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However, the underlying neurobiological heterogeneity has impeded targeted therapies and requires new approaches to identifying clinically relevant bio-behavioural subgroups. In the largest autism cohort to date, we comprehensively examined difficulties in facial expression recognition, a key process in social communication, as a bio-behavioural stratification biomarker, and validated them against clinical features and neurofunctional responses.\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Between 255 and 488 participants aged 6\u201330\u00a0years with autism, typical development and\/or mild intellectual disability completed the Karolinska Directed Emotional Faces task, the Reading the Mind in the Eyes Task and\/or the Films Expression Task. We first examined mean-group differences on each test. Then, we used a novel intersection approach that compares two centroid and connectivity-based clustering methods to derive subgroups based on the combined performance across the three tasks. Measures and subgroups were then related to clinical features and neurofunctional differences measured using fMRI during a fearful face-matching task.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found significant mean-group differences on each expression recognition test. However, cluster analyses showed that these were driven by a low-performing autistic subgroup (~\u200930% of autistic individuals who performed below 2SDs of the neurotypical mean on at least one test), while a larger subgroup (~\u200970%) performed within 1SD on at least 2 tests. The low-performing subgroup also had on average significantly more social communication difficulties and lower activation in the amygdala and fusiform gyrus than the high-performing subgroup.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Limitations<\/jats:title>\n                <jats:p>Findings of autism expression recognition subgroups and their characteristics require independent replication. This is currently not possible, as there is no other existing dataset that includes all relevant measures. However, we demonstrated high internal robustness (91.6%) of findings between two clustering methods with fundamentally different assumptions, which is a critical pre-condition for independent replication.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We identified a subgroup of autistic individuals with expression recognition difficulties and showed that this related to clinical and neurobiological characteristics. If replicated, expression recognition may serve as bio-behavioural stratification biomarker and aid in the development of targeted interventions for a subgroup of autistic individuals.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13229-022-00520-7","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T16:05:43Z","timestamp":1668096343000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Facial expression recognition is linked to clinical and neurofunctional differences in autism"],"prefix":"10.1186","volume":"13","author":[{"given":"Hannah","family":"Meyer-Lindenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Moessnang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Oakley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumana","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Mason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J. 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Nat Rev Drug Discov. 2011;10(11):817\u201333.","journal-title":"Nat Rev Drug Discov"}],"container-title":["Molecular Autism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-022-00520-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13229-022-00520-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-022-00520-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T16:11:48Z","timestamp":1668096708000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularautism.biomedcentral.com\/articles\/10.1186\/s13229-022-00520-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["520"],"URL":"https:\/\/doi.org\/10.1186\/s13229-022-00520-7","relation":{},"ISSN":["2040-2392"],"issn-type":[{"value":"2040-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]},"assertion":[{"value":"10 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the local ethical committees of the participating centres, and written informed consent was obtained from all participants. For minors or those without capacity to consent, ethics consent was obtained from a parent or guardian. KCL, UCAM: London Queen Square Health Research, Authority Research Ethics Committee (ID\/reference number: 13\/LO\/1156). RUNMC, UMCU: Instituut Waarborging Kwaliteit en Veiligheid, Commissie Mensgebonden Onderzoek, Regio Arnhem-Nijmegen (Radboud University Medical Centre Institute Ensuring, Quality and Safety Committee on Research Involving Human Subjects Arnhem-Nijmegen) (ID\/reference number: 2013\/455). CIMH: UMM Universitatsmedizin Mannheim, Medizinische Ethik Commission II (UMM University Medical Mannheim, Medical Ethics Commission II) (ID\/reference number: 2014-540 N-MA). UCBM: Universit\u00e0 Campus Bio-Medico di Roma, Comitato Etico (University Campus Bio-Medical Ethics Committee of Rome) (ID\/reference number: 18\/14 PAR ComET CBM).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"JT is a paid consultant to F. Hoffmann-La Roche Ltd. TC has served as a paid consultant to F. Hoffmann-La Roche Ltd. and Servier and has received royalties from Sage Publications and Guilford Publications. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Takeda, and Infectopharm. He received conference support or speaker\u2019s fee by Lilly, Medice, and Takeda. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. AM-L has received consultant fees in the past two years from Boehringer Ingelheim, Elsevier, Lundbeck Int. Neuroscience Foundation, Lundbeck AS, The Wolfson Foundation, Thieme Verlag, Sage Therapeutics, von Behring Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, CISSN. Furthermore, he has received speaker fees from Italian Society of biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern. JB has been in the past 3\u00a0years a consultant to\/member of advisory board of\/and\/or speaker for Takeda\/Shire, Roche, Medice, Angelini, Janssen, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. EL is an Associate Editor at Molecular Autism.\u00a0DM has been paid for advisory board work by F. Hoffmann-La Roche Ltd. and Servier, and for editorial work by Springer. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"43"}}