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Journal of Data Science : JDS Oct 2023Bayesian methods provide direct inference in functional data analysis applications without reliance on bootstrap techniques. A major tool in functional data applications...
Bayesian methods provide direct inference in functional data analysis applications without reliance on bootstrap techniques. A major tool in functional data applications is the functional principal component analysis which decomposes the data around a common mean function and identifies leading directions of variation. Bayesian functional principal components analysis (BFPCA) provides uncertainty quantification on the estimated functional model components via the posterior samples obtained. We propose central posterior envelopes (CPEs) for BFPCA based on functional depth as a descriptive visualization tool to summarize variation in the posterior samples of the estimated functional model components, contributing to uncertainty quantification in BFPCA. The proposed BFPCA relies on a latent factor model and targets model parameters within a mixed effects modeling framework using modified multiplicative gamma process shrinkage priors on the variance components. Functional depth provides a center-outward order to a sample of functions. We utilize modified band depth and modified volume depth for ordering of a sample of functions and surfaces, respectively, to derive at CPEs of the mean and eigenfunctions within the BFPCA framework. The proposed CPEs are showcased in extensive simulations. Finally, the proposed CPEs are applied to the analysis of a sample of power spectral densities (PSD) from resting state electroencephalography (EEG) where they lead to novel insights on diagnostic group differences among children diagnosed with autism spectrum disorder and their typically developing peers across age.
PubMed: 38883309
DOI: 10.6339/23-jds1085 -
Cureus May 2024Septo-optic dysplasia (SOD) is a rare congenital disorder characterized by optic nerve hypoplasia, brain midline structure anomalies, and hypothalamic-pituitary axis...
Septo-optic dysplasia (SOD) is a rare congenital disorder characterized by optic nerve hypoplasia, brain midline structure anomalies, and hypothalamic-pituitary axis hypoplasia. This case report aims to highlight the association between SOD and neurodevelopmental disorders, focusing on attention-deficit/hyperactivity disorder (ADHD) in addition to the well-established link with autism spectrum disorder (ASD). A six-year-old male diagnosed with SOD presented with behavioral concerns, including attention and impulse control issues. A comprehensive psychological evaluation confirmed the diagnosis of ADHD and ruled out ASD. Ophthalmological assessments were integral to understanding the patient's condition. This case underscores the importance of recognizing neurodevelopmental disorders in individuals with SOD, with a particular focus on the less common association with ADHD. The co-occurrence of these conditions underscores the complexity of neurodevelopmental disorders and the need for comprehensive evaluation and management. Collaboration between ophthalmologists and mental health specialists is crucial for addressing the diverse needs of these patients. Early identification and intervention for ADHD are essential for optimal developmental outcomes. This case underscores the necessity for further research to elucidate the relationship between SOD and ADHD, emphasizing the importance of holistic patient care and interdisciplinary collaboration in managing individuals with SOD spectrum conditions.
PubMed: 38883061
DOI: 10.7759/cureus.60441 -
Cureus May 2024Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a rising prevalence worldwide. While genetic factors are significantly associated with the...
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a rising prevalence worldwide. While genetic factors are significantly associated with the disorder, environmental factors are often speculated to contribute to its onset. The Middle East, exhibiting higher rates of ASD, also sees frequent consanguineous marriages, necessitating focused studies on potential etiological factors in the region. We report a unique case of a family with three children diagnosed with ASD. The parents, aged between 35 and 39 years at the birth of their first child, have no notable familial history of neurodevelopmental disorders. Interestingly, while both parents and two of the children had normal chromosomal patterns, one child displayed chromosomal abnormalities. This discrepancy raises questions about the interplay between genetics and external factors in the manifestation of ASD. The family's medical history, combined with the regional context of high ASD prevalence and consanguineous marriages, provides a compelling backdrop for the study. The presence of chromosomal abnormalities in only one child, despite no detectable genetic irregularities in parents or siblings, underscores the potential influence of environmental factors in the development of ASD. This case accentuates the importance of conducting in-depth genetic and environmental studies to unravel the intricate etiological web surrounding ASD in the Middle East.
PubMed: 38882979
DOI: 10.7759/cureus.60362 -
Acta Medica Philippina 2024To describe patterns of feeding difficulties and behaviors of Filipino children diagnosed with Autism Spectrum Disorder (ASD).
Survey on the Patterns of Feeding Difficulties and Behaviors in Filipino Children with Autism Spectrum Disorder Seen in a Philippine Tertiary Hospital and the Impact of the COVID-19 Pandemic.
OBJECTIVE
To describe patterns of feeding difficulties and behaviors of Filipino children diagnosed with Autism Spectrum Disorder (ASD).
METHODS
An electronic mealtime survey was administered to caregivers of 3- to 9-year-old children diagnosed with ASD in a Philippine tertiary government hospital. Descriptive statistics and correlation analyses between feeding difficulties measured as Mealtime Survey Score, sociodemographic data, and early feeding history were performed. The impact of the COVID-19 pandemic to these was analyzed through a binomial test.
RESULTS
All of the 115 study subjects reported at least one problematic feeding behavior, with picky eating being the most frequent (61.74%). Significantly, more feeding difficulties were observed among the children with reported early feeding difficulties during their 2 and 3 year of life. There were no documented statistically significant changes in feeding behaviors during the past six months of the COVID-19 pandemic.
CONCLUSION
There is a high prevalence of feeding difficulties and problematic feeding behavior among Filipino children with ASD, however no significant changes to these during the past six months of the COVID-19 pandemic were documented. Present feeding difficulties and behaviors were associated with history of early feeding difficulties, highlighting the need to include feeding difficulties in screening tools, and early training programs and interventions for children with ASD.
PubMed: 38882917
DOI: 10.47895/amp.v58i7.6340 -
Acta Medica Philippina 2024The COVID-19 pandemic has affected the well-being of children with Autism Spectrum Disorder (ASD) and their families. The core deficits of the condition and increased...
BACKGROUND
The COVID-19 pandemic has affected the well-being of children with Autism Spectrum Disorder (ASD) and their families. The core deficits of the condition and increased parental stress during this time made them more vulnerable.
OBJECTIVES
This study aims to explore how the pandemic has affected these families by identifying their needs and capabilities in order to provide support.
METHODS
A total of 227 parents of children with ASD completed an online survey consisting of items on socio-demographics, family needs, and coping strategies. Descriptive statistics were used and t-test and ANOVA/Kruskal Wallis were used to determine the relationship between parent and child factors with needs and coping.
RESULTS
Needs for Information, Community Services, and Finances are the top categories while the greatest identified need during this pandemic was for financial assistance. Religiosity, Problem-Solving, and Cognitive Reappraisal were the widely used coping strategies by the parents. Fathers, younger children, daughters with ASD, and having more than one child with ASD showed significant association with needs. Parents with primary and tertiary education were associated with use of the cognitive reappraisal strategy and those with jobs were associated with substance use.
CONCLUSION
Families of children with ASD have multiple needs during this pandemic, from autism-specific information and services, to more generic concerns such as financial assistance. Despite these challenges, these families have positive strategies in place to facilitate coping mechanisms.
PubMed: 38882907
DOI: 10.47895/amp.v58i7.6331 -
Brain, Behavior, & Immunity - Health Jul 2024Similar to the gut microbiome, oral microbiome compositions have been suggested to play an important role in the etiology of autism. However, empirical research on how...
Similar to the gut microbiome, oral microbiome compositions have been suggested to play an important role in the etiology of autism. However, empirical research on how variations in the oral microbiome relate to clinical-behavioral difficulties associated with autism remains sparse. Furthermore, it is largely unknown how potentially confounding lifestyle variables, such as oral health and nutrition, may impact these associations. To fill this gap, the current study examined diagnosis-related differences in oral microbiome composition between 80 school-aged autistic children (8-12 years; 64 boys, 16 girls) versus 40 age-matched typically developing peers (32 boys, 8 girls). In addition, associations with individual differences in social functioning (SRS-2), repetitive behavior (RBS-R) and anxiety (SCARED) were explored, as well as the impact of several lifestyle variables regarding nutrition and oral health. Results provide important indications that the bacterial genera , , and were significantly more abundant in autistic compared to non-autistic children. Furthermore, the former four bacteria that were significantly more abundant in the autistic children showed significant associations with parent-reported social difficulties, repetitive and restrictive behavior and with parent-reported anxiety-like behavior. Importantly, associations among oral microbiome and quantitative diagnostic characteristics were not significantly driven by differences in lifestyle variables. This exploratory study reveals significant differences in oral microbiome composition between autistic and non-autistic children, even while controlling for potential confounding lifestyle variables. Furthermore, the significant associations with clinical characteristics suggest that individual differences in microbiome composition might be involved in shaping the clinical phenotype of autism. However, these associations warrant further exploration of the oral microbiome's potential beyond the oral cavity and specifically with respect to neuropsychiatric conditions.
PubMed: 38882715
DOI: 10.1016/j.bbih.2024.100801 -
Molecular Autism Jun 2024Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and...
BACKGROUND
Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 rats.
METHODS
To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology.
RESULTS
Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca permeable AMPA receptor mediated currents are unchanged in Cdkl5 rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses.
CONCLUSIONS
Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity.
LIMITATIONS
This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.
Topics: Animals; Long-Term Potentiation; Receptors, N-Methyl-D-Aspartate; Receptors, AMPA; Spasms, Infantile; Disease Models, Animal; Rats; Protein Serine-Threonine Kinases; Hippocampus; Pyramidal Cells; Male; CA1 Region, Hippocampal; Epileptic Syndromes; Genetic Diseases, X-Linked; Synapses; Excitatory Postsynaptic Potentials
PubMed: 38877552
DOI: 10.1186/s13229-024-00601-9 -
Molecular Autism Jun 2024Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in...
BACKGROUND
Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS
To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS
We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D on the order of 1 × 10).
LIMITATIONS
We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS
This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Topics: Humans; Autistic Disorder; Phenotype; Male; Female; Linkage Disequilibrium; Multifactorial Inheritance; Child; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Intellectual Disability
PubMed: 38877467
DOI: 10.1186/s13229-024-00605-5 -
Translational Psychiatry Jun 2024Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced...
Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1 rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1 rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.
Topics: Animals; Haploinsufficiency; Rats; Schizophrenia; Male; Adaptor Proteins, Signal Transducing; Prefrontal Cortex; Autistic Disorder; CA1 Region, Hippocampal; Disease Models, Animal; Nerve Net; Behavior, Animal; Corpus Striatum; Ventral Striatum
PubMed: 38876996
DOI: 10.1038/s41398-024-02969-x -
EBioMedicine Jun 2024The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal...
BACKGROUND
The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted.
METHODS
We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types.
FINDINGS
After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons.
INTERPRETATION
Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy.
FUNDING
This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).
PubMed: 38876042
DOI: 10.1016/j.ebiom.2024.105197