cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.15154/1177023
title: Rare-Variant Extensions of the Transmission Disequilibrium Test: Application to Autism Exome Sequence Data

description: Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.
DOI: 10.15154/1195991
title: Development and validation of a brain maturation index using longitudinal neuroanatomical scans

description: Background
Major psychiatric disorders are increasingly being conceptualized as ‘neurodevelopmental’, because they are associated with aberrant brain maturation. Several studies have hypothesized that a brain maturation index integrating patterns of neuroanatomical measurements may reliably identify individual subjects deviating from a normative neurodevelopmental trajectory. However, while recent studies have shown great promise in developing accurate brain maturation indices using neuroimaging data and multivariate machine learning techniques, this approach has not been validated using a large sample of longitudinal data from children and adolescents.

Methods
T1-weighted scans from 303 healthy subjects aged 4.88 to 18.35 years were acquired from the National Institute of Health (NIH) pediatric repository (http://www.pediatricmri.nih.gov). Out of the 303 subjects, 115 subjects were re-scanned after 2 years. The least absolute shrinkage and selection operator algorithm (LASSO) was ‘trained’ to integrate neuroanatomical changes across chronological age and predict each individual's brain maturity. The resulting brain maturation index was developed using first-visit scans only, and was validated using second-visit scans.

Results
We report a high correlation between the first-visit chronological age and brain maturation index (r = 0.82, mean absolute error or MAE = 1.69 years), and a high correlation between the second-visit chronological age and brain maturation index (r = 0.83, MAE = 1.71 years). The brain maturation index captured neuroanatomical volume changes between the first and second visits with an MAE of 0.27 years.

Conclusions
The brain maturation index developed in this study accurately predicted individual subjects' brain maturation longitudinally. Due to its strong clinical potentials in identifying individuals with an abnormal brain maturation trajectory, the brain maturation index may allow timely clinical interventions for individuals at risk for psychiatric disorders.
DOI: 10.15154/1195992
title: The Sensitivity and Specificity of the Social Communication Questionnaire for  Autism Spectrum Disorder with Respect to Age

description: Scientific Abstract
The Social Communication Questionnaire (SCQ) assesses communication skills and social functioning in screening for symptoms of autism-spectrum disorder (ASD). The SCQ is recommended for individuals between 4 to 40 years with a cutoff score of 15 for referral. Mixed findings have been reported regarding the recommended cutoff score’s ability to accurately classify an individual as at-risk for ASD (sensitivity) versus an individual as not at-risk for ASD (specificity). Based on a sample from the National Database for Autism Research (n=344; age: 1.58 to 25.92 years old), the present study examined the SCQ’s sensitivity versus specificity across a range of ages. We recommend that the cutoff scores for the SCQ be re-evaluated with age as a consideration.
Lay Abstract
The age neutrality of the Social Communication Questionnaire (SCQ) was examined as a common screener for ASD. Mixed findings have been reported regarding the recommended cutoff score’s ability to accurately classify an individual as at-risk for ASD (sensitivity) versus accurately classifying an individual as not at-risk for ASD (specificity). With a sample from the National Database for Autism Research, the present study examined the SCQ’s sensitivity versus specificity. Analyses indicated that the actual sensitivity and specificity scores were lower than initially reported by the creators of the SCQ.
DOI: 10.15154/1195993
title: Revising the Social Communication Questionnaire scoring procedures for Autism Spectrum Disorder and potential Social Communication Disorder

description: In analyzing data from the National Database for Autism Research, we examine revising the Social Communication Questionnaire (SCQ), a commonly used screening instrument for Autism Spectrum Disorder. A combination of Item Response Theory and Mokken scaling techniques were utilized to achieve this and abbreviated scoring of the SCQ is suggested. The psychometric sensitivity of this abbreviated SCQ was examined via bootstrapped Receiver Operator Characteristic (ROC) curve analyses. Additionally, we examined the sensitivity of the abbreviated and total scaled SCQ as it relates to a potential diagnosis of Social (Pragmatic) Communication Disorder (SCD). As SCD is a new disorder introduced with the fifth edition of the Diagnostic and Statistical Manual (DSM-5), we identified individuals with potential diagnosis of SCD among individuals with ASD via mixture modeling techniques using the same NDAR data. These analyses revealed two classes or clusters of individuals when considering the two core areas of impairment among individuals with ASD: social communication and restricted, repetitive patterns of behavior.
DOI: 10.15154/1195994
title: Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort

description: Epigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features.  Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children.  We examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available.  Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)] &lt;0.05 associated with performance on the Autism Observational Scale for Infants (AOSI) at 12 months of age in offspring. The DMRs clustered near genes involved in developmental processes, including many genes in the SNORD family, within the Prader-Willi syndrome gene cluster. These results were consistent among the 75 probes on the Illumina 450K array that cover AOSI-associated DMRs from CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent differences in the cerebellums of autistic individuals compared with controls.  These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring, and provide evidence that directionally consistent, potentially related epigenetic mechanisms may be operating in the cerebellum of individuals with autism.
DOI: 10.15154/1206630
title: A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

description: The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.
DOI: 10.15154/1223791
title: Brain Hyperconnectivity in Children with Autism and its Links to Social Deficits

description: Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism.
DOI: 10.15154/1223858
title: Cortical underconnectivity coupled with preserved visuospatial cognition in autism: Evidence from an fMRI study of an embedded figures task.

description: Individuals with high-functioning autism sometimes exhibit intact or superior performance on visuospatial tasks, in contrast to impaired functioning in other domains such as language comprehension, executive tasks, and social functions. The goal of the current study was to investigate the neural bases of preserved visuospatial processing in high-functioning autism from the perspective of the cortical underconnectivity theory. We used a combination of behavioral, functional magnetic resonance imaging, functional connectivity, and corpus callosum morphometric methodological tools. Thirteen participants with high-functioning autism and 13 controls (age-, IQ-, and gender-matched) were scanned while performing an Embedded Figures Task. Despite the ability of the autism group to attain behavioral performance comparable to the control group, the brain imaging results revealed several group differences consistent with the cortical underconnectivity account of autism. First, relative to controls, the autism group showed less activation in the left dorsolateral prefrontal and inferior parietal areas and more activation in visuospatial (bilateral superior parietal extending to inferior parietal and right occipital) areas. Second, the autism group demonstrated lower functional connectivity between higher-order working memory/executive areas and visuospatial regions (between frontal and parietal-occipital). Third, the size of the corpus callosum (an index of anatomical connectivity) was positively correlated with frontal-posterior (parietal and occipital) functional connectivity in the autism group. Thus, even in the visuospatial domain, where preserved performance among people with autism is observed, the neuroimaging signatures of cortical underconnectivity persist.
DOI: 10.15154/1223859
title: Autonomy of lower-level perception from global processing in autism: evidence from brain activation and functional connectivity.

description: Previous behavioral studies have shown that individuals with autism are less hindered by interference from global processing during the performance of lower-level perceptual tasks, such as finding embedded figures. The primary goal of this study was to examine the brain manifestation of such atypicality in high-functioning autism using fMRI. Fifteen participants with high-functioning autism and fifteen age- and IQ-matched typical controls were asked to perform a lower-level perceptual line-counting task in the presence of a distracting depiction of a 3-D object, in which participants counted whether there were more red or more green contours (In a contrasting 3-D task, participants judged whether the same 3-D stimulus objects (but without color in any contours) depicted a possible or impossible 3-D object). We hypothesized that individuals with autism would be less likely than controls to process the global 3-D information (and would hence show fewer neural signs of such interfering 3-D processing) during the lower-level line-counting task. The fMRI results revealed that in the line-counting task, the autism group did not show the increased medial frontal activity (relative to the possibility task), or the increased functional connectivity between the medial frontal region and posterior visual-spatial regions, demonstrated by the control group. Both findings are indices of lesser effort and difficulty in the line-counting task for the autism group than for the control group, attributed to less interference from the 3-D processing in the autism group. In addition, in the line-counting task, the control group showed a positive correlation between a measure of spatial ability (Vandenberg scores) and activation in the medial frontal region, suggesting that more spatially able control participants did more suppression of the irrelevant 3-D background information in order to focus on the line-counting task. The findings collectively indicate that the global 3-D structure of the figure had a smaller effect, if any, on local processing in the group with autism compared to the control group. The results from this study provide the first direct neural evidence of reduced global-to-local interference in autism.
DOI: 10.15154/1223861
title: Distinctive Neural Processes during Learning in Autism

description: This functional magnetic resonance imaging study compared the neural activation patterns of 18 high-functioning individuals with autism and 18 IQ-matched neurotypical control participants as they learned to perform a social judgment task. Participants learned to identify liars among pairs of computer-animated avatars uttering the same sentence but with different facial and vocal expressions, namely those that have previously been associated with lying versus truth-telling. Despite showing a behavioral learning effect similar to the control group, the autism group did not show the same pattern of decreased activation in cortical association areas as they learned the task. Furthermore, the autism group showed a significantly smaller increase in interregion synchronization of activation (functional connectivity) with learning than did the control group. Finally, the autism group had decreased structural connectivity as measured by corpus callosum size, and this measure was reliably related to functional connectivity measures. The findings suggest that cortical underconnectivity in autism may constrain the ability of the brain to rapidly adapt during learning.
DOI: 10.15154/1223865
title: Association between pupillary light reflex and sensory behaviors in children with autism spectrum disorders.

description: Atypical pupillary light reflexes (PLR) has been observed in children with autism spectrum disorders (ASD), which suggests potential autonomic nervous system (ANS) dysfunction in ASD. ANS is also involved in modulating sensory processing and sensory dysfunction has been widely reported in children with ASD. However, the potential association between physiological measurements of PLR and behavioral observations (e.g. sensory behaviors) has not been examined extensively in literature. In this study, we investigated the potential correlation between PLR and frequently observed sensory behaviors in children with ASD. We found a significant association between PLR constriction amplitude and a set of sensory behaviors in the ASD group but not in typically developing children. Children with ASD who showed more atypical sensory behaviors also had smaller PLR constriction amplitudes. A smaller PLR constriction amplitude suggests lower parasympathetic modulation. This observation implies that some atypical sensory behaviors in children with ASD could be associated with decreased parasympathetic modulation.
DOI: 10.15154/1223868
title: Atypical pupillary light reflex and heart rate variability in children with autism spectrum disorder

description: We investigated pupillary light reflex (PLR) in 152 children with ASD, 116 typically developing (TD) children, and 36 children with non-ASD neurodevelopmental disorders (NDDs). Heart rate variability (HRV) was measured simultaneously to study potential impairments in the autonomic nervous system (ANS) associated with ASD. The results showed that the ASD group had significantly longer PLR latency, reduced relative constriction amplitude, and shorter constriction/redilation time than those of the TD group. Similar atypical PLR parameters were observed in the NDD group. A significant age effect on PLR latency was observed in children younger than 9 years in the TD group, but not in the ASD and NDD groups. Atypical HRV parameters were observed in the ASD and NDD groups. A significant negative correlation existed between the PLR constriction amplitude and average heart rate in children with an ASD, but not in children with typical development.
DOI: 10.15154/1223873
title: Identification of Infants at High-Risk for Autism Spectrum Disorder Using Multiparameter Multiscale White Matter Connectivity Networks

description: Autism spectrum disorder (ASD) is a wide range of disabilities that cause life-long cognitive
impairment and social, communication, and behavioral challenges. Early diagnosis and medical intervention
are important for improving the life quality of autistic patients. However, in the current practice,
diagnosis often has to be delayed until the behavioral symptoms become evident during
childhood. In this study, we demonstrate the feasibility of using machine learning techniques for identifying
high-risk ASD infants at as early as six months after birth. This is based on the observation that
ASD-induced abnormalities in white matter (WM) tracts and whole-brain connectivity have already
started to appear within 24 months after birth. In particular, we propose a novel multikernel support
vector machine classification framework by using the connectivity features gathered from WM connectivity
networks, which are generated via multiscale regions of interest (ROIs) and multiple diffusion
statistics such as fractional anisotropy, mean diffusivity, and average fiber length. Our proposed framework
achieves an accuracy of 76% and an area of 0.80 under the receiver operating characteristic curve
(AUC), in comparison to the accuracy of 70% and the AUC of 70% provided by the best singleparameter
single-scale network. The improvement in accuracy is mainly due to the complementary
information provided by multiparameter multiscale networks. In addition, our framework also provides
the potential imaging connectomic markers and an objective means for early ASD diagnosis.
DOI: 10.15154/1226467
title: Convergent and Discriminant Validity and Reliability of the Pediatric Anxiety Rating Scale in Youth with Autism Spectrum Disorders

description: The psychometric properties of the Pediatric Anxiety Rating Scale (PARS), a clinician-administered measure for assessing severity of anxiety symptoms, were examined in 72 children and adolescents diagnosed with an autism spectrum disorder (ASD). The internal consistency of the PARS was 0.59, suggesting that the items were related but not repetitive.The PARS was strongly correlated with clinician-ratings of overall anxiety severity and parent-
report anxiety measures, supporting convergent validity. Results for divergent validity were mixed. Although the PARS was not associated with the sum of the Social and Communication items on the Autism Diagnostic Observation System, it was moderately correlated with parent-reported inattention, aggression and externalizing behavior. Overall, these results suggest that the psychometric properties of the PARS are adequate for assessing anxiety
symptoms in youth with ASD, although additional clarification of divergent validity is needed.
DOI: 10.15154/1227279
title: Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms

description: Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.