Healthcare utilization and clinical characteristics of genetic epilepsy in electronic health records.

Understanding the clinical characteristics and medical treatment of individuals affected by genetic epilepsies is instrumental in guiding selection for genetic testing, defining the phenotype range of these rare disorders, optimizing patient care pathways and pinpointing unaddressed medical need by quantifying healthcare resource utilization. To date, a matched longitudinal cohort study encompassing the entire spectrum of clinical characteristics and medical treatment from childhood through adolescence has not been performed. We identified individuals with genetic and non-genetic epilepsies and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records and tested for cross-sectional and temporal associations with genetic epilepsy. We implemented a two-stage design: in the discovery cohort, individuals were stratified as being 'likely genetic' or 'non-genetic' by a natural language processing algorithm, and controls did not receive genetic testing. The validation cohort consisted of cases with genetic epilepsy confirmed by manual chart review and an independent set of controls who received negative genetic testing. The discovery and validation cohorts consisted of 503 and 344 individuals with genetic epilepsy and matched controls, respectively. The median age at the first encounter was 0.1 years and 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System annotations for statistical analysis across 9659 encounters. Individuals with genetic epilepsy received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared with the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (odds ratio 1.91, 95% confidence interval: 1.66-2.20, P = 6.16 × 10-19) linked to a spectrum of underrecognized epilepsy-associated genetic disorders. This case-control study leveraged real-world data to identify novel features associated with the likelihood of a genetic aetiology and quantified the healthcare utilization of genetic epilepsies compared with matched controls. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies.

The relationship between autism spectrum and sleep-wake traits.

Autistic children and adults often have sleep disturbances, which may affect their and their family's quality of life. Yet, the relationship between sleep-wake patterns and autism spectrum traits is understudied. Identifying such relationships could lead to future research elucidating common mechanistic underpinnings. Thus, we aimed to determine whether sleep-wake patterns, specifically related to sleep, physical activity, and the daily sleep-wake rhythm (i.e., circadian rhythm), are associated with autism spectrum-related traits. Accelerometer-derived sleep-wake parameters were estimated in individuals with autistic spectrum traits and their family members (N = 267). We evaluated autism spectrum traits using the Social Responsiveness Scale (SRS) to assess the presence and severity of social impairment and the Behavior Rating Inventory of Executive Function (BRIEF) to assess executive function. The linear multivariate regression analysis (using SOLAR-Eclipse) showed that in adults, increased core autism spectrum traits and executive dysfunction were associated with disruption of several sleep-wake parameters, particularly related to the daily sleep-wake rhythm, and that executive dysfunction was associated with disrupted sleep quality and level of physical activity. We highlight the interplay between daytime function and disrupted sleep-wake patterns, specifically related to the daily sleep-wake rhythm, that could guide future research into common mechanisms. LAY SUMMARY: Autistic children and adults often report sleep disturbances. To dissect the relationship between a range of autism spectrum traits and sleep-wake patterns, we assessed social interaction and executive function in participants who also wore actimetry watches on their wrists to assess their sleep-wake patterns. We found that increased impairments in social and executive function occurred with increased sleep-wake disturbances, particularly those related to the circadian rhythm, suggesting that these perturbations/disruptions in the sleep-wake cycle could be connected to autism spectrum traits.

Investigating the relationships between resilience, autism-related quantitative traits, and mental health outcomes among adults during the COVID-19 pandemic.

Resilience is a dynamic process through which people adjust to adversity and buffer anxiety and depression. The COVID-19 global pandemic has introduced a shared source of adversity for people across the world, with detrimental implications for mental health. Despite the pronounced vulnerability of autistic adults to anxiety and depression during the COVID-19 pandemic, relationships among autism-related quantitative traits, resilience, and mental health outcomes have not been examined. As such, we aimed to describe the relationships between these traits in a sample enriched in autism spectrum-related quantitative traits during the COVID-19 pandemic. We also aimed to investigate the impact of demographic and social factors on these relationships. Across three independent samples of adults, we assessed resilience factors, autism-related quantitative traits, anxiety symptoms, and depression symptoms during the COVID-19 pandemic. One sample (recruited via the Autism Spectrum Program of Excellence, n = 201) was enriched for autism traits while the other two (recruited via Amazon Mechanical Turk, n = 624 and Facebook, n = 929) drew from the general population. We found resilience factors and quantitative autism-related traits to be inversely related, regardless of the resilience measure used. Additionally, we found that resilience factors moderate the relationship between autism-related quantitative traits and depression symptoms such that resilience appears to be protective. Across the neurodiversity spectrum, resilience factors may be targets to improve mental health outcomes. This approach may be especially important during the ongoing COVID-19 pandemic and in its aftermath.

Contrasting Views of Autism Spectrum Traits in Adults, Especially in Self-Reports vs. Informant-Reports for Women High in Autism Spectrum Traits.

There is uncertainty among researchers and clinicians about how to best measure autism spectrum dimensional traits in adults. In a sample of adults with high levels of autism spectrum traits and without intellectual disability (probands, n = 103) and their family members (n = 96), we sought to compare self vs. informant reports of autism spectrum-related traits and possible effects of sex on discrepancies. Using correlational analysis, we found poor agreement between self- and informant-report measures for probands, yet moderate agreement for family members. We found reporting discrepancy was greatest for female probands, often self-reporting more autism-related behaviors. Our findings suggest that autism spectrum traits are often underrecognized by informants, making self-report data important to collect in clinical and research settings.

Heritability of quantitative autism spectrum traits in adults: A family-based study.

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h2  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.

Implicit and Explicit Attitudes Toward Autistic Adults.

Background: Research examining attitudes toward autistic adults has relied on explicit self-report measures, which may be susceptible to socially desirable responding. Because implicit attitudes predict behavioral rejection, understanding both implicit and explicit attitudes toward autistic adults is important. Furthermore, previous research has almost exclusively examined attitudes toward autistic children and has not investigated attitudes toward autistic adults who may also experience prejudice from their peers. Methods: We created an implicit association test (IAT) to examine implicit attitudes toward autistic adults. In Study 1, we examined 94 neurotypical adults' (mean [M]age = 31.37 years) implicit attitudes and explicit attitudes toward autistic adults as well as autistic behaviors. In Study 2 (n = 137; M age = 33.43 years), we assessed the same variables using an IAT with descriptive rather than stereotypical words. Results: Participants from both studies demonstrated negative implicit attitudes but positive explicit attitudes toward autistic adults. In Study 2, analyses examining self-reported traits related to autism revealed that more autistic behaviors were associated with less implicit bias. Conclusions: These findings may help explain why autistic adults report discrimination from their peers. The results suggest that there may be benefits in modifying interventions that reduce implicit bias toward other marginalized groups for use with implicit bias against autistic adults. Lay summary: Why was this study done?: The goal of this study was to understand how neurotypical adults in the United States feel and think about autistic adults. Negative attitudes can lead to discrimination against autistic adults or to harmful interactions between autistic and neurotypical adults. Although research has previously examined the attitudes that neurotypical adults have toward autistic adults, most of this work has directly asked people about their attitudes, assessing their explicit, or conscious, attitudes. Neurotypical adults, however, may not be able or willing to admit that they have negative attitudes toward autistic adults. Therefore, it is important to evaluate implicit attitudes, which are underlying attitudes at the unconscious level of awareness.What was the purpose of this study?: This study investigated the implicit and explicit attitudes that neurotypical adults in the general U.S. population have about autistic adults. Assessing both kinds of attitudes is important because each type of attitude predicts different sorts of behaviors toward and judgments of individuals.What did the researchers do?: We conducted this study online using a crowdsourcing method of data collection (Amazon's Mechanical Turk) that gave us access to adults throughout the United States. We developed and administered a reaction-time task to examine implicit attitudes toward autistic adults. In this task, participants rapidly categorized words associated with autism and words not associated with autism as being "good" or "bad." We assessed explicit attitudes with questions about people's knowledge of autism and their liking for autistic adults. Study 1 measured 94 neurotypical adults' (average age = 31.37 years) implicit and explicit attitudes toward autistic adults; Study 2 measured 137 neurotypical adults' (average age = 33.43 years) implicit and explicit attitudes. Whereas Study 1's implicit task used words associated with stereotypes about autistic adults (e.g., extraverted, independent), Study 2 used nonstereotypical words associated with autism (e.g., autistic, spectrum).What were the results of the studies?: Participants in both studies reported positive explicit attitudes but negative implicit attitudes toward autistic adults. In one study, we also found that neurotypical adults with more autistic traits themselves had more positive implicit attitudes toward autistic adults.What do these findings add to what was already known?: Although previous research examined neurotypical adults' explicit attitudes toward autistic adults, the current study demonstrated that neurotypical adults hold negative implicit attitudes toward autistic adults. These findings may help explain why autistic adults experience discrimination from neurotypical adults. Furthermore, our findings suggest that having more autistic traits can lead to a better understanding of the behaviors associated with autism.What are the potential weaknesses in the study?: Limitations of the study were that we collected the data online rather than in person and we only included neurotypical adults as participants.How will these findings help autistic adults now or in the future?: These results shed light on underlying reasons for the potential negative judgments and discrimination that autistic adults face from neurotypical adults. These findings should encourage policy makers to design and implement training programs to reduce neurotypical adults' negative attitudes toward autistic adults.

The Role of Synaptic Cell Adhesion Molecules and Associated Scaffolding Proteins in Social Affiliative Behaviors.

Social affiliative behaviors-engagement in positive (i.e., nonaggressive) social approach and reciprocal social interactions with a conspecific-comprise a construct within the National Institute of Mental Health Research Domain Criteria Social Processes Domain. These behaviors are disrupted in multiple human neurodevelopmental and neuropsychiatric disorders, such as autism, schizophrenia, social phobia, and others. Human genetic studies have strongly implicated synaptic cell adhesion molecules (sCAMs) in several such disorders that involve marked reductions, or other dysregulations, of social affiliative behaviors. Here, we review the literature on the role of sCAMs in social affiliative behaviors. We integrate findings pertaining to synapse structure and morphology, neurotransmission, postsynaptic signaling pathways, and neural circuitry to propose a multilevel model that addresses the impact of a diverse group of sCAMs, including neurexins, neuroligins, protocadherins, immunoglobulin superfamily proteins, and leucine-rich repeat proteins, as well as their associated scaffolding proteins, including SHANKs and others, on social affiliative behaviors. This review finds that the disruption of sCAMs often manifests in changes in social affiliative behaviors, likely through alterations in synaptic maturity, pruning, and specificity, leading to excitation/inhibition imbalance in several key regions, namely the medial prefrontal cortex, basolateral amygdala, hippocampus, anterior cingulate cortex, and ventral tegmental area. Unraveling the complex network of interacting sCAMs in glutamatergic synapses will be an important strategy for elucidating the mechanisms of social affiliative behaviors and the alteration of these behaviors in many neuropsychiatric and neurodevelopmental disorders.