Sex differences in attention-deficit hyperactivity disorder diagnosis and clinical care: a national study of population healthcare records in Wales.

BACKGROUND: Population-based studies have observed sex biases in the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions. METHODS: The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation and contact with social services. RESULTS: There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3-30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean = 10.9 vs. 12.6 years), more likely to be prescribed ADHD medication and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups. CONCLUSIONS: This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic overshadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis and treatment of ADHD in females.

Cool and hot executive function problems in young children: linking self-regulation processes to emerging clinical symptoms.

Self-regulation (SR) difficulties are implicated in a wide range of disorders which develop in childhood, including attention deficit hyperactivity disorder (ADHD), oppositional defiance disorder (ODD), anxiety and depression. However, the integration of the existing research evidence is challenging because of varying terminology and the wide range of tasks used, as well as the heterogeneity and comorbidity within and across diagnostic categories. The current study used the Research Domain Criteria (RDoC) framework to guide the examination of different SR processes in young children showing a wide range of symptomatology. Children (aged 4-8) referred by teachers for moderate-to-high conduct, hyperactivity and/or emotional problems at school (assessed using the Strengths and Difficulties Questionnaire (SDQ) subscales; n = 212), and children in SDQ typical ranges (n = 30) completed computerised cognitive control and decision-making tasks. Parents completed questionnaires to assess ADHD, ODD, anxiety and depression symptoms (n = 191). Compared to children with no teacher-reported difficulties, those with moderate-to-high problems showed poorer visuomotor control and decision-making. A factor analysis revealed that task variables adhered to RDoC dimensions and predicted variance in specific disorders: difficulties in cognitive control predicted ADHD symptoms, low reward-seeking was associated with depression and high reward-seeking was associated with ODD. This study highlights how the assessment of cognitive processes positioned within the RDoC framework can inform our understanding of disorder-specific and transdiagnostic difficulties in SR which are associated with diverse clinical symptoms in children.

Inattention symptom severity and cognitive processes in children at risk of ADHD: the moderating role of separation anxiety.

Impairments in cognitive processes and their associations with dimensional measures of inattention, hyperactivity-impulsivity and anxiety were examined in children at risk of Attention-Deficit Hyperactivity Disorder. Children referred by teachers for exhibiting ADHD-type problems (n = 116; 43 meeting full diagnostic criteria for ADHD; 4-8 years) completed computerized tasks measuring episodic memory, response inhibition, visuomotor control and sustained attention, while parents were interviewed (DAWBA) to assess ADHD and anxiety symptoms. Of the 116 children assessed, 72% exhibited impaired cognitive processes; 47% had impaired visuomotor control, 37% impaired response inhibition, and 35% had impaired episodic memory. Correlational and hierarchical regression analyses using our final analytic sample (i.e., children who completed all cognitive tasks and a vocabulary assessment, n = 114) showed that poorer task performance and greater within-subject variability were significantly associated with more severe inattention symptoms but not with hyperactivity-impulsivity severity. Symptoms of separation anxiety, which were reported in over half of the sample, moderated associations between inattention and episodic memory, and between inattention and inhibition. Only children without separation anxiety showed significant correlations between ADHD symptoms and poor performance. However, separation anxiety had no moderating effect on associations between inattention and visuomotor control or sustaining attention. Children exhibiting signs of ADHD show impairments across a range of cognitive tasks. Further research to improve our understanding of these processes may be useful in the development of early interventions. Our results suggest that separation anxiety should be taken into account when considering interventions to address emerging neuropsychological deficits associated with this disorder.

Young Adult ADHD Symptoms in the General Population and Neurocognitive Impairment.

OBJECTIVE: Neurocognitive impairments are associated with child and adult ADHD in clinical settings. However, it is unknown whether adult ADHD symptoms in the general population are associated with the same pattern of cognitive impairment. We examined this using a prospective, population-based cohort spanning birth to age 25 years. METHODS: We examined associations between self-reported adult ADHD symptoms and cognitive task performance (attention and response inhibition) in adulthood and childhood. RESULTS: Self-rated ADHD symptoms at age 25 were associated with poorer performance in age 25 cognitive tasks capturing ADHD-related functioning (attention B = -0.03, 95% CI [0.05, -0.01], p = .005; response inhibition B = -0.03, 95% CI [-0.05, -0.01], p = .002). CONCLUSIONS: Neurocognitive impairments linked to adult ADHD symptoms in the general population, are similar to those found in people with childhood ADHD symptoms and are consistent with findings in adult ADHD clinical samples.

Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Can a nation-wide e-cohort of ADHD and ASD in childhood be established using Welsh routinely available datasets?

OBJECTIVES: We investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) for future longitudinal research. DESIGN: Individuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD. SETTING: This study used data from the Welsh Secure Anonymised Information Linkage Databank in Wales, UK. Routinely collected data from primary care, emergency department and hospital admissions were linked at person level. PARTICIPANTS: All individuals in Wales, UK born between 1 January 1991 and 31 December 2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using International Classification of Diseases, 10th Revision and National Health Service (NHS) READ codes and matched to 3 controls each and 154 individuals with ADHD recruited from an established research study. OUTCOME MEASURES: Recorded service use for anxiety and depression, alcohol and drug use and self-harm including emergency department use in young adulthood (age 16-25 years). RESULTS: 7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); 1.4% and 0.9% of the population, respectively. Cox's regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR: 2.36, 95% CI: 2.20 to 2.53), self-harm (HR: 5.70, 95% CI: 5.07 to 6.40), alcohol (HR: 3.95, 95% CI: 3.42 to 4.56), drug use (HR: 5.88, 95% CI: 5.08 to 6.80) and emergency department service use (HR: 1.36, 95% CI: 1.31 to 1.41). Those with ASD were at increased risk of anxiety/depression (HR: 2.11, 95% CI: 1.91 to 2.34), self-harm (HR: 2.93, 95% CI: 2.45 to 3.50) and drug use (HR: 2.21, 95% CI: 1.66 to 2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort. CONCLUSIONS: Our identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.

Dimensional associations between executive function processes and symptoms of ADHD, ASD, oppositional defiance and anxiety in young school-referred children.

Executive function (EF) difficulties are implicated in Neurodevelopmental Disorders (NDDs), such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). Because NDDs are highly comorbid and frequently co-occur with additional clinical problems, it is unclear how specific EF problems are associated with symptoms of ASD and ADHD, whilst accounting for co-occurring anxiety or oppositional defiance disorder (ODD) symptoms. The current study utilised a large sample of young children (n = 438, aged 4-8) referred to Cardiff University's Neurodevelopment Assessment Unit (NDAU) by teachers for cognitive and/or socio-emotional problems. As part of the referral process, the teachers completed the Strengths and Difficulties Questionnaire (SDQ), which revealed that most children displayed moderate to high hyperactivity (86%) and prosocial (73%) problems, as well as high levels of symptoms in other clinical domains (41% emotional, 61% conduct and 68% peer problems). Children completed tasks to assess episodic memory, cognitive inhibition, cognitive flexibility and visuomotor control, whilst parents completed questionnaires to measure symptoms of ASD, ADHD, anxiety and ODD. Dimensional analyses showed that poorer cognitive inhibition and visuospatial episodic memory were significantly associated with ADHD symptoms, whereas cognitive flexibility was negatively associated with ODD symptoms. Having more ASD symptoms was associated with fewer cognitive inhibition problems, whereas anxiety was associated with better cognitive flexibility. Our approach to assessment and analysis shows that specific cognitive processes are associated with distinct neurodevelopmental and clinical symptoms, which is ultimately relevant to early identification of and intervention for young children at risk of cognitive and/or socio-emotional problems.

DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Sleep disturbances in ADHD: investigating the contribution of polygenic liability for ADHD and sleep-related phenotypes.

Sleep disturbances are common in attention deficit hyperactivity disorder (ADHD) and associated with poor outcomes. We tested whether, in children with ADHD, (1) polygenic liability for sleep phenotypes is over- or under-transmitted from parents, (2) this liability is linked to comorbid sleep disturbances, and (3) ADHD genetic risk is associated with comorbid sleep disturbances. We derived polygenic scores (PGS) for insomnia, chronotype, sleep duration, and ADHD, in 758 children (5-18 years old) diagnosed with ADHD and their parents. We conducted polygenic transmission disequilibrium tests for each sleep PGS in complete parent-offspring ADHD trios (N = 328) and an independent replication sample of ADHD trios (N = 844). Next, we tested whether insomnia, sleep duration, and ADHD PGS were associated with co-occurring sleep phenotypes (hypersomnia, insomnia, restless sleep, poor sleep quality, and nightmares) in children with ADHD. Children's insomnia and chronotype PGS did not differ from mid-parent average PGS but long sleep duration PGS were significantly over-transmitted to children with ADHD. This was supported by a combined analysis using the replication sample. Insomnia, sleep duration, and ADHD PGS were not associated with comorbid sleep disturbances. There is weak evidence that children with ADHD over-inherit polygenic liability for longer sleep duration and do not differentially inherit polygenic liability for insomnia or chronotype. There was insufficient evidence that childhood sleep disturbances were driven by polygenic liability for ADHD or sleep traits, suggesting that sleep disturbances in ADHD may be aetiologically different to general population sleep phenotypes and do not index greater ADHD genetic risk burden.

Relative age in the school year and risk of mental health problems in childhood, adolescence and young adulthood.

PURPOSE: Relative age within the school year ('relative age') is associated with increased rates of symptoms and diagnoses of mental health disorders, including ADHD. We aimed to investigate how relative age influences mental health and behaviour before, during and after school (age range: 4-25 years). METHOD: We used a regression discontinuity design to examine the effect of relative age on risk of mental health problems using data from a large UK population-based cohort (Avon Longitudinal Study of Parents and Children (ALSPAC); N = 14,643). We compared risk of mental health problems between ages 4 and 25 years using the parent-rated Strengths and Difficulties Questionnaire (SDQ), and depression using self-rated and parent-rated Short Mood and Feelings Questionnaire (SMFQ) by relative age. RESULTS: The youngest children in the school year have greater parent-rated risk of mental health problems, measured using parent-rated SDQ total difficulties scores. We found no evidence of differences before school entry [estimated standardised mean difference (SMD) between those born on 31 August and 1 September: .02 (-.05, .08)]. We found that estimates of effect size for a 1-year difference in relative age were greatest at 11 years [SMD: .22 (.15, .29)], but attenuated to the null at 25 years [SMD: -.02 (-.11, .07)]. We did not find consistent evidence of differences in self-rated and parent-rated depression by relative age. CONCLUSIONS: Younger relative age is associated with poorer parent-rated general mental health, but not symptoms of depression.

Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population. METHODS: Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios. RESULTS: ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status. CONCLUSIONS: The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.

Preschool development, temperament and genetic liability as early markers of childhood ADHD: A cohort study.

Background: ADHD is associated with multiple adverse outcomes and early identification is important. The present study sets out to identify early markers and developmental characteristics during the first 30 months of life that are associated with ADHD 6 years later. Methods: 9201 participants from the prospective Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were included. Outcome measures were parent-rated ADHD symptom scores (Strengths and Difficulties Questionnaire, SDQ) and ADHD diagnosis (Development and Wellbeing Assessment, DAWBA) at age 7. Seventeen putative markers were identified from previous literature and included: pre- and peri-natal risk factors, genetic liability (ADHD polygenic risk scores, PRS), early development, temperament scores and regulatory problems. Associations were examined using regression analysis. Results: Univariable regression analysis showed that multiple early life factors were associated with future ADHD outcomes, even after controlling for sex and socio-economic status. In a multivariable linear regression model; temperament activity scores (B = 0.107, CI = 0.083-0.132), vocabulary delay (B = 0.605, CI = 0.211-0.988), fine motor delay (B = 0.693, CI = 0.360-1.025) and ADHD PRS (B = 0.184, CI = 0.074-0.294) were associated with future symptoms (R 2 = 10.7%). In a multivariable logistic regression model, ADHD PRS (OR = 1.39, CI = 1.10-1.77) and temperament activity scores (OR = 1.09, CI = 1.04-1.16) showed association with ADHD diagnosis. Conclusion: As well as male sex and lower socio-economic status, high temperament activity levels and motor and speech delays in the first 30 months of life, are associated with childhood ADHD. Intriguingly, given that genetic risk scores are known to explain little of the variance of ADHD outcomes, we found that ADHD PRS added useful predictive information. Future research needs to test whether predictive models incorporating aspects of early development and genetic risk scores are useful for predicting ADHD in clinical practice.

Early manifestations of genetic liability for ADHD, autism and schizophrenia at ages 18 and 24 months.

Background: ADHD and autism are neurodevelopmental conditions, for which non-specific precursors or early signs include difficulties with language and motor skills, and differences in temperament in the first and second year of life. These early features have also been linked to later diagnosis of schizophrenia which is widely considered to have neurodevelopmental origins. Given that ADHD, autism and schizophrenia are all highly heritable, we tested the hypothesis that in the general population, measures of toddler language development, motor development and temperament are associated with genetic liability to ADHD, autism and/or schizophrenia. Methods: Data were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC) which included motor development scores at age 18 months and language development and temperament scores at age 24 months (N=7498). Genetic liability was indexed by polygenic risk scores (PGS) for ADHD, autism and schizophrenia. Results: ADHD PGS were associated with specific temperament scales (higher activity ß=0.07, 95% CI=0.04, 0.09 and lower withdrawal ß=-0.05, 95% CI=-0.07, -0.02) as well as better gross motor scores (ß=0.04, 95% CI=0.01, 0.06). Schizophrenia PGS were associated with one specific temperament scale (negative mood ß=0.04, 95% CI=0.02, 0.07). We did not find strong evidence of association of autism PGS with any of the toddler measures; there was also not strong evidence of association with motor or language delays for any of the PGS. Conclusions: This study suggests that some specific aspects of early temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions.

Understanding de novo onset of anxiety during COVID-19: Pre-pandemic socio-emotional functioning in vulnerable children.

Background: There is a need to understand and mitigate the psychological impacts of the COVID-19 pandemic for children known to be vulnerable. Data from prior to the pandemic are required to provide robust assessments of the socio-emotional impacts of COVID-19 and identify those who are more vulnerable. Method: This study capitalises on an ongoing UK study of primary school children (4-8 years) identified prior to the pandemic as "at risk" for mental health problems by teachers. We collected mental health and social-emotional functioning data prior to the pandemic (Time 1) and re-assessed this cohort (N = 143) via researcher-led videocalls during lockdown (Time 2, summer 2020) and post-lockdown, 12 months later (Time 3; summer 2021). Results: Mental health problems, particularly clinically significant anxiety, increased from 34% to 43% during lockdown and to 48% post-lockdown. Parental mental health difficulties (anxiety and depression) were prevalent during lockdown (40%) but had decreased 1 year later (20%). Children who developed clinically significant anxiety during the pandemic had impaired socio-emotional functioning at Time 1 (i.e., impaired emotion recognition, low self-esteem and social problems) and a high proportion (44%) had no contact with any peers during lockdown, which may have contributed to their anxiety, especially their school anxiety. Conclusion: The pandemic appears to have exacerbated anxiety in already vulnerable children. A profile of socio-emotional problems identified a group of children who developed significant anxieties during the pandemic. These socio-emotional processes can be targeted for intervention to mitigate the negative mental health consequences of the pandemic and contribute to resilience in children.

Genetics of Attention-Deficit Hyperactivity Disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) has long been recognized as being a highly heritable condition and our understanding of the genetic contributions to ADHD has grown over the past few decades. This chapter will discuss the studies that have examined its heritability and the efforts to identify specific genetic risk-variants at the molecular genetic level. We outline the various techniques that have been used to characterize genetic contributions to ADHD, describing what we have learnt so far, what there is still to learn and the methodologies that can be used to further our knowledge. In doing so we will discuss research into rare and common genetic variants, polygenic risk scores, and gene-environment interplay, while also describing what genetic studies have revealed about the biological processes involved in ADHD and what they have taught us about the overlap between ADHD and other psychiatric and somatic disorders. Finally, we will discuss the strengths and limitations of the current methodologies and clinical implications of genetic research to date.

Investigating the associations between irritability and hot and cool executive functioning in those with ADHD.

BACKGROUND: Irritability is especially pertinent to those with Attention Deficit Hyperactivity Disorder (ADHD) as it is highly prevalent and associated with a more severe clinical presentation and poorer longitudinal outcomes. Preliminary evidence suggests that top-down cognitive processes taking place in emotional contexts (i.e., hot executive functions) as opposed to those evoked in abstract scenarios (i.e., cool executive functions) may be relevant to the presentation of irritability in ADHD. This study explored the cognitive mechanisms underlying irritability in young people with ADHD, hypothesising that irritability would be associated with hot, but not cool, executive function impairments. METHODS: Our sample included 219 individuals with ADHD. A composite irritability score was derived extracting items from a parent interview, with scores ranging from 0 to 5. Associations were investigated using linear regression analyses, between irritability and four hot tasks measuring sensitivity to risk, risk-taking behaviour following reward or punishment, acceptance of reward delay and reaction to unfair behaviour from others, and two cool tasks measuring set-shifting and motor inhibition. RESULTS: As hypothesised, there were no significant associations between irritability and cool executive functions in those with ADHD; however, contrary to expectations, there was also no significant evidence that hot executive functions were associated with irritability. CONCLUSIONS: These results, in a large well characterised sample and using a comprehensive task battery, suggest that the variation in irritability in those with ADHD may not be associated with differences in hot or cool executive function performance.

Cord serum brain-derived neurotrophic factor levels at birth associate with temperament outcomes at one year.

Altered serum levels of brain-derived neurotrophic factor (BDNF) are consistently linked with neurological disorders. BDNF is also increasingly implicated in the pathogenesis of neurodevelopmental disorders, particularly those found more frequently in males. At birth, male infants naturally have significantly lower serum BDNF levels (∼10-20% lower than females), which may render them more vulnerable to neurodevelopmental disorders. We previously characterized serum BDNF levels in mothers and their newborn infants as part of the Grown in Wales Study. Here, we analyzed whether cord serum BDNF levels at birth correlate with sex-specific outcomes at one year. The Bayley Scale of Infant Development, Third Edition (BSID-III) and Laboratory Temperament Assessment Battery (Lab-TAB) tasks were used to assess infant behavior and neurodevelopment at 12-14 months (mean ± SD: 13.3 ± 1.6 months; 46% male; n = 56). We found no relationship between serum BDNF levels at birth and BSID-III neurodevelopmental outcomes (cognitive or language), nor with infant behaviors in the Lab-TAB unpredictable mechanical toy or maternal separation tasks. In the sustained attention task, there was a significant positive relationship between serum BDNF and infant negative affect (B = 0.06, p = 0.018) and, for boys only, between serum BDNF and intensity of facial interest (B = 0.03, p = 0.005). However, only the latter remained after correction for multiple testing. This sex-specific association between cord serum BDNF and a parameter of attention at 12-14 months provides some support for the hypothesis that reduced serum BDNF levels at birth are linked to an increased risk for neurodevelopmental disorders.

Collecting genetic samples and linked mental health data from adolescents in schools: protocol coproduction and a mixed-methods pilot of feasibility and acceptability.

OBJECTIVES: To coproduce a school-based protocol and examine acceptability and feasibility of collecting saliva samples for genetic studies from secondary/high school students for the purpose of mental health research. DESIGN: Protocol coproduction and mixed-methods feasibility pilot. SETTING: Secondary schools in Wales, UK. PARTICIPANTS: Students aged 11-13 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Coproduced research protocol including an interactive science workshop delivered in schools; school, parental and student recruitment rates; adherence to protocol and adverse events; ability to extract and genotype saliva samples; student enjoyment of the science workshop and qualitative analysis of teacher focus groups on acceptability and feasibility. RESULTS: Five secondary schools participated in the coproduction phase, and three of these took part in the research study (eligible sample n=868 students). Four further schools were subsequently approached, but none participated. Parental opt-in consent was received from 98 parents (11.3% eligible sample), three parents (0.3%) actively refused and responses were not received for 767 (88.4%) parents. We obtained saliva samples plus consent for data linkage for 79 students. Only one sample was of insufficient quality to be genotyped. The science workshop received positive feedback from students. Feedback from teachers showed that undertaking research like this in schools is viewed as acceptable in principle, potentially feasible, but that there are important procedural barriers to be overcome. Key recommendations include establishing close working relationships between the research team and school classroom staff, together with improved methods for communicating with and engaging parents. CONCLUSIONS: There are major challenges to undertaking large-scale genetic mental health research in secondary schools. Such research may be acceptable in principle, and in practice DNA collected from saliva in classrooms is of sufficient quality. However, key challenges that must be overcome include ensuring representative recruitment of schools and sufficient parental engagement where opt-in parental consent is required.

"Late-onset" ADHD symptoms in young adulthood: Is this ADHD?

Objective: We investigated whether "late-onset" ADHD that emerges in adolescence/adulthood is similar in risk factor profile to: (1) child-onset ADHD, but emerges later because of scaffolding/compensation from childhood resources; and (2) depression, because it typically onsets in adolescence/adulthood and shows symptom and genetic overlaps with ADHD. Methods: We examined associations between late-onset ADHD and ADHD risk factors, cognitive tasks, childhood resources and depression risk factors in a population-based cohort followed-up to age 25 years (N=4224-9764). Results: Parent-rated late-onset ADHD was like child-onset persistent ADHD in associations with ADHD polygenic risk scores and cognitive task performance, although self-rated late-onset ADHD was not. Late-onset ADHD was associated with higher levels of childhood resources than child-onset ADHD and did not show strong evidence of association with depression risk factors. Conclusions: Late-onset ADHD shares characteristics with child-onset ADHD when parent-rated, but differences for self-reports require investigation. Childhood resources may delay the onset of ADHD.

Early-Life Injuries and the Development of Attention-Deficit/Hyperactivity Disorder.

Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10-18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward-treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5.Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55-1.66) in males (HR = 1.59; 1.53-1.65) and females (HR = 1.65; 1.54-1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00-1.14), with a genetic correlation of 0.53 (0.21-0.85).Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.