1. Asif M, Martiniano H, Lamurias A, Kausar S, Couto FM. DGH-GO: dissecting the genetic heterogeneity of complex diseases using gene ontology. BMC bioinformatics. 2023; 24(1): 171.

BACKGROUND: Complex diseases such as neurodevelopmental disorders (NDDs) exhibit multiple etiologies. The multi-etiological nature of complex-diseases emerges from distinct but functionally similar group of genes. Different diseases sharing genes of such groups show related clinical outcomes that further restrict our understanding of disease mechanisms, thus, limiting the applications of personalized medicine approaches to complex genetic disorders. RESULTS: Here, we present an interactive and user-friendly application, called DGH-GO. DGH-GO allows biologists to dissect the genetic heterogeneity of complex diseases by stratifying the putative disease-causing genes into clusters that may contribute to distinct disease outcome development. It can also be used to study the shared etiology of complex-diseases. DGH-GO creates a semantic similarity matrix for the input genes by using Gene Ontology (GO). The resultant matrix can be visualized in 2D plots using different dimension reduction methods (T-SNE, Principal component analysis, umap and Principal coordinate analysis). In the next step, clusters of functionally similar genes are identified from genes functional similarities assessed through GO. This is achieved by employing four different clustering methods (K-means, Hierarchical, Fuzzy and PAM). The user may change the clustering parameters and explore their effect on stratification immediately. DGH-GO was applied to genes disrupted by rare genetic variants in Autism Spectrum Disorder (ASD) patients. The analysis confirmed the multi-etiological nature of ASD by identifying four clusters of genes that were enriched for distinct biological mechanisms and clinical outcome. In the second case study, the analysis of genes shared by different NDDs showed that genes causing multiple disorders tend to aggregate in similar clusters, indicating a possible shared etiology. CONCLUSION: DGH-GO is a user-friendly application that allows biologists to study the multi-etiological nature of complex diseases by dissecting their genetic heterogeneity. In summary, functional similarities, dimension reduction and clustering methods, coupled with interactive visualization and control over analysis allows biologists to explore and analyze their datasets without requiring expert knowledge on these methods. The source code of proposed application is available at https://github.com/Muh-Asif/DGH-GO.

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2. Chin WC, Chang HL, Chao KY. Exploring Coping Strategies of Parents of Children With Autism Spectrum Disorder in Taiwan: A Qualitative Study. The journal of nursing research : JNR. 2023.

BACKGROUND: Children with autism spectrum disorder (ASD) experience impairments in their social interactions, language communication, and stereotypical patterns of behavior. Parents of children with ASD experience higher levels of stress and more depression and anxiety than parents of children with other disabilities or typically developing children. Parents of children with disabilities develop coping strategies to counteract the stresses associated with raising a child with special needs. Understanding coping strategies to help counteract the stresses associated with parenting a child with ASD may enhance well-being in parents of children with ASD, improve the quality of care provided to these children, and foster better parent-child relationships. PURPOSE: The purpose of this study was to explore the coping strategies used by parents in Taiwan parenting a child with ASD. METHODS: In this descriptive qualitative study, thematic analysis was conducted on data collected during face-to-face interviews. Fourteen parents of children with ASD were recruited using purposive sampling. Researchers employed a teamwork approach for data analysis to increase the dependability and consistency of the transcribed interviews. Team members discussed coding and identified the themes collaboratively. RESULTS: Taiwanese parents of children with ASD coped with the psychological impacts of parenting by employing problem-focused and emotion-focused strategies. Problem-focused strategies included communication, support, and management, whereas emotion-focused strategies included acceptance and adaptation. Findings showed that both coping strategies were useful in addressing specific situations and circumstances. Social and clinical support improved parents’ mental health and children’s external behaviors. CONCLUSIONS/IMPLICATION FOR PRACTICE: Healthcare providers should evaluate how parents are coping with the stresses related to raising a child with ASD and consider the cultural factors that might influence how they accept and adapt to parenting children with ASD. Understanding these variables may be used to tailor strategies appropriate to reducing stress and improving the well-being of parents and their children. Support and resource referrals should be considered, including parent support groups, books, web-based services, and recommendations for professional consultations with social workers or therapists.

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3. DeVries L, Dempsey J, Wilson R. Improving Access to Diagnostic Evaluations for Developmental Disabilities Through an Initial Assessment Model. Journal of developmental and behavioral pediatrics : JDBP. 2023.

OBJECTIVE: This study aimed to evaluate a novel model of care to improve access to diagnostic evaluations for autism spectrum disorder and/or developmental delays for school-age children. METHODS: An « initial assessment » (IA) model for children aged 7 to 9 years was implemented at a large regional pediatric hospital. Referral patterns and the number of patients evaluated with the IA model were obtained through the electronic health record (EHR). Referral patterns from the EHR were checked against clinician surveys. RESULTS: Total IA volume had a strong negative association with school-age WL volume (r(22) = -0.92, p < 0.001), indicating that as IA volume increased, the WL volume declined. Evaluation of referral patterns after IAs revealed that approximately 1 in 3 children seen for IA did not require further evaluation and could be immediately removed from the WL. CONCLUSION: Results indicate that implementation of a novel IA model was strongly associated with a decrease in WL volume for neurodevelopmental evaluations of school-age children. These findings support a "right-fit" approach to optimize clinical resources and improve access to neurodevelopmental evaluations.

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4. Falkovich R, Danielson EW, Perez de Arce K, Wamhoff EC, Strother J, Lapteva AP, Sheng M, Cottrell JR, Bathe M. A synaptic molecular dependency network in knockdown of autism- and schizophrenia-associated genes revealed by multiplexed imaging. Cell reports. 2023; 42(5): 112430.

The complex functions of neuronal synapses depend on their tightly interconnected protein network, and their dysregulation is implicated in the pathogenesis of autism spectrum disorders and schizophrenia. However, it remains unclear how synaptic molecular networks are altered biochemically in these disorders. Here, we apply multiplexed imaging to probe the effects of RNAi knockdown of 16 autism- and schizophrenia-associated genes on the simultaneous joint distribution of 10 synaptic proteins, observing several protein composition phenotypes associated with these risk genes. We apply Bayesian network analysis to infer hierarchical dependencies among eight excitatory synaptic proteins, yielding predictive relationships that can only be accessed with single-synapse, multiprotein measurements performed simultaneously in situ. Finally, we find that central features of the network are affected similarly across several distinct gene knockdowns. These results offer insight into the convergent molecular etiology of these widespread disorders and provide a general framework to probe subcellular molecular networks.

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5. Fu S, Bury LAD, Eum J, Wynshaw-Boris A. Autism-specific PTEN p.Ile135Leu variant and an autism genetic background combine to dysregulate cortical neurogenesis. American journal of human genetics. 2023.

Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). The contribution of genetic backgrounds, in addition to ASD risk genes, on cortical neurogenesis remains understudied. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN c.403A>C (p.Ile135Leu) variant found in an ASD-affected individual with macrocephaly dysregulates cortical neurogenesis in an ASD-genetic-background-dependent fashion. Transcriptome analysis at both bulk and single-cell level revealed that the PTEN c.403A>C variant and ASD genetic background affected genes involved in neurogenesis, neural development, and synapse signaling. We also found that this PTEN p.Ile135Leu variant led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. These findings provide experimental evidence that both the PTEN p.Ile135Leu variant and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.

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6. Gao S, Wang X, Su Y. Examining whether adults with autism spectrum disorder encounter multiple problems in theory of mind: a study based on meta-analysis. Psychonomic bulletin & review. 2023.

Theory of mind (ToM) represents a complex ability, while persons with autism spectrum disorder (ASD) encounter difficulties in the processing of ToM. The present ToM-focused studies on adults with ASD report inconsistent results, possibly owing to the differences between tasks. For instance, different ToM-related tasks involve different cognitive abilities, but the development of these cognitive abilities is different among adults with ASD, thereby leading to different behaviors by the same individual with ASD in different tasks. Therefore, it is of vital significance to explore the potential reasons for inconsistencies in the existing studies based on the task classification perspective. Hence, this study primarily reviews the existing ToM tasks used in studies on adults with ASD; afterward, based on the forms and characteristics of the task, the current ToM tasks are classified into four categories-reading comprehension, perceptual scene comprehension, comprehensive scene comprehension , and self-other processing. Subsequently, a meta-analysis is undertaken to determine the difference in each ToM task category between the ASD group and the typically developing (TD) group. As a result, 110 research papers (including 3,205 adults with ASD and 3,675 TD adults) that fulfilled the stated criteria are examined in this study. The study findings suggest that adults with ASD demonstrate worse performance in terms of all four ToM task categories as compared to TD adults. Furthermore, compared with tasks of self-other processing and perceptual scene comprehension, adults with ASD perform worse in reading comprehension and comprehensive scene comprehension. This shows that the differences between tasks may exert a potential influence on the study results. Future studies should focus on different abilities involved in ToM processing and the choice of ToM tasks, in order to elucidate the critical problems of ToM in adults with ASD.

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7. Lu Q, Chen J, Wang Y, Huang L, Jiang Z, Nguchu BA, Chen S, Qiu B, Wang X. Cerebellar Structural Abnormality in Autism Spectrum Disorder: A Magnetic Resonance Imaging Study. Psychiatry investigation. 2023; 20(4): 334-40.

OBJECTIVE: This study uses structural magnetic resonance imaging to explore changes in the cerebellar lobules in patients with autism spectrum disorder (ASD) and further analyze the correlation between cerebellar structural changes and clinical symptoms of ASD. METHODS: A total of 75 patients with ASD and 97 typically developing (TD) subjects from Autism Brain Imaging Data Exchange dataset were recruited. We adopted an advanced automatic cerebellar lobule segmentation technique called CEREbellum Segmentation to segment each cerebellar hemisphere into 12 lobules. Normalized cortical thickness of each lobule was recorded, and group differences in the cortical measures were evaluated. Correlation analysis was also performed between the normalized cortical thickness and the score of Autism Diagnostic Interview-Revised. RESULTS: Results from analysis of variance showed that the normalized cortical thickness of the ASD group differed significantly from that of the TD group; specifically, the ASD group had lower normalized cortical thickness than the TD group. Post-hoc analysis revealed that the differences were more predominant in the left lobule VI, left lobule Crus I and left lobule X, and in the right lobule VI and right lobule Crus I. Lowered normalized cortical thickness in the left lobule Crus I in the ASD patients correlated positively with the abnormality of development evident at or before 36 months subscore. CONCLUSION: These results suggest abnormal development of cerebellar lobule structures in ASD patients, and such abnormality might significantly influence the pathogenesis of ASD. These findings provide new insights into the neural mechanisms of ASD, which may be clinically relevant to ASD diagnosis.

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8. Rabot J, Rødgaard EM, Joober R, Dumas G, Bzdok D, Bernhardt B, Jacquemont S, Mottron L. Genesis, modelling and methodological remedies to autism heterogeneity. Neuroscience and biobehavioral reviews. 2023: 105201.

Diagnostic criteria used in autism research have undergone a shift towards the inclusion of a larger population, paralleled by increasing, but variable, estimates of autism prevalence across clinical settings and continents. A categorical diagnosis of autism spectrum disorder is now consistent with large variations in language, intelligence, comorbidity, and severity, leading to a heterogeneous sample of individuals, increasingly distant from the initial prototypical descriptions. We review the history of autism diagnosis and subtyping, and the evidence of heterogeneity in autism at the cognitive, neurological, and genetic levels. We describe two strategies to address the problem of heterogeneity: clustering, and truncated-compartmentalized enrollment strategy based on prototype recognition. The advances made using clustering methods have been modest. We present an alternative, new strategy for dissecting autism heterogeneity, emphasizing incorporation of prototypical samples in research cohorts, comparison of subgroups defined by specific ranges of values for the clinical specifiers, and retesting the generality of neurobiological results considered to be acquired from the entire autism spectrum on prototypical cohorts defined by narrow specifiers values.

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9. Saga T, Tanaka H, Matsuda Y, Morimoto T, Uratani M, Okazaki K, Fujimoto Y, Nakamura S. Automatic evaluation-feedback system for automated social skills training. Scientific reports. 2023; 13(1): 6856.

Social skills training (SST), which is a rehabilitation program for improving daily interpersonal communication, has been used for more than 40 years. Although such training’s demand is increasing, its accessibility is limited due to the lack of experienced trainers. To tackle this issue, automated SST systems have been studied for years. An evaluation-feedback pipeline of social skills is a crucial component of an SST system. Unfortunately, research that considers both the evaluation and feedback parts of automation remains insufficient. In this paper, we collected and analyzed the characteristics of a human-human SST dataset that consisted of 19 healthy controls, 15 schizophreniacs, 16 autism spectrum disorder (ASD) participants, and 276 sessions with score labels of six clinical measures. From our analysis of this dataset, we developed an automated SST evaluation-feedback system under the supervision of professional, experienced SST trainers. We identified their preferred or most acceptable feedback methods by running a user-study on the following conditions: with/without recorded video of the role-plays of users and different amounts of positive and corrective feedback. We confirmed a reasonable performance of our social-skill-score estimation models as our system’s evaluation part with a maximum Spearman’s correlation coefficient of 0.68. For the feedback part, our user-study concluded that people understood more about what aspects they need to improve by watching recorded videos of their own performance. In terms of the amount of feedback, participants most preferred a 2-positive/1-corrective format. Since the average amount of feedback preferred by the participants nearly equaled that from experienced trainers in human-human SSTs, our result suggests the practical future possibilities of an automated evaluation-feedback system that complements SSTs done by professional trainers.

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10. Santos S, Martins B, Sereno J, Martins J, Castelo-Branco M, Gonçalves J. Neurobehavioral sex-related differences in Nf1(+/-) mice: female show a « camouflaging »-type behavior. Biology of sex differences. 2023; 14(1): 24.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). This condition has been associated with an increase of gamma-aminobutyric acid (GABA) neurotransmission and, consequently, an excitation/inhibition imbalance associated with autistic-like behavior in both human and animal models. Here, we explored the influence of biological sex in the GABAergic system and behavioral alterations induced by the Nf1(+/-) mutation in a murine model. METHODS: Juvenile male and female Nf1(+/-) mice and their wild-type (WT) littermates were used. Hippocampus size was assessed by conventional toluidine blue staining and structural magnetic resonance imaging (MRI). Hippocampal GABA and glutamate levels were determined by magnetic resonance spectroscopy (MRS), which was complemented by western blot for the GABA(A) receptor. Behavioral evaluation of on anxiety, memory, social communication, and repetitive behavior was performed. RESULTS: We found that juvenile female Nf1(+/-) mice exhibited increased hippocampal GABA levels. Moreover, mutant female displays a more prominent anxious-like behavior together with better memory performance and social behavior. On the other hand, juvenile Nf1(+/-) male mice showed increased hippocampal volume and thickness, with a decrease in GABA(A) receptor levels. We observed that mutant males had higher tendency for repetitive behavior. CONCLUSIONS: Our results suggested a sexually dimorphic impact of Nf1(+/-) mutation in hippocampal neurochemistry, and autistic-like behaviors. For the first time, we identified a « camouflaging »-type behavior in females of an animal model of ASD, which masked their autistic traits. Accordingly, like observed in human disorder, in this animal model of ASD, females show larger anxiety levels but better executive functions and production of normative social patterns, together with an imbalance of inhibition/excitation ratio. Contrary, males have more externalizing disorders, such as hyperactivity and repetitive behaviors, with memory deficits. The ability of females to camouflage their autistic traits creates a phenotypic evaluation challenge that mimics the diagnosis difficulty observed in humans. Thus, we propose the study of the Nf1(+/-) mouse model to better understand the sexual dimorphisms of ASD phenotypes and to create better diagnostic tools.

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11. Tessier E, Webster H, Aziz NA, Flannagan J, Zaidi A, Charlett A, Dabrera G, Lamagni T. The impact of COVID-19 on residents of long-term care facilities with learning disabilities and/or autism. Influenza and other respiratory viruses. 2023; 17(4): e13139.

BACKGROUND: The COVID-19 pandemic has had disproportionate impact on vulnerable populations including those with learning disabilities. Assessing the incidence and risk of death in such settings can improve the prevention of COVID-19. We describe individuals who tested positive for SARS-CoV-2 while residing in care homes for learning disabilities and/or autism and investigate the risk of death compared with individuals living in their own homes. METHODS: Surveillance records for COVID-19 infections in England from 02 February 2020 to 31 March 2022 were extracted. Data on property type, variant wave, vaccination, hospitalisation and death were derived through data linkage and enrichment. Care home residents with learning disabilities and/or autism and diagnosed with COVID-19 were identified and analysed, and logistic regression analyses compared the risk of death of individuals living in private residence. We assessed interaction parameters by post-estimation analyses. RESULTS: A total of 3501 individuals were identified as diagnosed with SARS-CoV-2 whilst living in 632 care home properties for learning disabilities and/or autism. Of the 3686 episodes of infection, 80.4% were part of an outbreak. The crude case fatality rate was 2.6% and 0.6% among care home residents with autism and/or learning disabilities and their counterparts in households, respectively.The post-estimation analyses found over eight times the odds of death among care home residents in 60 years old compared with their counterparts living in private homes. CONCLUSIONS: Care home residents with learning disabilities and/or autism have a greater risk of death from COVID-19. Optimising guidance to meet their needs is of great importance.

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12. Wang L, Li S, Wang C. Using Pivotal Response Treatment to Improve Language Functions of Autistic Children in Special Schools: A Randomized Controlled Trial. Journal of autism and developmental disorders. 2023: 1-13.

Language difficulties exert profound negative effects on the cognitive and social development of autistic children. Pivotal Response Treatment (PRT) is a promising intervention for improving social communication in autistic children, but there is a lack of a comprehensive examination of language functions. This study aimed to investigate the effectiveness of PRT in promoting the primary language functions (requesting, labeling, repeating, responding) defined by (Skinner, B. F. (1957). Verbal behavior. Martino Publishing.) theory of verbal behavior in autistic children. Thirty autistic children were randomly divided into the PRT group (M(age) = 6.20, SD(age) = 1.21) and control group (M(age) = 6.07, SD(age) = 1.49). The PRT group were provided with an 8-week training of the PRT motivation component in addition to treatment as usual (TAU) in their schools, whereas the control group only received TAU. Parents of the PRT group were also trained to practice the PRT motivation procedures at home. The PRT group demonstrated greater improvements in all four measured language functions compared to the control group. The improvement in language functions in the PRT group was generalized and maintained at the follow-up assessment. In addition, the PRT intervention enhanced untargeted social and communicative functioning, cognition, motor skills, imitation, and adaptive behaviors in the autistic children. In conclusion, language intervention using the motivation component of PRT is effective in promoting language functions as well as widespread untargeted cognitive and social functions in autistic children.

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13. Yu G, Xu M, Chen Y, Ke H. 25(OH)Vitamin D and autism spectrum disorder: genetic overlap and causality. Genes & nutrition. 2023; 18(1): 8.

OBJECTIVE: To identify whether there exists a genetic correlation and causal relationship between 25(OH)D and autism spectrum disorder (ASD). METHODS: Based on large-scale genome-wide association studies, a series of genetic approaches were adopted to obtain summary statistics. Using linkage disequilibrium score regression, we assessed the shared polygenic structure between traits and performed pleiotropic analysis under composite null hypothesis (PLACO) to identify pleiotropic loci between complex traits. A bidirectional Mendelian randomization (MR) analysis was applied to investigate whether there is a causal relationship between 25(OH)D and ASD. RESULTS: The linkage disequilibrium score regression (LDSC) showed a negative genetic correlation between 25(OH)D and ASD (r(g) = – 0.227, P < 0.05), and PLACO analysis identified 20 independent pleiotropic loci matched to 24 pleiotropic genes, of which the function reveals an underlying mechanism on 25(OH)D and ASD. In Mendelian randomization analysis, the inverse variance-weighted (IVW) method with OR = 0.941 (0.796, 1.112) and p < 0.474 did not show a causal relationship between 25(OH)D and ASD, while, in the reverse Mendelian randomization analysis, IVW method showed OR = 1.042 (0.930, 1.169), indicating no causal relationship either. CONCLUSION: This study provides evidence for a shared genetic overlap between 25(OH)D and ASD. Bidirectional MR analysis also did not show a definite causal relationship between 25(OH)D and ASD.

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