Victoria Hallett

Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample

IMPORTANCE Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. OBJECTIVES To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. DESIGN, SETTING, AND PARTICIPANTS We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs). MAIN OUTCOMES AND MEASURES Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. RESULTS On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]). CONCLUSIONS AND RELEVANCE The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.

Measuring Anxiety as a Treatment Endpoint in Youth with Autism Spectrum Disorder

Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.

Effect of Parent Training vs Parent Education on Behavioral Problems in Children With Autism Spectrum Disorder: A Randomized Clinical Trial

IMPORTANCE Disruptive behavior is common in children with autism spectrum disorder. Behavioral interventions are used to treat disruptive behavior but have not been evaluated in large-scale randomized trials. OBJECTIVE To evaluate the efficacy of parent training for children with autism spectrum disorder and disruptive behavior. DESIGN, SETTING, AND PARTICIPANTS This 24-week randomized trial compared parent training (n = 89) to parent education (n = 91) at 6 centers (Emory University, Indiana University, Ohio State University, University of Pittsburgh, University of Rochester, Yale University). We screened 267 children; 180 children (aged 3-7 years) with autism spectrum disorder and disruptive behaviors were randomly assigned (86% white, 88% male) between September 2010 and February 2014. INTERVENTIONS Parent training (11 core, 2 optional sessions; 2 telephone boosters; 2 home visits) provided specific strategies to manage disruptive behavior. Parent education (12 core sessions, 1 home visit) provided information about autism but no behavior management strategies. MAIN OUTCOMES AND MEASURES Parents rated disruptive behavior and noncompliance on co-primary outcomes: the Aberrant Behavior Checklist-Irritability subscale (range, 0-45) and the Home Situations Questionnaire-Autism Spectrum Disorder (range, 0-9). On both measures, higher scores indicate greater severity and a 25% reduction indicates clinical improvement. A clinician blind to treatment assignment rated the Improvement scale of the Clinical Global Impression (range, 1-7), a secondary outcome, with a positive response less than 3. RESULTS At week 24, the Aberrant Behavior Checklist-Irritability subscale declined 47.7% in parent training (from 23.7 to 12.4) compared with 31.8% for parent education (23.9 to 16.3) (treatment effect, -3.9; 95% CI, -6.2 to -1.7; P < .001, standardized effect size = 0.62). The Home Situations Questionnaire-Autism Spectrum Disorder declined 55% (from 4.0 to 1.8) compared with 34.2% in parent education (3.8 to 2.5) (treatment effect, -0.7; 95% CI, -1.1 to -0.3; P < .001, standardized effect size = 0.45). Neither measure met the prespecified minimal clinically important difference. The proportions with a positive response on the Clinical Global Impression-Improvement scale were 68.5% for parent training vs 39.6% for parent education (P < .001). CONCLUSIONS AND RELEVANCE For children with autism spectrum disorder, a 24-week parent training program was superior to parent education for reducing disruptive behavior on parent-reported outcomes, although the clinical significance of the improvement is unclear. The rate of positive response judged by a blinded clinician was greater for parent training vs parent education. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01233414.

Association of Autistic-Like and Internalizing Traits During Childhood: A Longitudinal Twin Study

OBJECTIVE Children with autism spectrum disorders often experience severe anxiety and depression, yet the explanation for this association remains unclear. The authors examined the longitudinal relationship between autistic-like and internalizing traits across middle to late childhood in a population-representative twin sample. METHOD Participants were approximately 6,000 twin pairs born in England and Wales from 1994 to 1996. Parental reports of autistic-like and internalizing traits were analyzed at ages 7 and 8 (timepoint 1) and again at age 12 (timepoint 2). The direction and etiology of the associations between these traits were examined within a cross-lagged design. RESULTS Findings revealed an asymmetric bidirectional association between autistic-like and internalizing traits over time. Autistic-like traits at age 7 made a modest but significant contribution to the presence of internalizing traits at age 12. Earlier internalizing traits also influenced the development of later autistic-like traits, although this association was approximately one-half the magnitude. While both traits were moderately to highly heritable, they were largely independent with regard to their genetic influences. Stronger associations were found between the modest shared environmental influences on each trait. Of note, it was autistic-like communication difficulties, rather than social deficits, that made a significant contribution to later internalizing traits. CONCLUSIONS The association between autistic-like and internalizing traits was attributable to reciprocal processes occurring across childhood, suggesting that these traits may serve to exacerbate each other over time. Autistic-like communication difficulties had the most notable impact. This association must now be explored within samples of children with diagnosed autism spectrum disorders and internalizing disorders, since this may help to inform the best timing and targeting of clinical intervention.

Exploring the cognitive features in children with autism spectrum disorder, their co-twins, and typically developing children within a population-based sample

BACKGROUND The behavioural symptoms of autism spectrum disorder (ASD) are thought to reflect underlying cognitive deficits/differences. The findings in the literature are somewhat mixed regarding the cognitive features of ASD. This study attempted to address this issue by investigating a range of cognitive deficits and the prevalence of multiple cognitive atypicalities in a large population-based sample comprising children with ASD, their unaffected co-twins, and typically developing comparison children. METHODS Participants included families from the Twins Early Development Study (TEDS) where one or both children met diagnostic criteria for ASD. Overall, 181 adolescents with a diagnosis of ASD and 73 unaffected co-twins were included, plus an additional 160 comparison control participants. An extensive cognitive battery was administered to measure IQ, central coherence, executive function, and theory of mind ability. RESULTS Differences between groups (ASD, co-twin, control) are reported on tasks assessing theory of mind, executive function, and central coherence. The ASD group performed atypically in significantly more cognitive tasks than the unaffected co-twin and control groups. Nearly a third of the ASD group presented with multiple cognitive atypicalities. CONCLUSIONS Multiple cognitive atypicalities appear to be a characteristic, but not universal feature, of ASD. Further work is needed to investigate whether specific cognitive atypicalities, either alone or together, are related to specific behaviours characteristic of ASD.

Examination of aggression and self-injury in children with autism spectrum disorders and serious behavioral problems.

This study identified subtypes of aggression in a sample of 206 children with autism spectrum disorder (ASD) who participated in 2 risperidone trials. The narratives were derived from a parent interview about each childs 2 most pressing problems. Five subtypes of aggression emerged: hot aggression only, cold aggression only, self-injurious behavior (SIB) only, aggression and SIB, and nonaggressive. All groups showed a high rate of positive response to risperidone with no differences across subtypes. These study findings extend understanding of aggression in ASD and may be useful to guide further study on biological mechanisms and individualized treatment in ASD.

Investigating the Association Between Autistic-Like and Internalizing Traits in a Community-Based Twin Sample

OBJECTIVES Recent research has suggested that children with autistic spectrum disorders often experience comorbid symptoms of anxiety and depression. However, despite this overlap, no quantitative genetic studies have addressed the phenotypic overlap and the etiologic association between internalizing and autistic-like traits within the general population. This study aimed to investigate the phenotypic and etiologic relation between internalizing and autistic-like traits using a community-based twin sample. METHOD We investigated the co-occurrence of these traits in a population-based sample of 3,233 twin pairs aged 8 to 9 years, using both parent- and teacher-report questionnaires. Bivariate structural equation modeling techniques were used to determine the extent to which internalizing and autistic-like traits shared common genetic and environmental influences. RESULTS Our results showed that there was a modest phenotypic correlation (r = 0.26-0.29) between autistic-like and internalizing traits. The traits were both substantially heritable but were largely independent with regard to their genetic influences (r(G) = 0.12-0.19). Shared environmental influences were modest but were largely common to both traits. Similar results were found using both parent- and teacher-reported data. CONCLUSIONS Internalizing and autistic-like traits showed moderate phenotypic overlap within the general population. This association was explained in small part by shared genetic factors, but the results suggested that most genetic influences were specific to either internalizing traits or autistic traits. Given these findings, we discuss the potential mechanisms that may underlie the relation between these traits.

Phenotypic and genetic differentiation of anxiety-related behaviors in middle childhood

Background: Anxiety‐related behaviors (ARBs) are commonly observed during typical development, yet few studies have investigated their etiology in middle childhood. This study aimed to examine both the phenotypic and genetic differentiation of ARB subtypes within the general population at age 7 and 9. It constituted a follow‐up to an earlier study of ARBs in preschool children. Methods: We investigated the phenotypic structure of ARBs in a large population‐based twin sample, comprising 7,834 twin pairs at age 7 and 3,644 twin pairs at age 9. Quantitative genetic modeling techniques were then used to determine the relative influences of genetic and environmental factors upon different types of ARB and upon the covariation between them. Results: Factor analysis supported the presence of five ARB factors at both ages: negative cognitions, negative affect, fear, obsessive–compulsive behaviors, and social anxiety. Multivariate genetic analyses revealed significant genetic effects and a small but significant influence of shared environment for all ARB subtypes. There was a moderate level of genetic specificity for each subtype as well as some shared genetic effects. Shared environmental influences correlated highly across all types of ARB, whereas nonshared environmental effects were largely subtype specific. Conclusions: The current results suggest that ARBs can be differentiated both phenotypically and genetically within middle childhood, with subtypes reflecting symptom groupings of diagnosable disorders but also aspects of temperament. Although some etiological risk factors lead to a generalized vulnerability to anxiety, others may serve to differentiate between different types of ARBs. Depression and Anxiety, 2009.

Diagnosing Autism Spectrum Disorder in community settings using the development and well-being assessment: validation in a UK population-based twin sample

Background Increasing numbers of people are being referred for the assessment of autism spectrum disorder (ASD). The NICE (UK) and the American Academy of Pediatrics recommend gathering a developmental history using a tool that operationalises ICD/DSM criteria. However, the best‐established diagnostic interview instruments are time consuming, costly and rarely used outside national specialist centres. What is needed is a brief, cost‐effective measure validated in community settings. We tested the Development and Well‐Being Assessment (DAWBA) for diagnosing ASD in a sample of children/adolescents representative of those presenting in community mental health settings. Methods A general population sample of twins (TEDS) was screened and 276 adolescents were selected as at low (CAST score < 12; n = 164) or high risk for ASD (CAST score ≥ 15 and/or parent reported that ASD suspected/previously diagnosed; n = 112). Parents completed the ASD module of the DAWBA interview by telephone or online. Families were visited at home: the ADI‐R and autism diagnostic observation schedule (ADOS) were completed to allow a best‐estimate research diagnosis of ASD to be made. Results Development and Well‐Being Assessment ASD symptom scores correlated highly with ADI‐R algorithm scores (ρ = .82, p < .001). Good sensitivity (0.88) and specificity (0.85) were achieved using DAWBA computerised algorithms. Clinician review of responses to DAWBA questions minimally changed sensitivity (0.86) and specificity (0.87). Positive (0.82–0.95) and negative (0.90) predictive values were high. Eighty‐six per cent of children were correctly classified. Performance was improved by using it in conjunction with the ADOS. Conclusions The DAWBA is a brief structured interview that showed good sensitivity and specificity in this general population sample. It requires little training, is easy to administer (online or by interview) and diagnosis is aided by an algorithm. It holds promise as a tool for assisting with assessment in community settings and may help services implement the recommendations made by NICE and the American Academy of Pediatrics regarding diagnosis of young people on the autism spectrum.

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations

OBJECTIVE Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire. METHOD Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes. RESULTS More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD. CONCLUSION Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.