A conditional multi-label model to improve prediction of a rare outcome: An illustration predicting autism diagnosis.

OBJECTIVE: This study aimed to develop a novel approach using routinely collected electronic health records (EHRs) data to improve the prediction of a rare event. We illustrated this using an example of improving early prediction of an autism diagnosis, given its low prevalence, by leveraging correlations between autism and other neurodevelopmental conditions (NDCs). METHODS: To achieve this, we introduced a conditional multi-label model by merging conditional learning and multi-label methodologies. The conditional learning approach breaks a hard task into more manageable pieces in each stage, and the multi-label approach utilizes information from related neurodevelopmental conditions to learn predictive latent features. The study involved forecasting autism diagnosis by age 5.5 years, utilizing data from the first 18 months of life, and the analysis of feature importance correlations to explore the alignment within the feature space across different conditions. RESULTS: Upon analysis of health records from 18,156 children, we are able to generate a model that predicts a future autism diagnosis with moderate performance (AUROC=0.76). The proposed conditional multi-label method significantly improves predictive performance with an AUROC of 0.80 (p < 0.001). Further examination shows that both the conditional and multi-label approach alone provided marginal lift to the model performance compared to a one-stage one-label approach. We also demonstrated the generalizability and applicability of this method using simulated data with high correlation between feature vectors for different labels. CONCLUSION: Our findings underscore the effectiveness of the developed conditional multi-label model for early prediction of an autism diagnosis. The study introduces a versatile strategy applicable to prediction tasks involving limited target populations but sharing underlying features or etiology among related groups.

Neural Mechanisms of Facial Emotion Recognition in Autism: Distinct Roles for Anterior Cingulate and dlPFC.

OBJECTIVE: The present study sought to measure and internally validate neural markers of facial emotion recognition (FER) in adolescents and young adults with ASD to inform targeted intervention. METHOD: We utilized fMRI to measure patterns of brain activity among individuals with ASD (N = 21) and matched controls (CON; N = 20) 2 s prior to judgments about the identity of six distinct facial emotions (happy, sad, angry, surprised, fearful, disgust). RESULTS: Predictive modeling of fMRI data (support vector classification; SVC) identified mechanistic roles for brain regions that forecasted correct and incorrect identification of facial emotion as well as sources of errors over these decisions. BOLD signal activation in bilateral insula, anterior cingulate (ACC) and right dorsolateral prefrontal cortex (dlPFC) preceded accurate FER in both controls and ASD. Predictive modeling utilizing SVC confirmed the utility of ACC in forecasting correct decisions in controls but not ASD, and further indicated that a region within the right dlPFC was the source of a type 1 error signal in ASD (i.e. neural marker reflecting an impending correct judgment followed by an incorrect behavioral response) approximately two seconds prior to emotion judgments during fMRI. CONCLUSIONS: ACC forecasted correct decisions only among control participants. Right dlPFC was the source of a false-positive signal immediately prior to an error about the nature of a facial emotion in adolescents and young adults with ASD, potentially consistent with prior work indicating that dlPFC may play a role in attention to and regulation of emotional experience.

Autistic and alexithymic traits modulate distinct aspects of face perception.

BACKGROUND: Atypical face processing is a prominent feature of autism spectrum disorder (ASD) but is not universal and is subject to individual variability. This heterogeneity could be accounted for by reliable yet unidentified subgroups within the diverse population of individuals with ASD. Alexithymia, which is characterized by difficulties in emotion recognition and identification, serves as a potential grouping factor. Recent research demonstrates that emotion recognition impairments in ASD are predicted by its comorbidity with alexithymia. The current study assessed the relative influence of autistic versus alexithymic traits on neural indices of face and emotion perception. METHODS: Capitalizing upon the temporal sensitivity of event-related potentials (ERPs), it investigates the distinct contributions of alexithymic versus autistic traits at specific stages of emotional face processing in 27 typically developing adults (18 female). ERP components reflecting sequential stages of perceptual processing (P100, N170 and N250) were recorded in response to fear and neutral faces. RESULTS: The results indicated that autistic traits were associated with structural encoding of faces (N170), whereas alexithymic traits were associated with more complex emotion decoding (N250). CONCLUSIONS: These findings have important implications for deconstructing heterogeneity within ASD.

A computer-generated animated face stimulus set for psychophysiological research.

Human faces are fundamentally dynamic, but experimental investigations of face perception have traditionally relied on static images of faces. Although naturalistic videos of actors have been used with success in some contexts, much research in neuroscience and psychophysics demands carefully controlled stimuli. In this article, we describe a novel set of computer-generated, dynamic face stimuli. These grayscale faces are tightly controlled for low- and high-level visual properties. All faces are standardized in terms of size, luminance, location, and the size of facial features. Each face begins with a neutral pose and transitions to an expression over the course of 30 frames. Altogether, 222 stimuli were created, spanning three different categories of movement: (1) an affective movement (fearful face), (2) a neutral movement (close-lipped, puffed cheeks with open eyes), and (3) a biologically impossible movement (upward dislocation of eyes and mouth). To determine whether early brain responses sensitive to low-level visual features differed between the expressions, we measured the occipital P100 event-related potential, which is known to reflect differences in early stages of visual processing, and the N170, which reflects structural encoding of faces. We found no differences between the faces at the P100, indicating that different face categories were well matched on low-level image properties. This database provides researchers with a well-controlled set of dynamic faces, controlled for low-level image characteristics, that are applicable to a range of research questions in social perception.

Erratum to: A computer-generated animated face stimulus set for psychophysiological research.

Erratum to: Behav Res. DOI 10.3758/s13428-014-0491-x. The affiliations for four authors were erroneously printed. The correct affiliation for Adam Naples and James C. McPartland is: Yale Child Study Center, 230 South Frontage Road, New Haven 06520, CT, USA. The correct affiliation for Raphael Bernier and Anna Kresse is: University of Washington, Seattle, WA, USA.

Telehealth regulating together pilot trial: emotion regulation intervention for autistic children and adolescents.

Introduction: Autistic children and adolescents frequently experience emotion dysregulation, or difficulties with appropriately modifying their emotional reactions. Caregivers of autistic teens frequently seek psychotherapy support for navigating challenges associated with emotion dysregulation. During the COVID-19 pandemic, access to clinical services became limited, with interventions halted or transitioned into a telehealth format. Methods: This study evaluates the feasibility, acceptability, and initial efficacy of a telehealth adaptation to an existing intervention for emotion dysregulation for children and teens with autism, Regulating Together. A within-subjects trial was conducted for Child (ages 8-12) and Teen groups (ages 13-18). The trial consisted of a 5-week-control lead-in period, a 5-week-intervention, and 5-and 10-weeks-post-intervention follow-ups. Results: Twenty-eight youth with ASD + ED (n=13 Child and n=15 Teens, 71% male) participated. We observed a 93% retention rate across both groups. Improvements were found in reactivity, irritability, emotion and behavioral regulation, and flexibility immediately post-intervention and 10-weeks post-intervention in both groups. Additional improvements in dysphoria, cognitive regulation, and emotional control were observed in teens. Discussion: Our results suggest promising improvements in ED through telehealth delivery of an emotion regulation intervention in autistic children and adolescents, along with possible improvements in accessibility of this intervention.

Examining the feasibility and utility of heart rate variability on intervention outcomes targeting emotion regulation in autism: a brief report.

Autistic youth experience several behavioral and emotional characteristics that can predispose them to emotion dysregulation (ED). Current literature examining ED in autism spectrum disorder (ASD) is limited to parent- and self-reported measures, indicating a need for biological or physiological methods to better assess emotion regulation in ASD. Utilizing the autonomic nervous system, specifically heart rate variability (HRV), may be a promising method to objectively measure ED in ASD, given it is one of the body's primary means of regulating physiological arousal. Our pilot study is one of the first to examine the feasibility, utility, and construct validity of HRV along with clinical measures within an intervention targeting ED-specific symptoms in ASD. Participants included 30 autistic youth ages 8-17 years who participated in the pilot study of Regulating Together, a group-based intervention targeting emotion regulation. We demonstrate HRV is feasible, demonstrates adequate test-retest reliability, and is complimentary to clinician- and parent-reported measures. Our preliminary findings also point to certain HRV profiles being indicative of long-term outcomes after receiving treatment. HRV may be a useful, objective tool in determining differential needs of long-term follow-up care for treatment maintenance at screening or baseline stages.

Health Related Quality of Life in Autistic Youth and Their Families.

PURPOSE: The construct Quality of Life (QoL) involves a range of factors related to one's well-being. Individuals on the autism spectrum have been previously reported to have lower QoL. The purpose of the present study is to examine QoL in autistic individuals and their families and to evaluate associations between QoL and measures of functioning using the PedsQL 4.0. METHOD: Thirty-six autistic youth (ages 9-21 years) and their caregivers completed the PedsQL. Caregivers completed additional measures of their children's adaptive, social, behavioral, and emotional functioning. RESULTS: Parents and youth generally agreed on the PedsQL, with the exception of the Social Functioning domain, which youth rated higher. The parent rated PedsQL did not correlate with most areas of caregiver-rated functioning; however, there were significant negative correlations between irritability and family functioning. CONCLUSION: Limitations of this study included small sample size; broad range of intellectual functioning; lack of sample diversity; and likely recruiting bias for a drug treatment study. Despite limitations, HRQoL is an important feature that should be measured in addition to features of autism or symptoms of co-occurring symptoms.

Social Anxiety Symptoms Predict Poorer Facial Emotion Recognition in Autistic Male Adolescents and Young Adults Without Intellectual Disability.

Utilizing a novel computerized task, we aimed to examine whether social anxiety symptoms would be related to individual differences in facial emotion recognition (FER) in a sample of autistic male adolescents and young adults without intellectual disability. Results indicated that social anxiety and IQ predicted poorer FER, irrespective of specific emotion type. When probing specific effects within emotion and condition types, social anxiety impacted surprise and disgust FER during a truncated viewing condition and not full viewing condition. Collectively, results suggest that social anxiety in autism may play a larger role in FER than previously thought. Future work should consider the role of social anxiety within autism as a factor that may meaningfully relate to FER assessment and intervention.

Regulating Together: Emotion Dysregulation Group Treatment for ASD Youth and Their Caregivers.

Individuals with autism spectrum disorder (ASD) experience behavioral and emotional symptoms hypothesized to arise from emotion dysregulation (ED), difficulty modulating emotional experience, expression, and intensity in an acceptable and contextually appropriate manner. We developed Regulating Together (RT)-an intensive-outpatient, caregiver-assisted group program to meet the ASD + ED intervention critical need. A within-subjects trial was conducted (5-week-control lead-in period, 5-week-treatment, and 5-and 10-weeks-post-treatment follow-ups). Forty-four youth with ASD + ED (25 8-12, 19 13-18 yr-olds, 88% male, mean FSIQ of 96) participated. Improvements were found in reactivity, emotion regulation knowledge, and flexibility post-treatment and 10-weeks post-treatment. A reduction in inpatient hospitalization rates by 16% from the 12 months pre-RT to 12 months post-RT was observed. RT shows promise to reduce ED in ASD.

Systematic Review: Emotion Dysregulation in Syndromic Causes of Intellectual and Developmental Disabilities.

OBJECTIVE: To summarize the current state of the literature regarding emotion dysregulation (ED) in syndromic intellectual disabilities (S-IDs) in 6 of the most common forms of S-IDs-Down syndrome, fragile X syndrome (FXS), tuberous sclerosis complex, Williams syndrome, Prader-Willi syndrome, and Angelman syndrome-and to determine future research directions for identification and treatment of ED. METHOD: PubMed bibliographic database was searched from date of inception to May 2021. PRISMA 2020 guidelines were followed with the flowchart, table of included studies, list of excluded studies, and checklist provided. Filters applied included human research and English. Only original research articles were included in the final set, but review articles were used to identify secondary citations of primary studies. All articles were reviewed for appropriateness by 2 authors and summarized. Inclusion criteria were met by 145 articles (Down syndrome = 29, FXS = 55, tuberous sclerosis complex = 11, Williams syndrome = 18, Prader-Willi syndrome = 24, Angelman syndrome = 8). RESULTS: Each syndrome review was summarized separately and further subdivided into articles related to underlying neurobiology, behaviors associated with ED, assessment, and targeted intervention. FXS had the most thorough research base, followed by Down syndrome and Prader-Willi syndrome, with the other syndromes having more limited available research. Very limited research was available regarding intervention for all disorders except FXS. CONCLUSION: Core underlying characteristics of S-IDs appear to place youth at higher risk for ED, but further research is needed to better assess and treat ED in S-IDs. Future studies should have a standard assessment measure of ED, such as the Emotion Dysregulation Inventory, and explore adapting established curricula for ED from the neurotypical and autism spectrum disorder fields.

Relationship between quantitative digital behavioral features and clinical profiles in young autistic children.

Early behavioral markers for autism include differences in social attention and orienting in response to one's name when called, and differences in body movements and motor abilities. More efficient, scalable, objective, and reliable measures of these behaviors could improve early screening for autism. This study evaluated whether objective and quantitative measures of autism-related behaviors elicited from an app (SenseToKnow) administered on a smartphone or tablet and measured via computer vision analysis (CVA) are correlated with standardized caregiver-report and clinician administered measures of autism-related behaviors and cognitive, language, and motor abilities. This is an essential step in establishing the concurrent validity of a digital phenotyping approach. In a sample of 485 toddlers, 43 of whom were diagnosed with autism, we found that CVA-based gaze variables related to social attention were associated with the level of autism-related behaviors. Two language-related behaviors measured via the app, attention to people during a conversation and responding to one's name being called, were associated with children's language skills. Finally, performance during a bubble popping game was associated with fine motor skills. These findings provide initial support for the concurrent validity of the SenseToKnow app and its potential utility in identifying clinical profiles associated with autism. Future research is needed to determine whether the app can be used as an autism screening tool, can reliably stratify autism-related behaviors, and measure changes in autism-related behaviors over time.

Effects of nonsocial and circumscribed interest images on neural mechanisms of emotion regulation in autistic adults.

Introduction: Emotion dysregulation is commonly reported among autistic individuals. Prior work investigating the neurofunctional mechanisms of emotion regulation (ER) in autistic adults has illustrated alterations in dorsolateral prefrontal cortex (dlPFC) activity, as well as concurrent atypical patterns of activation in subcortical regions related to affect during cognitive reappraisal of social images. Whereas most research examining ER in autism has focused on regulation of negative emotions, the effects of regulating positive emotions has been generally understudied. This is surprising given the relevance of positive motivational states to understanding circumscribed interests (CI) in autism. Methods: Accordingly, the purpose of this study was to use fMRI with simultaneous eye-tracking and pupillometry to investigate the neural mechanisms of ER during passive viewing and cognitive reappraisal of a standardized set of nonsocial images and personalized (self-selected) CI images. Results: The autistic group demonstrated comparatively reduced modulation of posterior cingulate cortex (PCC) activation during cognitive reappraisal of CI images compared to viewing of CI, although no eye-tracking/pupillometry differences emerged between-groups. Further, the autistic group demonstrated increased PCC connectivity with left lateral occipital and right supramarginal areas when engaging in cognitive reappraisal vs. viewing CI. Discussion: In autistic adults, CI may be differentially modulated via PCC. Considering the documented role of the PCC as a core hub of the default mode network, we further postulate that ER of CI could potentially be related to self-referential cognition.

A Preliminary Psychometric Analysis of the Difficulties with Emotion Regulation Scale (DERS) Among Autistic Adolescents and Adults: Factor Structure, Reliability, and Validity.

Emotion dysregulation is common among autistic people, yet few measures have received psychometric evaluation in this population. We examined the factor structure, reliability, and validity of a commonly-used measure of emotion dysregulation, the Difficulties with Emotion Regulation Scale (DERS), in a sample of 156 autistic adolescents and adults. Data were drawn from the NIH National Database for Autism Research (NDAR) and an author's existing dataset. Results demonstrated that the factor structure generally conformed to the original 6-factor model, with modifications. Reliability analyses revealed good-to-excellent internal consistencies. Validity analyses indicated that the DERS was positively associated with measures of anxiety, depression, and alexithymia. Our findings provide preliminary evidence for the utility of the DERS in a small autistic sample, with minor modifications.

Experiences of student and trainee autism researchers during the COVID-19 pandemic.

Circumstances surrounding the COVID-19 pandemic have resulted in significant personal and professional adjustments. Students and trainees, including those in autism research, face unique challenges to accomplishing their training and career goals during this unprecedented time. In this commentary, we, as members of the International Society for Autism Research Student and Trainee Committee, describe our personal experiences, which may or may not align with those of other students and trainees. Our experiences have varied both in terms of the ease (or lack thereof) with which we adapted and the degree to which we were supported in the transition to online research and clinical practice. We faced and continue to adjust to uncertainties about future training and academic positions, for which opportunities have been in decline and have subsequently negatively impacted our mental health. Students and trainees' prospects have been particularly impacted compared to more established researchers and faculty. In addition to the challenges we have faced, however, there have also been unexpected benefits in our training during the pandemic, which we describe here. We have learned new coping strategies which, we believe, have served us well. The overarching goal of this commentary is to describe these experiences and strategies in the hope that they will benefit the autism research community moving forward. Here, we provide a set of recommendations for faculty, especially mentors, to support students and trainees as well as strategies for students and trainees to bolster their self-advocacy, both of which we see as crucial for our future careers. LAY SUMMARY: The COVID-19 pandemic has affected students and trainees, including those in autism research, in different ways. Here, we describe our personal experiences. These experiences include challenges. For example, it has been difficult to move from in-person to online work. It has also been difficult to keep up with work and training goals. Moreover, working from home has made it hard to connect with our supervisors and mentors. As a result, many of us have felt unsure about how to make the best career choices. Working in clinical services and getting to know and support our patients online has also been challenging. Overall, the pandemic has made us feel more isolated and some of us have struggled to cope with that. On the other hand, our experiences have also included benefits. For example, by working online, we have been able to join meetings all over the world. Also, the pandemic has pushed us to learn new skills. Those include technical skills but also skills for well-being. Next, we describe our experiences of returning to work. Finally, we give recommendations for trainees and supervisors on how to support each other and to build a strong community.

Recent advances in understanding the neural bases of autism spectrum disorder.

PURPOSE OF REVIEW: This article reviews current work investigating the neural bases of autism spectrum disorder (ASD) within the discipline of electrophysiological brain research. The manuscript focuses primarily on advances in understanding related to social information processing and interconnectivity among brain systems in ASD. RECENT FINDINGS: Recent research indicates anomalous function of social brain regions in ASD and highlights the specificity of processing problems to these systems. Atypical activity in this circuitry may reflect genetic susceptibility for ASD, with increased activity in compensatory areas marking the distinction between developing and not developing the disorder. Advances in understanding connectivity in ASD are highlighted by novel work providing initial evidence of atypical interconnectivity in infancy. SUMMARY: Emerging understanding of neural dysfunction in ASD indicates consistent but heterogeneous dysfunction across brain systems in ASD. Key objectives for the immediate future include the use of multimethod approaches that encompass temporal and spatial imaging; behavioral phenotyping carried out in developmental context to reveal subgroups defined uniquely by trajectories; and individual-specific profiles of behavioral performance and brain function.

Modeling temporal dynamics of face processing in youth and adults.

A hierarchical model of temporal dynamics was examined in adults (n = 34) and youth (n = 46) across the stages of face processing during the perception of static and dynamic faces. Three ERP components (P100, N170, N250) and spectral power in the mu range were extracted, corresponding to cognitive stages of face processing: low-level vision processing, structural encoding, higher-order processing, and action understanding. Youth and adults exhibited similar yet distinct patterns of hierarchical temporal dynamics such that earlier cognitive stages predicted later stages, directly and indirectly. However, latent factors indicated unique profiles related to behavioral performance for adults and youth and age as a continuous factor. The application of path analysis to electrophysiological data can yield novel insights into the cortical dynamics of social information processing.

Examination of Correlates to Health-Related Quality of Life in Individuals with Fragile X Syndrome.

Health-related quality of life (HRQoL) is a multidimensional concept involving physical, psychological, social, and cognitive aspects of life. Individuals with Fragile X syndrome (FXS) experience a life-long disorder that impacts the HRQoL of the affected individual and their family. Thus, HRQoL may be an important outcome measure following intervention. However, it is yet not known whether HRQoL concerns relate to observed impairments in FXS. In the present study, we examined the nature and degree of association between HRQoL and established measures of functioning in FXS using the Parent Report for Children version of the PedsQL 4.0 Generic Core Scales and Cognitive Functioning Scale. We observed significant relationships between HRQoL a nd measures of adaptive behavior, maladaptive behaviors, and social functioning. The present study has implications for treatment outcomes for clinical trials in FXS.

Attention Bias Modification Treatment for Adolescents With Social Anxiety Disorder.

Social anxiety disorder (SAD) tends to emerge during the early teenage years and is particularly refractory to change even when standard evidence-based CBT treatments are delivered. Efforts have been made to develop novel, mechanistic-driven interventions for this disorder. In the present study, we examined Attention Bias Modification Treatment (ABMT) for youth with SAD. Participants were 58 adolescents (mean age = 14.29 years) who met diagnostic criteria for SAD and who were randomized to ABMT or a placebo control condition, Attention Control Training (ACT). We predicted that ABMT would result in greater changes in both threat biases and social anxiety symptoms. We also explored potential moderators of change including the severity of social anxiety symptoms, the level of threat bias at pretreatment, and the degree of temperament-defined attention control. Contrary to our hypotheses, changes in attention bias were not observed in either condition, changes in social anxiety symptoms and diagnosis were small, and significant differences were not observed between the ABMT and ACT conditions. Little support for the proposed moderators was obtained. Reasons for our failure to find support for ABMT and its potential moderators are explored and recommendations for changes in the ABMT paradigm are suggested.

Sibling Relationships: Parent-Child Agreement and Contributions of Siblings With and Without ASD.

Research on the experiences of siblings of individuals with ASD and the quality of their sibling relationships has yielded mixed results. The present study examined the significance of parent- versus child-report of both positive and negative behaviors exhibited by siblings and their brothers and sisters with ASD within sibling dyads. Findings indicated that siblings were more positive in their assessment of the sibling relationship than were their parents. Siblings exhibited more positive behaviors within the sibling relationship than did their brothers and sisters with ASD, and were recipients of aggression. These findings are consistent with prior research suggesting that siblings tend to take on a caretaking role, and point to important targets for intervention.