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      Unsupervised data-driven stratification of mentalizing heterogeneity in autism

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          Abstract

          Individuals affected by autism spectrum conditions (ASC) are considerably heterogeneous. Novel approaches are needed to parse this heterogeneity to enhance precision in clinical and translational research. Applying a clustering approach taken from genomics and systems biology on two large independent cognitive datasets of adults with and without ASC (n = 694; n = 249), we find replicable evidence for 5 discrete ASC subgroups that are highly differentiated in item-level performance on an explicit mentalizing task tapping ability to read complex emotion and mental states from the eye region of the face (Reading the Mind in the Eyes Test; RMET). Three subgroups comprising 45–62% of ASC adults show evidence for large impairments (Cohen’s d = −1.03 to −11.21), while other subgroups are effectively unimpaired. These findings delineate robust natural subdivisions within the ASC population that may allow for more individualized inferences and accelerate research towards precision medicine goals.

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          Most cited references 32

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          Autism spectrum disorders: developmental disconnection syndromes.

          Autism is a common and heterogeneous childhood neurodevelopmental disorder. Analogous to broad syndromes such as mental retardation, autism has many etiologies and should be considered not as a single disorder but, rather, as 'the autisms'. However, recent genetic findings, coupled with emerging anatomical and functional imaging studies, suggest a potential unifying model in which higher-order association areas of the brain that normally connect to the frontal lobe are partially disconnected during development. This concept of developmental disconnection can accommodate the specific neurobehavioral features that are observed in autism, their emergence during development, and the heterogeneity of autism etiology, behaviors and cognition.
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            The role of age and verbal ability in the theory of mind task performance of subjects with autism.

             F Happé (1995)
            A number of studies have reported that most children with autism fail theory of mind tasks. It is unclear why certain children with autism pass such tests and what might be different about these subjects. In the present study, the role of age and verbal ability in theory of mind task performance was explored. Data were pooled from 70 autistic, 34 mentally handicapped, and 70 normal young subjects, previously tested for a number of different studies. The analysis suggested that children with autism required far higher verbal mental age to pass false belief tasks than did other subjects. While normally developing children had a 50% probability of passing both tasks at the verbal mental age of 4 years, autistic subjects took more than twice as long to reach this probability of success (at the advanced verbal mental age of 9-2). Possible causal relations between verbal ability and the ability to represent mental states are discussed.
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              Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders.

              Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                18 October 2016
                2016
                : 6
                Affiliations
                [1 ]Center for Applied Neuroscience, Department of Psychology, University of Cyprus , Nicosia, Cyprus
                [2 ]Autism Research Centre, Department of Psychiatry, University of Cambridge , Cambridge, UK
                [3 ]Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Department of Psychiatry, University of Toronto , Toronto, Canada
                [4 ]Department of Psychiatry, National Taiwan University Hospital and College of Medicine , Taipei, Taiwan
                [5 ]School of Philosophy, Psychology and Language Sciences, Department of Psychology, University of Edinburgh , Edinburgh, UK
                [6 ]Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading , Reading, UK
                [7 ]Brain Mapping Unit, Department of Psychiatry, University of Cambridge , Cambridge, UK
                [8 ]Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge , United Kingdom
                [9 ]Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London, UK
                [10 ]Autism Research Group, Department of Psychiatry, University of Oxford, UK
                [11 ]MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London , London, UK
                [12 ]Department of Child & Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe-University , Frankfurt am Main, Germany
                [13 ]National Autism Unit, Bethlem Royal Hospital, SLAM NHS Foundation Trust , UK
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep35333
                10.1038/srep35333
                5067562
                27752054
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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