Detecting connectivity changes in autism spectrum disorder using large-scale Granger causality

2019 ◽  
Author(s):  
Anas Z. Abidin ◽  
Adora M. DSouza ◽  
Axel Wismüller
Keyword(s):  
Autism Spectrum Disorder ◽  
Granger Causality ◽  
Large Scale ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Increased burden of deleterious variants in essential genes in autism spectrum disorder

2016 ◽  
Vol 113 (52) ◽  
pp. 15054-15059 ◽  
Author(s):  
Xiao Ji ◽  
Rachel L. Kember ◽  
Christopher D. Brown ◽  
Maja Bućan
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
De Novo ◽  
Autism Spectrum ◽  
Essential Genes ◽  
Spectrum Disorder ◽  
Model Organisms ◽  
Disease Genes ◽  
Priority List ◽  
Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

scholarly journals Reproducible functional connectivity alterations are associated with autism spectrum disorder

2018 ◽  
Author(s):  
Štefan Holiga ◽  
Joerg F. Hipp ◽  
Christopher H. Chatham ◽  
Pilar Garces ◽  
Will Spooren ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Functional Connectivity ◽  
Large Scale ◽  
Clinical Symptoms ◽  
Brain Activity ◽  
Network Connectivity ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Replication Procedure ◽  
Medication Status

AbstractDespite the high clinical burden little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here we address these questions in the most comprehensive, large-scale effort to date comprising evaluation of four large ASD cohorts. We followed a strict exploration and replication procedure to identify core rs-fMRI functional connectivity (degree centrality) alterations associated with ASD as compared to typically developing (TD) controls (ASD: N=841, TD: N=984). We then tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status and clinical symptom severity. We find reproducible patterns of ASD-associated functional hyper- and hypo-connectivity with hypo-connectivity being primarily restricted to sensory-motor regions and hyper-connectivity hubs being predominately located in prefrontal and parietal cortices. We establish shifts in between-network connectivity from outside to within the identified regions as a key driver of these abnormalities. The magnitude of these alterations is linked to core ASD symptoms related to communication and social interaction and is not affected by age, sex or medication status. The identified brain functional alterations provide a reproducible pathophysiological phenotype underlying the diagnosis of ASD reconciling previous divergent findings. The large effect sizes in standardized cohorts and the link to clinical symptoms emphasize the importance of the identified imaging alterations as potential treatment and stratification biomarkers for ASD.

scholarly journals Mind the gap: an intervention to support caregivers with a new autism spectrum disorder diagnosis is feasible and acceptable

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Suzannah Iadarola ◽  
Melanie Pellecchia ◽  
Aubyn Stahmer ◽  
Hyon Soo Lee ◽  
Lindsay Hauptman ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
Controlled Trial ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Relationship Building ◽  
Service Access ◽  
Retention Data ◽  
Poverty Level ◽  
Children With Asd

Abstract Introduction Children with autism spectrum disorder (ASD) benefit when their caregivers can effectively advocate for appropriate services. Barriers to caregiver engagement such as provider mistrust, cultural differences, stigma, and lack of knowledge can interfere with timely service access. We describe Mind the Gap (MTG), an intervention that provides education about ASD, service navigation, and other topics relevant to families whose children have a new ASD diagnosis. MTG was developed via community partnerships and is explicitly structured to reduce engagement barriers (e.g., through peer matching, meeting flexibility, culturally-informed practices). We also present on the results of a pilot of MTG, conducted in preparation for a randomized controlled trial. Methods MTG was evaluated using mixed methods that included qualitative analysis and pre/post-test without concurrent comparison group. Participants (n=9) were primary caregivers of children (ages 2-7 years) with a recent ASD diagnosis and whose annual income was at or below 185% of the federal poverty level. In order to facilitate trust and relationship building, peer coaches delivered MTG. The coaches were parents of children with ASD who we trained to deliver the intervention. MTG consisted of up to 12 meetings between coaches and caregivers over the course of 18 weeks. Coaches delivered the intervention in homes and other community locations. Coaches shared information about various “modules,” which were topics identified as important for families with a new ASD diagnosis. Coaches worked with families to answer questions, set weekly goals, assess progress, and offer guidance. For the pilot, we focused on three primary outcomes: feasibility, engagement, and satisfaction. Feasibility was measured via enrollment and retention data, as well as coach fidelity (i.e., implementation of MTG procedures). Engagement was measured via number of sessions attended and percentage completion of the selected outcome measures. For completers (n=7), satisfaction was measured via a questionnaire (completed by caregivers) and open-ended interviews (completed by caregivers and coaches). Results We enrolled 56% of referred caregivers and 100% of eligible families. Retention was high (78%). Coaches could deliver the intervention with fidelity, completing, on average, 83% of program components. Engagement also was high; caregivers attended an average of 85% of total possible sessions and completed 100% of their measures. Caregivers indicated moderately high satisfaction with MTG. Qualitative data indicated that caregivers and coaches were positive about intervention content, and the coach-caregiver relationship was important. They also had suggestions for changes. Conclusion Mind the Gap demonstrates evidence of feasibility, and data from the pilot suggest that it addresses intervention engagement barriers for a population that is under-represented in research. The results and suggestions from participants were used to inform a large-scale RCT, which is currently underway. Overall, MTG shows promise as an intervention that can be feasibly implemented with under-resourced and ethnic minority families of children with ASD Trial registration This study is registered with ClinicalTrials.gov: NCT03711799.

scholarly journals Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Katherine Cummings ◽  
Alice Watkins ◽  
Chris Jones ◽  
Renuka Dias ◽  
Alice Welham
Keyword(s):  
Systematic Review ◽  
Autism Spectrum Disorder ◽  
Developmental Delay ◽  
Large Scale ◽  
Meta Analysis ◽  
Suppressor Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Psychological Variables ◽  
Pooled Prevalence

Abstract Background Phosphatase and tensin homologue (PTEN) is a cancer suppressor gene. Constitutional mutations affecting this gene are associated with several conditions, collectively termed PTEN hamartoma tumour syndromes (PHTS). In addition to hamartomas, PTEN aberrations have been associated with a range of non-tumoural phenotypes such as macrocephaly, and research indicates possibly increased rates of developmental delay and autism spectrum disorder (ASD) for people with germline mutations affecting PTEN. Method A systematic review of literature reporting behavioural and psychological variables for people with constitutional PTEN mutations/PHTS was conducted using four databases. Following in-depth screening, 25 articles met the inclusion criteria and were used in the review. Fourteen papers reported the proportion of people with PTEN mutations/PTHS meeting criteria for or having characteristics of ASD and were thus used in a pooled prevalence meta-analysis. Results Meta-analysis using a random effects model estimated pooled prevalence of ASD characteristics at 25% (95% CI 16–33%), although this should be interpreted cautiously due to possible biases in existing literature. Intellectual disability and developmental delay (global, motor and speech and language) were also reported frequently. Emotional difficulties and impaired cognitive functioning in specific domains were noted but assessed/reported less frequently. Methods of assessment of psychological/behavioural factors varied widely (with retrospective examination of medical records common). Conclusions Existing research suggests approximately 25% of people with constitutional PTEN mutations may meet criteria for or have characteristics of ASD. Studies have also begun to establish a range of possible cognitive impairments in affected individuals, especially when ASD is also reported. However, further large-scale studies are needed to elucidate psychological/behavioural corollaries of this mutation, and how they may relate to physiological/physical characteristics.

scholarly journals Autism spectrum disorder in a community-based sample with neurodevelopmental problems in Lagos, Nigeria

2017 ◽  
Vol 7 (2) ◽  
Author(s):  
Yewande O. Oshodi ◽  
Andrew T. Olagunju ◽  
Motunrayo A. Oyelohunnu ◽  
Elizabeth A. Campbell ◽  
Charles S. Umeh ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Neurodevelopmental Disorders ◽  
Challenging Behavior ◽  
Large Scale ◽  
Information Dissemination ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Learning Disorders ◽  
Spectrum Disorder ◽  
Community Based

Autism Spectrum Disorder (ASD) is a globally prevalent neurodevelopmental disorder for which early diagnosis and intervention is the mainstay of management. In the African continent, limited data is available regarding the non-clinic based samples. Lack of information available to caregivers and inadequate skilled manpower often limit early detection and access to the few available though under resourced services in the community. Community based screening can be an important drive to create awareness and improve information dissemination regarding services available for those living with this disorder. This is a descriptive cross-sectional study utilizing data obtained from participants of a community-based autism screening exercise. The surveillance exercise was part of the annual Orange Ribbon initiative for autism awareness and screening held in 2014. Data was obtained from 85 participants involved in the Autism Surveillance screening exercise within the Lagos community. Community public service radio announcements state wide and word of mouth were used to invite and enroll eligible participants to the screening and consultation exercise. A second stage screening and a brief sociodemographic questionnaire followed by a third stage clinical interview and evaluation using the Diagnostic and Statistical Manual of Mental Disorders - 5 Edition (DSM 5) were used. Appropriate consultation and referrals to services in the community were given. Participants had a mean age of 7.53 years (SD 4.35). Twenty-nine (34.5%) met the diagnosis of ASD. Other diagnosis included attention deficit hyperactivity disorder (ADHD), language and speech disorder, intellectual disability (8.3%) and learning disorders (9.5%). Main health concerns to caregivers were poor language development in all (100%), of which 11 (40.7%) were non-verbal; gaze avoidance was seen in 14 (48.3%) and challenging behavior in 12 (42.9%). Comorbidities included seizure disorders (3.4%) and ADHD (6.9%). Persons with autism had history of ASD behavior more often when compared to the other neurodevelopmental disorders and these findings were statistically significant. Referrals were given to caregivers to engage in services within the community. As seen in this study, community understanding of ASD is poor in such locations, in which many persons with other neurodevelopmental disorders are often presented as having autism. Caregivers in the study location are distressed by many symptoms associated with autism and their comorbid conditions. Currently there is an evident role for frequent large scale community based screening and autism awareness exercises possibly using inter-sectoral collaboration as a strategy.

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