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      The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

      research-article
      1 , 2 , , 3 , 4 , 3 , 4 , 5 , 2 , 6 , 7 , 8 , 9 , 10 ,   6 , 10 , 11 , 5 , 10 , 12 , 13 , 14 , 11 , 11 , 6 , 15 , 2 , 11 , 1 , 2 , 14 , 9 , 1 , 16 , 2 , 17 , 18 , 17 , 2 , 19 , 18 , 6 , 4 , 13 , 20 , 21 , 6 , 22 , 18 , 6 , 23 , 5 , 9 , 24 , 24 , 10 , 11 , 11 , 9 , 25 , 8 , 26 , 6 , 27 , 2 , 8 , 2 , 28 , 14 , 24 , 6 , 5 , 11 , 18 , 1 , 2 , 11
      Molecular Autism
      BioMed Central
      Biomarkers, Cognition, Neuroimaging, MRI, EEG, Eye-tracking, Genetics

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD.

          Methods

          LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability.

          Results

          Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted).

          Conclusion

          We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13229-017-0146-8) contains supplementary material, which is available to authorized users.

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          Most cited references71

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          Mechanisms of gamma oscillations.

          Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.
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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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              Distinct genetic influences on cortical surface area and cortical thickness.

              Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51-59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.
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                Author and article information

                Contributors
                eva.loth@kcl.ac.uk
                tony.charman@kcl.ac.uk
                xxlukexx@gmail.com
                Julian.tillmann@kcl.ac.uk
                ubejon01@mail.bbk.ac.uk
                caroline.wooldridge@kcl.ac.uk
                jumana.ahmad@kcl.ac.uk
                ba251@medschl.cam.ac.uk
                c.brogna@unicampus.it
                s.ambrosinodibruttopilo-3@umcutrecht.nl
                tobias.banaschewski@zi-mannheim.de
                sb205@cam.ac.uk
                sarah.baumeister@zi-mannheim.de
                c.beckmann@donders.ru.nl
                michael.brammer@kcl.ac.uk
                daniel.brandeis@zi-mannheim.de
                Sven.bolte@ki.se
                thomasb@pasteur.fr
                Carsten.Bours@radboudumc.nl
                Yvette.deBruijn@radboudumc.nl
                bc249@cam.ac.uk
                daisy.crawley@kcl.ac.uk
                Ineke.Cornelissen@radboudumc.nl
                flavio.dellacqua@kcl.ac.uk
                guillaume.dumas@pasteur.fr
                sarahdurston@gmail.com
                christine.ecker@kcl.ac.uk
                jessica.faulkner@kcl.ac.uk
                vincent.frouin@cea.fr
                pilar.garces@roche.com
                David.GOYARD@cea.fr
                hannah.hayward@kcl.ac.uk
                lindsay_mark.ham@roche.com
                joerg.hipp@roche.com
                rh465@medschl.cam.ac.uk
                mark.johnson@bbk.ac.uk
                johan.isaksson@ki.se
                prantik.kundu@mssm.edu
                mcl45@cam.ac.uk
                xavier.liogier_dardhuy@roche.com
                mvlombardo@gmail.com
                davelythgoe@gmail.com
                rmandl@umcutrecht.nl
                A.Meyer-Lindenberg@zi-mannheim.de
                carolin.moessnang@zi-mannheim.de
                nico.mueller@zi-mannheim.de
                larodwyer@gmail.com
                M.Oldehinkel@donders.ru.nl
                B.Oranje-2@umcutrecht.nl
                gpandina@its.jnj.com
                apersico@unime.it
                ar560@cam.ac.uk
                barbara.ruggeri@kcl.ac.uk
                jessica.ebrahimi-sabet@kcl.ac.uk
                R.Sacco@unicampus.it
                antonia.sanjose@kcl.ac.uk
                emily.simonoff@kcl.ac.uk
                rto@pasteur.fr
                heike.tost@zi-mannheim.de
                jdw72@medschl.cam.ac.uk
                steve.williams@kcl.ac.uk
                m.zwiers@fcdonders.ru.nl
                will.spooren@roche.com
                declan.murphy@kcl.ac.uk
                J.Buitelaar@psy.umcn.nl
                Journal
                Mol Autism
                Mol Autism
                Molecular Autism
                BioMed Central (London )
                2040-2392
                23 June 2017
                23 June 2017
                2017
                : 8
                : 24
                Affiliations
                [1 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; De Crespigny Park, Denmark Hill, London, SE5 8AF UK
                [2 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; De Crespigny Park, Denmark Hill, London, SE5 8AF UK
                [3 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Clinical Child Psychology, Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; De Crespigny Park, Denmark Hill, London, SE5 8AF UK
                [4 ]ISNI 0000 0001 2161 2573, GRID grid.4464.2, Centre for Brain and Cognitive Development, Birkbeck, , University of London, ; Henry Wellcome Building, Malet Street, London, WC1E 7HX UK
                [5 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; De Crespigny Park, Denmark Hill, London, SE5 8AF UK
                [6 ]ISNI 0000000121885934, GRID grid.5335.0, Autism Research Centre, Department of Psychiatry, , University of Cambridge, ; Douglas House, 18b Trumpington Road, Cambridge, CB2 8AH UK
                [7 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Department of Psychology, The School of Philosophy, Psychology, and Language Sciences, , University of Edinburgh, ; Dugald Stewart Building, 3 Charles Street, Edinburgh, EH8 9AD UK
                [8 ]ISNI 0000 0004 1757 5329, GRID grid.9657.d, , University Campus Bio-Medico, ; via Álvaro del Portillo, 21, Rome, Italy
                [9 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Psychiatry, Brain Center Rudolf Magnus, , University Medical Center Utrecht, ; Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
                [10 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, , University of Heidelberg, ; J5, 68159 Mannheim, Germany
                [11 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Donders Institute for Brain, Cognition and Behaviour, , Radboud University Nijmegen Medical Centre, ; Kapittelweg 29, 6525 EN Nijmegen, The Netherlands
                [12 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, , University of Zürich, ; Neumünsterallee 9, 8032 Zürich, Switzerland
                [13 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, , Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND), ; Stockholm, Sweden
                [14 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Human Genetics and Cognitive Functions Unit, , Institut Pasteur, ; 25 Rue du Docteur Roux, Paris, Cedex 15 France
                [15 ]ISNI 0000 0004 0457 9566, GRID grid.9435.b, Centre for Autism, School of Psychology and Clinical Language Sciences, , University of Reading, ; Whiteknights, Reading, RG6 6AL UK
                [16 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, , Goethe University, ; Deutschordenstrasse 50, 60528 Frankfurt, Germany
                [17 ]Neurospin Centre CEA, Saclay, 91191 Gif sur Yvette, France
                [18 ]Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, B.001 N.667, CH-4070 Basel, Switzerland
                [19 ]Regulatory Affairs, Product Development, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
                [20 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Neuroscience, , Uppsala University, ; Uppsala, Sweden
                [21 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Radiology, , Icahn School of Medicine at Mount Sinai, ; NY, USA
                [22 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Child and Youth Mental Health Collaborative, Centre for Addiction and Mental Health and The Hospital for Sick Children, Department of Psychiatry, , University of Toronto, ; 80, Workman Way, Toronto, ON M6J 1H4 Canada
                [23 ]ISNI 0000000121167908, GRID grid.6603.3, Center for Applied Neuroscience, Department of Psychology, , University of Cyprus, ; PO Box 20537, 1678 Nicosia, Cyprus
                [24 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, , University of Heidelberg, ; 68159 Mannheim, Germany
                [25 ]Janssen Research & Development, 1125 Trenton Harbourton Road, Titusville, NJ 08560 USA
                [26 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Child and Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, , University of Messina, ; Via Consolare Valeria 1, I-98125 Messina, Italy
                [27 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; Denmark Hill, London, UK
                [28 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Child and Adolescent Psychiatry, Institute of Psychology, Psychiatry and Neuroscience, , King’s College London, ; De Crespigny Park, Denmark Hill, London, SE5 8AF UK
                Author information
                http://orcid.org/0000-0001-9458-9167
                Article
                146
                10.1186/s13229-017-0146-8
                5481887
                28649312
                8f6cbf7c-3ef8-410d-8e0d-9353f480f48e
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 November 2016
                : 19 May 2017
                Funding
                Funded by: Innovative Medicines Initiative
                Award ID: FP7/2007-2013
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurosciences
                biomarkers,cognition,neuroimaging,mri,eeg,eye-tracking,genetics
                Neurosciences
                biomarkers, cognition, neuroimaging, mri, eeg, eye-tracking, genetics

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