RESUMO
Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (ß = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (ß = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression.
RESUMO
The human brain shows remarkable development of functional brain activity from childhood to adolescence. Here, we investigated whether electroencephalogram (EEG) recordings are suitable for predicting the age of children and adolescents. Moreover, we investigated whether overestimation or underestimation of age was stable over longer time periods, as stable prediction error can be interpreted as reflecting individual brain maturational level. Finally, we established whether the age-prediction error was genetically determined. Then, 3 min eyes-closed resting-state EEG data from the longitudinal EEG studies of Netherlands Twin Register (NTR; n = 836) and Washington University in St. Louis (n = 702) were used at ages 5, 7, 12, 14, 16, and 18. Longitudinal data were available within childhood (5-7 years) and adolescence (16-18 years). We calculated power in 1 Hz wide bins (1-24 Hz). Random forest (RF) regression and relevance vector machine with sixfold cross-validation were applied. The best mean absolute prediction error was obtained with RF (1.22 years). Classification of childhood versus puberty/adolescence reached over 94% accuracy. Prediction errors were moderately to highly stable over periods of 1.5-2.1 years (0.53 < r < 0.74) and signifcantly affected by genetic factors (heritability between 42 and 79%). Our results show that age prediction from low-cost EEG recordings is comparable in accuracy to those obtained with magnetic resonance imaging. Children and adolescents showed stable overestimation or underestimation of their age, which means that some participants have stable brain activity patterns that reflect those of an older or younger age, and could therefore reflect individual brain maturational level. This prediction error is heritable, suggesting that genes underlie maturational level of functional brain activity. We propose that age prediction based on EEG recordings can be used for tracking neurodevelopment in typically developing children, in preterm children, and in children with neurodevelopmental disorders.
