Are adults who were born preterm or with low birth weight less likely to experience social transitions normative of adulthood, such as romantic partnerships, sexual intercourse, or parenthood?In this systematic review and meta-analysis of 21 studies describing up to 4.4 million participants, adults who were born preterm or with low birth weight were less likely to experience a romantic partnership, sexual intercourse, or parenthood than their peers who were born full-term. The likelihood of experiencing these social transitions decreased with lower gestational age and birth weight, and was similar in both young and middle adulthood.The findings suggest that adults who were born preterm or with low birth weight are less likely to have sexual or partner relationships than adults born full-term, which might put them at increased risk of decreased well-being and poorer physical and mental health. This systematic review and meta-analysis investigates the association between preterm birth or low birth weight and social relationships in adulthood. Social relationships are important determinants of well-being, health, and quality of life. There are conflicting findings regarding the association between preterm birth or low birth weight and experiences of social relationships in adulthood.To systematically investigate the association between preterm birth or low birth weight and social outcomes in adulthood.PubMed, PsycINFO, Web of Science, and Embase were searched for peer-reviewed articles published through August 5, 2018.Prospective longitudinal and registry studies reporting on selected social outcomes in adults who were born preterm or with low birth weight (mean sample age ≥18 years) compared with control individuals born at term.g, which were meta-analyzed using random-effects models.The meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The data were collected and extracted by 2 independent reviewers. Pooled analyses were based on odds ratios (ORs) with 95% confidence intervals and Hedges Ever being in a romantic partnership, ever having experienced sexual intercourse, parenthood, quality of romantic relationship, and peer social support.Twenty-one studies were included of the 1829 articles screened. Summary data describing a maximum of 4 423 798 adult participants (179 724 preterm or low birth weight) were analyzed. Adults born preterm or with low birth weight were less likely to have ever experienced a romantic partnership , to have had sexual intercourse , or to have become parents  than adults born full-term. A dose-response association according to degree of prematurity was found for romantic partnership and parenthood. Overall, effect sizes did not differ with age and sex. When adults born preterm or with low birth weight were in a romantic partnership or had friends, the quality of these relationships was not poorer compared with adults born full-term.These findings suggest that adults born preterm or with low birth weight are less likely to experience a romantic partnership, sexual intercourse, or to become parents. However, preterm birth or low birth weight does not seem to impair the quality of relationships with partners and friends. Lack of sexual or partner relationships might increase the risk of decreased well-being and poorer physical and mental health. These differences may predispose PT/LBW individuals to face greater difficulties in establishing romantic and peer relationships.Close, intimate, and supportive relationships are associated with increased happiness and well-being,25 or to be parents,25 prospective studies have reported conflicting findings across28 and within29 studies. Regarding the latter, a Canadian cohort study29 of extremely low-birth-weight infants reported different findings for social outcomes at distinct time points: while no differences were found in rates of marriage or cohabitation and parenthood between the extremely low-birth-weight individuals and those born full term at ages 22 to 26 years,29 adults with extremely low birth weight were less likely to be married or cohabitating and to have had children during the fourth decade of life.2 Additionally, there is a lack of research that has analyzed the impact of preterm birth on the quality of close relationships, such as with partners31 and friends.34In contrast, research on social outcomes of adults born preterm is not conclusive. While Scandinavian registry studies have found that adults born PT/LBW were less likely to ever be in a registered partnershipHence, there are inconsistent and scarce findings about the social lives of PT/LBW adults. This systematic review and meta-analysis systematically investigates the association between being born PT/LBW and social outcomes in adulthood, such as ever being in a romantic partnership, ever having had sexual intercourse, parenthood, quality of romantic relationship, and peer social support. Furthermore, we investigate whether there is a dose-response association according to degree of prematurity and whether outcomes are moderated by type of study , age, or sex.PRISMA) reporting guideline35 and was registered with PROSPERO International prospective register of systematic reviews (PROSPERO identifier: CRD42017078286).This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses  AND  AND (adult*).Studies were eligible for review according to the following criteria: (1) the sample included individuals who were born PT (<37 weeks’ gestation) or LBW (<2500 g at birth); (2) term control group; (3) adult participants ; (4) measured at least 1 of the following social outcomes in adulthood: romantic partnership , quality of romantic relationship , sexual intercourse , parenthood , or social support ; and (5) the study was published in a peer-reviewed journal. If data from the same sample were published in multiple works for the same social outcome, we retained (1) the study with the longest follow-up interval ; and (2) the study with the largest sample size and the broadest concept coverage.Two of us (M.M. and A.B.) reviewed titles and abstracts of traced articles. The title and abstract screening was followed by the analyses of full texts to check inclusion criteria. Discordances were resolved by discussion among all authors. When reported information was unclear or numerical data were not obtainable, relevant corresponding authors were contacted for clarification.36 When information was available, we used 4 different gestational age subgroups: extremely preterm , very preterm , moderate-to-late preterm , and full-term . When studies referred to preterm birth without mentioning gestational weeks, data were included in the MLPT subgroup.Studies reporting on PT or LBW were grouped into the same category because infants with low birth weight are mostly born preterm.63 , type of study , type of social outcome, and outcome data 63 . The ext37  using the Newcastle-Ottawa Scale38 for each social outcome. We used pooled odds ratios (ORs) with 95% confidence intervals for studies presenting dichotomous outcomes  and Hedges g for studies presenting continuous outcomes  with random effects. Heterogeneity among studies was assessed with Cochran Q , Higgins I2, and τ2. Low heterogeneity was defined as an I2 value of 0% to 25%, moderate heterogeneity as an I2 of 25% to 75%, and high heterogeneity as an I2 of 75% to 100%. To explore heterogeneity, we conducted subgroup analyses (dependent on data availability) for degree of prematurity , type of study , age groups , and sex.Meta-analysis of the overall comparison between adults born PT/LBW and their FT peers was carried out with Comprehensive Meta-analysis version 2 software (Biostat)39 ; (2) the Begg-Mazumdar rank correlation test to examine the likelihood of bias in favor of small sample size studies,40 in which nonsignificance of correlation indicates no publication bias; and (3) Egger test to examine whether publication bias was related to the direction of study findings.41 The intercept value provided by this test shows the level of funnel plot asymmetry from the standard precision.Publication bias analysis was assessed through (1) the trim and fill procedure to examine the symmetry of effect sizes plotted by the inverse of the standard errorBecause PT and LBW were combined into 1 group, it is essential to prove that the findings of the meta-analysis are not dependent on this decision. Therefore, a sensitivity analysis was undertaken in which we repeated the analysis excluding the studies that reported on LBW only.43 but they were not included in the quantitative synthesis  owing to the different ways the number of friends was assessed across studies. The studies included in the meta-analysis were conducted in 12 countries . The number of participants included in each analysis of summary data ranged from 4 423 798 (179 724 PT/LBW) for parenthood to 648 (276 PT/LBW) for peer social support  with the EPT subgroup being the least likely to have ever been in a romantic partnership . Comparisons of type of study  . HeterogQ = 22.30; P < .001), with the EPT subgroup being the least likely to have become a parent . When comparing the type of study, PT adults were less often reported to be parents in cohort studies, but not in registry studies. Subgroup analysis for age groups revealed no differences between PT/LBW and FT individuals in the younger age group, but PT/LBW adults in the older age group were less likely to be parents compared with FT adults of the same age. No moderation effect was found for sex.There was also a significant association between PT/LBW and parenthood, with adults born PT/LBW less likely to be parents than FT adults . Heterogeneity analysis indicated significant variation in parenthood effects between studies. Subgroup analysis for degree of prematurity revealed a dose-response association of degree of prematurity and parenthood  for romantic partnership, 0.04  for quality of romantic relationship, 0.54  for ever having experienced sexual intercourse, 0.78  for parenthood, and 0.15  for peer social support. With the use of trim and fill, these values remained unchanged for all relational outcomes, indicating no publication bias. The Begg-Mazumdar rank correlation and Egger test were not statistically significant for all outcomes, indicating no evidence of publication bias.Results remained the same after excluding studies that reported only birth weight. Hence, PT adults were less likely to be in a partnership , to have ever had sexual intercourse , and to be parents  in comparison with FT adults.Our findings revealed that adults born PT/LBW are less likely to experience romantic partnerships, sexual intercourse, or parenthood. Nevertheless, when they were in a romantic partnership or had friends, the quality of these relationships was similar to those experienced by FT adults.45 Furthermore, our findings are in line with evidence of a preterm behavior phenotype that follows into adulthood,24 which might be associated with more difficulty engaging in these transitions for individuals born PT/LBW.Using summary data from prospective studies with more than 4 million participants provided evidence for a temporal association between being born PT/LBW and establishing social transitions into adulthood, here defined as romantic partnership, sexual intercourse, and parenthood. The associations were robust across degree of prematurity, age groups, and sex. These findings are consistent with the increasing recognition of the impact that early life influences have on outcomes in adulthood.We verified that the strength of the associations between PT/LBW and social transitions were in general small for romantic partnership and parenthood and moderate for sexual intercourse. The associations diverged depending on degree of prematurity, type of study, and age group. The subgroup analysis for degree of prematurity revealed that the likelihood of PT/LBW experiencing a romantic partnership, sexual intercourse, or parenthood decreased with lower gestational age. Indeed, a significant dose-response association was found between degree of prematurity and rates of romantic partnership and parenthood, with adults born EPT 67% less likely to be in a romantic partnership and 69% less likely to be parents than those born FT.With respect to the type of study, we found that PT/LBW adults were less likely to have experienced romantic partnership or parenthood in cohort studies compared with registry studies. This difference may be related to the fact that cohort studies included mainly individuals born at less than 32 weeks’ gestational age, whereas registry studies included the full range of preterm birth, and the likelihood of occurrence of these transitions decreases with lower gestational ages.28 The current findings do not support this hypothesis. We verified that the difference of experiencing these transitions in comparison with FT individuals did not alter in the older age group and, in some cases, it was even greater in the older age group. To illustrate, while at ages 18 to 25 years, individuals born PT/LBW were 50% less likely than those born FT to have ever experienced sexual intercourse, after the age of 25 years the decreased likelihood for PT/LBW went up to 95%. These findings may be cautiously interpreted, as only 2 studies9 could be included in the older age group for this analysis. Alternatively, we may speculate that new ways of dating, such as dating applications, may be used more often by the younger age group of PT/LBW individuals.46It has been suggested that PT/LBW individuals might take longer to accomplish the milestones normative of adult life, such as employment, romantic partnership, and parenthood.2 A likely explanation is that, consistent with the general trend for first parenthood to take place in the late 20s or early 30s,47 few participants in the FT group were parents, yielding no difference between groups. However, once parenthood was assessed in middle adulthood, the differences between PT/LBW and FT groups emerged. At a societal or population level, it suggests that prematurity is associated with a cross-generational fertility loss. Adults born PT/LBW are less likely to become parents and their parents were already less likely to have subsequent children after their preterm child was born.48Adults born PT/LBW were overall less likely than those born FT to be parents. However, this difference was not significant in the younger age group. This finding is in line with the findings of Saigal et al.50 such as lower wealth, social isolation, and poorer physical and mental health. Both biological and environmental factors, such as alterations in the so-called social brain as part of the neurodevelopmental sequelae of preterm birth51 or parental stress in the early stages of life,52 have been found to contribute to social difficulties for PT/LBW individuals, such as being more timid and withdrawn. However, more investigation is required to shed light on the mechanisms through which biological and environmental factors interplay during PT/LBW individuals’ development. These findings highlight, on the one hand, the need for more prospective studies over the life course of PT/LBW individuals and the analysis of early predictors of social outcomes and, on the other hand, the importance of continued monitoring and adequate support of PT/LBW individuals throughout life.Overall, rather than a delay, our findings suggest persistent difficulties in making these social transitions that have been associated with negative outcomes later in life,28 Although it was possible to pool data from more than 1200 participants in these analyses, the lack of studies reporting on sex highlight the need for future research to clarify its moderating role.With respect to sex, it was only possible to include 4 to 5 studies in these subgroup analyses. We verified that both men and women born PT/LBW were less likely to have experienced romantic partnerships or sexual intercourse than their counterparts born FT. No differences were found for parenthood; however, it is important to note that there were few participants with children in this subgroup analysis. Previous studies have not been consistent when analyzing the role of sex on social outcomes.53 than FT adults. In addition, studies on PT/LBW children and adolescents reported poorer-quality relationships with peers54 than those born FT, including being bullied by peers more often.55 Hence, our findings suggest that despite fewer close relationships, relationship quality was not poorer when PT/LBW adults had friends or a partner, or the quality of relationships in PT/LBW individuals improves into adulthood. Longitudinal studies are required to explore these alternative explanations.We found that PT/LBW individuals perceived their romantic relationships slightly more positively than FT individuals, and that there was no difference for perceptions of peer social support between both groups. Although it was not possible to assess the amount of friends in this meta-analysis, most studies have found that PT/LBW adults had fewer friendsThis comprehensive study of social outcomes of premature birth uses large sample sizes of PT/LBW individuals in comparison with FT individuals, particularly in the analysis of romantic partnership and parenthood. However, there are limitations for the other outcome measures—having ever experienced sexual intercourse, quality of romantic relationships, and peer social support—that included a smaller number of studies and PT/LBW participants. There are also considerable variations of how peer support and quality of romantic relationships were measured across studies. For example, quality of romantic relationships included studies reporting on satisfaction with partner and intimacy, and social support included studies reporting on emotional closeness with friends to self-reported quality of social network. We recommend individual studies use similar valid measures to make comparisons less problematic.45 and information on disability was not available for most studies. Thus, it could not be assessed whether functional deficits or disability moderated the association between PT/LBW and social outcomes. In this study, PT and LBW were treated as 1 factor. Although these constructs show high comorbidity and our sensitivity analyses revealed consistent results, it would be important to disentangle the effects of PT and LBW and their possible additive effects on social outcomes. This would involve considering data on birth weights appropriate for gestational age or small for gestational age, which most studies included in the meta-analyses did not report. Future research should address these limitations by conducting individual participant meta-analysis and obtaining data directly from the study authors.Furthermore, the degree of prematurity is associated with physical and mental health and cognitive development,The heterogeneity of studies was high, indicating considerable variation. This might arise from incorporating cohort and registry studies with various sample sizes. To address this possibility, we used a random-effects model in the analysis and conducted moderator analyses. Nevertheless, our moderator analysis explained only some of the heterogeneity. Thus, the findings from the current study should be interpreted with caution and analysis should be repeated when more adulthood data becomes available from the cohort studies. Also, only English publications were considered in this meta-analysis and, therefore, potential language bias should be taken into account.56 and lack of romantic partner support9 are associated with lower levels of happiness and poorer physical and mental health. Future research is needed to identify the predictors and promotive factors of social outcomes in PT/LBW individuals to allow for timely interventions in aiding the transition into adulthood.This systematic review and meta-analysis provides a qualitative and quantitative overview of the current state of knowledge concerning social outcomes in adults born PT/LBW. Pooling data from multiple cohort and registry studies provided evidence that fewer adults born PT/LBW experience romantic partnerships, sexual intercourse, or parenthood. These associations are stronger the lower the gestational age and were found in young and middle adulthood. However, when PT/LBW individuals were in a romantic partnership or had friends, the quality of these relationships was at least as good compared with FT individuals. Hence, analyzing both objective indicators about the occurrence of social transitions and subjective measures about the quality of close relationships provided distinct and complementary information on the social lives of adults born PT. The implications of the current findings are that PT/LBW adults are at increased risk of never experiencing sexual intercourse, being without a supportive partner, and being less likely to experience parenthood. Lack of sexual activity


Preterm birth is associated with heightened risk for attention-deficit/hyperactivity disorder (ADHD)-like symptoms and neurocognitive impairments, including impairments in performance monitoring. Here, we investigate the cognitive and neurophysiological processes from a performance-monitoring task in preterm-born adolescents and examine whether these processes in preterm-born adolescents reflect identical neurophysiological impairments to those observed in term-born adolescents with ADHD. We compared 186 preterm-born individuals to 69 term-born individuals with ADHD and 135 term-born controls on cognitive-performance measures and event-related potentials (ERPs) of conflict monitoring (N2) and error processing  from a flanker task. Preterm-born adolescents demonstrated reduced N2, ERN and Pe amplitudes, compared to controls, and similar ERN and Pe impairments to term-born adolescents with ADHD. While ADHD symptoms correlated with ERN amplitude at FCz among the preterm-born, ERN amplitude at Fz, N2 and Pe amplitude were not associated with ADHD symptoms. Preterm-born individuals show impairments on neurophysiological indices of conflict monitoring (N2) and error processing (ERN and Pe). Early neurophysiological error processing may be a marker underlying the processes linked to the increased risk for ADHD among preterm-born individuals. Error detection processes are malleable and potential targets for non-pharmacological interventions. Preterm-born individuals are likely to benefit from early interventions. An estimated 15 million babies worldwide are born preterm (before 37 completed weeks of gestation) every year, with a mean preterm birth rate of 8.6% in the developed world , the surPreterm-born individuals are not only at an increased risk for the behavioral symptoms of ADHD, but also for similar cognitive impairments as observed in individuals with ADHD ,4, such Cognitive-performance data, however, only affords indirect insight into covert processing. Electrical potentials generated by the brain following internal or external events (such as stimuli and responses), known as event-related potentials (ERPs) , insteadERP studies in preterm-born individuals in childhood, adolescence and adulthood are scarce. Most ERP research carried out in preterm-born children has focused on auditory ERP measures –15. AudiDirect comparisons between individuals born preterm and individuals with ADHD are rare but can explicate whether the impairments observed in preterm groups are truly identical to those found in individuals with ADHD or part of wider-ranging impairments. This could aid in identifying biomarkers for the underlying processes linked to the increased risk for ADHD among preterm-born individuals, and effectively in planning targeted interventions. Only one small-scale ERP study  investigated attentional processing in preterm-born children of very low birth weight (<34 weeks and <1501g) with and without ADHD, as well as in term-born controls and term-born individuals with ADHD, using a visual oddball paradigm . CompareIn addition to impairments in attention and inhibition, neurocognitive impairments in ADHD include deficits in performance monitoring ,19. The The objective of the current study is to examine the cognitive and neurophysiological processes from a performance-monitoring task in preterm-born adolescents and young adults. Building on the cognitive-performance and ERP measures, which sensitively captured the performance monitoring impairments in adolescents and young adults with ADHD , we furtThe sample comprised 194 adolescents and young adults born preterm (<37 weeks of gestation), 93 ADHD participants and 166 controls. Exclusion criteria for all groups were IQ<70, general learning difficulties, cerebral palsy or any other medical conditions that affects motor co-ordination including epilepsy, as well as brain disorders and any genetic or medical disorder that might mimic ADHD. In addition, preterm birth was an exclusion criterion in the ADHD and control groups, because this study aimed to establish whether the cognitive impairments associated with preterm birth reflect identical neurophysiological impairments in term-born individuals with ADHD.The preterm group was recruited from secondary schools in Southeast England. All preterm participants had one full sibling available for ascertainment, and were born before 37 weeks’ gestation. Siblings of preterm-born individuals were included in the preterm group if they were also born preterm (before 37 weeks’ gestation) to maximize the number of participants in the preterm group. Term-born siblings of preterm-born individuals were not included in this analysis. Seven individuals from the preterm sample were excluded because medical birth records could not corroborate preterm status  < 37 weeks). One individual was excluded because of IQ<70. While preterm-born individuals were unselected for ADHD status, eight preterm-born individuals met diagnostic criteria for a research diagnosis of ADHD. Since here preterm birth is investigated as a potential risk factor for ADHD, preterm-born individuals who demonstrated high levels of ADHD symptoms were not excluded from the analysis   to all pThe task was an adaptation of the Eriksen Flanker paradigm  designedThe EEG was recorded from a 62-channel DC-coupled recording system (extended 10–20 montage), using a 500Hz sampling-rate, impedances under 10kΩ, and FCz as the recording reference. The electro-oculograms (EOGs) were recorded from electrodes above and below the left eye and at the outer canthi. EEG data were analyzed using Brain Vision Analyzer 2.0 . Raw EEG recordings were down-sampled to 256Hz, re-referenced to the average of all electrodes, and filtered using Butterworth band-pass filters . All trials were visually inspected for electrical artifacts or obvious movement, and sections of data containing artifacts were removed manually. Ocular artifacts were identified using the infomax Independent Component Analysis (ICA) algorithm . SectionData were segmented based on 1) stimulus-locked trials where a correct response was made and (2) response-locked (error-related) trials where an incorrect response was made. Individual averages were created based on each condition, requiring ≥20 clean segments for each participant. After averaging, the electrodes and latency windows for ERP analyses were selected based on previous studies ,23,25, t stimulusTwo preterm-born participants (1.1%) were excluded from the ERP analysis of the N2 and 14 preterm-born participants (7.5%) were excluded from the ERP analysis of the ERN/Pe due to having fewer than 20 artifact-free segments available for analysis. Two participants with ADHD (2.9%) were excluded from the ERP analysis of the N2 and seven participants with ADHD (10.1%) were excluded from the ERP analysis of the ERN/Pe due to having fewer than 20 artifact-free segments available for analysis. Fourteen control participants (10.4%) were excluded from the ERP analysis of the ERN/Pe due to having fewer than 20 artifact-free segments available for analysis. These exclusion ratios across groups reflect similar ratios reported in previous studies using this paradigm ,25.Data were analyzed using random intercept models in Stata, to control for non-independence of the data (i.e. data coming from siblings of one family), using the ‘robust cluster’ method to estimate standard errors . We ran The random intercept model yielded a significant main effect of group for MRT , RTV , DSB , N2 , Pe  and ERN  amplitude  and ERN . No significant group-by-congruency interaction emerged for N2 , MRT , RTV  or errors . No significant group-by-congruency-by-electrode site interaction emerged for N2 amplitude .Post-hoc analyses found that the preterm group had significantly reduced N2 and ERN amplitude at FCz, as well as reduced DSB and Pe amplitude compared to the control group, with medium-to-large effect sizes . CompareAmong those born preterm, DIVA ADHD symptoms correlated with ERN amplitude at FCz , but not with ERN amplitude at Fz , Pe amplitude , N2 amplitude at Fz  or N2 amplitude at FCz .Controlling for IQ, group effects on MRT in the congruent condition became significant  and neurophysiological error processing (ERN and Pe). The early (ERN) and late (Pe) error detection impairments observed in the preterm-born individuals were similar to those found in term-born individuals with ADHD. While the impairments in early error processing (ERN) were significantly associated with ADHD symptoms, such that smaller ERN amplitude at FCz was linked to higher ADHD symptom severity, Pe amplitude did not correlate with ADHD symptoms in the preterm group. Early electrophysiological error processing may, therefore, be a putative marker for the underlying processes linked to the increased risk for ADHD among those born preterm.Reduced N2 amplitude at FCz, indexing conflict-monitoring impairments, was observed in the preterm-born individuals. Previous research had found increased NoGo-N2 amplitude in children born very preterm (<32 weeks) using an auditory oddball paradigm . The disPreterm-born individuals further demonstrated impairments in Pe amplitude, compared to term-born controls. While the functional importance of the Pe is still unclear, the Pe has frequently been linked with conscious awareness of having committed an error . In lineWe further identified impaired early error processing, indexed by reduced ERN amplitude at FCz, in the preterm group. This impairment is similar to that in individuals with ADHD who also demonstrated reduced ERN amplitude compared to controls . The sigWe repeated the analyses with IQ as a covariate to examine any potential contribution from IQ to the results. When removing the effects of IQ, differences on MRT and RTV between the groups became non-significant, suggesting that group differences on this measure may reflect impairments related to IQ. These findings may also explain the discrepancy between this study and previous studies ,22, whicOne limitation of this analysis is that we cannot completely rule out the possibility of background factors accounting for our ERP findings, because we were not able to investigate risk factors for preterm birth . Yet, population-based quasi-experimental designs found that the link between psychiatric morbidity and preterm birth is largely independent of shared familial confounds and measured covariates, in line with a causal relationship . NeverthThis study provides evidence for impairments in performance monitoring, including conflict monitoring (N2) and neurophysiological error processing (ERN and Pe) in preterm-born individuals. While the conflict monitoring impairments in the preterm group do not seem to be identical to those in individuals with ADHD, early neurophysiological error processing may be a biomarker linked to the increased risk for ADHD. Since previous studies have demonstrated that error detection processes are malleable  and alsoS1 FileAppendix A–Excluding preterm-born individuals with a research diagnosis of ADHD from the analysis. Appendix B–Analysis controlling for IQ. Appendix C–Analysis of the males only. Appendix D–Analysis of the age-matched subsample.(DOCX)Click here for additional data file.S1 Dataset(CVS)Click here for additional data file.


TaxonSluice. We explore ecological factors driving community structure and potential function of biofilms by comparing our sequence data to previous amplicon and metagenomic surveys of this habitat. We reveal that biofilm community structure is driven by temperature rather than minerology, and that rare planktonic lineages colonize the crustal biofilms. Based on 16S rRNA gene overlap, we partition metagenome assembled genomes into planktonic and biofilm fractions and suggest that there are functional differences between these community types, emphasizing the need to separately examine each to accurately describe subseafloor microbe-rock-fluid processes. Lastly, we report that some rare lineages present in our warm and anoxic study site are also found in cold and oxic crustal fluids in the Mid-Atlantic Ridge, suggesting global crustal biogeography patterns.The crustal subseafloor is the least explored and largest biome on Earth. Interrogating crustal life is difficult due to habitat inaccessibility, low-biomass and contamination challenges. Subseafloor observatories have facilitated the study of planktonic life in crustal aquifers, however, studies of life in crust-attached biofilms are rare. Here, we investigate biofilms grown on various minerals at different temperatures over 1–6 years at subseafloor observatories in the Eastern Pacific. To mitigate potential sequence contamination, we developed a new bioinformatics tool –  FLOCS deployed at depth downhole were exposed to in situ conditions within the anoxic 64°C crustal subseafloor aquifer, whereas FLOCS deployed at the wellhead are inoculated with the same crustal fluid sourced from below but are chilled in the surrounding 2°C oxic bottom water at the seafloor  crushed (<250 μm grain size) and autoclaved prior to deployment as described elsewhere , geochemical analyses of the fluids exiting the FLOCS units, DNA extraction, quantitative polymerase chain reaction analysis of the small subunit ribosomal RNA (16S rRNA) gene, 16S rRNA gene amplicon sequencing via Illumina, and data processing steps are described in detail in the mothur  at the 9i.e.: roughly 104 cells ml–1 , validation efforts on mock communities, and additional user information (dependencies and user-set parameters) for this tool are publicly available on GitHub1. Briefly, TaxonSluice implements a novel heuristic algorithm , NP crustal fluid [NCBI BioSamples SAMN07571231–SAMN07571245 for Holes U1382A and U1383C at various sampling times and depths, see PRJNA264811  than those observed from wellhead deployments . While tArcobacter and were highly similar to sequences from previous Hole U1301A wellhead enrichments (There was nearly no overlap between OTUs from cold (2°C) wellhead and warm (64°C) downhole incubations –S9. Phylichments .Ammonifex sp. The Aminicenantes (OP8), reported in JdF crustal fluid communities  were also observed in both categories, while a polysulfide-carrier heterodimer (soxYZ) associated with the sox thiosulfate oxidation pathway  and dissimilatory nitrate reductases  are observed in both fractions, while dissimilatory nitrite reduction (nirBD) and denitrification (nirS) genes are only observed in the biofilm-linked MAGs. Five groups of hydrogenases  are also observed in both biofilm and plankton fractions. Genes associated with the dissimilarity iron reduction and oxidation were absent from the planktonic and biofilm fractions.Hidden Markov Models were used to further evaluate the genetic potential of the JdF MAGs grouped into biofilm and plankton fractions . Genetic pathway  is only i.e., sourcing subsurface JdF crustal fluids but incubated under cold conditions at the observatory wellhead) recruit metagenomic 16S rRNA gene reads mostly from the cool and oxic NP crustal fluids  recruit metagenomic 16S rRNA gene reads from the JdF crustal fluids  exclusivl fluids .Both rock-attached biofilms and free-floating plankton live in the crustal subseafloor; therefore, assessing the factors governing plankton recruitment onto crustal surfaces and, subsequently, differences in composition and potential activities of biofilm and plankton is necessary for a comprehensive ecological description of this habitat. In this study, we examine the influence of incubation conditions on subseafloor rock-attached biofilm composition . Further3–106 cells per gram of rock based on quantitative PCR analysis of 16S rRNA genes in pooled DNA extracts  represent globally distributed denizens of the crustal subsurface biosphere. Although rare in the anoxic warm JdF crustal fluids, these cold-adapted aerobic groups are present in the aquifer and respond to changing environmental conditions  to dominate wellhead incubations (Colwellia and Arcobacter spp. between this study and that of Colwellia spp. reside) on subsurface basalts. We hypothesize that these microbial groups are sourced from bottom seawater and persist even in highly altered crustal fluids to rebound when conditions become favorable again.Similarities between wellhead biofilm members and taxa in crustal fluids from a different cool and oxic crustal subsurface ecosystem , 7 suggeubations . The conCa. Desulfopertinax/terrestrial Ca. Desulforudis lineage, commonly observed in JdF crustal fluids and terrestrial subsurface sites  present in both biofilm and planktonic fractions in similar relative abundances, with the Calvin cycle gene RuBisCO only observed in plankton . Prior sin situ rates of this process are unknown. The potential for microbial sulfate reduction on the rocks has also been documented by sulfur stable isotopes ; however, the subset of MAGs used in our analyses did not contain this gene. Iron is relatively abundant in the host rocks, as iron oxides comprise roughly 10% of the basalt (by weight) in this system, and iron oxyhydroxides are the second most abundant mineral alteration product. These phases indicate the potential for iron oxidation/reduction. Thermodynamic calculations suggest that utilization of iron is energetically favorable  but lacking mrcA have been recently reported from JdF crustal fluids (The reductant-oxidant pairs in the JdF subsurface that fuel chemotrophy are unclear. Hydrogen and methane in JdF fluids could provide very low levels of free energy when coupled to various electron acceptors . We detel fluids . We detel fluids . Furtherl fluids , to the l fluids .The use of amino acids  is suppoThe nature of biofilm cellular recruitment from plankton in subseafloor crust is explored in this study. We show that temperature, and possibly redox state, drive recruitment of planktonic cells from crustal fluids into mineral-attached biofilms, supporting prior hypotheses about the global ecological structuring of this habitat . CompariPRJNA472057; BioSample accession numbers: SAMN09228041–SAMN09228055.The datasets generated for this study can be found in NCBI Short Read Archive, BioProject BO and CW conceived the study. GR, BO, and CW conducted the field deployments/recoveries. GR, BO, CW, AL, and TD performed the sample analyses. GR and AG performed the bioinformatic analyses and developed the software tools. GR, AG, CW, and BO interpreted the data. GR wrote the manuscript with input from all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Slow waves (1–4.5 Hz) are the most characteristic oscillations of deep non-rapid eye movement sleep. The EEG power in this frequency range  parallels changes in cortical connectivity  during development. In patients with attention-deficit/hyperactivity disorder (ADHD), prefrontal cortical development was shown to be delayed and global gray matter volumes to be smaller compared to healthy controls. Using data of all-night recordings assessed with high-density sleep EEG of 50 children and adolescents with ADHD  and 86 age- and sex-matched healthy controls , we investigated if ADHD patients differ in the level of SWA. Furthermore, we examined the effect of stimulant medication. ADHD patients showed a reduction in SWA across the whole brain (−20.5%) compared to healthy controls. A subgroup analysis revealed that this decrease was not significant in patients who were taking stimulant medication on a regular basis at the time of their participation in the study. Assuming that SWA directly reflects synaptic density, the present findings are in line with previous data of neuroimaging studies showing smaller gray matter volumes in ADHD patients and its normalization with stimulant medication. Yet, a wide range of neuroimaging studies revealed that lower gray matter volumes in different brain regions, e.g. the basal ganglia3, and lower cortical thickness5 are associated with the disorder. According to longitudinal magnetic resonance imaging (MRI) data, there is evidence that a delay in brain maturation underlies these differences8.Despite attention-deficit/hyperactivity disorder (ADHD) is one of the most studied developmental disorders from child- to adulthood, the genetic and neuronal factors underlying the development of ADHD are not fully understood9. Using this technique, studying sleep EEG slow waves, oscillations of about 1–4.5 Hz characterizing deep non-rapid eye movement (NREM) sleep, offer a promising readout of the functional output of neuronal connectivity11. Slow-wave activity (SWA) is defined as the EEG power in the slow wave frequency band. During the first two decades of life, SWA follows an inverted U-shaped curve12, similar to gray matter development. Moreover, the predominant location of SWA undergoes a posterior–anterior shift across the scalp from early childhood to late adolescence13, which again parallels cortical maturation15. In children with ADHD, SWA was shown to be relatively increased over central brain regions16. Since this pattern resembles that of healthy children of younger age, it supports the assumption that ADHD is characterized by a delay in cortical maturation. Apart from this study, little is known about ADHD-related topographical alterations in SWA during sleep.In recent years, a new imaging modality proved useful in tracking brain maturation in humans, i.e. high-density electroencephalography (hd EEG) recordings during sleep18.In the present study, we included data of all-night recordings assessed with high spatial resolution sleep hd EEG of 50 children and adolescents with ADHD and 86 age- and sex- matched healthy controls. Our aim was to investigate whether ADHD patients differ from healthy controls in terms of sleep SWA across the cortex. Additionally, we aimed to assess the effects of psychostimulants on SWA, because standard prescribed drugs, i.e. psychostimulants, not only improve specific and broader clinical symptoms, but also seem to normalize gray matter maturation16), 2013 (unpublished) and 2017 (unpublished), respectively. 10 ADHD patients  reported regular intake of stimulant medication for the treatment of ADHD  including the morning of measurement. Another 18 patients  reported regular intake of psychostimulants but refrained from medication during the 24 h before the evening of the night measurement. Sixteen of them received methylphenidate  with dosages ranging from 10 to 46 mg per day (mean: 28 mg/day) and two lisdexamphetamine . According to personal reports, medication was usually taken five (workdays) to seven days per week. However, we did not use a standardized drug diary in the weeks before the experimental night. Five patients were medicated with methylphenidate during the time of measurement, but details on the concentration and last time of drug intake before the sleep assessment were not assessed. Six patients  received psychostimulant medication in the past but had stopped medical treatment before the start of the study  and did no longer receive stimulant drugs, and 11 were drug-naïve . Details of diagnosis across these medication subgroups can be found in Table Fifty patients 13 female) between 8 and 16 years (mean: 12.2 years) diagnosed with ADHD  were included in the analysis , resulting in 121 possible healthy control participants. From this pool, the maximal amount of participants was chosen such that their age (mean and standard deviation) as well as the proportion of sexes precisely matched the ADHD group, leading to a sample size of n = 86. Recruitment of control participants was done via local schools, advertisements and social media.Eighty-six sex- and age-matched healthy control participants  who were never diagnosed with a psychiatric disorder were included in the analysis. Matching of the control group was done as follows: all children in the same age range as the ADHD patients (8–16 years) were selected from three studies that were performed in 2008–2013Of note: both, in the patient and control group, subjects were pooled from several, independent studies. All studies were performed in the same rooms, with the same equipment , followed the same general procedure and the experimenters were always master- or PhD students of the same research group. Furthermore, none of the participants reported to suffer from a diagnosed sleep disorder at the time of measurement.22  or from the TONI-423 (16 controls). No differences in IQ were found between the control group and any of the ADHD subgroups. Within the ADHD subgroups, IQ was significantly lower in patients who were medicated in the past as compared to unmedicated patients  was estimated from either German (short-) versions of the WISC-III or WISC-IV intelligence testFor all participants, written informed consent was obtained from a parent and/or legal guardian and in addition from adolescent participants 14 years and older. All studies were approved by the local ethics committee  and performed according to the Declaration of Helsinki.During 7 days prior to the sleep assessment, participants were instructed to stick to a regular sleep–wake rhythm with deviations of bed and get up times of less than 1 h. Regular bedtimes were verified with wrist accelerometry  and sleep diaries including bed and get up times and alcohol/caffeine consumption. Participants were further asked to restrict their caffeine consumption to a maximum amount of two servings per day. Medication was only permitted in patients with ADHD. Whole-night EEG recordings took place in the sleep laboratory of the University Children’s Hospital Zurich. Sleep times were scheduled according to habitual bedtimes.24. Artifacts were rejected based on visual inspection during scoring on a 20 s basis. Additionally, artifacts were removed on a semiautomatic basis if power exceeded a threshold based on mean power values in the 0.75–4.5 Hz and 20–30 Hz bands. On average, 17% of epochs were excluded in the ADHD group and 14% in the control group. Data of each participant were then re-referenced to the average value across all electrode channels excluding the lowest row.All-night sleep hd EEG was recorded . All electrodes were filled with an electrolyte gel . Four additional gold electrodes  were attached to the chin (EMG) and earlobes. EEG data were referenced to the vertex and sampled at 500 Hz (filtered between 0.01 and 200 Hz). Data were offline bandpass filtered between 0.5 and 40 Hz and down-sampled to 128 Hz. Sleep was visually scored in 20 s epochs according to the AASM Manual for scoring sleep16, the larger sample size allowed the comparison of absolute SWA values . Therefore, power values were averaged over the first hour of artifact-free NREM sleep (stages N2 and N3) and 1–4.5 Hz and then logarithmized to ensure normal distribution of the data (Shapiro-Wilk tests). Electrode-wise group comparisons were performed using two-tailed Student’s unpaired t tests and statistical nonparametric mapping (SnPM), using a supratreshold cluster analysis25 to control for multiple comparisons. The subgroup analysis was performed by means of both electrode-wise and across electrodes ANCOVA with cofactor age. For pairwise comparisons, Tukey-Kramer post hoc tests were used because of unequal sample sizes, but equal within-group variances across the groups . The alpha level of all statistical tests was set to 0.05. All analyses were performed with the software package MATLAB  and R i386 (version 3.4.2).Sleep parameters and data of sleep diaries were compared between the groups using ANCOVA with cofactor age and Tukey-Kramer post hoc tests. EEG power was calculated for all channels and for 20 s epochs by means of a fast Fourier transform routine . EEG channels with poor signals were excluded and the power value was interpolated using spherical linear interpolation. The lowest row of electrodes was excluded for analysis resulting in 109 included channels. In contrast to our previous studyn = 6), ADHD patients who had never received stimulant medication , ADHD patients who received psychostimulants on a regular basis but refrained from taking them during the 24 h prior to the EEG assessment , ADHD patients who received psychostimulants on a regular basis including the morning of measurement  and healthy controls (n = 86). Bed time, get up time and time in bed during the week before the measurement did not differ between groups. Furthermore, no differences were observed in mean caffeine consumption per day, which was very low for all groups  and a longer sleep duration . Thus, we expressed all sleep stages and wake after sleep onset as percentage of total sleep time or time spent in bed. We found no group differences neither in the composition of sleep stages, nor in sleep latency or wake after sleep onset, with the exception of that the ADHD group “med-day before” spent significantly less time in stage N1 as compared to the control group (p < 0.05) and that the ADHD group “med-day of measurement” had a longer sleep latency than the groups “ADHD-unmed” (p < 0.01), “ADHD-med day before” (p < 0.01) and healthy controls (p < 0.01). Sleep quality as represented by sleep efficiency was high in all groups  for the following reasons: (1) for some participants EEG data were only available for the beginning of the night due to EEG-net removal, (2) the EEG recordings were shorter in healthy controls, and (3) most consolidated sleep results in a most stable estimate of sleep pressure at the beginning of the night. To assure that the composition of the first NREM sleep hour is similar between groups, we compared absolute length, sleep architecture as well as time awake during this time window and found no differences between ADHD and healthy control participants (Supplementary Table 10) between ADHD and healthy control participants were performed. SWA of ADHD patients showed a significant decrease of 20.5 ± 0.32% (mean over electrodes ± SEM) in 101 out of 109 electrodes compared to healthy controls . Moreover, a strong effect of age on SWA was observed . Pairwise comparisons (Tukey-Kramer post hoc tests) showed that SWA was decreased in both the “ADHD-unmed” group and the “ADHD-med in past” group as compared to both the “ADHD-med measurement day” group and the control group. In addition, the “ADHD-med in past” group showed significantly lower SWA than the “ADHD-med day before” group . Pairwise comparisons revealed that the “ADHD-med in past” group experienced significantly more wake and N1 as compared to the “ADHD-med day before” group  with cofactor age revealed a significant effect of group on SWA in each electrode Fig. . Due to oup Fig. . Since t28. Moreover, psychostimulant medication has been shown to normalize both gray matter18 and cortical thickness29. This parallelism between sleep SWA and cortical gray matter might not be surprising given that several studies have established a direct relationship between the two30.The main result of this study is that sleep EEG SWA is reduced across the scalp in children and adolescents with ADHD compared to healthy controls. Interestingly, we found that the SWA reduction was mostly driven by patients without stimulant medication at the time of their participation in the study. Both of these findings are in agreement with the well-established anatomical differences in ADHD patients. Specifically, several studies found that children with ADHD exhibit widespread reductions in gray matter volume and cortical thickness31. These slow oscillations of cortical neurons during deep sleep are the result of an unique alternating activity pattern between active “on” states and completely silent “off” states. The more neurons are involved and the more synchronized they display these “on”/“off” states, the larger the amplitude of the surface slow wave32. Thus, higher synaptic connectivity and stronger synaptic connections result in larger and highly synchronized networks of neurons involved in slow oscillations and in more SWA recorded on the cortical surface.Our knowledge about how slow waves are generated supports a close relationship between SWA and gray matter. Slow waves on the cortical surface reflect slow oscillations of cortical neurons33, (2) the regional maturation along the posterior-anterior axis35, and (3) experience-dependent changes in synaptic plasticity, which are favored by processes of brain maturation36. These close relationships seem not to be exclusive for gray matter, but specific aspects of slow waves may also relate to the maturation of white matter microstructure37.This relationship might explain why particularly during development, when major reorganization processes take place, sleep SWA parallels major maturational changes in cortical gray matter, i.e. (1) the inverted U-shape time course during the first two decades of life36. As such, this electrophysiological readout potentially contributes to the understanding of why ADHD patients show reduced cortical gray matter for the following reasons. It was proposed that a delay in cortical maturation underlies the brain anatomical differences7. Indeed, in our previous work published in 2013 by Ringli and coworkers, we concluded, based on the topographical differences in SWA, that children with ADHD show a less mature pattern than healthy control participants. Our novel analysis with a larger study population, allowing a comparison of absolute SWA, reveals a global reduction of SWA in patients with ADHD. This observation does not exclude that additional local changes are present. The directionality of the relationship between sleep SWA and a maturational delay is unknown. In other words, whether decreased SWA supports a cortical developmental delay, or alternatively whether a maturational delay results in decreased SWA remains to be established with longitudinal studies. Two observations, which both support an active role of SWA in cortical gray matter maturation, encourage the exploration in more detail: (1) cortical maturation assessed by SWA precedes gray matter maturation measured by means of MRI38 and (2) good evidence exists that SWA plays a critical role in synaptic plasticity39. Thus, reduced SWA in ADHD patients may actively contribute to the delay of brain development.Sleep EEG SWA represents a promising readout of age-dependent changes in functional neuronal connectivity and may thus complement the anatomical markers of brain maturationFinally, we would like to discuss major confounders and potential limitations of the study.41, we observed an acute medication effect on sleep onset latency  with those of healthy controls (n = 86) and found that ADHD patients tended to wake up even fewer times than healthy controls (p = 0.04). When performing a medication-subgroup analysis, we counted significantly more awakenings for the ADHD group “med in past” as compared to the ADHD group “med day before” , which is consistent with different durations of wake and N1 in the same subgroups (see above). Thus, apart from the “ADHD-med in past” group, decreased SWA in ADHD patients cannot be explained by more sleep fragmentation.Fourth, one might speculate that global SWA changes in ADHD patients result from disturbed sleep in this patient group. By looking at the architecture of the first NREM sleep hour we could show that durations of wake and sleep stage N1 did not differ between ADHD and control subjects. A more direct measure for sleep fragmentation is the number of awakenings. Thus, we compared awakening counts during the first NREM sleep hour of ADHD patients  in children with ADHDHaving these limitations in mind, our results show that children and adolescents diagnosed with ADHD experience a reduction in EEG SWA during NREM sleep. Stimulant medication seems to have normalizing effects on SWA. These findings are in line with neuroimaging studies showing decreased levels of gray matter, possibly caused by a maturational delay in ADHD patients. This parallelism between ADHD-related gray matter changes and SWA changes needs to be further investigated by assessing both MRI and sleep EEG in a large patient sample.Supplemental Material


Literature emphasizes the relationship between attention deficit-hyperactivity disorder (ADHD) and suicidal behavior (SB). However, the link between ADHD and the severity of SB is yet to be determined. We investigated the association between a probable diagnosis of ADHD and the severity of SB in 539 hospitalized suicide attempters, and determined the role of comorbid psychiatric diagnoses. The severity of SB was defined as the number of suicide attempts, age at first suicide attempt, seriousness and violence of suicide attempts. A diagnosis of probable adult ADHD (probable ADHD) was defined as the presence of both current ADHD symptoms and ADHD symptoms in childhood. We evaluated the combined effect of high impulsive-aggression levels and probable ADHD. Probable ADHD was not associated with early or frequent suicide attempts after adjustment for psychiatric disorders and treatment intake. High levels of impulsive-aggression increased the risk of an early suicide attempt, particularly in patients with ADHD symptoms, and independently of other clinical factors. The association between serious suicide attempts and probable ADHD remained significant after adjustment. Although ADHD is involved in suicidal vulnerability, psychiatric comorbidities and impulsive-aggression appear to largely explain the severity of SB in adult attempters with ADHD symptoms. According to World Health Organization (WHO) surveys, its prevalence averages 2.2% among children worldwide and is followed by adult ADHD in 57% of the cases3 although prevalence of adult ADHD is likely to be underestimated4.Attention Deficit Hyperactivity Disorder (ADHD) is a highly prevalent condition associated with substantial psychosocial and health burden5. Recent studies have shown higher rates of comorbid Axis I and Axis II disorders in adults with ADHD compared to those without6. ADHD is also associated with divorce and impaired interpersonal relationships7. Together, poor social and psychiatric conditions associated with ADHD may trigger suicidal ideation and suicidal behaviors (SB) in patients10.ADHD has profound consequences on daily functioning11. A Taiwanese study also found that ADHD adolescents were more likely to make deliberate self-poisonings than those without ADHD after adjusting for potential confounders12. Another study showed that adolescent attempters with ADHD were older, more often bullying perpetrators and showed higher depression levels than non-attempters13.There is substantial evidence linking ADHD with different types of suicidal behaviors, such as suicide attempts and completed suicide, and suicidal ideation in young individuals and adult populations. In adolescents, a Finnish birth cohort study (n = 457) showed an independent association between ADHD diagnoses and suicidal ideation (or deliberate self-harm) within the last two years14. Suicide attempters show higher ADHD rates than non-attempters, with OR ranging from 2.6 to 7.315. A recent adult psychiatric morbidity survey (7403 respondents) pointed out a positive association between severity of adult ADHD symptoms and the presence of lifetime or past-12 months suicide attempts, even when taking into account psychiatric comorbid conditions16. Common genetic factors, mainly related to impulsivity, were suggested to explain the independent association between SB and ADHD17. Indeed, results from a previous prospective follow-up study outlined the existence of shared impulsivity traits between patients with ADHD and those attempting suicide18.Similarly, the severity of ADHD symptoms has been linked with frequent suicidal ideation in adults. This association may be mediated by difficulties in coping with stressful situationsIn summary, some large epidemiological studies have suggested an association between ADHD and SB but their results were not consistently replicated in clinical samples. The severity of SB associated to a probable diagnosis of ADHD in adults as well as the role of comorbid diagnoses is yet to be determined. We hypothesized that the severity of suicide attempts is positively correlated with probable adult ADHD.20, recent findings showed that a large majority of adults meeting criteria for ADHD had other mental disorders and/ or substance use disorder better explaining the symptoms21. Hence, we used the term “probable ADHD” for patients with a diagnosis of ADHD in adulthood when patients reported both current ADHD symptoms and ADHD symptoms in childhood.Although birth cohort studies have suggested the possibility of late-onset ADHD emerging in adulthoodWe studied the characteristics and severity features of suicidal behavior , as well as the role of potential confounders such as impulsive-aggression traits, in a large sample of adult suicide attempters with and without ADHD symptoms.Of the 684 patients with an evaluation of ADHD symptoms, 78 had missing data for characteristics of suicide, 27 for assessment of impulsive-aggression and 40 for adjustment covariables; they were thus excluded from the present study (n = 145). These patients had a higher educational level, were more frequently smokers, and had less lifetime episodes of major depression than the patients included .The final sample consisted in 539 patients , the median age was 42.86 years (ranging from 18.01 to 83.45). Almost half of them  lived with a partner at the time of inclusion. The most frequent psychiatric diagnoses were anxiety disorders , followed by major depressive disorder , alcohol use disorder  and bipolar disorder . Most patients  had at least two comorbid diagnoses among bipolar, major depressive, anxiety, substance use, alcohol use or eating disorder. There were 223 early attempters (41.37%) and 181 frequent suicide attempters (33.58%). Violent and serious suicide attempts occurred respectively in 21.34% (n = 115) and 27.27% (n = 147) of the sample. A family history of suicidal behaviors was reported by 248 (46.01%) patients.Childhood ADHD symptoms (i.e. positive WURS-25 screening) were found in 161 patients (29.87%). At the time of the inclusion, 254 patients (47.12%) presented with current ADHD symptoms, defined as a positive ASRS screening. Ninety (16.70%) patients screened positive for both childhood and current ADHD symptoms and were thus classified as probable ADHD diagnoses.Adults with high impulsive-aggression level (BDHI scores >47) were more likely to be screened positive for current ADHD symptoms .Compared to late attempters, early attempters were significantly more likely females, and less frequently in couple. They were younger at the time of evaluation and more frequently tobacco users (p = 0.005 for both comparisons). Early attempters were also more frequently diagnosed with anxiety disorder (p = 0.008), substance use and eating disorders (p < 0.0001 for both comparisons) and were prescribed mood stabilizers more often. Finally, high levels of impulsive-aggression were more frequent in early attempters (p < 0.0001) . The association between current ADHD symptoms and being early attempter remained significant after adjustment for smoking status, anxiety, eating, substance use disorders and treatment intake  . In contrast, the association between a young age at first suicide attempt and probable ADHD disappeared when considering psychiatric disorders (anxiety and eating disorder), substance use disorders and treatment intake .High levels of impulsive-aggression were associated with early suicide attempts in unadjusted and adjusted models . The strength of the association between impulsive-aggression and early suicide attempts increased in patients with probable ADHD .Compared to non-frequent suicide attempters, frequent attempters were associated with female gender (p = 0.0002), eating disorder (p < 0.0001), bipolar disorder (p = 0.0001) and a positive family history of SB (p = 0.03). They also displayed higher impulsive-aggression scores (p = 0.02) and were less likely to be diagnosed with major depressive disorder (p = 0.006) or treated with antidepressants (p = 0.02). However, they were more often treated with mood stabilizers than non-frequent suicide attempters (p = 0.0003) (Supplementary Table Probable ADHD was associated with frequent suicide attempts. These associations remained significant after adjustment for socio-demographic variables and study site (model 0 and model 1) but disappeared when controlling for psychiatric comorbidities , familial history of SA, alcohol use disorder, antidepressant, mood stabilizers and antipsychotic treatment,  , had lower educational level (p = 0.01) and were more likely to receive an anxiety disorder diagnosis (p = 0.002) or antidepressant treatment (p = 0.007) than non-violent attempters. However, they received antipsychotics more often (p = 0.008) (Supplementary Table Serious suicide attempters were associated with older age (p = 0.02), eating disorder (p = 0.02), and antipsychotic treatment (p = 0.005) compared to patients who did not make a serious attempt (Supplementary Table Serious suicide attempters were more likely to have a probable ADHD (model 2: OR 1.96 95%CI [1.17–3.29]). No association was found with impulsive-aggression Table .Table 4SIn this study, we examined various aspects of SB severity and their relationship with lifetime ADHD symptoms and impulsive-aggression levels in a large and well-characterized sample of adult inpatients with a history of suicide attempts. While the associations of young age at first suicide attempt and frequent suicide attempts with probable adult ADHD disappeared when psychiatric disorders and treatment prescriptions were considered, the association between serious suicide attempts and probable ADHD remained significant. Probable ADHD did not impact the violence of lifetime suicide attempts.High levels of impulsive-aggression were associated with early suicide attempts, independently of the psychiatric diagnoses, current treatment and ADHD status. The combined effect of impulsive-aggression and probable ADHD increased the risk of making an early suicide attempt. While comorbid psychiatric diagnoses moderated the association between early onset of SB and positive screens for ADHD, high impulsive-aggression levels appeared to be by and large the most important determinant of an early onset of SB in our sample.22 and impulsive-aggression is a frequent comorbidity in ADHD children23 that also characterizes many suicide attempters. Impulsivity, hostility and aggression constructs are also highly correlated and share common features, especially among suicide attempters24. Thus, we considered the impulsive-aggression dimension as an independent variable. Our findings fit other results reporting the role of impulsive traits in SB among ADHD populations. Girls diagnosed with a combined type of ADHD (i.e. with attention deficit and hyperactivity) were at higher risk to attempt suicide and self-harm than those with an inattentive type25. Children with the hyperactive-impulsive ADHD subtype were at greater risk of attempting suicide than healthy controls, contrary to children with the inattentive subtype18.Impulsivity is a diagnostic characteristic of ADHD17. Along the same line, the study led by Stickley et al.16 in a representative sample of the general population (n = 7403) found that the odds for a lifetime suicide attempt ranged from 1.6 to 2.4 in subjects with ADHD symptoms compared to those without16. Accordingly, our results show that probable ADHD is associated with highly lethal suicide attempts (leading to admission in an intensive care unit) independently of comorbid psychiatric disorders, treatment or impulsive-aggression levels. Serious suicide attempters, if they survive, often complete suicide later in life27.Previous epidemiological studies have suggested the existence of an independent link between ADHD and the risk of SB, i.e. after adjustment for associated psychiatric disorders. A Swedish cohort including over 50 000 subjects with ADHD showed that they were more likely to attempt (OR = 3.6) and complete suicide (OR = 5.9) than matched controlset al.28, reported increased odds ratios for lifetime suicide attempts among male adolescents with comorbid ADHD and substance use disorder compared with those with substance use disorder only 28. Substance use may exacerbate ADHD symptoms leading to violent acts such as suicide attempts29, and may contribute to a poorer prognosis of ADHD30. A cross sectional self-report survey on 4 938 Turkish students showed that lifetime drug and alcohol use was associated with more ADHD symptoms31. ADHD may lead to an earlier onset and longer duration of substance use33, which in turn increase the risk for suicidal ideation and SB among adolescents34. Indeed, early initiation of substance use is associated with risk factors for suicide in high school students, including suicidal ideation and suicide attempts35. The prospective Minnesota twin family study showed that the hyperactivity/impulsivity component of ADHD, but not inattention, predicted the onset of substance use by 1836. Hence, higher impulsivity traits in patients with co-existing ADHD and substance use may facilitate the early onset of SB.The importance of comorbid substance use disorder in the severity features of SB are consistent with results of previous studies. Kelly 38 and literature shows greater incidence of suicide attempts in patients with ADHD and bipolar disorder than in patients with only bipolar disorder 39. Depression mediates also the relationship between symptom severity of ADHD and suicidal ideation and SB in adults14.Similarly, the association between ADHD status and frequent or early suicide attempts was moderated by mood disorders in our study. Indeed, comorbidity between bipolar disorder and ADHD is frequentet al.40 in pediatric patients treated with atomoxetine, but recent cohort studies and meta-analysis did not find any significant relationship between atomoxetine or methylphenidate use and the emergence of suicide attempts or suicide deaths during follow-up44. Furthermore, participants treated with psychotropic non-stimulant medication were more likely to have a past history of suicidal behaviors, with earlier and more frequent suicide attempts than those admitted without psychotropic treatment. Indeed, ADHD worsens the severity and the outcome of comorbid psychiatric diagnoses45. Individuals with ADHD show earlier onset of bipolar disorder and major depressive mood disorder compared with those without ADHD38. Additionally, patients with ADHD comorbid with bipolar disorder were more frequently depressed and had shorter periods of wellness46. Hence, patients with bipolar disorder or depression comorbid to ADHD may demonstrate poorer outcome resulting in more frequent and earlier suicidal behaviors, and may be more likely to need psychotropic treatment at the time of evaluation.Finally, current psychotropic treatment intake also mediates the relationship between ADHD status and frequent or early suicide attempts. An increased risk for suicidal ideation has been reported in the meta-analysis conducted by Bangs 47.Our findings should be interpreted in light of some methodological issues: (i) our sample is composed of patients recruited in the aftermath of a suicide attempt and treated in a post-acute care unit; ii) we did not perform a structured clinical interview to confirm the diagnosis of ADHD in patients with positive screening; (iii) we did not perform objective neuropsychological testing to assess executive functioning, memory and motivation impairments, these factors potentially mediating the relationships between ADHD, impulsive-aggression symptoms and characteristics of suicidal behaviors; iv) the retrospective assessment of ADHD symptoms in childhood with the WURS may introduce a recall bias; and iv) the independent use of ASRS leads to a high rate of false positive cases, 47.1% in our study, especially in patients with bipolar disorder or substance use disorders. However, the use of WURS scale has the advantage of evaluating ADHD symptoms before the onset of most psychiatric disorders, and we used a conservative cut-off (>46) which is adapted to psychiatric populations. The combination of both ASRS and WURS found a rate of probable ADHD diagnosis (16.7%) similar to those obtained in other clinical samples of patients with psychiatric diseases48. Importantly, results were adjusted by psychopharmacological treatments and psychiatric comorbidities, including substance use disorders.This is the first study to evaluate the association between probable ADHD and SB severity in a large and well-characterized clinical sample of suicide attempters. ADHD was evaluated through two validated specific scales, a method which has been previously applied to detect adult patients with ADHDIn summary, our results improve the characterization of SBs among ADHD patients. The association between ADHD and severity features of suicide attempts appears to be driven to a large extent by psychiatric comorbidities and impulsive-aggression levels, especially concerning early suicide attempts. Overall, our results suggest that impulsive-aggression levels predict severity of SB in ADHD and should be systematically controlled in suicidal patients with ADHD. However, ADHD symptoms persisting into adulthood may predict suicide attempts of high medical lethality independently of other clinical factors. These points deserve further research in prospective samples.Patients included in the present study were recruited as part of a multi-site study involving three French cities: Nancy, Creteil, and Montpellier. Overall, 684 consecutive French speaking adult patients admitted in post-acute care units after a suicide attempt were recruited between 2005 and 2016 and received evaluation of ADHD and impulsive-aggression symptoms during the first week of their hospitalization. Patients were included after receiving a full explanation of the nature of the study and providing their written informed consent. All experimental methods were carried out in accordance with the ethical guidelines determined by the National Ministry of Health, Labour and Welfare and the Declaration of Helsinki. This study was approved by the local ethics committee . Patients with current psychotic symptoms or lifetime diagnosis of schizophrenia were not included in the present study. All patients had a structured interview by trained psychiatrists or psychologists.Wender Utah Rating Scale (WURS), a 61-item retrospective self-report questionnaire of childhood symptoms. Twenty-five items assess the presence of ADHD symptomatology in childhood49. Each item is measured on a five-point Likert scale (0–4), and item responses are summed. The cut-off score of 46/100, which is adapted to screen ADHD in psychiatric populations50, was used51.Symptoms of ADHD were assessed with two validated self-report questionnaires. The Adult ADHD Self-Report Scale (ASRS)52, based entirely on the six items with the most stable psychometric properties of the DSM-IV-TR “A” criteria. The World Health Organization (WHO) recommended ASRS for screening of ADHD symptoms in adults and it has been used in numerous studies for the categorization of ADHD in adult patients53. According to the ASRS screener, patients with at least four out of six items rated with a pathological intensity were categorized as having current ADHD symptoms.Patients also completed the screener version of the 48.Patients with both childhood and current ADHD symptoms, according to WURS and ASRS scales respectively, were classified as having a probable adult ADHD diagnosis (hereafter probable ADHD)54 and Section O of the Diagnostic Interview for Genetics Studies (DIGS)55. A suicide attempt was defined according to the National Institute of Mental Health as a self-destructive behavior with some degree of intent to end one’s own life56. We defined four principal outcomes to characterize the severity of lifetime SB: the frequency of suicide attempts, the age at first suicide attempt, the seriousness and the violence of suicide attempts58.SB was assessed with the Columbia Suicide History Form59. A frequent suicide attempter was defined as having more than two lifetime suicide attempts.Age at first suicide attempt was defined as the age at which the patient first made a suicide attempt and categorized according to a previously established cut-off (>26 and ≤26 years)60. Suicide attempts were considered as serious if admission to intensive care unit was needed61. A family history of SB was also assessed.Suicide attempts were considered violent if one of the following methods were used: hanging, firearms, cutting requiring surgical care, throwing oneself under a train and jumping from heights. Conversely, drug overdose and superficial wrist cutting were considered to be non-violent62. At the time of inclusion, 493 (95.73%) patients were taking psychotropic drugs .All patients had a structured clinical interview to assess socio-demographic and lifestyle variables, such as age at inclusion, gender, tobacco use, marital status, and educational level. The main psychiatric diagnoses  were assessed with the Mini-International Neuropsychiatric Interview (MINI)63. In the absence of validated pathological thresholds, the BDHI total score was divided into tertiles. A cut-off of 47 (corresponding to the highest tertile of the distribution) indicates a high impulsive-aggression level.Traits of impulsive-aggression were assessed using the Buss-Durkee Hostility Inventory (BDHI), a 75 items self-report questionnaireAssociations between sociodemographic, lifestyle, comorbid psychiatric disorders, impulsive-aggression levels, and SB severity features  were analyzed using Chi-square test  and Student’s t-test (for continuous variables). Study site and variables associated with SB severity features (at p < 0.15) were included in logistic models to estimate adjusted odds ratios (OR) and their 95% confidence intervals (CI) for childhood and current ADHD symptoms, and probable ADHD. Significance level was set at p < 0.05. Statistical analyses were performed using SAS statistical software .Dataset 1


Objective: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. The genetic cause of ADHD is still unclear, but the dopaminergic, serotonergic, and noradrenergic pathways have shown a strong association. In particular, monoamine oxidase A (MAOA) plays an important role in the catabolism of these neurotransmitters, suggesting that the MAOA gene is associated with ADHD. Therefore, we evaluated the relationship between the MAOA gene polymorphisms (uVNTR and rs6323) and ADHD. Materials and methods: We collected a total of 472 Korean children (150 ADHD cases and 322 controls) using the Korean version of the Dupaul Attention Deficit Hyperactivity Disorder Rating Scales (K-ARS). Genotyping was performed by PCR and PCR-RFLP. The Behavior Assessment System for Children Second Edition (BASC-2) was used to evaluate the problem behaviors within ADHD children. Results: We observed significant associations between the rs6323 and ADHD in girls (p < 0.05) and the TT genotype was observed as a protective factor against ADHD in the recessive model . The 3.5R-G haplotype showed a significant association in ADHD boys (p = 0.043). The analysis of subtype also revealed that the 4.5R allele of uVNTR was a risk factor for the development of ADHD in the combined symptom among girls . In the BASC-2 analysis, the MAOA uVNTR polymorphism was associated with activities of daily living in ADHD boys (p = 0.017). Conclusion: These results suggest the importance of the MAOA gene polymorphisms in the development of ADHD in Korean children. A larger sample set and functional studies are required to further elucidate of our findings. DRD4 and DAT1 gene VNTR polymorphisms of the dopaminergic pathway, HTR1B gene polymorphisms (rs6296 and rs6298) of the serotonergic pathway, and NET gene polymorphisms  of the noradrenergic pathway have shown a consistent association with ADHD in the various populations [Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders with a prevalence of 8.5% among the Korean children . It is culations .MAOA) gene is located on the X chromosome (Xp11.23) [MAOA gene has been noted in a variety of neurodevelopmental disorders and behavioral studies in both animals and human subjects [MAOA gene polymorphisms  and patients with schizophrenia [MAOA gene was significantly associated with major depressive disorder (MDD) [MAOA gene uVNTR and panic disorder [MAOA gene knockout mice showed elevated levels of dopamine, serotonin, and norepinephrine, which resulted in increased aggressive behavior [The monoamine oxidase A  . Thus, tsubjects . Kim et ophrenia . The stuer (MDD) . Reif etdisorder . The MAObehavior .MAOA gene and behavior phenotypes is known to be regulated by the environmental factors including stress, alcohol dependence, physical activity, and food deprivation [MAOA, and showed higher impulsivity/aggression behaviors [In general, the relationship between the rivation ,19,20. Kehaviors . Howeverehaviors . Likewisehaviors , which mMAOA gene are associated with ADHD [MAOA gene rs6323 polymorphism was associated with behavioral problems in ADHD males in the Indian population [MAOA enzymes [MAOA gene rs6323 G allele and ADHD in the Taiwanese population [MAOA gene polymorphisms (rs6323 and uVNTR) and ADHD in a UK population [MAOA gene polymorphisms on ADHD.Many studies have reported that the upstream variable number tandem repeats (uVNTR) in the promoter and the rs6323 of ith ADHD ,24. Recepulation . These p enzymes ,27. Prev enzymes . Xu et apulation ,24,29,30pulation . Such diMAOA gene polymorphisms (uVNTR and rs6323) will contribute to the development of ADHD and behavior phenotypes in Korean children. To assess this hypothesis, we collected a total of 472 samples , and used the BASC-2 behavior scales.Therefore, we hypothesized that the We analyzed a total of 472 samples from the Children’s Health and Environmental Research (CHEER) cohort study and a previous study described in . Of thesThe Behavior Assessment System for Children Second Edition (BASC-2) is a standardized multi-dimensional rating system that is used in schools to evaluate of skills, adaptive behaviors, and problem behaviors by teacher, parents and/or the children themselves . In thisTM llb Genomic DNA Extraction kit  or the GeneAll Exgene Clinic SV mini kit . uVNTR and rs6323 were genotyped using PCR and PCR-RFLP, respectively. The primer set for the determination of the uVNTR was described by Sabol et al. (1998) [2, 10 × PCR buffer and 1.0 U NV DNA polymerase . The PCR amplification was conducted C1000 Touch thermal cycler  under the following conditions: 95 °C for 5 min, followed by 35 cycles of 94 °C for 1 min, 60 °C for 1 min, and 72 °C for 1 min, and then a final extension at 72 °C for 10 min. The PCR products of uVNTR were present for 2.5R (294 bp), 3.5R (324 bp), 4.5R (354 bp), and 5.5R (384 bp). The amplification product of rs6323 was digested with 1.0 U Fnu4H I restriction enzyme  for 8 h at 37 °C and electrophoresed in 3% agarose gel . The polymorphic Fnu4H I site was detected by restriction fragment length polymorphism that produced fragments of 141, 84, 72 bp  or 156, 141 bp .DNA was extracted from leukocytes using the G-DEX. (1998)  and the . (1998) . Genomict-test was performed to compare the variables  using the SPSS 21 Statistics software . The test of cross tabulation analyses, and odds ratio (OR) with 95% confidence intervals (CI) were calculated in a 2 × 2 table using the genotype and allele frequencies of the cases and controls in web-based statistical tools . Haplotypes and linkage disequilibrium (LD) were estimated using the SNPstats web-based tool . The Bonferroni correction was applied to adjust the α-level according to the number of markers (<0.05/2 = 0.025). It has been reported that approximately 210 subjects are needed to obtain a 95% sample power in a case-control study of ADHD in the Korean population [MAOA gene polymorphisms and ADHD.Independent (unpaired) samples pulation . In thisp = 0.130) and gender  between the ADHD children and the controls (p = 0.023) (p = 0.033)   and ADHD= 0.033) . Since mMAOA gene rs6323 polymorphism between the ADHD girls and control girls (p < 0.05) (p = 0.022). In contrast, no significant differences were observed between the MAOA uVNTR and incidence of ADHD (p > 0.05). In the subtype analysis, the G/T genotype of the rs6323 polymorphism was revealed a significant association with the development of ADHD combined symptom among girls in the over-dominant model  (p = 0.031). In addition, this trend was also observed in the analysis of genotype and dominant model (p < 0.05) (p = 0.043)  (We found significant associations in the genetic models of  < 0.05) . Especia= 0.013) . The 4.5 < 0.05) . These t < 0.05) ; the 3.5= 0.043) . Correla= 0.017) . The rs6MAOA gene polymorphisms (uVNTR and rs6323) in the development of ADHD and investigated the effects of ADHD symptoms.We evaluated the role of p < 0.05). It is known that a deviation from the Hardy-Weinberg equilibrium in the case group presents a genetic association with disease [MAOA gene rs6323 polymorphism between ADHD girls and control girls (p < 0.05)  . The frelalanine . It has activity . Xu et aactivity . Domschkactivity . In partp-value [p = 0.043)  analysis, the standardized estimate of LD was calculated as D’ and the corresponding p-value . We conf= 0.043) . It has AOA gene . PreviouAOA gene ,42. Xu eAOA gene . Accordiectively . Thus, oMAOA gene polymorphisms (uVNTR and rs6323) and ADHD girls (p < 0.05). Previously, Brookes et al. (2006) reported the association between SNPs of the MAOA gene and ADHD-combined subtype [We performed the subtype  analysis of ADHD. Inattentive (I) and Hyperactive-Impulsive (HI) subtypes were not analyzed due to the small sample size . In the  subtype . The 4.5 subtype ,45. ThisMAOA uVNTR (p < 0.05). Many studies have reported that the MAOA uVNTR polymorphism was related to various behaviors such as aggression, impulsivity and antisocial behaviors in males [MAOA uVNTR was a risk factor for antisocial behavior [MAOA uVNTR and BASC-2 scales is still unclear. Therefore, additional functional studies can help to find the underlying evidence for our results.Merrell (2008) suggested the BASC-2 scales as one of the best tools for diagnosing behavioral disorder . Among tin males ,50,51. Ibehavior . These fThere were some important limitations to this study. First, some significant results did not survive after the Bonferroni correction. However, several studies have reported that with the strict statistical threshold of the Bonferroni method, it would be possible to miss significant effects . Second,In contrast to the limitations, our study also has certain advantages. First, our subjects were matched for sex and age to adjust the effects of these variables. Second, this study used population-based samples. The total subjects were selected by a questionnaire survey from the whole population within the main 10 cities in Korea through the CHEER cohort study and sampling were completely random. Thus, it can be said that the samples can represent the Korean population. Third, all the sample individuals were chosen using the clinical evaluation and DSM-IV diagnosis by child psychiatrists. It strictly distinguished the ADHD children and control groups. Therefore, our ADHD children samples can be defined as “pure ADHD” without comorbidity.MAOA gene polymorphisms were shown to be associated with the development of ADHD and behavioral traits. In particular, we observed that the rs6323 TT genotype was a protective factor against ADHD in Korean children. The MAOA uVNTR polymorphism was associated with the activities of daily living on BASC-2 behavior scales. Therefore, our results imply that the MAOA gene polymorphisms may provide a significant effect on the occurrence of ADHD. However, since ADHD is influenced by various variables, further studies are needed on larger sample sizes that consider these variables in order to clarify our findings.In summary,


ADHD has been assumed to be a continuation of childhood‐onset ADHD. However, recent studies have identified individuals with ADHD in adulthood who have not had ADHD in childhood. Whether or not these individuals have a ‘typical’ neurodevelopmental profile is not clear.Adult ADHD symptomatology using the ALSPAC epidemiological cohort, by grouping individuals according to their scores on the Strengths and Difficulties Questionnaire (SDQ) hyperactivity subscale at ages 12 and 17 years. First, we tested whether some of those with apparent late‐onset ADHD symptoms had been potentially misclassified on the basis of earlier SDQ hyperactivity scores  or of subthreshold symptoms at age 12 years. Second, we investigated the possibility that those with ‘genuine’ late‐onset ADHD symptoms had a delayed manifestation of the same liability that underlies childhood‐onset symptoms, by investigating whether they had a similar profile of neurodevelopmental impairments  as those with typical childhood‐onset ADHD.We tested two explanations for the emergence of apparent late‐onset N = 56/75 (75%) of those with apparent late‐onset ADHD had had high ADHD scores at least one point in childhood, suggesting that they may have been misclassified on the basis of their score at age 12 years. The remaining 19 individuals (25%) with genuine late‐onset ADHD symptoms did not show a profile of neurodevelopmental impairment typically seen in ADHD, instead showing similar levels of autistic symptoms, language skills, executive functioning ability and IQ to those without ADHD symptoms. The only exceptions were that this group showed reading and spelling problems at age 9 years.Our work suggests that this small number of individuals with genuine late‐onset symptoms may not be most appropriately considered as having a typical neurodevelopmental disorder. Attention deficit hyperactivity disorder (ADHD) is conceptualised by the DSM‐5  study who initially screened positive on checklists for late‐onset ADHD did not actually meet criteria for a diagnosis, with the occurrence of ADHD symptoms only in the context of heavy substance misuse being the most common reason for this . For families with multiple births, we included the oldest sibling. We included individuals in our analyses when primary data on ADHD symptoms were available for at ages 12 and 17 years, .ALSPAC is a well‐established ongoing prospective longitudinal birth cohort study which started in September 1990. The enrolled core sample consisted of 14,541 mothers living in Avon, England, who had expected delivery dates between April 1, 1991, and December 31, 1992. Of these pregnancies, 13,988 children were alive at 1 year. When the oldest children were aged around 7 years, the sample was increased by ADHD symptoms were assessed at five time points during childhood and adolescence  using the parent‐rated 5‐item SDQ subscale which includes hyperactive and inattentive symptoms (score range 0–10) Goodman, . In our The following variables were examined for descriptive purposes. Family income was classified as below average or above average using a (within‐sample) median split. Scores on the SDQ emotional problems, conduct problems, prosocial behaviour and peer problems subscales were used to describe difficulties in these domains at ages 12 and 17 years. All SDQ subscales are scored out of 10; higher scores represent greater impairment except for prosocial behaviour, where lower scores represent lower levels of prosocial traits which reflects more impairment Goodman, . The selAutistic traits were measured at age 8 years using the Social Communication Disorders Checklist  the low symptoms group  and (b) the childhood‐onset persistent group  on a range of neurodevelopmental characteristics, using logistic/linear regression as appropriate. The groups were compared on established indicators of neurodevelopmental risk and symptomatology known to be associated with ADHD . Of these individuals, the number of respondents with complete data on other variables in the analysis ranged from 3,383 (for adolescent IQ) to 4,953 (for child sex). Missing data were imputed using multivariate imputation by chained equations  were categorised in the low symptoms group, n = 119 (2.4%) were in the childhood‐limited group, n = 55 (1.1%) were in the childhood‐onset persistent group and n = 87 (1.7%) were in the apparent late‐onset group.Of 4,953 individuals with SDQ hyperactivity data at ages 12 and 17 years, n = 12 (13.8%) had insufficient data prior to age 11/12 years to establish whether they belonged to the misclassification or genuine late‐onset group (n = 12). Of the n = 75 with sufficient data, n = 56 (74.7%) were categorised as potential misclassification (based on the presence of slightly raised/high symptoms on at least one childhood time point), with n = 19 (25.3%) categorised as genuine late‐onset. A flowchart demonstrating the numbers in the groups is shown in Figure Of the 87 individuals with apparent late‐onset symptoms, p = .620; genuine late‐onset vs. childhood‐onset persistent OR = 0.60 , p = .425].A total of 44.1% of the low symptoms group, 63.3% of the persistent group and 51.1% of the genuine late‐onset group were classified as below the median family income ; however, there was little evidence that it differed from the childhood‐onset persistent group [mean = 7.23: mean difference = 2.81  p = .193].There was weak evidence that the mean score for alcohol use was higher for the genuine late‐onset compared to the low symptoms group .Finally, 28.1% of the low symptoms group, 32.9% of the persistent group and 52.8% of the genuine late‐onset group reported cannabis use by age 17 years [genuine late‐onset vs. low symptoms OR = 2.87 , As shown in Table In this UK longitudinal population‐based cohort, using updated SDQ cut‐points and excluding those with high scores at one time point during childhood, we find lower rates of genuine late‐onset ADHD (0.4%) than other population‐based studies  or the profile of neurodevelopmental and social adversity often associated with ADHD. These individuals need further characterisation in the context of both epidemiological and possibly clinic‐based and treatment studies. Our work suggests that they may not be most appropriately considered as having a neurodevelopmental disorder and a crucial issue is whether treatments currently recommended for ADHD are effective in this group. Due to the transitional age of the individuals involved, this has implications for practice in both child and adolescent mental health services and adult psychiatric services.ADHD is currently conceptualised as a childhood‐onset neurodevelopmental disorder.Recent research has challenged this assumption, with several longitudinal studies finding evidence for a group of individuals with ADHD symptoms arising for the first time after childhood.Using the ALSPAC dataset, we have identified a small group of individuals with ADHD symptoms arising in late adolescence who do not have a profile of neurodevelopmental impairments typical of ADHD.Our work suggests that this group may not be most appropriately considered as having a neurodevelopmental disorder, and a crucial issue for further exploration is whether treatments currently recommended for ADHD are effective in this group.Table S1. Comparisons of the ADHD symptom groups on emotional, behavioural and social problems using complete cases.Table S2. Comparisons of the ADHD symptom groups on neurodevelopmental characteristics and educational attainment using complete cases.Table S3. Association with sample retention.Click here for additional data file.