Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

Early motor signs of attention-deficit hyperactivity disorder: a systematic review.

ADHD is a common neurodevelopmental disorder with onset of symptoms typically in early childhood. First signs of the disorder, including language delay, motor delay and temperament characteristics, may be evident as early as infancy. The present review describes published evidence about early motor signs of either children with later symptoms of ADHD or a later diagnosis of the disorder. Nine published cohort studies were included after a systematic search of related terms in PubMed and PsycInfo databases. Study eligibility criteria included: (1) report on early motor function or any motor-related signs; (2) the presence of a participants' assessment by/at 12 months of age; (3) report of a later presence of ADHD symptoms. The limited number of reports included suggests an association between mild early neurological markers and later developmental coordination disorder and motor overflow movements. Unfortunately, due to their small sample sizes and focus on group reports rather than individuals, they have limited power to find strong associations. Early motor indicators of ADHD, if present, appear to be non-specific, and therefore not yet useful in clinical screening. Spontaneous motility seems to be a promising measure for early ADHD detection, although further studies with large cohorts are recommended to determine its clinical role in children at risk for ADHD.

Psychosocial risk factors for suicidality in children and adolescents.

Suicidality in childhood and adolescence is of increasing concern. The aim of this paper was to review the published literature identifying key psychosocial risk factors for suicidality in the paediatric population. A systematic two-step search was carried out following the PRISMA statement guidelines, using the terms 'suicidality, suicide, and self-harm' combined with terms 'infant, child, adolescent' according to the US National Library of Medicine and the National Institutes of Health classification of ages. Forty-four studies were included in the qualitative synthesis. The review identified three main factors that appear to increase the risk of suicidality: psychological factors (depression, anxiety, previous suicide attempt, drug and alcohol use, and other comorbid psychiatric disorders); stressful life events (family problems and peer conflicts); and personality traits (such as neuroticism and impulsivity). The evidence highlights the complexity of suicidality and points towards an interaction of factors contributing to suicidal behaviour. More information is needed to understand the complex relationship between risk factors for suicidality. Prospective studies with adequate sample sizes are needed to investigate these multiple variables of risk concurrently and over time.

Development and psychometric properties of the "Suicidality: Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales" in adolescents.

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity-the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test-retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS-the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = - 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents.

A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms.

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.

Autism spectrum disorders and autistic traits share genetics and biology.

Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.

Autism spectrum disorders and autistic traits share genetics and biology.

This corrects the article DOI: 10.1038/mp.2017.98.

Emotional face recognition in male adolescents with autism spectrum disorder or disruptive behavior disorder: an eye-tracking study.

Autism Spectrum Disorder (ASD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD) are often associated with emotion recognition difficulties. This is the first eye-tracking study to examine emotional face recognition (i.e., gazing behavior) in a direct comparison of male adolescents with Autism Spectrum Disorder or Oppositional Defiant Disorder/Conduct Disorder, and typically developing (TD) individuals. We also investigate the role of psychopathic traits, callous-unemotional (CU) traits, and subtypes of aggressive behavior in emotional face recognition. A total of 122 male adolescents (N = 50 ASD, N = 44 ODD/CD, and N = 28 TD) aged 12-19 years (M = 15.4 years, SD= 1.9) were included in the current study for the eye-tracking experiment. Participants were presented with neutral and emotional faces using a Tobii 1750 eye-tracking monitor to record gaze behavior. Our main dependent eye-tracking variables were: (1) fixation duration to the eyes of a face and (2) time to the first fixation to the eyes. Since distributions of eye-tracking variables were not completely Gaussian, non-parametric tests were chosen to investigate gaze behavior across the diagnostic groups with Autism Spectrum Disorder, Oppositional Defiant Disorder/Conduct Disorder, and Typically Developing individuals. Furthermore, we used Spearman correlations to investigate the links with psychopathy, callous, and unemotional traits and subtypes of aggression as assessed by questionnaires. The relative total fixation duration to the eyes was decreased in both the Autism Spectrum Disorder group and the Oppositional Defiant Disorder/Conduct Disorder group for several emotional expressions. In both the Autism Spectrum Disorder and the Oppositional Defiant Disorder/Conduct Disorder group, increased time to first fixation on the eyes of fearful faces only was nominally significant. The time to first fixation on the eyes was nominally correlated with psychopathic traits and proactive aggression. The current findings do not support strong claims for differential cross-disorder eye-gazing deficits and for a role of shared underlying psychopathic traits, callous-unemotional traits, and aggression subtypes. Our data provide valuable and novel insights into gaze timing distributions when looking at the eyes of a fearful face.

Practitioner Review: Psychological treatments for children and adolescents with conduct disorder problems - a systematic review and meta-analysis.

BACKGROUND: This meta-analysis evaluates the efficacy of nonpharmacological treatments for conduct disorder (CD) problems in children and adolescents, based on child, parent and teacher report. METHODS: PubMed, PsycINFO and EMBASE were searched for peer-reviewed articles published between January 1970 and March 2015. Main inclusion criteria were nonpharmacological treatment, participants younger than 18 years, clinical CD problems/diagnosis, randomized controlled trials and inclusion of at least one CD problem-related outcome. Treatment efficacy is expressed in effect sizes (ESs) calculated for each rater (parent, teacher, self and blinded observer). RESULTS: Of 1,549 articles retrieved, 17 (published between June 2004 and January 2014) describing 19 interventions met the inclusion criteria. All studies used psychological treatments; only three studies included a blinded observer to rate CD problems. Most studies were of very poor to fair quality. ESs were significant but small for parent-reported outcomes (0.36, 95% CI = 0.27-0.47), teacher-reported outcomes (0.26, 95% CI = 0.12-0.49) and blinded observer outcomes (0.26, 95% CI = 0.06-0.47), and they were nonsignificant for self-reported outcomes (-0.01, 95% CI = -0.25 to 0.23). Comorbidity, gender, age, number of sessions, duration, intervention type, setting, medication use or dropout percentage did not influence the effect of treatment. CONCLUSIONS: Psychological treatments have a small effect in reducing parent-, teacher- and observer-rated CD problems in children and adolescents with clinical CD problems/diagnosis. There is not enough evidence to support one specific psychological treatment over another. Future studies should investigate the influence of participant characteristics (e.g. age of CD onset), use more homogeneous outcome measures and allow better evaluation of study quality. Many reports failed to provide detailed information to allow optimization of psychological treatment strategies.

Development and psychometric properties of the Suicidality: Treatment Occurring in Paediatrics (STOP) Suicidality Assessment Scale (STOP-SAS) in children and adolescents.

BACKGROUND: To create a self-reported, internet-based questionnaire for the assessment of suicide risk in children and adolescents. METHODS: As part of the EU project 'Suicidality: Treatment Occurring in Paediatrics' (STOP project), we developed web-based Patient Reported Outcome Measures (PROMs) for children and adolescents and for proxy reports by parents and clinicians in order to assess suicidality. Based on a literature review, expert panels and focus groups of patients, we developed the items of the STOP Suicidality Assessment Scale (STOP-SAS) in Spanish and English, translated it into four more languages, and optimized it for web-based presentation using the HealthTrackerTM platform. Of the total 19 questions developed for the STOP-SAS, four questions that assess low-level suicidality were identified as screening questions (three of them for use with children, and all four for use with adolescents, parents and clinicians). A total of 395 adolescents, 110 children, 637 parents and 716 clinicians completed the questionnaire using the HealthTrackerTM, allowing us to evaluate the internal consistency and convergent validity of the STOP-SAS with the clinician-rated Columbia Suicide Severity Rating Scale (C-SSRS). Validity was also assessed with the receiver operating characteristic (ROC) area of the STOP-SAS with the C-SSRS. RESULTS: The STOP-SAS comprises 19 items in its adolescent, parent, and clinician versions, and 14 items in its children's version. Good internal consistency was found for adolescents (Cronbach's alpha: 0.965), children (Cronbach's alpha: 0.922), parents (Cronbach's alpha: 0.951) and clinicians (Cronbach's alpha: 0.955) versions. A strong correlation was found between the STOP-SAS and the C-SSRS for adolescents (r:0.670), parents (r:0.548), clinicians (r:0.863) and children (r:0.654). The ROC area was good for clinicians' (0.917), adolescents' (0.834) and parents' (0.756) versions but only fair (0.683) for children's version. CONCLUSIONS: The STOP-SAS is a comprehensive, web-based PROM developed on the HealthTrackerTM platform, and co-designed for use by adolescents, children, parents and clinicians. It allows the evaluation of aspects of suicidality and shows good reliability and validity.

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

BACKGROUND: Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. METHOD: Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. RESULTS: The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. CONCLUSIONS: These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

Combined stimulant and antipsychotic treatment in adolescents with attention-deficit/hyperactivity disorder: a cross-sectional observational structural MRI study.

Meta-analyses suggest normalizing effects of methylphenidate on structural fronto-striatal abnormalities in patients with attention-deficit/hyperactivity disorder (ADHD). A subgroup of patients receives atypical antipsychotics concurrent with methylphenidate. Long-term safety and efficacy of combined treatment are unknown. The current study provides an initial investigation of structural brain correlates of combined methylphenidate and antipsychotic treatment in patients with ADHD. Structural magnetic resonance imaging was obtained in 31 patients who had received combined methylphenidate and antipsychotic treatment, 31 matched patients who had received methylphenidate but not antipsychotics, and 31 healthy controls (M age 16.7 years). We analyzed between-group effects in total cortical and subcortical volume, and in seven frontal cortical and eight subcortical-limbic volumes of interest, each involved in dopaminergic neurotransmission. Patients in the combined treatment group, but not those in the methylphenidate only group, showed a reduction in total cortical volume compared to healthy controls (Cohen's d = 0.69, p < 0.004), which was apparent in most frontal volumes of interest. Further, the combined treatment group, but not the methylphenidate group, showed volume reduction in bilateral ventral diencephalon (Left Cohen's d = 0.48, p < 0.04; Right Cohen's d = 0.46, p < 0.05) and the left thalamus (Cohen's d = 0.47, p < 0.04). These findings may indicate antipsychotic treatment counteracting the normalizing effects of methylphenidate on brain structure. However, it cannot be ruled out that pre-existing clinical differences between both patient groups may have resulted in anatomical differences at the time of scanning. The absence of an untreated ADHD group hinders unequivocal interpretation and implications of our findings.

[Neural activation and connectivity during response inhibition in adolescents with ADHD]. / Neurale activatie en connectiviteit tijdens responsinhibitie bij adolescenten met ADHD.

BACKGROUND: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD, their unaffected siblings and controls. Response inhibition is a key executive function deficit of attentiondeficit/hyperactivity disorder (ADHD). AIM: To obtain new insight into the biological nature of response inhibition deficits in adolescents with ADHD. METHOD: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD (n = 185), their siblings unaffected by ADHD (n = 111) and controls (n = 126). We took fmri measurement while the subjects performed the stop-task; this allowed us to investigate neural activation and neural connectivity. RESULTS: Our results indicate that adolescents with ADHD show reduced brain activation and reduced connectivity in their response inhibition network. Our neural measurements correlated with subjects' performance on the stop-task and with the number of ADHD symptoms in the adolescents with ADHD. Unaffected siblings showed similar but less severe neural deviations but no cognitive deficits; unaffected siblings also showed unique patterns of compensatory connectivity. CONCLUSION: These results provide new insights into the biological background of response inhibition and of ADHD. Neural measurements can give us a better understanding of the familial patterns of biological alterations, even if no behavioral deficits could be detected in the unaffected siblings. These neural correlates can also help to explain part of the ADHD phenotype.

[Efficacy of frequency-neurofeedback and Cogmed JM-working memory training in children with ADHD]. / Effectiviteit van frequentieneurofeedback en Cogmed JM-werkgeheugentraining bij kinderen met ADHD.

BACKGROUND: The need for and the interest in non-pharmacological treatments for children with ADHD are increasing. The treatments include electro-encephalogram (EEG) frequency-neurofeedback and Cogmed working memory training. AIM: To investigate the efficacy of frequency-neurofeedback and Cogmed working memory training in children with ADHD. METHOD: Forty-one children with ADHD (aged 8-15 years) were assigned to frequency-neurofeedback or to placebo-neurofeedback in a randomized double-blind trial. We took measurements to find out whether frequency-neurofeedback had reduced the severity of the ADHD-symptoms, and/or had improved neurocognitive ability and global clinical functioning. Fifty-one children with ADHD (aged 5-7 years) were assigned to the active Cogmed JM-working memory training or to the placebo working memory training in a randomised double-blind trial. We took measurements to find out whether Cogmed JM-working memory training had reduced the ADHD symptoms, and/or had improved neurocognitive ability, daily performance and global clinical functioning. RESULTS: The ADHD symptoms and global clinical functioning of the children in both neurofeedback groups improved. However, frequency-neurofeedback did nor produce any significantly better treatment results than did the placebo neurofeedback. At the neurocognitive level, frequency-neurofeedback did not yield any measurements that were significantly superior to those achieved with placebo feedback. Various outcome measurements improved in both groups with memory training. However, the active working memory training was not found to have produced significantly better results than the placebo training with regards to the ADHD symptoms, neurocognitive ability and daily and global functioning. Children from the active working memory training group showed improvements in trained working memory tasks but not on untrained tasks. CONCLUSION: Neither study produced any conclusive evidence for the efficacy of the investigated treatments in children with ADHD. However, both types of treatments can be further improved. Furthermore, the controlled designs may have restricted the embedding of the treatments. Because of possible improvements in the treatments in the future and because of the design restrictions affecting the treatments in their present form, it is still too early to draw any definitive conclusions about the validity and advantages of the two treatment methods.

[Somatic screening in child and adolescent psychiatry: a descriptive pilot study]. / Somatische screening in kinder- en jeugdpsychiatrie: een descriptieve pilotstudie.

BACKGROUND: Somatic disorders occur more often in psychiatric patients than in the general population. Somatic symptoms can cause or increase psychiatric symptoms. Psychiatric symptoms and their treatment can have an effect on the physical state of the patient. A pilot study involving an adult outpatient population has demonstrated that 62% of the patients studied had new clinically relevant symptoms. So far, no other data are available relating to somatic screening in child and adolescent psychiatry. AIM: To assess whether somatic screening of children and adolescents newly referred to a department of child and adolescent psychiatry in the Netherlands gives added value to the diagnosis and treatment policy. METHOD: In a pilot study 43 newly referred patients aged between 6 and 18 were screened by means of somatic history, a physical examination and blood parameters. On this basis we could calculate the percentage of somatic symptoms and , where necessary, follow-up treatment could be applied. RESULTS: One or more clinically relevant disorders were found in almost 56% of the children and adolescents investigated. The disorders included dysmorphic anomalies, weight and height deviations, raised thyroid hormone levels, dyslipidaemia, anaemia and vitamin D and B12 deficiency. Advice about a healthy lifestyle was given to 44% of the patients. An antipsychotic medication in 25% of the patients was changed, in the case of 16% of the patients a family doctor was contacted about subsequent treatment and 19% of the patients were referred to a medical specialist. CONCLUSION: Although the results of the pilot study indicate that somatic screening does provide added value, more research is needed in order to optimise the screening procedure.

Attention deficit hyperactivity disorder (ADHD) and executive functioning in affected and unaffected adolescents and their parents: challenging the endophenotype construct.

BACKGROUND: The results of twin and sibling studies suggest that executive functioning is a prime candidate endophenotype in attention deficit hyperactivity disorder (ADHD). However, studies have not assessed the co-segregation of executive function (EF) deficits from parents to offspring directly, and it is unclear whether executive functioning is an ADHD endophenotype in adolescents, given the substantial changes in prefrontal lobe functioning, EF and ADHD symptoms during adolescence. METHOD: We recruited 259 ADHD and 98 control families with an offspring average age of 17.3 years. All participants were assessed for ADHD and EF [inhibition, verbal (VWM) and visuospatial working memory (VsWM)]. Data were analysed using generalized estimating equations (GEEs). RESULTS: Parental ADHD was associated with offspring ADHD and parental EF was associated with offspring EF but there were no cross-associations (parental ADHD was not associated with offspring EF or vice versa). Similar results were found when siblings were compared. EF deficits were only found in affected adolescents and not in their unaffected siblings or (un)affected parents. CONCLUSIONS: The core EFs proposed to be aetiologically related to ADHD, that is working memory and inhibition, seem to be aetiologically independent of ADHD in adolescence. EF deficits documented in childhood in unaffected siblings were no longer present in adolescence, suggesting that children 'grow out' of early EF deficits. This is the first study to document ADHD and EF in a large family sample with adolescent offspring. The results suggest that, after childhood, the majority of influences on ADHD are independent from those on EF. This has potential implications for current aetiological models of causality in ADHD.

[Adjustment and alteration of the quality indicators in the Basic Set (GGZ) for use in child and adolescent psychiatry]. / Aanpassing en aanvulling van kwaliteitsindicatoren uit de basisset ggz voor gebruik in de kinder- en jeugdpsychiatrie.

BACKGROUND: Transparency by means of quality indicators is regarded as a method for monitoring and improving the quality of care. In the Dutch mental health service (GGZ) a generic basic set of indicators has been developed, but it is not clear whether the set is suitable for use in child and adolescent psychiatry. AIM: To assess whether the GGZ Basic Set of performance indicators for 2007-2008 was suitable for use in a child and adolescent psychiatric setting and to detect any omissions in that set. METHOD: A heterogeneous national group of eight health professionals and five 'stakeholders' in child and adolescent mental health judged the existing Basic Set by means of a Delphi procedure consisting of two written rounds and a panel discussion. The experts assessed potential indicators with regard to necessity, validity, clarity and applicability to child and adolescent psychiatry using a scale of 0 to 9. Indicators scoring more than 7 were considered to be appropriate. RESULTS: Only two of the 54 indicators were considered appropriate. A lower cut-off point would leave 16 indicators, of which 10 related to the outcome of treatment. One of the nine proposed innovative indicators was added. CONCLUSION: Very few of the indicators in the Basic Set were considered to be suitable for use in child and adolescent psychiatry. Respondents expressed a preference for a limited number of indicators that emphasised the opinion of the patient and of parents rather than the outcomes of treatment.

Functional improvement and correlations with symptomatic improvement in adults with attention deficit hyperactivity disorder receiving long-acting methylphenidate.

BACKGROUND: Data on the relationship between core symptoms and daily functioning in adults with attention deficit hyperactivity disorder (ADHD) are limited. Daily functioning was assessed as part of an open-label extension, and associations with symptom scores were evaluated. METHOD: After a 5-week double-blind study with adults with ADHD receiving osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo, participants were eligible for a 7-week open-label extension in which all patients received OROS MPH. Data for the Conners' Adult ADHD Rating Scale - Observer: Screening Version (CAARS-O:SV) (primary endpoint) have been presented previously. Secondary endpoints included the observer self-reported short version of the CAARS (CAARS-S:S) and the Clinical Global Impressions - Severity Scale (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) respectively. In post-hoc analyses, changes in CAARS-O:SV were evaluated in subgroups. Relationships between symptom and functional outcomes were evaluated in a multivariate regression analysis. RESULTS: A total of 370 patients entered the open-label extension. Significant improvements from baseline in CAARS-O:SV were similar regardless of sex, ADHD subtype, prior treatment or psychiatric co-morbidity. Significant improvements from double-blind baseline were also seen for the CAARS-S:S, CGI-S, SDS and Q-LES-Q. Improvements in the CAARS-O:SV Hyperactivity/Impulsivity subscale were associated with improvements in SDS total and subscale scores, and in the Q-LES-Q score at open-label endpoint. Improvements in CAARS-O:SV Inattention subscale and CGI-S scores were not significantly associated with functional changes. CONCLUSIONS: Improvements in ADHD symptoms relating to hyperactivity and impulsivity in adults receiving OROS MPH are associated with improvements in daily functioning and quality of life.

A theoretical molecular network for dyslexia: integrating available genetic findings.

Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network.