Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers.

Mind the Gap: Executive Function Is Associated with the Discrepancy Between Cognitive and Adaptive Functioning in Autistic Children Without Cognitive Delay.

Adaptive functioning is central to autistic individuals' independence and well-being. However, autism spectrum disorder (ASD) is associated with poor adaptive functioning, even in the absence of cognitive delays or deficits. This study examined how age and executive function associate with adaptive functioning-particularly the gap between cognitive and adaptive functioning. We addressed our research questions separately for a school-age (N = 101 ages 7-12) cohort and a preschool (N = 48 ages 2 and 4) cohort of autistic children without cognitive delays. Both cohorts of parents reported on their children's adaptive and executive functioning skills. The difference between adaptive and cognitive skills was computed for each participant. For each cohort, we evaluated whether adaptive skills decline with age. Next, we measured, in each cohort, whether children's executive function corresponded with this gap between their adaptive and cognitive skills. Adaptive functioning did not decline relative to cognitive ability in the younger cohort, but the gap was present in the school-age cohort. Yet, reduced executive function consistently corresponded with a greater cognitive-adaptive gap in socialization domains for both preschool and school-age children. Targeting EF, specifically emotional control, during preschool years may support both adaptive functioning and social connectedness for autistic children without cognitive delays.

Autism-associated brain differences can be observed in utero using MRI.

Developmental changes that occur before birth are thought to be associated with the development of autism spectrum disorders. Identifying anatomical predictors of early brain development may contribute to our understanding of the neurobiology of autism spectrum disorders and allow for earlier and more effective identification and treatment of autism spectrum disorders. In this study, we used retrospective clinical brain magnetic resonance imaging data from fetuses who were diagnosed with autism spectrum disorders later in life (prospective autism spectrum disorders) in order to identify the earliest magnetic resonance imaging-based regional volumetric biomarkers. Our results showed that magnetic resonance imaging-based autism spectrum disorder biomarkers can be found as early as in the fetal period and suggested that the increased volume of the insular cortex may be the most promising magnetic resonance imaging-based fetal biomarker for the future emergence of autism spectrum disorders, along with some additional, potentially useful changes in regional volumes and hemispheric asymmetries.

Irritability as a Transdiagnostic Risk Factor for Functional Impairment in Autistic and Non-autistic Toddlers and Preschoolers.

Trait irritability in toddlerhood is a powerful risk factor for later internalizing and externalizing challenges in non-autistic children, but the predictive clinical utility of irritability is unknown in autism. Irritability is a trait-level emotional response (i.e., frustration) to a blocked goal and is one source of disruptive behavior. Irritability has two facets: Frustration is the degree to which emotion is elevated after a blocked goal, while soothability is the rate of recovery from peak distress. We aimed to: (1) compare and describe the two facets of irritability in non-autistic and young autistic children, and (2) assess whether children's reward sensitivity and executive function moderate the relation between irritability and clinical symptoms. Participants were 90 autistic (n=43) and non-autistic (n = 47) 2- and 4-year-olds. Autistic children did not have different levels of frustration but were more difficult to soothe compared to non-autistic children, according to parents. Further, frustration and soothability were less strongly correlated for autistic compared to non-autistic children. For all children, executive function (specifically, inhibition) moderated, or ameliorated the strength of, the relation between irritability (both soothability and frustration) and externalizing challenges. This study provides evidence for irritability as a transdiagnostic risk factor for clinically significant emotion regulation challenges. Further, the effect of trait irritability may be ameliorated by children's executive function in a transdiagnostic manner. Future work should examine the unique aspects of soothability to how irritability presents within autism, as well as evaluate and modify emotion regulation interventions for autistic toddlers and preschoolers.

Short report: Recommendations for education, clinical practice, research, and policy on promoting well-being in autistic youth and adults through a positive focus on sexuality and gender diversity.

LAY ABSTRACT: In this article, we propose recommendations on what we can do to promote that autistic people can enjoy their sexuality and gender identity, because that contributes to overall well-being.First, we briefly summarize the existing research on sexuality and gender diversity in autistic individuals.Next, we propose recommendations for how to promote sexual and gender diversity-related health and well-being. Based on what is known about sexuality, gender diversity, and relationships in autistic adolescents and adults, we convened an international group of autistic and non-autistic researchers, advocates, parents, and professionals to develop recommendations to promote sexual and gender health in autistic people.The resulting recommendations were checked through an online survey distributed to autistic people across the world. The online participants endorsed the importance of eight final recommendations related to:1. Providing education and information on sexuality, relationships, and gender diversity to autistic individuals and their families;2. Improving expertise in and accessibility to healthcare for sexuality, relationships, and gender-related questions, with specific attention to prevention of and support after sexual victimization; and3. Meaningfully including the autism community in future research that addresses well-being relating to sexuality, relationships, and gender diversity.These community-driven recommendations aim to promote sexual health and well-being in autistic individuals internationally.

The Selective Social Attention task in children with autism spectrum disorder: Results from the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) feasibility study.

The Selective Social Attention (SSA) task is a brief eye-tracking task involving experimental conditions varying along socio-communicative axes. Traditionally the SSA has been used to probe socially-specific attentional patterns in infants and toddlers who develop autism spectrum disorder (ASD). This current work extends these findings to preschool and school-age children. Children 4- to 12-years-old with ASD (N = 23) and a typically-developing comparison group (TD; N = 25) completed the SSA task as well as standardized clinical assessments. Linear mixed models examined group and condition effects on two outcome variables: percent of time spent looking at the scene relative to scene presentation time (%Valid), and percent of time looking at the face relative to time spent looking at the scene (%Face). Age and IQ were included as covariates. Outcome variables' relationships to clinical data were assessed via correlation analysis. The ASD group, compared to the TD group, looked less at the scene and focused less on the actress' face during the most socially-engaging experimental conditions. Additionally, within the ASD group, %Face negatively correlated with SRS total T-scores with a particularly strong negative correlation with the Autistic Mannerism subscale T-score. These results highlight the extensibility of the SSA to older children with ASD, including replication of between-group differences previously seen in infants and toddlers, as well as its ability to capture meaningful clinical variation within the autism spectrum across a wide developmental span inclusive of preschool and school-aged children. The properties suggest that the SSA may have broad potential as a biomarker for ASD.

Reduced Visual Evoked Potential Amplitude in Autistic Children with Co-Occurring Features of Attention-Deficit/Hyperactivity Disorder.

Provided the significant overlap in features of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), there is a critical need to identify transdiagnostic markers that could meaningfully stratify subgroups. The objective of this study was to compare the visual evoked potential (VEP) between 30 autistic children, 17 autistic children with co-occurring ADHD presentation (ASD + ADHD), and 21 neurotypical children (NTC). Electroencephalography was recorded while children passively viewed a pattern-reversal stimulus. Mean amplitude of the P1 event-related potential was extracted from a midline occipital channel and compared between groups. P1 mean amplitude was reduced in the ASD + ADHD group compared to the ASD and NTC groups, indicating a distinct pattern of brain activity in autistic children with co-occurring ADHD features.

A functional model for studying common trends across trial time in eye tracking experiments.

Eye tracking (ET) experiments commonly record the continuous trajectory of a subject's gaze on a two-dimensional screen throughout repeated presentations of stimuli (referred to as trials). Even though the continuous path of gaze is recorded during each trial, commonly derived outcomes for analysis collapse the data into simple summaries, such as looking times in regions of interest, latency to looking at stimuli, number of stimuli viewed, number of fixations or fixation length. In order to retain information in trial time, we utilize functional data analysis (FDA) for the first time in literature in the analysis of ET data. More specifically, novel functional outcomes for ET data, referred to as viewing profiles, are introduced that capture the common gazing trends across trial time which are lost in traditional data summaries. Mean and variation of the proposed functional outcomes across subjects are then modeled using functional principal components analysis. Applications to data from a visual exploration paradigm conducted by the Autism Biomarkers Consortium for Clinical Trials showcase the novel insights gained from the proposed FDA approach, including significant group differences between children diagnosed with autism and their typically developing peers in their consistency of looking at faces early on in trial time.

Evaluation of clinical assessments of social abilities for use in autism clinical trials by the autism biomarkers consortium for clinical trials.

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials.

Here's the Story: Narrative Ability and Executive Function in Autism Spectrum Disorder.

Background: Difficulties with narrative have been reported in individuals diagnosed with autism spectrum disorder (ASD), but the role of executive function on narrative ability has not been examined in ASD. In this study, we aimed to (1) examine whether narrative abilities of ASD children differed from neurotypical (NT) children who did not differ in age, sex, and IQ; and (2) investigate relations between executive function and narrative ability in ASD children. Method: Narratives were elicited from 64 ASD children and 26 NT children using a wordless picture book and coded to derive several aspects of narrative ability such as propositions, evaluative devices, and self-repairs. Executive functions (specifically, inhibition and working memory) were measured using both experimenter-administered assessment and parent-report measures. Results: Compared to NT children, ASD children produced fewer propositions but did not differ in their use of evaluative devices and self-repairs during narrative production. Greater inhibitory challenges related to more self-repairs involving repetition of story elements, whereas working memory did not relate to any of the measures of narrative ability among ASD children. Conclusions: This study revealed that narratives by verbally fluent ASD children were shorter and less complex than those by NT children but did not differ in the specific features of narratives. Furthermore, although ASD children did not make more self-repairs than NT children, difficulty with inhibition was related to more self-repairs, indicating more dysfluent narrative production in ASD children, which has implications for intervention.

Attention Allocation During Exploration of Visual Arrays in ASD: Results from the ABC-CT Feasibility Study.

Visual exploration paradigms involving object arrays have been used to examine salience of social stimuli such as faces in ASD. Recent work suggests performance on these paradigms may associate with clinical features of ASD. We evaluate metrics from a visual exploration paradigm in 4-to-11-year-old children with ASD (n = 23; 18 males) and typical development (TD; n = 23; 13 males). Presented with arrays containing faces and nonsocial stimuli, children with ASD looked less at (p = 0.002) and showed fewer fixations to (p = 0.022) faces than TD children, and spent less time looking at each object on average (p = 0.004). Attention to the screen and faces correlated positively with social and cognitive skills in the ASD group (ps < .05). This work furthers our understanding of objective measures of visual exploration in ASD and its potential for quantifying features of ASD.

The Autism Biomarkers Consortium for Clinical Trials: Initial Evaluation of a Battery of Candidate EEG Biomarkers.

OBJECTIVE: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials. METHODS: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations. RESULTS: Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170. CONCLUSIONS: In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.

Concomitant medication use in children with autism spectrum disorder: Data from the Autism Biomarkers Consortium for Clinical Trials.

LAY ABSTRACT: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

Sexual Knowledge, Experiences, and Pragmatic Language in Adults With and Without Autism: Implications for Sex Education.

Autistic adults have similar levels of desire for sexual and romantic relationships as their non-autistic peers. However, autistic adults are less likely to be in relationships and have less dating experience. We compared sexual knowledge, experiences, and pragmatic language ability in a community sample of young adults with (n = 27, mean age = 22.11) and without autism (n = 122, mean age = 19.47). Receipt of sex education and sexual knowledge did not differ between groups. However, autistic adults had significantly fewer partnered experiences and impaired pragmatic language. Within both groups, pragmatic skill predicted accurate sexual knowledge above and beyond general communication abilities. Findings suggest that sex education for autistic adults must address the social communication component of healthy romantic and sexual relationships.

Identifying Age Based Maturation in the ERP Response to Faces in Children With Autism: Implications for Developing Biomarkers for Use in Clinical Trials.

Recent proposals have suggested the potential for neural biomarkers to improve clinical trial processes in neurodevelopmental conditions; however, few efforts have identified whether chronological age-based adjustments will be necessary (as used in standardized behavioral assessments). Event-related potentials (ERPs) demonstrate early differences in the processing of faces vs. objects in the visual processing system by 4 years of age and age-based improvement (decreases in latency) through adolescence. Additionally, face processing has been proposed to be related to social skills as well as autistic social-communication traits. While previous reports suggest delayed latency in individuals with autism spectrum disorder (ASD), extensive individual and age based heterogeneity exists. In this report, we utilize a sample of 252 children with ASD and 118 children with typical development (TD), to assess the N170 and P100 ERP component latencies (N170L and P100L, respectively), to upright faces, the face specificity effect (difference between face and object processing), and the inversion effect (difference between face upright and inverted processing) in relation to age. First, linear mixed models (LMMs) were fitted with fixed effect of age at testing and random effect of participant, using all available data points to characterize general age-based development in the TD and ASD groups. Second, LMM models using only the TD group were used to calculate age-based residuals in both groups. The purpose of residualization was to assess how much variation in ASD participants could be accounted for by chronological age-related changes. Our data demonstrate that the N170L and P100L responses to upright faces appeared to follow a roughly linear relationship with age. In the ASD group, the distribution of the age-adjusted residual values suggest that ASD participants were more likely to demonstrate slower latencies than would be expected for a TD child of the same age, similar to what has been identified using unadjusted values. Lastly, using age-adjusted values for stratification, we found that children who demonstrated slowed age-adjusted N170L had lower verbal and non-verbal IQ and worse face memory. These data suggest that age must be considered in assessing the N170L and P100L response to upright faces as well, and these adjusted values may be used to stratify children within the autism spectrum.

Multilevel hybrid principal components analysis for region-referenced functional electroencephalography data.

Electroencephalography experiments produce region-referenced functional data representing brain signals in the time or the frequency domain collected across the scalp. The data typically also have a multilevel structure with high-dimensional observations collected across multiple experimental conditions or visits. Common analysis approaches reduce the data complexity by collapsing the functional and regional dimensions, where event-related potential (ERP) features or band power are targeted in a pre-specified scalp region. This practice can fail to portray more comprehensive differences in the entire ERP signal or the power spectral density (PSD) across the scalp. Building on the weak separability of the high-dimensional covariance process, the proposed multilevel hybrid principal components analysis (M-HPCA) utilizes dimension reduction tools from both vector and functional principal components analysis to decompose the total variation into between- and within-subject variance. The resulting model components are estimated in a mixed effects modeling framework via a computationally efficient minorization-maximization algorithm coupled with bootstrap. The diverse array of applications of M-HPCA is showcased with two studies of individuals with autism. While ERP responses to match vs mismatch conditions are compared in an audio odd-ball paradigm in the first study, short-term reliability of the PSD across visits is compared in the second. Finite sample properties of the proposed methodology are studied in extensive simulations.

Patterns of Intervention Utilization Among School-Aged Children with Autism Spectrum Disorder: Findings from a Multi-Site Research Consortium.

When designing and interpreting results from clinical trials evaluating treatments for children on the autism spectrum, a complicating factor is that most children receive a range of concurrent treatments. Thus, it is important to better understand the types and hours of interventions that participants typically receive as part of standard of care, as well as to understand the child, family, and geographic factors that are associated with different patterns of service utilization. In this multi-site study, we interviewed 280 caregivers of 6-to-11-year-old school-aged children on the autism spectrum about the types and amounts of interventions their children received in the prior 6 weeks. Reported interventions were coded as "evidence-based practice" or "other interventions," reflecting the level of empirical support. Results indicated that children received a variety of interventions with varying levels of empirical evidence and a wide range of hours (0 to 79.3 hours/week). Children with higher autism symptom levels, living in particular states, and who identified as non-Hispanic received more evidence-based intervention hours. Higher parental education level related to more hours of other interventions. Children who were younger, had lower cognitive ability, and with higher autism symptom levels received a greater variety of interventions overall. Thus, based on our findings, it would seem prudent when designing clinical trials to take into consideration a variety of factors including autism symptom levels, age, cognitive ability, ethnicity, parent education and geographic location. Future research should continue to investigate the ethnic, racial, and socioeconomic influences on school-aged intervention services.

Beyond group differences: Exploring the preliminary signals of target engagement of an executive function training for autistic children.

Understanding both for whom and how interventions work is a crucial next step in providing personalized care to children with autism spectrum disorder (ASD). Autistic children present with heterogeneity both within core ASD criteria and with respect to co-occurring mental health challenges, which may affect their ability to benefit from intervention. In a secondary data analysis of a randomized control trial evaluating an executive function (EF) training with 70 7- to 11-year-old autistic children, we explored: (1) whether co-occurring attention-deficit/hyperactivity disorder (ADHD) features or anxiety features at baseline moderated the extent to which children benefited from the EF training. In other words, we asked, "For whom is training effective?" We also explored: (2) the extent to which changes in a brain-based measure of target engagement predicted the clinical outcomes of the EF training. This is a step towards asking, "How is training effective?" We found that EF training improved behavioral inhibition only for children with clinically significant co-occurring ADHD features. Anxiety features, while prevalent, did not moderate EF training efficacy. Finally, for the EF training group only, there was a significant correlation between pre-to-post change in an EEG-based measure of target engagement, N2 incongruent amplitude during a flanker task, and change in repetitive behaviors, a behavioral outcome that was reported in the parent RCT to have improved with training compared to waitlist control. This study provides preliminary evidence that EF training may differentially affect subgroups of autistic children and that changes at the neural level may precede changes in behavior. LAY SUMMARY: Understanding both for whom and how interventions work will help us provide personalized care to children with autism spectrum disorder (ASD). Autistic children present with many different strengths and challenges. Co-occurring mental health challenges may affect how much autistic children benefit from intervention. We analyzed secondary data from a rigorously designed pilot intervention study, a randomized control trial (RCT), that enrolled 70 7- to 11-year-old autistic children to assess whether a set of computer-based executive function (EF) training games improved their performance. Executive functions include being able to shift between tasks, inhibit a response, and keep information in working memory. In the current study, we explored: (1) whether children's co-occurring attention-deficit/hyperactivity disorder (ADHD) features or anxiety features, measured before the EF training began, affected how much they benefited from the EF training. In other words, we asked, "For whom is training effective?" We also explored: (2) whether children's brain-based changes in EF predicted their performance in everyday life (e.g., parent report on a survey). This is a step toward asking, "How is training effective?" We found that EF training improved children's inhibition ability, but only for children with clinically significant ADHD features. While many children in our sample also had anxiety features, we found that anxiety levels did not affect how well the EF training worked. Finally, for children who received the EF training, changes in a brain-based measure of conflict monitoring (i.e., being able to noticing differences in stimuli) predicted changes in children's repetitive behaviors. This study provides early evidence that EF training may be more effective for some autistic children than others, especially those with ADHD features.

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials.

BACKGROUND: Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD). METHODS: The autism biomarkers consortium for clinical trials conducted a multisite, observational study of 6-11-year-old children with ASD (n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications. RESULTS: All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills. LIMITATIONS: No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts. CONCLUSIONS: All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA's Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials.

A preliminary randomized, controlled trial of executive function training for children with autism spectrum disorder.

LAY ABSTRACT: Executive function, which is a set of thinking skills that includes stopping unwanted responses, being flexible, and remembering information needed to solve problems, is a challenge for many children on the autism spectrum. This study tested whether executive function could be improved with a computerized executive function training program under the guidance of a coach who reinforced the use of executive function skills. Seventy children with autism spectrum disorder from age 7 to 11 years of age participated in the study. They were randomly assigned to receive training or to a waiting group. The tests most likely to determine whether the training may be effective were chosen from a larger battery before the study started and included one task measuring brain responses, two measures of executive function in the lab, and a parent questionnaire. Changes in social functioning and repetitive behaviors were also explored. All children assigned to training completed the program and families generally reported the experience was positive. Brain responses of the training group changed following training, but not within the waiting group during a similar time period. Children who received training did not exhibit behavioral changes during the two the lab-based tasks. Parent report on questionnaires indicated that neither group showed a significant change in their broad use of executive function in other settings. Yet, children who received training were reported to have fewer restricted and repetitive behaviors following training. These initial findings suggest that short executive function training activities are feasible and may improve some functioning of school-aged children on the autism spectrum.