Hal S. Stern’s research while affiliated with University of California, Irvine and other places

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Publications (170)


Figure 3. ACEs (PEARLS) and unpredictability (QUIC-5) screens predict child mental health outcomes. Odds ratios and 95% confidence intervals. Panels A-B show associations for caregiver reports. Youth self-report in panels C-D.
Contribution of an under-recognized adversity to child health risk: large-scale, population-based ACEs screening
  • Preprint
  • File available

February 2025

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12 Reads

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Charles Golden

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Background and Objectives: Whereas adverse early life experiences (ACEs) correlate with cognitive, emotional and physical health at the population level, existing ACEs screens are only weakly predictive of outcomes for an individual child. This raises the possibility that important elements of the early-life experiences that drive vulnerability and resilience are not being captured. We previously demonstrated that unpredictable parental and household signals constitute an ACE with cross-cultural relevance. We created the 5-item Questionnaire of Unpredictability in Childhood (QUIC-5) that can be readily administered in pediatric clinics. Here, we tested if combined screening with the QUIC-5 and an ACEs measure in this real-world setting significantly improved prediction of child health outcomes. Methods: Leveraging existing screening with the Pediatric ACEs and Related Life Events Screener (PEARLS) at annual well-child visits, we implemented QUIC-5 screening in 19 pediatric clinics spanning the diverse sociodemographic constituency of Orange County, CA. Children (12yr+) and caregivers (for children 0-17years) completed both screens. Health diagnoses were abstracted from electronic health records (N=29,305 children). Results: For both screeners, increasing exposures were associated with a higher probability of a mental (ADHD, anxiety, depression, externalizing problems, sleep disorder) or physical (obesity abdominal pain, asthma, headache) health diagnosis. Across most diagnoses, PEARLS and QUIC provided unique predictive contributions. Importantly, for three outcomes (depression, obesity, sleep disorders) QUIC-5 identified vulnerable individuals that were missed by PEARLS alone. Conclusions: Screening for unpredictability as an additional ACE in primary care is feasible, acceptable and provides unique, actionable information about child psychopathology and physical health.

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Figure 4. Early Life Unpredictability Is Associated with Task-Based Functional Connectivity of the Right Amygdala in a Sex-Specific Manner. A) Synthesized examples of raw signals occurring in a Psychophysiological Interaction (PPI, upper left panel) and their taskdependent correlation structure (upper right panel). B) Empirical scatter plot showing sexspecific associations between early-life unpredictability (QUIC) and PPI-based task-dependent correlations. In a sex-stratified analysis, QUIC scores were significantly (p<0.05) associated with PPI measures in both sexes but in opposing directions. C) QUIC by sex interactions are depicted across the observed amygdala and hippocampus ROIs.
Sex-Specific Effects of Early Life Unpredictability on Hippocampal and Amygdala Responses to Novelty in Adolescents

September 2024

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50 Reads

Background Unpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala. Methods Participants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes. Results Exposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally. Conclusion Exposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.


Fig. 1. Methylation is influenced by age. A) Timeline of sample collection and assessments in 110 infants. B) Heatmap depicting distinct patterns of methylation distinguishing DNA methylation profiles from newborn and 1-year old children. C) Average percentage methylation at selected sites increases with age. D) Using PCA, the first principal component, explaining 25% of the variance, accounts for the age of sample collection. **p < 0.001, bars represent mean, lines represent individual sites.
Fig. 2. localization and gene ontology of the sites differentially methylated (DMS) between neonatal and one year old samples. (A). Chromosomal distribution of the DMS demonstrates that the reside on all autosomes. Numbers on the left denote the percentage of the overall DMS that localize to each chromosome. (B) Alignment of the DMS with genes and their structures: 13983 of the 14037 DMS localized to within 1000 kb of transcription a start site (TSS), and these 13983 DMS associated with 2764 unique genes. (C) Gene ontology identified developmental processes as the key theme of genes associated with DMS between 10-day old and one year old samples of the same child. n = 110 infants.
Fig. 3. Methylation-changes of individual infants between the ages of 10 days and one year predict effortful control at 5 years. A) The first component of the principal component analysis (PCA) of methylation changes in the ~14,000 differentially methylated sites reflect the average change in methylation (n = 110). B) Average methylation changes from newborn to one year of age of an individual child predicts effortful control performance at five years of age (n = 90). C) Average percent methylation in newborns does not predict outcome. D) Similarly, average percent methylation at one year of age does not predict outcome. Note that analogous results were observed when using all 1.74 million methylated sites, as shown in the Supplemental Fig.S-3. Points represent individual samples, circles = females, triangles = males. Line represents linear regression. R represents Pearson correlation coefficient.
Top sites contributing to the impact score.
Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome

May 2024

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35 Reads

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4 Citations

Neurobiology of Stress

Adverse early-life experiences (ELA) affect a majority of the world's children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold. DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent ‘impact score’ based on sites that most contributed to methylation changes. Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.




Within-subject changes in DNA-methylome profile identify individual signatures of early-life adversity, with a potential to predict neuropsychiatric outcome.

December 2023

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86 Reads

Background Adverse early-life experiences (ELA), including poverty, trauma and neglect, affect a majority of the world’s children. Whereas the impact of ELA on cognitive and emotional health throughout the lifespan is well-established, it is not clear how distinct types of ELA influence child development, and there are no tools to predict for an individual child their vulnerability or resilience to the consequences of ELAs. Epigenetic markers including DNA-methylation profiles of peripheral cells may encode ELA and provide a predictive outcome marker. However, the rapid dynamic changes in DNA methylation in childhood and the inter-individual variance of the human genome pose barriers to identifying profiles predicting outcomes of ELA exposure. Here, we examined the relation of several dimensions of ELA to changes of DNA methylation, using a longitudinal within-subject design and a high threshold for methylation changes in the hope of mitigating the above challenges. Methods We analyzed DNA methylation in buccal swab samples collected twice for each of 110 infants: neonatally and at 12 months. We identified CpGs differentially methylated across time, calculated methylation changes for each child, and determined whether several indicators of ELA associated with changes of DNA methylation for individual infants. We then correlated select dimensions of ELA with methylation changes as well as with measures of executive function at age 5 years. We examined for sex differences, and derived a sex-dependent ‘impact score’ based on sites that most contributed to the methylation changes. Findings Setting a high threshold for methylation changes, we discovered that changes in methylation between two samples of an individual child reflected age-related trends towards augmented methylation, and also correlated with executive function years later. Among the tested factors and ELA dimensions, including income to needs ratios, maternal sensitivity, body mass index and sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, an interaction was observed between a measure of high early-life unpredictability and methylation changes, in presaging executive function. Interpretation These findings establish longitudinal, within-subject changes in methylation profiles as a signature of some types of ELA in an individual child. Notably, such changes are detectable beyond the age-associated DNA methylation dynamics. Future studies are required to determine if the methylation profile changes identified here provide a predictive marker of vulnerabilities to poorer cognitive and emotional outcomes. Funding Supported by NIH P50 MH096889, a Precision Medicine Initiative grant from the State of California (OPR20141) and the Bren Foundation. Research in context Evidence before this study Identification of individuals at risk for cognitive and emotional problems is required for targeted interventions. At the population level, experiencing early-life adversity has been consistently linked to an elevated susceptibility to various mental illnesses. However, recent studies have revealed a significant limitation in the ability of early-life adversity to predict individual-level risk, and there is presently no reliable tool available to determine whether a child experiencing adversity will develop future mental health problems. Promising efforts to discover predictive markers by examining DNA methylation in peripheral cells are challenged by extensive genetic and epigenetic population variability and the rapid methylation changes taking place during childhood, rendering the identification of clinically valuable predictive markers a complex endeavor. Added value of this study This study examined neurodevelopmental outcomes following several dimensions of ELA, including a recently identified dimension-unpredictability of parental and environmental signals to the child. It demonstrates changes in DNA methylation in children exposed to a spectrum of ELA dimensions and severity using alternative approaches to those used previously: It employs a longitudinal within-subject design, enabling assessment of DNA changes within an individual over time rather than a cross section comparison of different groups, and focuses on the first year of life, an understudied epoch of development. The study uses reduced representation bisulfite sequencing to measure methylation, an approach compromising between targeted sequencing and a whole genome approach, and sets a high threshold for methylation changes, in consideration of the large changes of DNA methylation during childhood. Finally, in accord with emerging discoveries of the differential effects of ELA on males and females, the study uncovers sex-effects arising already before puberty. Implications of all the available evidence Collectively, our study, together with a robust existing literature (1) identifies early-life unpredictability as an additional determinant of DNA methylation changes, (2) indicates that within-subject changes in methylation profiles of peripheral cells hold promise as precision medicine tools for predicting risk and resilience to the adverse consequences of early-life hardships on mental health, and (3) suggests that sex-differences should be explored even prior to puberty. Our study contributes significantly to the important goal of early identification of predictive “epigenetic scars” caused by adverse early-life experiences. Such markers are required for targeting interventions to those most at need.




FIG. 1. Simplified version of ACE-V workflow.
FIG. 2. Posterior medians with 95% credible intervals for 25 simulated data sets in each case are shown with the black line indicating the true value. The results from different simulated data sets are represented along the x-axis. Here, the setting indicates the percentage of samples that received repeated assessments by the examiner.
FIG. 3. Posterior medians with 95% credible intervals for the parameters are shown with 25 simulated data sets in each case. The horizontal black line indicates the true value of the parameters.
Combining reproducibility and repeatability studies with applications in forensic science

October 2023

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261 Reads

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2 Citations

Law Probability and Risk

Studying the repeatability and reproducibility of decisions made during forensic examinations is important in order to better understand variation in decisions and establish confidence in procedures. For disciplines that rely on comparisons made by trained examiners such as for latent prints, handwriting, and cartridge cases, it has been recommended that ‘black-box’ studies be used to estimate the reliability and validity of decisions. In a typical black-box study, examiners are asked to judge samples of evidence as they would in practice, and their decisions are recorded; the ground truth about samples is known by the study designers. The design for such studies includes repeated assessments on forensic samples by different examiners and additionally, it is common for a subset of examiners to provide repeated assessments on the same evidence samples. We demonstrate a statistical approach to analyse the data collected across these repeated trials that offers the following advantages: i) we can make joint inference about repeatability and reproducibility while utilizing both the intra-examiner and inter-examiner data, ii) we can account for examiner–sample interactions that may impact the decision-making process. We demonstrate the approach first for continuous outcomes such as where decisions are made on an ordinal scale with many categories. The approach is next applied to binary decisions and results are presented on the data from two black-box studies.


Citations (61)


... Indeed, experiences such as childhood maltreatment or pregnancy can influence epigenetic clock ageing 4,5 . Numerous differences can be driven by psychosocial and biological experiences conferred, in part, through epigenetic changes that do not affect XX and XY genotypes similarly 6,7 . Indeed, X inactivation, the process by which an X chromosome in each cell becomes inactivated, results in a mosaic of populations of different cell types that can have functional differences and result in phenotype variability 8 . ...

Reference:

Leveraging research into sex differences and steroid hormones to improve brain health
Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome

Neurobiology of Stress

... Unpredictability is also associated with increased anxiety, depression and post-traumatic stress disorder symptoms in humans independent of other forms of adversity (7,16). Therefore, it is increasingly important to understand the underlying neural circuits and mechanisms involved. ...

Childhood unpredictability is associated with increased risk for long- and short-term depression and anhedonia symptoms following combat deployment
  • Citing Article
  • December 2023

Journal of Mood and Anxiety Disorders

... Moreover, compelling evidence indicates that early life unpredictability alters child exploration behaviors, including exploration of novelty (15). Importantly, these behavioral phenotypes are consistent with observed associations between early life unpredictability and anxiety symptoms (20)(21)(22)(23)(24), thus motivating examination of . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...

Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors
  • Citing Article
  • February 2024

Journal of Affective Disorders

... There is also a large body of literature documenting how prenatal stress is related to changes in the stress hormone cortisol and programming of the fetal Hypothalamic-Pituitary-Adrenal axis (Davis & Sandman, 2006). A growing literature is also advancing the hypothesis that prenatal exposure to maternal unpredictable mood is related to emotional processing in adolescence as assessed by resting state functional Magnetic Resonance Imaging (Jirsaraie et al., 2024). As reviewed above, there is also evidence for the association between prenatal exposure to unpredictable environments and epigenetic alterations in stress-responsive genes (Grassi et al., 2017). ...

Prenatal Exposure to Maternal Mood Entropy Is Associated With a Weakened and Inflexible Salience Network in Adolescence
  • Citing Article
  • August 2023

... Social media has provided front-row access to the murder of George Floyd and many other instances of police brutality on Brown and Black bodies (Eboigbe et al., 2023). They continue to witness and experience increased violence towards minoritized groups such as Asian, Jewish and Muslim people (Abu Khalaf et al., 2023;Liu et al., 2023). Adolescents' developing brain capacity for emotional regulation leaves teens with racial/ethnic minority identities more vulnerable to developing depression because of racism (Liu et al., 2023). ...

Experiences of COVID-19-Related Racism and Impact on Depression Trajectories Among Racially/Ethnically Minoritized Adolescents

Journal of Adolescent Health

... Although being evolutionarily adaptive, faster life history strategies are associated with adverse developmental outcomes in the long-term, especially incurring more risky and aggressive behaviors, which are typical types of externalizing problems (Ellis et al., 2009(Ellis et al., , 2022Ellis, Shakiba, Adkins, & Lester, 2021;Martinez et al., 2022). The associations between unpredictability and internalizing problems, however, are less consistent (Farkas, Baptista, Speranza, Wyart, & Jacquet, 2024;Li & Belsky, 2022;Li, Sturge-Apple, Jones-Gordils, & Davies, 2022;Lindert et al., 2022;Spadoni et al., 2022). Informed by the life history theory, recent studies started to highlight the unique role of unpredictability in children's development above and beyond the other dimensions (Li et al., 2023;Liu & Fisher, 2022;Wang, Cao, Zheng, Chen, & Zhu, 2023); however, it remains uncertain how unpredictability shapes socioemotional development. ...

Exposure to unpredictability and mental health: Validation of the brief version of the Questionnaire of Unpredictability in Childhood (QUIC-5) in English and Spanish

... One of the major challenges in BPA is distinguishing between different types of bloodstain patterns, particularly determining whether a pattern results from firearms, impacts, or other mechanisms, and whether it is an impact spatter or a cast-off spatter. Early classification tasks are conducted by pattern analysts, which tends to result in subjective conclusions based on the knowledge background of the experts [7] [8], and it can easily be influenced by contextual bias [9]. A black box study reveals frequent errors and contradictions among BPA analysts, which can pose serious consequences in casework and court testimony [10]. ...

Towards a Likelihood Ratio Approach for Bloodstain Pattern Analysis
  • Citing Article
  • November 2022

Forensic Science International

... These findings align with observations in face recognition systems. For example, Friedman et al. [14] investigated how test size affects identification and authentication tasks. They reported a linear decline in identification performance with the logarithm of enrollment size but found that the EER for authentication tasks remained stable. ...

Biometric Performance as a Function of Gallery Size

Applied Sciences

... Infants are exposed to a variety of maternal sensory signals, which include olfactory, tactile, visual, and auditory cues, as well as provision of nutrients (among others) that are embedded in mother-infant interactions (Hofer et al., 1978). Importantly, these cues act as "hidden regulators" of behavioral, physiological and neural development in the offspring across species (e.g., humans, non-human primates, rodents) (Hofer et al., 1978;Davis et al., 2022). Thus, mother-infant relationships can exert both short-and long-term (i. ...

Early Life Exposure to Unpredictable Parental Sensory Signals Shapes Cognitive Development Across Three Species

... Pre-clinical and clinical studies have reported persistent changes in the function of CRF + caused by ELA that could significantly impact how individuals process and respond to threat [35][36][37] , including driving an augmented startle reflex [11][12][13][38][39][40] . Enhanced startle has been used as a diagnostic symptom for GAD, PTSD, and panic disorder and has been associated with elevated levels of CRF [41][42][43][44][45][46] . ...

Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala

Neurobiology of Stress