Automated movement tracking of young autistic children during free play is correlated with clinical features associated with autism.

LAY ABSTRACT: Play-based observations allow researchers to observe autistic children across a wide range of ages and skills. We recorded autistic children playing with toys in the center of a room and at a corner table while a caregiver remained seated off to the side and used video tracking technology to track children's movement and location. We examined how time children spent in room regions and whether or not they approached each region during play related to their cognitive, social, communication, and adaptive skills to determine if tracking child movement and location can meaningfully demonstrate clinical variation among autistic children representing a range of ages and skills. One significant finding was that autistic children who spent more time in the toy-containing center of the room had higher cognitive and language abilities, whereas those who spent less time in the center had higher levels of autism-related behaviors. In contrast, children who spent more time in the caregiver region had lower daily living skills and those who were quicker to approach the caregiver had lower adaptive behavior and language skills. These findings support the use of movement tracking as a complementary method of measuring clinical differences among autistic children. Furthermore, over 90% of autistic children representing a range of ages and skills in this study provided analyzable play observation data, demonstrating that this method allows autistic children of all levels of support needs to participate in research and demonstrate their social, communication, and attention skills without wearing any devices.

Eye-tracking measures of social versus nonsocial attention are related to level of social engagement during naturalistic caregiver-child interactions in autistic children.

Eye-tracking (ET) measures indexing social attention have been proposed as sensitive measures related to autism, but less is known about the relationship between social and nonsocial attention and naturalistic measures of social engagement and whether sex moderates this relationship. This study investigated ET measures of social attention as predictors of social engagement during a naturalistic caregiver-child interaction (CCI). Participants included 132, 2-7-year-old autistic children (77% male) and their caregivers. Participants engaged in a CCI and an ET task in which they viewed a video of an actor making dyadic bids toward the child with toys in the background. Pearson correlations and multiple regression analyzes revealed that ET measures correlated with social engagement behaviors, including degree of attention to the caregiver and objects, joint engagement with the caregiver, and language-based joint engagement. Children who spent more time looking at toys were more likely to be unengaged during social interaction. Those who spent more time looking at the actor's mouth were more likely to engage in coordinated play with and without language. Sex moderated the relationship between time looking at toys and unengagement during play; males who spent more time looking at toys spent more time unengaged during play, whereas females who spent more time looking at toys spent less time unengaged during play. Overall, ET measures of social and nonsocial attention correlated with the level of social engagement during naturalistic play, with some sex differences. Eye-tracking measures that predict interaction patterns may provide insight into promoting social engagement between caregivers and their autistic children and can inform outcome monitoring and intervention development.

Associations between executive function and attention abilities and language and social communication skills in young autistic children.

LAY ABSTRACT: Executive functioning describes a set of cognitive processes that affect thinking and behavior. Past research has shown that autistic individuals often have delays in the acquisition of executive function abilities. Our study explored how differences in executive function and attention abilities relate to social abilities and communication/language in 180 young autistic children. Data were gathered via caregiver report (questionnaires/interviews) and an assessment of vocabulary skills. The ability to sustain attention to a dynamic video was measured via eye tracking. We found that children with higher levels of executive function skills demonstrated lower levels of social pragmatic problems, a measure of having difficulties in social contexts. Furthermore, children who were able to sustain their attention longer to the video displayed higher levels of expressive language. Our results emphasize the importance of executive function and attention skills across multiple areas of functioning in autistic children, in particular those that involve language and social communication.

Shorter average look durations to dynamic social stimuli are associated with higher levels of autism symptoms in young autistic children.

LAY ABSTRACT: Many studies of autism look at the differences in how autistic research participants look at certain types of images. These studies often focus on where research participants are looking within the image, but that does not tell us everything about how much they are paying attention. It could be useful to know more about how well autistic research participants can focus on an image with people in it, because those who can look at images of people for longer duration without stopping may be able to easily learn other skills that help them to interact with people. We measured how long autistic research participants watched the video without breaking their attention. The video sometimes had a person speaking, and at other times had toys moving and making sounds. We measured the typical amount of time autistic research participants could look at the video before they looked away. We found that research participants with more severe autism tended to look at the video for shorter amounts of time. The ability to focus without stopping may be related to social skills in autistic people.

Distance from Typical Scan Path When Viewing Complex Stimuli in Children with Autism Spectrum Disorder and its Association with Behavior.

Eye-tracking is often used to study attention in children with autism spectrum disorder (ASD). Previous research has identified multiple atypical patterns of attention in children with ASD based on areas-of-interest analysis. Fewer studies have investigated gaze path, a measure which is dependent on the dynamic content of the stimulus presented. Here, rather than looking at proportions of looking time to areas of interest, we calculated mean fixations frame-by-frame in a group of typically developing children (36 to 72 months) and determined the distance from those typical fixations for 155 children with ASD (27-95 months). Findings revealed that distance from the typical scan path among the children with ASD was associated with lower communication abilities and greater ASD symptomatology.

Gastrointestinal problems are associated with increased repetitive behaviors but not social communication difficulties in young children with autism spectrum disorders.

LAY ABSTRACT: Individuals with autism spectrum disorder are more likely than typically developing individuals to experience a range of gastrointestinal abnormalities, including chronic diarrhea, constipation, food sensitivities, and abdominal pain. These gastrointestinal symptoms have been associated with higher levels of irritability and aggressive behavior, but less is known about their relationship with core autism spectrum disorder symptoms. We investigated the relationship between autism spectrum disorder symptom severity and gastrointestinal symptoms while accounting for three associated behavioral symptom domains (Irritability, Aggressiveness, and Specific Fears), in a sample of 176 children (140 males and 36 females) ages 2-7 years old with autism spectrum disorder. A large majority (93.2%) of the sample had at least one reported gastrointestinal symptom, and most (88.1%) participants had more than one gastrointestinal symptom. Various types of gastrointestinal symptoms were reported; the most common symptoms reported were constipation, food limits, gas/bloating, and stomach pain. After accounting for each associated behavioral symptom domain, repetitive behaviors and stereotypies were significantly associated with gastrointestinal symptom severity. Increased severity of autism spectrum disorder symptoms was correlated with increased gastrointestinal symptom severity. Social and communication difficulties were not significantly associated with gastrointestinal symptom severity after accounting for associated behavioral symptoms. Our findings replicate a previously described association between irritability and aggression and gastrointestinal symptoms. Furthermore, we found that repetitive behaviors, but not social or communication symptoms, are associated with gastrointestinal symptom severity, even after accounting for associated behavioral symptoms. This suggests that gastrointestinal symptoms may exacerbate repetitive behaviors, or vice versa, independent from other associated behavioral symptoms.

A Phase II Randomized Clinical Trial of the Safety and Efficacy of Intravenous Umbilical Cord Blood Infusion for Treatment of Children with Autism Spectrum Disorder.

OBJECTIVE: To evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD). STUDY DESIGN: This prospective, randomized, placebo-controlled, double-blind study included 180 children with ASD, aged 2-7 years, who received a single intravenous autologous (n = 56) or allogeneic (n = 63) CB infusion vs placebo (n = 61) and were evaluated at 6 months postinfusion. RESULTS: CB infusion was safe and well tolerated. Analysis of the entire sample showed no evidence that CB was associated with improvements in the primary outcome, social communication (Vineland Adaptive Behavior Scales-3 [VABS-3] Socialization Domain), or the secondary outcomes, autism symptoms (Pervasive Developmental Disorder Behavior Inventory) and vocabulary (Expressive One-Word Picture Vocabulary Test). There was also no overall evidence of differential effects by type of CB infused. In a subanalysis of children without intellectual disability (ID), allogeneic, but not autologous, CB was associated with improvement in a larger percentage of children on the clinician-rated Clinical Global Impression-Improvement scale, but the OR for improvement was not significant. Children without ID treated with CB showed significant improvements in communication skills (VABS-3 Communication Domain), and exploratory measures including attention to toys and sustained attention (eye-tracking) and increased alpha and beta electroencephalographic power. CONCLUSIONS: Overall, a single infusion of CB was not associated with improved socialization skills or reduced autism symptoms. More research is warranted to determine whether CB infusion is an effective treatment for some children with ASD.

Impact of a digital Modified Checklist for Autism in Toddlers-Revised on likelihood and age of autism diagnosis and referral for developmental evaluation.

LAY ABSTRACT: This was a project in primary care for young children (1-2 years old). We tested a parent questionnaire on a tablet. This tablet questionnaire asked questions to see whether the child may have autism. We compared the paper and pencil version of the questionnaire to the tablet questionnaire. We read the medical charts for the children until they were 4 years old to see whether they ended up having autism. We found that doctors were more likely to recommend an autism evaluation when a parent used the tablet questionnaire. We think that the tablet's automatic scoring feature helped the doctors. We also think that the doctors benefited from the advice the tablet gave them.

Relative Average Look Duration and its Association with Neurophysiological Activity in Young Children with Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is characterized by early attentional differences that often precede the hallmark symptoms of social communication impairments. Development of novel measures of attentional behaviors may lead to earlier identification of children at risk for ASD. In this work, we first introduce a behavioral measure, Relative Average Look Duration (RALD), indicating attentional preference to different stimuli, such as social versus nonsocial stimuli; and then study its association with neurophysiological activity. We show that (1) ASD and typically developing (TD) children differ in both (absolute) Average Look Duration (ALD) and RALD to stimuli during an EEG experiment, with the most pronounced differences in looking at social stimuli; and (2) associations between looking behaviors and neurophysiological activity, as measured by EEG, are different for children with ASD versus TD. Even when ASD children show attentional engagement to social content, our results suggest that their underlying brain activity is different than TD children. This study therefore introduces a new measure of social/nonsocial attentional preference in ASD and demonstrates the value of incorporating attentional variables measured simultaneously with EEG into the analysis pipeline.

White Matter Tract Changes Associated with Clinical Improvement in an Open-Label Trial Assessing Autologous Umbilical Cord Blood for Treatment of Young Children with Autism.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by social communication deficits and the presence of restricted interests and repetitive behaviors. We have previously reported significant improvements in behavior, including increased social functioning, improved communication abilities, and decreased clinical symptoms in children with ASD, following treatment with a single infusion of autologous cord blood in a phase I open-label trial. In the current study, we aimed to understand whether these improvements were associated with concurrent changes in brain structural connectivity. Twenty-five 2- to 6-year-old children with ASD participated in this trial. Clinical outcome measures included the Vineland Adaptive Behavior Scales-II Socialization Subscale, Expressive One-Word Picture Vocabulary Test-4, and the Clinical Global Impression-Improvement Scale. Structural connectivity was measured at baseline and at 6 months in a subset of 19 children with 25-direction diffusion tensor imaging and deterministic tractography. Behavioral improvements were associated with increased white matter connectivity in frontal, temporal, and subcortical regions (hippocampus and basal ganglia) that have been previously shown to show anatomical, connectivity, and functional abnormalities in ASD. The current results suggest that improvements in social communication skills and a reduction in symptoms in children with ASD following treatment with autologous cord blood infusion were associated with increased structural connectivity in brain networks supporting social, communication, and language abilities. Stem Cells Translational Medicine 2019;8:138&10.

On Target Shift in Adversarial Domain Adaptation.

Discrepancy between training and testing domains is a fundamental problem in the generalization of machine learning techniques. Recently, several approaches have been proposed to learn domain invariant feature representations through adversarial deep learning. However, label shift, where the percentage of data in each class is different between domains, has received less attention. Label shift naturally arises in many contexts, especially in behavioral studies where the behaviors are freely chosen. In this work, we propose a method called Domain Adversarial nets for Target Shift (DATS) to address label shift while learning a domain invariant representation. This is accomplished by using distribution matching to estimate label proportions in a blind test set. We extend this framework to handle multiple domains by developing a scheme to upweight source domains most similar to the target domain. Empirical results show that this framework performs well under large label shift in synthetic and real experiments, demonstrating the practical importance.

Electrophysiological Biomarkers Predict Clinical Improvement in an Open-Label Trial Assessing Efficacy of Autologous Umbilical Cord Blood for Treatment of Autism.

This study was a phase I, single-center, and open-label trial of a single intravenous infusion of autologous umbilical cord blood in young children with autism spectrum disorder (ASD). Twenty-five children between the ages of 2 and 6 with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit were enrolled. Safety results and clinical outcomes measured at 6 and 12 months post-infusion have been previously published. The purpose of the present analysis was to explore whether measures of electroencephalography (EEG) theta, alpha, and beta power showed evidence of change after treatment and whether baseline EEG characteristics were predictive of clinical improvement. The primary endpoint was the parent-reported Vineland adaptive behavior scales-II socialization subscale score, collected at baseline, 6- and 12-month visits. In addition, the expressive one word picture vocabulary test 4 and the clinical global impression-improvement scale were administered. Electrophysiological recordings were taken during viewing of dynamic social and nonsocial stimuli at 6 and 12 months post-treatment. Significant changes in EEG spectral characteristics were found by 12 months post-infusion, which were characterized by increased alpha and beta power and decreased EEG theta power. Furthermore, higher baseline posterior EEG beta power was associated with a greater degree of improvement in social communication symptoms, highlighting the potential for an EEG biomarker to predict variation in outcome. Taken together, the results suggest that EEG measures may be useful endpoints for future ASD clinical trials. Stem Cells Translational Medicine 2018;7:783-791.

Validation of eye-tracking measures of social attention as a potential biomarker for autism clinical trials.

Social communication impairments are a core feature of autism spectrum disorder (ASD), and this class of symptoms is a target for treatments for the disorder. Measures of social attention, assessed via eye-gaze tracking (EGT), have been proposed as an early efficacy biomarker for clinical trials targeting social communication skills. EGT measures have been shown to differentiate children with ASD from typical children; however, there is less known about their relationships with social communication outcome measures that are typically used in ASD clinical trials. In the present study, an EGT task involving viewing a videotape of an actor making bids for a child's attention was evaluated in 25 children with ASD aged 24-72 months. Children's attention to the actor during the dyadic bid condition measured via EGT was found to be strongly associated with five well-validated caregiver-reported outcome measures that are commonly used to assess social communication in clinical trials. These results highlight the convergent validity of EGT measures of social attention in relation to caregiver-reported clinical measures. EGT holds promise as a non-invasive, quantitative, and objective biomarker that is associated with social communication abilities in children with ASD. Autism Res 2018, 11: 166-174. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Eye-gaze tracking (EGT), an automated tool that tracks eye-gaze patterns, might help measure outcomes in clinical trials investigating interventions to treat autism spectrum disorders. In this study, an EGT task was evaluated in children with ASD, who watched a video with an actor talking directly to them. Patterns of eye-gaze were associated with caregiver-reported measures of social communication that are used in clinical trials. We show EGT may be a promising objective tool measuring outcomes.

Extracting Relationships by Multi-Domain Matching.

In many biological and medical contexts, we construct a large labeled corpus by aggregating many sources to use in target prediction tasks. Unfortunately, many of the sources may be irrelevant to our target task, so ignoring the structure of the dataset is detrimental. This work proposes a novel approach, the Multiple Domain Matching Network (MDMN), to exploit this structure. MDMN embeds all data into a shared feature space while learning which domains share strong statistical relationships. These relationships are often insightful in their own right, and they allow domains to share strength without interference from irrelevant data. This methodology builds on existing distribution-matching approaches by assuming that source domains are varied and outcomes multi-factorial. Therefore, each domain should only match a relevant subset. Theoretical analysis shows that the proposed approach can have a tighter generalization bound than existing multiple-domain adaptation approaches. Empirically, we show that the proposed methodology handles higher numbers of source domains (up to 21 empirically), and provides state-of-the-art performance on image, text, and multi-channel time series classification, including clinical outcome data in an open label trial evaluating a novel treatment for Autism Spectrum Disorder.