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Forecasting autism gene discovery with machine learning and genome-scale data
[article]
2018
bioRxiv
pre-print
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Genes are one of the most powerful windows into the biology of autism, and it has been estimated that perhaps a thousand or more genes may confer risk. However, less than 100 genes are currently viewed as having robust enough evidence to be considered true "autism genes". Massive genetic studies are underway to produce data to implicate additional genes, but this approach, although necessary, is costly and slow-moving. Here, we approach autism gene discovery as a machine learning problem,
doi:10.1101/370601
fatcat:fpznxidyanaptgi56svsw6ncqq
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... than a genetic association problem, and use genome-scale data as predictors for identifying further genes that have similar properties in the feature space compared to established autism risk genes. This approach, which we call forecASD, integrates spatiotemporal gene expression, heterogeneous network data, and previous gene-level predictors of autism association to yield a single score that represents each gene's likelihood of being involved in the etiology of autism. We demonstrate that forecASD has substantially increased sensitivity and specificity compared to previous gene-level predictors of autism association, including genetic-based measures such as TADA. On an independent test set, consisting of newly-released pilot data from the SPARK Genomics Consortium, we show that forecASD best predicts which genes will have an excess of likely gene disrupting (LGD) mutations. Using forecASD results, we show which molecular pathways are currently under-represented in the autism literature and likely represent under-appreciated biological mechanisms of autism. Finally, the larger importance of this work is that by enumerating the genes that are most likely involved in the pathogenesis of autism, we have an opportunity to consider what molecular research in autism might look like in a post-gene discovery era.
cerebroViz: An R package for anatomical visu-alization of spatiotemporal brain data
2016
Bioinformatics
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As communication networks increase in performance and complexity, and more dependence is placed upon them, it becomes ever more important that their behaviour is understood in an efficient and timely manner. Visualisation is an established technique for the presentation of the vast volume of data yielded in monitoring such networks. It is apparent, however, that much of the work in this area has been performed in isolation, and it is timely that a review of this research is conducted. This
doi:10.1093/bioinformatics/btw726
pmid:28011779
pmcid:PMC5870797
fatcat:c4lsiuw7ufdynck4rcjcfqpr54
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... surveys the techniques for the visualisation of communication networks and related measurements. The research is classified by the type of visualisation used, and is separated into three classes: geographic visualisations, where the data is presented with respect to the physical location of nodes in the network; abstract topological visualisations, where the relationships between nodes are presented independently of * The spelling 'visualisation' is used throughout this document, however, as most of the work on this subject uses the 'ize' spelling, the title has been left in this form 1 This paper is a postprint of a paper submitted to and accepted for publication in IET Communications and is subject to Institution of Engineering and Technology Copyright. The copy of record is available at IET Digital Library. physical location; and plot-based visualisation, where the focus is a single point in the network, often presented with respect to time. The research in this area is reviewed and the techniques proposed are discussed in terms of the three classes.
VCFdbR: A method for expressing biobank-scale Variant Call Format data in a SQLite database using R
[article]
2020
bioRxiv
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As exome and whole-genome sequencing cohorts grow in size, the data they produce strains the limits of current tools and data structures. The Variant Call Format (VCF) was originally created as part of the 1,000 Genomes project. Flexible and concise enough to describe the genetic variations of thousands of samples in a single flat file, the VCF has become the standard for communicating the results of large-scale sequencing experiments. Because of its static and text-based structure, VCFs remain
doi:10.1101/2020.04.28.066894
fatcat:jkgbxlu7f5djraqsfohhp72iue
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... cumbersome to parse and filter in an interactive way, even with the aid of indexing. Iterating on previous concepts, we propose here a pipeline for converting VCFs to simple SQLite databases, which allow for rapid searching and filtering of genetic variants while minimizing memory overhead. Code can be found at https://github.com/tkoomar/VCFdbR
Clinical autism subscales have common genetic liability that is heritable, pleiotropic, and generalizable to the general population
[article]
2021
medRxiv
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The complexity of autism's phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is unclear whether clinical autism instruments such as the Social Communication Questionnaire (SCQ), Repetitive Behaviors Scale-Revised (RBS-R), and Developmental Coordination Disorder Questionnaire (DCDQ) are more genetically informative than case-control. We employed the SPARK autism cohort (N = 6,449) to illuminate the genetic etiology of these twelve
doi:10.1101/2021.08.30.21262845
fatcat:u7uhglciczaild5rhzux25mftq
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... es. In comparison to the heritability of autism case-control at 0.12, the RBS-R subscales were increased, ranging from 0.18 to 0.30 (all p < 0.05). Heritability of the DCDQ subscales ranged from 0.07 to 0.09 and the SCQ subscales from 0 to 0.09 (all p > 0.05). We also found evidence for genetic correlations among the RBS-R, SCQ, and DCDQ. GWAS followed by projection of polygenic scores (PGS) into ABCD revealed significant associations with CBCL social and thought problems, while the autism case-control PGS did not significantly associate. In phenotypic correlation analyses, the autism case-control PGS did not predict the subscales in SPARK, and sex-stratified correlations showed no effect in males and a surprising negative effect in females. Notably, other PGS did predict the subscales, with the strongest being educational attainment negatively correlated, while ADHD and major depression were positively correlated. Overall, our analyses suggest that clinical subscales are more genetically powerful than case-control, and that of the three instruments investigated, the RBS-R shows the greatest evidence of common genetic signal in both autistic and general population samples.
Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability
[article]
2021
medRxiv
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Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted
doi:10.1101/2021.11.22.21266703
fatcat:gkxzlyhsq5fqdc4wx2jj7cuuzy
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... gion, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".
Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort
2021
Frontiers in Psychiatry
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This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based
doi:10.3389/fpsyt.2021.668297
pmid:34177659
pmcid:PMC8221394
fatcat:f7awyr4auvbb5d6acup7ur4qr4
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... clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.
Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk
2018
Molecular Case Studies
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Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a
doi:10.1101/mcs.a003285
pmid:30559312
pmcid:PMC6318775
fatcat:2hc3rxzcezgh5nj2cx5kj6unua
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... of male monozygotic twins with ASD and ID. At the time of the study, the probands were 7 yr old and largely nonverbal. Medical records indicated a history of motor delays, sleep difficulties, and significant cognitive deficits. Through whole-genome sequencing of the probands and their parents, we uncovered elevated common polygenic risk, a coding de novo point mutation in CENPE, an ultra-rare homozygous regulatory variant in ANK3, inherited rare variants in NRXN3, and a maternally inherited X-linked deletion situated in a noncoding regulatory region between ZNF81 and ZNF182 Although each of these genes has been directly or indirectly associated with NDDs, evidence suggests that no single variant adequately explains the probands' phenotype. Instead, we propose that the probands' condition is due to the confluence of multiple rare variants in the context of a high-risk genetic background. This case emphasizes the multifactorial nature of genetic risk underlying most instances of NDDs and aligns with the "female protective model" of ASD.
Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts
[article]
2020
medRxiv
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Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is one paradigm for investigating this male bias, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been inconsistent and the relationships between androgen exposure and behavior remains unclear. Here, we measured both digit ratio
doi:10.1101/2020.08.03.20155671
fatcat:iz3g6yy4r5hgnasae5ezvpnvyi
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... culinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N=763) and compared these proxies of androgen exposure to clinical and parent-reported features. We found that FLM was significantly associated with diagnostic burden in males and females (Z=3.1, p=0.002), while DRM was not (Z=-1.6, p=0.11). When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior (Z=3.1, p=0.002; Z=2.1, p=0.03, respectively), also in a sex-invariant manner. Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels (t=2.0, p=0.04), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels (t=-2.3, p=0.02). Finally, using the SPARK cohort (N=9,419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning (t=-2.5, p=0.01, and t=4.5, p=6e-6 for testosterone and SHBG, respectively). Remarkably, these quantitative sex effects on social functioning were on the same order of magnitude as the effect of binary sex itself (binary male:-0.23 +/- 0.05; testosterone:-0.07 +/- 0.026 per SD of PRS; SHBG: 0.11 +/- 0.026 per SD of PRS). These findings and their replication in the large SPARK cohort lend strong support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.
Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts
2021
Molecular Autism
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Background Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain
doi:10.1186/s13229-021-00450-w
pmid:34108004
pmcid:PMC8190870
fatcat:upvvlclmonczfnvaarm4ddjkji
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... lear. Methods Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all $$p<0.05$$ p < 0.05 ), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ($$\rho =0.19$$ ρ = 0.19 , $$p=0.004$$ p = 0.004 ; $$\rho =0.2$$ ρ = 0.2 , $$p=0.004$$ p = 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ($$t=4.0$$ t = 4.0 , $$p=8.8\times 10^{-5}$$ p = 8.8 × 10 - 5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ($$t=-3.3$$ t = - 3.3 , $$p=0.001$$ p = 0.001 ). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ($$t=-2.3$$ t = - 2.3 , $$p=0.02$$ p = 0.02 , and $$t=4.2$$ t = 4.2 , $$p={3.2\times 10^{-5}}$$ p = 3.2 × 10 - 5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: $$-0.22\pm 0.05$$ - 0.22 ± 0.05 ; testosterone: $$-0.35\pm 0.15$$ - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: $$0.64\pm 0.15$$ 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.
Genome-wide association analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people
[article]
2021
bioRxiv
pre-print
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The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, we present a multicohort genome-wide association study (GWAS) of five traits assessed individually using
doi:10.1101/2021.11.04.466897
fatcat:zlkwrbchpfeilcn36lx5oicfcm
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... sychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13-0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.
Effectiveness of paediatric occupational therapy for children with disabilities: A systematic review
2019
Australian Occupational Therapy Journal
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., 2014; Hanna & Rodger, 2002; Howe & Wang, 2013; Kuhaneck, Madonna, Novak & Pearson, 2015; Lawler, Taylor & Shields, 2013; Tanner, Hand, O'toole & Lane, 2015; Zwi, Jones, Thorgaard, York & Dennis, 2011 ...
within practice cannot be made with certainty (Boyd & Hays, 2001; Brown & Burns, 2001; Case-Smith & Arbesman, 2008; Case-Smith et al., 2013; Case-Smith et al., 2014; Lang et al., 2012; May-Benson & Koomar ...
doi:10.1111/1440-1630.12573
pmid:30968419
pmcid:PMC6850210
fatcat:pfmedzwzrzgqbos2dh64wsdaee
Efectos de Programas Interprofesionales Terapéuticos Basados en el Juego para Niños con Discapacidades del Desarrollo
2020
Revista Chilena de Terapia Ocupacional
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Tanner, Schmidt, Martin, & Bassi, 2020) . ...
Durante esta sesión, algunos de los elementos de proceso de fidelidad a la Integración Sensorial de Ayres (ASI) (Parham, Roley, May-Benson, Koomar, Brett-Green, Burke, & Schaaf, 2011) como garantizar la ...
doi:10.5354/0719-5346.2020.60537
fatcat:ujq3rueijzf65efdaryag2basm
TiSAn: estimating tissue-specific effects of coding and non-coding variants
2018
Bioinformatics
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We also thank Tanner Koomar for editorial assistance with the manuscript.
Funding This work was supported by the National Institutes of Health [MH105527 and DC014489 to J.J.M.]. ...
doi:10.1093/bioinformatics/bty301
pmid:29912365
fatcat:md3ipz5nhnfzdc5n5teo6zprje