Cognitive and social adaptation in autism spectrum disorder: A prospective cohort study.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Prior research suggests that genetic susceptibility and environmental exposures, such as maternal preeclampsia (PE) during pregnancy, play key roles in ASD pathogenesis. However, the specific effects of the interaction between genetic and environmental factors on ASD phenotype severity remain unclear. This study aims to investigate how interactions between de novo variants (DNVs) and common variants in individual genomes and PE exposure affect ASD symptom severity by constructing a gene-environment model. Phenotypic data were obtained from the Simons Simplex Collection (SSC) database for idiopathic ASD patients aged 4-18. Subjects were divided based on maternal PE status: PE+ (exposed) and PE- (unexposed) groups. Those without DNVs were divided into DNV-PE+ and DNV-PE- groups, and those with DNVs into DNV+PE+ and DNV+PE- groups. Based on polygenic risk scores (PRS), subjects below the median were classified into PRSlowPE+ and PRSlowPE- groups, and those at or above the median into PRShighPE+ and PRShighPE- groups. Core ASD phenotypic assessed included adaptive and cognitive abilities, social reciprocity, language and communication skills, and repetitive behaviors. Adaptive and cognitive abilities were scored using adaptive behavior composite scores from the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), along with verbal intelligence quotient (VIQ) and nonverbal intelligence quotient (NVIQ) scores from the SSC database. Social reciprocity abilities were measured using the social domain scores from the Autism Diagnostic Interview-Revised (ADI-R SD), social affective domain scores from the Autism Diagnostic Observation Schedule (ADOS SA), and normalized scores from the Social Responsiveness Scale (SRS). Language and communication abilities were assessed through verbal communication domain (ADI-R VC), nonverbal communication domain (ADI-R NVC) scores from ADI-R, and the communication and social domain scores from ADOS (ADOS CS). Repetitive behaviors were measured using the restricted and repetitive behaviors domain scores from ADI-R (ADI-R RRB), the repetitive domain scores from ADOS (ADOS REP), and the overall scores from the Repetitive Behavior Scale-Revised (RBS-R). Linear regression models were constructed to explore the impact of PE exposure and its interaction with individual genomes (including DNVs and common variants) on core ASD phenotypes. Additionally, ASD candidate genes associated with DNVs underwent gene ontology (GO) enrichment analysis via Metascape, and temporal and spatial gene expression patterns were examined using RNA sequencing (RNA-seq) data from the BrainSpan database. A total of 2 439 ASD patients with recorded DNV information and confirmed PE exposure status were included, with 146 in the PE+ group and 2 293 in the PE- group. There was a trend toward differences between these two groups in SRS (β=2.01, P=0.08) and ADI-R NVC (β=-0.62, P=0.09). Among the 2 439 participants, there were 1 454 in the DNV-PE- group, 90 in the DNV-PE+ group, 839 in the DNV+PE- group, and 56 in the DNV+PE+ group. Analysis of the main effect of PE exposure showed significant impacts on SRS (β=3.71, P=0.01) and RBS-R (β=4.54, P=0.05). Interaction analysis between DNVs and PE exposure revealed a trend toward significance in SRS (β=-4.17, P=0.06). In the 2 236 participants with available PRS data, there were 1 033 in the PRSlowPE- group, 72 in the PRSlowPE+ group, 1 069 in the PRShighPE- group, and 62 in the PRShighPE+ group. Analysis of the main effect of PE exposure showed significant impacts on SRS (β=4.32, P<0.001) and RBS-R (β=5.87, P=0.02). The interaction between PRS and PE exposure showed significant effects on SRS (β=-4.90, P=0.03) and ADI-R NVC (β=-1.43, P=0.04), with trends in NVIQ (β=9.61, P=0.08) and RBS-R (β=-6.20, P=0.08). Additionally, DNV-enriched genes in PE-exposed patients were associated with regulatory of epithelial-to-mesenchymal transition and DNA-binding transcription factor activity. Temporal and spatial expression pattern analysis indicated that genes enriched in these regulatory processes showed higher expression levels prenatally compared to postnatally. PE exposure, an environmental factor influencing ASD, is associated with increased ASD symptom severity. The interaction of PE exposure with genetic factors is crucial in modulating ASD phenotypes. Among PE-exposed individuals, ASD patients with high genetic risk for common variants may show improvements in social reciprocity and communication skills. In contrast, while DNVs may also aid in symptom improvement, their impact is less pronounced than that of common variants. These differences suggest that under similar PE exposure conditions, ASD patients with DNVs or high-risk common variants may exhibit varying degrees of symptom changes. ASD pathology research should consider the combined influence of genetic and environmental factors.

Facteurs liés à l’évolution des compétences adaptatives chez 77 jeunes enfants avec troubles du spectre autistique (TSA)

The VinelandTM Adaptive Behavior Scale is often used in autism spectrum disorder (ASD) trials. The Adaptive Behavior Composite Score (VABS-ABC) is the standardized overall score (the average of the Socialization, Communication and Daily Living skills domains), and the standardized 2-Domain Composite Score (VABS-2DC) is a novel outcome measure (average of the Socialization and Communication domains). A within-person meaningful change threshold (MCT) has not been established for the VABS-2DC. This paper presents a quantitative and qualitative interpretation of what constitutes a meaningful change in these scores to individuals with ASD without Intellectual Disability (ID; IQ≥70) and their families, as reported by their study partners (SPs). Data were obtained from the aV1ation clinical trial in children and adolescents with ASD and associated exit interviews. The intent-to-treat (ITT) clinical trial population included 308 individuals with autism (85.4% male; average age: 12.4 years [standard deviation (SD)=2.97]); 124 in the child cohort (aged 5 to 12 years; average age: 9.4 years [SD=1.86]), and 184 in the adolescent cohort (aged 13 to 17 years; average age: 14.5 years [SD=1.39]). Study partners of 86 trial participants were included in the Exit Interview Population (EIP): participants represented were 83.7% male, average age: 12.3 years [SD=2.98]). Anchor and distribution-based methods were used to estimate within-person change to support a responder definition, to aid interpretation of the clinical trial data; qualitative data were used to contextualize the meaning of changes observed. A within-person MCT range of 4 to 8 points was proposed for both VABS-ABC and VABS-2DC, which was associated with at least a 1-point improvement on 4 different anchors. Evidence for this within-person MCT was further supported by qualitative data, which suggested any change was considered meaningful to the individual with ASD, as reported by their SP, no matter what the magnitude. A change in standardized score of 4 to 8 points constitutes a within-person MCT on both VABS-ABC and novel VABS-2DC in those with ASD and no ID. A change of this, or more, was reported by the SPs in this trial to be meaningful and highly impactful upon the individuals with ASD and their family.

Children with Autism Spectrum Disorders: Three Case Studies

Relatively little is known about education placements for children with autism spectrum disorder (ASD) in China. While disparities in ASD diagnoses and services for the population broadly are often documented, the presence and determinants of differences in the educational placement of ASD children are less studied and understood. By identifying who is likely to be in segregated settings, we can discern how to best support them and facilitate a possible transition to a less restrictive setting. This study describes four placements (regular schools, special schools, institutions, homes) and their influencing factors retrospectively in a large sample (n = 2,190) of Chinese primary school-aged children (6-12 years old). We divided ASD into severe and mild to moderate categories for analysis. Children with ASD were more likely to study in a regular school (48.60%), while 13.88% were in a special school. Children with severe ASD were placed in less regular settings than children with mild to moderate ASD. However, families with higher socioeconomic status (SES) were more likely to place their children in regular schools than lower SES families if their children experienced mild to moderate symptoms. Children with severe ASD were more likely to be placed in expensive institutions for families with higher SES than those with lower SES. SES disparities in educational placement existed and had two manifestations. It is important to characterize educational placements of students with ASD to determine the extent to which they are placed in general education settings, which are often the preferred placement.

Girls/women with autism spectrum disorder (ASD) are suggested to exhibit different symptom profiles than boys/men with ASD. Accumulating evidence suggests that intellectual disability (ID) may affect sex/gender differences in ASD. However, a systematic review and meta-analysis on this topic is missing. Two databases (MEDLINE and PsycINFO) were used to search for studies reporting sex/gender differences (girls/women versus boys/men) in social communication and interaction, restrictive and repetitive behaviour and interests (RRBIs), sensory processing, and linguistic and motor abilities in ASD. The final sample consisted of 79 studies. The meta-analysis was performed with Review Manager using a random-effects model. Participants with ASD without and with ID were analysed as separate subgroups, and the effects in these two subgroups were also compared with each other. Girls/women with ASD without ID displayed fewer RRBIs, more sensory symptoms and less problems in linguistic abilities than their boys/men counterparts. In contrast, girls/women with ASD with ID displayed more social difficulties and RRBIs, poorer linguistic abilities and more motor problems than boys/men with ASD with ID. Comparisons of groups of participants with ASD without ID versus participants with ASD with ID confirmed differences in sex/gender effects on social difficulties, sensory processing, linguistic abilities and motor abilities. Our results clearly suggest that thefemale phenotype of ASD is moderated by ID. Among individuals with ASD with ID, girls/women seem to be more severely affected than boys/men, whereas among individuals with ASD without ID, girls/women with ASD may have less symptoms than boys/men. Such phenotypic differences could be a potential cause of underrecognition of girls/women with ASD, and it is also possible that observed phenotypic differences may reflect underdiagnosing of girls/women with ASD.

Adaptive behavior (AB) is defined as the skills acquired in response to everyday life demands. AB profiles of genetic syndromes have been proposed, but the literature on them has not been conclusive, mainly due to the large number of these syndromes and marked within-profile variability. The aim of the present study was to analyze the different ABs observed in subjects with Williams-Beuren Syndrome (WBS), Down Syndrome (DS) and Autistic Spectrum Disorder (ASD) through a literature review using the PubMed and Scopus database. The results indicated that Socialization strongly affects WBS; however, this group demonstrated the greatest amount of difficulty in the domain of daily living. The DS group demonstrated better performance in Socialization and Daily Living compared to Communication. The ASD group displayed better performance in Daily Living and Communication and the worst performance in socialization. Although the reviewed studies appear to demonstrate controversial results related to how ABs occur in each group, the main skills and shortages remained similar to each corresponding diagnostic behavioral characteristic. We conclude that it is possible to build AB profiles in the analyzed diagnostic groups, and we believe that these profiles may facilitate the construction of intervention plans. Keywords: Adaptive behavior, Autistic spectrum disorder, Down syndrome, Williams-beuren syndrome, vineland scale, daily living domain, socialization domain, communication domain.

BackgroundAttention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children and is associated with several adverse life outcomes. Comorbidity with autism spectrum disorder (ASD) is highly prevalent. Pharmacological treatment for ADHD symptoms has been shown to be effective. However, the prevailing perception is that children with ADHD and concomitant ASD symptoms report poorer efficacy and more side effects. This has been supported by studies on this population, but prospective studies directly comparing children with ADHD and different levels of ASD symptoms are lacking. We aimed to assess if children with ADHD and concomitant ASD symptoms differ regarding effects and side-effects of pharmacological ADHD treatment compared to children with ADHD without ASD traits. This is to our knowledge the second study to directly compare the effect of ADHD medication between ADHD patients with different levels of ASD symptoms.MethodsIn a non-randomized, observational, prospective cohort study, 323 patients aged 6 to 17 years who were diagnosed with ADHD and starting pharmacological treatment were divided into two groups: one with high level of ASD symptoms (ASD group, N=71) and one with low level of ASD symptoms (non-ASD group, N = 252). Treatment outcome was measured as ADHD symptoms, and evaluated using the Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV). Side-effects were evaluated using the Pediatric Side Effects Checklist (P-SEC), at 3 months follow-up.ResultsFrom baseline to 3 months, there was no significant difference in neither treatment effect nor number of clinically significant adverse events experienced between the ASD group and the non-ASD group.ConclusionsOur results did not implicate that ADHD patients with concomitant ASD symptoms have decreased treatment effect of ADHD medication than patients with ADHD without concomitant ASD symptoms. Neither did the results support that ADHD patients with ASD symptoms experienced significantly more side-effects than ADHD patients without ASD symptoms. Although, we did not analyze different medications separately, this is in line with the only previous study directly comparing methylphenidate treatment in children with or without ASD.Trial registrationNCT02136147, May 12, 2014.

Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case–control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case–control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose–effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different genetic etiologies. Prospective examination of familial-risk infants informs understanding of developmental trajectories preceding ASD diagnosis, potentially improving early detection. To compare outcomes and trajectories associated with varying familial risk for ASD across the first 3 years of life. This longitudinal, prospective cohort study used data from 11 sites in the Baby Siblings Research Consortium database. Data were collected between 2003 and 2015. Infants who were younger siblings of children with ASD were followed up for 3 years. Analyses were conducted in April 2018. Of the initial 1008 infants from the database, 573 were removed owing to missing necessary data, diagnostic discrepancies, or only having 1 older sibling. Number of siblings with ASD. Outcomes included ASD symptoms, cognitive abilities, and adaptive skills. Diagnosis (ASD or no ASD) was given at 36-month outcome. The no-ASD group was classified as atypical (developmental delays and/or social-communication concerns) or typical for some analyses. Generalized linear mixed models examined developmental trajectories by ASD outcome and familial-risk group. In the 435 analyzed participants (age range at outcome, 32-43 months; 246 male [57%]), 355 (82%) were from single-incidence families (1 sibling with ASD and ≥1 sibling without ASD) and 80 (18%) were from multiplex families (≥2 siblings with ASD). There were no significant group differences in major demographics. Children from multiplex families were more likely than those from single-incidence families to be classified as having ASD (29 of 80 [36%] vs 57 of 355 [16%]; 95% CI, 9%-31%; P < .001) and less likely as typical (26 of 80 [33%] vs 201 of 355 [57%]; 95% CI, -36% to -13%; P < .001), with similar rates of atypical classifications (25 of 80 [31%] vs 97 of 355 [27%]; 95% CI, -7% to 15%; P = .49). There were no differences in ASD symptoms between multiplex and single-incidence groups after controlling for ASD outcome (95% CI, -0.02 to 0.20; P = .18). During infancy, differences in cognitive and adaptive abilities were observed based on ASD outcome in the single-incidence group only. At 36 months, the multiplex/no-ASD group had lower cognitive abilities than the single-incidence/no-ASD group (95% CI, -11.89 to -2.20; P = .02), and the multiplex group had lower adaptive abilities than individuals in the single-incidence group after controlling for ASD outcome (95% CI, -9.01 to -1.48; P = .02). Infants with a multiplex family history of ASD should be monitored early and often and referred for early intervention at the first sign of concern. Direct examination of genetic contributions to neurodevelopmental phenotypes in infants with familial risk for ASD is needed.

Interval Timing Deficits and Abnormal Cognitive Development

Background and aims The academic development of children with autism spectrum disorders is important to investigate as it can provide opportunities for higher education, independent living, and successful employment in adulthood. Although educational data find that children with autism spectrum disorders can achieve similar levels of academic achievement in inclusive settings as neurotypical children, little is known about how children with diverse language experiences with autism spectrum disorders develop academically. Research on neurotypical, bilingual children finds that although many may lag behind their monolingual peers on measures of academic achievement, these gaps can be minimized with bilingual education programs. Within clinical practice, concerns are still raised about bilingual exposure in children with autism spectrum disorders, with assumptions and recommendations made to limit the language of exposure to minimize risks to development. To improve the evidence-base on bilingual experience in children with autism spectrum disorders, the present study will examine whether basic academic skills (i.e., word reading, numerical operations, spelling) vary as a function of language experience (i.e., monolingual vs. bilingual). Methods The data presented in this study were based on medical records of children with autism spectrum disorders who visited a clinic in a large, urban city in the United States. Records were included for this study if children had information/data on language status, nonverbal cognition, and standardized scores for reading, math, and spelling on a standardized academic achievement test. The final sample included children with autism spectrum disorders with monolingual language experience ( n = 18) or bilingual language experience ( n = 13). Results Repeated measures analysis of variance analyses found that children with autism spectrum disorders with monolingual experience had higher scores on word reading skills when compared to children with autism spectrum disorders with bilingual experience. However, a different pattern was found for numerical operations, with children with autism spectrum disorders with bilingual experience outperforming children with autism spectrum disorders with monolingual experience. No differences were found between groups on spelling skills. Conclusions The preliminary findings suggest that bilingual language experience may be related to early literacy and math skills in children with autism spectrum disorders. It may be that word reading skills are slower to develop among children with autism spectrum disorders with bilingual experience due to the development of two linguistic profiles. Math skills may be enhanced in children with autism spectrum disorders with bilingual experience through the mediation of other cognitive skills (e.g., executive functioning). Implications: This preliminary study demonstrates that bilingual experience does not negatively affect the development of academic skills in children with autism spectrum disorders. Further exploration of how bilingual experience may benefit children with autism spectrum disorders is needed.

The diagnosis of autism spectrum disorder is a challenging task. Most of the current assessment scales have been developed in the West. The present study examines the applicability of one of the most used scales (the Autism Diagnostic Interview-Revised) in a Middle-Eastern culture. Two studies were undertaken. In the first, the Autism Diagnostic Interview-Revised ratings given to 420 children with autism spectrum disorder, aged 4-11 years, and 110 typically developing children were contrasted. In Study 2, the Autism Diagnostic Interview-Revised ratings of 720 children with autism spectrum disorder were compared with those of 172 children with intellectual disabilities to find out whether the Autism Diagnostic Interview-Revised scale would discriminate between these two types of developmental disabilities. The studies confirmed the acceptability of the scale to Iranian parents and assessors. However, the summary scores used to determine whether a child was likely to have autism spectrum disorder were recalculated on the two domains of social communication and repetitive behaviours, which were identified in the statistical analyses that are recommended for the evaluation of assessment scales. Thus the translated scale with the modified domain scoring proved very suitable for identifying Iranian children with autism spectrum disorder. Having a common tool such as Autism Diagnostic Interview-Revised will strengthen the opportunities to undertake cross-cultural research into the impact of autism spectrum disorder on the child and families.

Individuals with autism spectrum disorder and average IQ exhibit a widening discrepancy between lagging adaptive skills relative to their cognitive potential, but it is unknown when this discrepancy emerges in development. To address this important question, we measured adaptive and cognitive skills longitudinally, from 12-36 months, in 96 low-risk typically developing infants and 69 high-risk siblings of children with autism spectrum disorder who at 36 months were diagnosed with autism spectrum disorder (N = 21), the broader autism phenotype (N = 19), or showed no concerns (unaffected; N = 29). Results indicate that both cognitive and adaptive communication skills remained stable over time for all four groups, but toddlers with autism spectrum disorder and the broader autism phenotype failed to keep pace with unaffected and typically developing toddlers with regard to adaptive socialization skills and, to a lesser extent, daily living skills. The odds of having a discrepant developmental profile, with average cognitive skills and below average adaptive skills, was significantly greater for socialization and daily living skills in toddlers with autism spectrum disorder or the broader autism phenotype and increased over time from 12 to 36 months. The discrepancy between adaptive skills and cognition emerges early and widens over time for infants with autism spectrum disorder symptomology, supporting early assessment and intervention of adaptive socialization and daily living skills.

Autism spectrum disorder (ASD) and food allergy (FA) are global public health problems. Several studies have explored the association between ASD and FA, but the conclusions were inconsistent. The aim of this review was to evaluate the relationship between ASD and FA. The PubMed, Embase, and Web of Science databases were searched from inception to February 2, 2020. Studies investigating the association between ASD and FA were included. A random effects model was used to pool risk estimates. Subgroup analysis and sensitivity analysis were used to explore the potential sources of heterogeneity. Fifteen studies with a total of 293,130 participants were included in this review. The pooled prevalence of FA in individuals with ASD was 13% (95% confidence interval (CI): 0.10–0.17), while the pooled prevalence of FA in controls was 5% (95% CI: 0.04–0.07). The pooled odds ratio (OR) for FA in individuals with ASD was 2.45 (95% CI: 2.25–2.67). One study examined the prevalence of ASD in participants with FA. The prevalence of ASD in individuals with FA was 3.5% (95% CI: 0.029–0.042), while the prevalence of ASD in the control group was 1.6% (95% CI: 0.015–0.017). Five study examined the OR of ASD in participants with FA. The OR for ASD in individuals with FA was 1.95 (95% CI: 1.73–2.19). The results of this systematic review and meta‐analysis seem to reveal a significant association between ASD and FA.Lay SummaryThis systematic review and meta‐analysis evaluate the relationship between ASD and FA. We found that the prevalence of FA was higher in participants with ASD than in controls and participants with ASD were at risk of developing FA and the prevalence of ASD was higher in participants with FA than in controls and participants with FA were at risk of developing ASD. Additional research such as a prospective cohort study is required to better understand the relationship between ASD and FA.