximately 30% endorse 4 or more aces and ~33% endorse one or more pearls, indicating a high-risk sample. Supported by key preliminary data, the proposed specific aims will: 1) determine the longitudinal relations between infant and maternal measures of MAL and oxidative stress with child neurodevelopment; 2) examine the relations between environmental factors and biomarkers of toxic stress and parasympathetic activity; and 3) investigate how parasympathetic activity modifies the association of MAL with child neurodevelopment over time. Longitudinal, multivariate measures are incorporated to analyze initial adaptive and later (MAL)adaptive responses and their relation to neurodevelopment. The proposed studies use a combination of newly applied biological measures in children to determine relations with neurodevelopment and to address the knowledge GAP in identifying and characterizing a toxic stress response in children.