| Examining the validity of the use of ratio IQs in psychological assessments | 10.15154/1522624 | IQ tests are amongst the most used psychological assessments, both in research and clinical settings. For participants who cannot complete IQ tests normed for their age, ratio IQ scores (RIQ) are routinely computed and used as a proxy of IQ, especially in large research databases to avoid missing data points. However, because it has never been scientifically validated, this practice is questionable. In the era of big data, it is important to examine the validity of this widely used practice. In this paper, we use the case of autism to examine the differences between standard full-scale IQ (FSIQ) and RIQ. Data was extracted from four databases in which ages, FSIQ scores and subtests raw scores were available for autistic participants between 2 and 17 years old. The IQ tests included were the MSEL (N=12033), DAS-II early years (N=1270), DAS-II school age (N=2848), WISC-IV (N=471) and WISC-V (N=129). RIQs were computed for each participant as well as the discrepancy (DSC) between RIQ and FSIQ. We performed two linear regressions to respectively assess the effect of FSIQ and of age on the DSC for each IQ test, followed by additional analyses comparing age subgroups as well as FSIQ subgroups on DSC. Participants at the extremes of the FSIQ distribution tended to have a greater DSC than participants with average FSIQ. Furthermore, age significantly predicted the DSC, with RIQ superior to FSIQ for younger participants while the opposite was found for older participants. These results question the validity of this widely used alternative scoring method, especially for individuals at the extremes of the normal distribution, with whom RIQs are most often employed. | 166/17423 | Secondary Analysis | Shared |
| The evolution and population diversity of human-specific segmental duplications | 10.15154/1338620 | Segmental duplications contribute to human evolution, adaptation and genomic instability but are often poorly characterized. We investigate the evolution, genetic variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs based on analysis of 322 deeply sequenced archaic and contemporary hominid genomes. We sequence 550 human and nonhuman primate genomic clones to reconstruct the evolution of the largest, most complex regions with protein-coding potential (n=80 genes/33 gene families). We show that HSDs are non-randomly organized, associate preferentially with ancestral ape duplications termed “core duplicons”, and evolved primarily in an interspersed inverted orientation. In addition to Homo sapiens-specific gene expansions (e.g., TCAF1/2), we highlight ten gene families (e.g., ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing, and no common gene-disruptive mutations are observed in the general population. Such duplicates are candidates for the evolution of human-specific adaptive traits. | 1/6360 | Primary Analysis | Shared |
| The importance of low IQ to early diagnosis of autism | 10.15154/1528140 | Some individuals can flexibly adapt to life’s changing demands while others, in particular those with Autism Spectrum Disorder (ASD), find it challenging. The origin of early individual differences in cognitive abilities, the putative tools with which to navigate novel information in life, including in infants later diagnosed with ASD remains unexplored. Moreover, the role of intelligence quotient (IQ) vis-à-vis core features of autism remains debated. We systematically investigate the contribution of early IQ in future autism outcomes in an extremely large, population-based study of 8,000 newborns, infants, and toddlers from the US between 2 and 68 months with over 15,000 cross-sectional and longitudinal assessments, and for whom autism outcomes are ascertained or ruled out by about 2-4 years. This population is representative of subjects involved in the National Institutes of Health (NIH)-funded research, mainly on atypical development, in the US. Analyses using predetermined age bins showed that IQ scores are consistently lower in ASD relative to TD at all ages (p<0.001), and IQ significantly correlates with calibrated severity scores (total CSS, as well as non-verbal and verbal CSS) on the ADOS. Note, VIQ is no better than the full-scale IQ to predict ASD cases. These findings raise new, compelling questions about potential atypical brain circuitry affecting performance in both verbal and nonverbal abilities and that precede an ASD diagnosis. This study is the first to establish prospectively that low early IQ is a major feature of ASD in early childhood. | 84/6323 | Secondary Analysis | Shared |
| Prognostic early snapshot stratification of autism based on adaptive functioning | 10.15154/0z1c-1d37 | A major goal of precision medicine is to predict prognosis based on individualized information at the earliest possible points in development. Using early snapshots of adaptive functioning and unsupervised data- driven discovery methods, we uncover highly stable early autism subtypes that yield information relevant to later prognosis. Data from the National Institute of Mental Health Data Archive (NDA) (n = 1,098) was used to uncover three early subtypes (<72 months) that generalize with 96% accuracy. Outcome data from NDA (n = 2,561; mean age, 13 years) also reproducibly clusters into three subtypes with 99% generalization accuracy. Early snapshot subtypes predict developmental trajectories in non-verbal cognitive, language and motor domains and are predictive of membership in different adaptive functioning outcome subtypes. Robust and prognosis- relevant subtyping of autism based on early snapshots of adaptive functioning may aid future research work via prediction of these subtypes with our reproducible stratification model. | 16/3517 | Secondary Analysis | Shared |
| The striatal matrix compartment is expanded in autism spectrum disorder. | 10.15154/khn8-jf08 | Background: Autism spectrum disorder (ASD) is the second-most common neurodevelopmental disorder in childhood. This complex developmental disorder that manifests with restricted interests, repetitive behaviors, and difficulties in communication and social awareness. The inherited and acquired causes of ASD impact many and diverse brain regions, challenging efforts to identify a shared neuroanatomical substrate for this range of symptoms. The striatum and its connections are among the most implicated sites of abnormal structure and/or function in ASD. Striatal projection neurons develop in segregated tissue compartments, the matrix and striosome, that are histochemically, pharmacologically, and functionally distinct. Immunohistochemical assessment of ASD and animal models of autism described abnormal matrix:striosome volume ratios, with an possible shift from striosome to matrix volume. Shifting the matrix:striosome ratio could result from expansion in matrix, reduction in striosome, spatial redistribution of the compartments, or a combination of these changes. Each type of ratio-shifting abnormality may predispose to ASD but yield different combinations of ASD features.
Methods: We developed a cohort of 426 children and adults (213 matched ASD-control pairs) and
performed connectivity-based parcellation (diffusion tractography) of the striatum. This identified voxels with matrix-like and striosome-like patterns of structural connectivity.
Results: Matrix-like volume was increased in ASD, with no evident change in the volume or organization of the striosome-like compartment. The inter-compartment volume difference (matrix minus striosome) within each individual was 31% larger in ASD. Matrix-like volume was increased in both caudate and putamen, and in somatotopic zones throughout the rostral-caudal extent of the striatum. Subjects with moderate elevations in ADOS (Autism Diagnostic Observation Schedule) scores had increased matrix-like volume, but those with highly elevated ADOS scores had 3.7-fold larger increases in matrix-like volume.
Conclusions: Matrix and striosome are embedded in distinct structural and functional networks, suggesting that compartment-selective injury or maldevelopment may mediate specific and distinct clinical features. Previously, assessing the striatal compartments in humans required post mortem tissue. Striatal parcellation provides a means to assess neuropsychiatric diseases for compartment-specific abnormalities in vivo. While this ASD cohort had increased matrix-like volume, other mechanisms that shift the matrix:striosome ratio may also increase the chance of developing the diverse social, sensory, and motor phenotypes of ASD.
| 16/2166 | Secondary Analysis | Shared |
| Unravelling the Collective Diagnostic Power Behind the Features in the Autism Diagnostic Observation Schedule | 10.15154/1421921 | Background: Autism is a group of heterogeneous disorders defined by deficits in social interaction and communication. Typically, diagnosis depends on the results of a behavioural examination called the Autism Diagnostic Observation Schedule (ADOS). Unfortunately, administration of the ADOS exam is time-consuming and requires a significant amount of expert intervention, leading to delays in diagnosis and access to early intervention programs. The diagnostic power of each feature in the ADOS exam is currently unknown. Our hypothesis is that certain features could be removed from the exam without a significant reduction in diagnostic accuracy, sensitivity or specificity.
Objective: Determine the smallest subset of predictive features in ADOS module-1 (an exam variant for patients with minimal verbal skills).
Methodology: ADOS module-1 datasets were acquired from the Autism Genetic Resource Exchange and the National Database for Autism Research. The datasets contained 2572 samples with the following labels: autism (1763), autism spectrum (513), and non-autism (296). The datasets were used as input to 4 different cost-sensitive classifiers in Weka (functional trees, LADTree, logistic model trees, and PART). For each classifier, a 10-fold cross validation was preformed and the number of predictive features, accuracy, sensitivity, and specificity was recorded.
Results & Conclusion: Each classifier resulted in a reduction of the number of ADOS features required for autism diagnosis. The LADtree classifier was able to obtain the largest reduction, utilizing only 10 of 29 ADOS module-1 features (96.8% accuracy, 96.9% sensitivity, and 95.9% specificity). Overall, these results are a step towards a more efficient behavioural exam for autism diagnosis.
| 3/1832 | Secondary Analysis | Shared |
| Imbalanced social-communicative and restricted repetitive behavior subtypes in autism spectrum disorder exhibit different neural circuitry | 10.15154/1524418 | Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry. | 14/1708 | Secondary Analysis | Shared |
| Derivation of Brain Structure Volumes from MRI Neuroimages hosted by NDAR using C-PAC pipeline and ANTs | 10.15154/1165646 | An automated pipeline was developed to reference Neuroimages hosted by the National Database for Autism Research (NDAR) and derive volumes for distinct brain structures using Advanced Normalization Tools (ANTs) and the Configurable-Pipeline for the Analysis of Connectomes (C-PAC) platform. This pipeline utilized the ANTs cortical thickness methodology discuessed in "Large-Scale Evaluation of ANTs and Freesurfer Cortical Tchickness Measurements" [http://www.ncbi.nlm.nih.gov/pubmed/24879923] to extract a cortical thickness volume from T1-weighted anatomical MRI data gathered from the NDAR database. This volume was then registered to an stereotaxic-space anatomical template (OASIS-30 Atropos Template) which was acquired from the Mindboggle Project webpage [http://mindboggle.info/data.html]. After registration, the mean cortical thickness was calculated at 31 ROIs on each hemisphere of the cortex and using the Desikan-Killiany-Tourville (DKT-31) cortical labelling protocol [http://mindboggle.info/faq/labels.html] over the OASIS-30 template.
**NOTE: This study is ongoing; additional data my be available in the future.**
As a result, each subject that was processed has a cortical thickness volume image and a text file with the mean thickness ROIs (in mm) stored in Amazon Web Services (AWS) Simple Storage Service (S3). Additionally, these results were tabulated in an AWS-hosted database (through NDAR) to enable simple, efficient querying and data access.
All of the code used to perform this analysis is publicly available on Github [https://github.com/FCP-INDI/ndar-dev]. Additionally, as a computing platform, we developed an Amazon Machine Image (AMI) that comes fully equipped to run this pipeline on any dataset. Using AWS Elastic Cloud Computing (EC2), users can launch our publicly available AMI ("C-PAC with benchmark", AMI ID: "ami-fee34296", N. Virginia region) and run the ANTs cortical thickness pipeline. The AMI is fully compatible with Sun Grid Engine as well; this enables users to perform many pipeline runs in parallel over a cluster-computing framework. | 107/1428 | Secondary Analysis | Shared |
| Derivation of Brain Structure Volumes from MRI Neuroimages hosted by NDAR using LONI Workflows | 10.15154/1169189 | LONI utilized de-identified data from NDAR's cloud and a LONI Pipeline (pipeline.loni.usc.edu) processing workflow to perform a secondary structural MRI examination. The workflow used in this study pulls data from and provided by NDAR to an instance on the LONI compute cluster, aligns data to a standard orientation using FSLreorient2stsd, and undergoes further image processing to eventually identify, extract, and analyze cortical and sub-cortical structures in different MRI brain volumes. Two methods were used for this image processing: the first uses Freesurfer Recon_All to extract brain cortical parcellation and surfaces, align the data to an atlas, and identify, and analyze regions of interest; the second uses FSL to extract the brain (BET), align the data to an atlas, and extract ROIs including sub-cortical regions using FSL FIRST. The second method also uses Freesurfer (mri_segstats) to perform statistical analysis of these ROIs. Lastly, the LONI Pipeline workflow updates and returns the data processed and extracted by Freesurfer and FSL as a miNDAR back to NDAR's cloud storage instance. These results can be used to assess quality control or be used to perform post-hoc comparisons of cortical and sub-cortical brain architecture between subject types. See also, Torgerson et al. (2015) Brain Imaging and Behavior, for additional details on using LONI Pipeline to access and process NDAR data. | 106/740 | Secondary Analysis | Shared |
| Derivation of Quality Measures for Structural Images by Neuroimaging Pipelines | 10.15154/1149599 | Using the National Database for Autism Research cloud platform, MRI data were analyzed using neuroimaging pipelines that included packages available as part of the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) Computational Environment to derive standardized measures of MR image quality. Structural QA was performed according to Haselgrove, et al (http://journal.frontiersin.org/Journal/10.3389/fninf.2014.00052/abstract) to provide values for Signal to Noise (SNR) and Contrast to Noise (CNR) Ratios that can be compared between subjects within NDAR and between other public data releases. | 108/423 | Secondary Analysis | Shared |
| Derivation of Brain Structure Volumes from MRI Neuroimages hosted by NDAR using NITRC-CE | 10.15154/1149600 | A draft publication is in progress.
GitHub repository with code for working with NDAR Data is available here: https://github.com/chaselgrove/ndar
**Note this study is ongoing; additional may be added.** | 107/356 | Secondary Analysis | Shared |
| Derivation of Quality Measures for Time-Series Images by Neuroimaging Pipelines | 10.15154/1149598 | Using the National Database for Autism Research cloud platform, MRI data were analyzed using neuroimaging pipelines that included packages available as part of the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) Computational Environment to derive standardized measures of MR image quality. Time series QA was performed according to Friedman, et al. (http://www.ncbi.nlm.nih.gov/pubmed/16952468) providing values for Signal to Noise Ratio that can be compared to other subjects. | 107/356 | Secondary Analysis | Shared |
| comparing EEG metrics during eyes closed versus eyes open rest in autism | 10.15154/1528590 | Understanding the complex relationship between brain dynamics and mental disorders has proved difficult. Sample sizes have often been small, and brain dynamics have often been evaluated in only one state. Here, data obtained from the NIMH data archive were used to create a sample of 395 individuals with both eyes open and eyes closed resting state EEG data. All data were submitted to a standard pipeline to extract power spectra, peak alpha frequency, the slope of the 1/f curve, multi scale sample entropy, phase amplitude coupling, and intersite phase clustering. These data along with the survey data collected at the time of data collection form a valuable resource for interogating the relationship between brain state changes and autism diagnosis. | 3/336 | Secondary Analysis | Shared |
| Mapping Along-Tract Commissural and Association White Matter Microstructural Differences in Autistic Children and Young Adults | 10.15154/91w9-gc71 | Previous diffusion magnetic resonance imaging (dMRI) research has indicated altered white matter microstructure in autism, but the implicated regions are inconsistent across studies. Such prior work has largely used conventional dMRI analysis methods, including the traditional microstructure model, diffusion tensor imaging (DTI). However, these methods are limited in their ability to precisely map microstructural differences and accurately resolve complex fiber configurations. In our study, we investigated white matter microstructure alterations in autism using the refined along-tract analytic approach, BUndle ANalytics (BUAN), with both an advanced microstructure model, the tensor distribution function (TDF) and DTI. We analyzed dMRI data from 365 autistic and neurotypical participants (5-24 years; 34% female) from 10 cohorts to examine commissural and association tracts. Autism was associated with lower fractional anisotropy and higher diffusivity in localized portions of nearly every commissural and association tract examined; these tracts inter-connected a wide range of brain regions, including frontal, temporal, parietal, and occipital regions. Taken together, BUAN and TDF allow robust and spatially precise mapping of microstructural properties in autism. Our findings rigorously demonstrate that white matter microstructure alterations in autism may be greater within specific regions of individual tracts, and that the implicated tracts are distributed across the brain. | 1/259 | Secondary Analysis | Shared |
| Cortico-Basal Ganglia Brain Structure and Links to Restricted, Repetitive Behavior in Autism Spectrum Disorder | 10.15154/1528130 | Restricted repetitive behavior (RRB) is one of two criteria domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding alterations associated with RRB. In this study we utilized neuroimaging data available from the National Database for Autism Research to assess volume in the basal ganglia and cerebellum, as well as microstructure in basal ganglia and cerebellar white matter tracts in ASD. We also investigated whether these measures differed between males and females with ASD, and how these factors correlated with clinical measures of RRB from the same individuals. We found that individuals with ASD had significant differences in free-water corrected fractional anisotropy (FAT) and free-water in cortico-basal ganglia white matter tracts, but that these measures did not differ between males versus females with ASD. Moreover, both FAT and free-water in these tracts were significantly correlated with measures of RRB. Despite no differences in volumetric measures in basal ganglia and cerebellum, these findings suggest the links between RRB and brain structure are within specific cortico-basal ganglia white matter tracts. | 2/192 | Secondary Analysis | Shared |