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, We recognize the many investigators who contributed research that we cannot 1511 cite due to space limits. C.L. is supported by the Eunice Kennedy Shriver National Institute of Child 1512 Health and Human Development (NICHHD; R01 HD081199), the National Institute of Mental Health 1513 (NIMH; R01MH081873-01A1) and the Simons Foundation. T.S.B. is supported by grants from the Health 1514 and Social Care Information Centre, Leeds, and the National Institute for Health Research (NIHR HTA 1515 [Grant ref NIHR127337]). T.C. is supported by grants from Innovative Medicines Initiative 2 (No 777394), 1516 the Medical Research Council (MRC; grants MR/K021389/1), and the NIHR (grant 13/119/18). J.C. is 1517 funded by Autistica, Task Sharing, and Early Intervention. Curr. Treat. Options Psychiatry, 2019.

, ES/R009368/1), the Innovative Medicines Initiative, vol.2

, Simons Foundation (609081). R.J. would like to acknowledge the Mortimer D. Sackler Family and the 1521 NIMH: R01MH114999. J.L.T. is supported by grants from the FAR fund and the National Institutes of 1522 Mental Health (R34 MH104428, R03 MH 112783, p.1523

, Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College 1524

N. London and . Nf-si, the 1526 Overlook International Foundation and the Simons Foundation. J.V. is supported by the National 1527 Institutes of Health (NIH; MH016434, MH094604), the Simons Foundation, 0617-10120. M.S. is supported by the National Institute of Health (NIH, 1525 MH106934, MH109901, MH110928, MH116487 MH102342, MH111662, MH105575, MH115747), 1528.

, Psychiatric Institute. The views expressed are those of the authors and not necessarily those of the NHS, 1529 the NIHR or the Department of Health and Social Care

, All authors read and edited the full document. Introduction (C.L.), Epidemiology (T, p.1533

G. W. Mechanisms/pathophysiology-(m, R. M. , T. C. , and E. J. , Diagnosis, screening and prevention 1534, p.1535

(. C. Outlook and A. P. , Overview of Primer (C.L.)

, Competing Interests

C. , acknowledges the receipt of royalties from Western Psychological Services for the sale of the Autism 1539 Diagnostic Interview-Revised (ADIR), the Autism Diagnostic Observation Schedule (ADOS) and the Social 1540 Communication Questionnaire (SCQ). T.S.B. has received royalties from, p.1541

, T.F. has received federal funding 1543 research support from, acted as a consultant to, received travel support from, and/or received a 1544 speaker's honorarium from the Brain and Behavior Research Foundation, p.1545

, Ingalls Foundation, IntegraGen , Kugona LLC, 1546 National Institutes of Health, Roche Pharma, Shire Development and the Simons Foundation

, Western Psychological Services. M.S. serves on the scientific 1549 advisory boards and has stock or stock options for ARett Pharmaceuticals and BlackThorn Therapeutics

J. , has consulted or served on an advisory board for Novartis, Roche Pharmaceuticals and SynapDx, has 1551 received research funding from Forest, p.1552

. Synapdx, W. J. Springer, E. J. , R. J. , and G. D. ,

, Publisher's note

, Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional 1557 affiliations

, Peer review information

, Other proposed mechanisms include 1579 maturational lags in neurophysiology 94 andcognitive mechanisms such as joint engagement 176,261 . With 1580 the search for pathways to and sometimes out of autism 262 on many levels, conceptualization of 1581 positive outcomes has been more recent, but has also varied markedly. In the 1970s, autism societies 1582 and collaborative clinical programs focused on community integration and de-institutionalization (such 1583 as National Autistic Society (NAS) and National Society for Autistic Children (NSAC)) 263 . Priorities shifted 1584 in the 1980s and 1990s, with still unreplicated claims of 'recovery' in children who participated in 1585 intensive behavioural interventions 179 , new advocacy groups focusing on biomedical discoveries to yield 1586 potential biological treatments and even 'cures' (such as National Alliance for Autism Research (NAAR) 1587 and Cure Autism Now 255 ) and the neurodiversity movement 264 which rejected 'cures' and called for 1588 adaptation of environments to support autistic people, using terminology preferred by self-advocates 1589 and community participation. Recognition of the marked heterogeneity within autism began in the 1590 1970's with the triad of impairments in language, play and social interaction characterizing many 1591 children with intellectual disabilities (ID) or those with classical autism 265 . The first twin study 1592 demonstrated that monozygotic twin pairs, Nature Reviews Disease Primers thanks P. Szatmari, S. Spence and the other, anonymous, reviewer(s) 1561 for their contribution to the peer review of this work. 1562 1563 1564 Original descriptions of the cardinal features of autism were attributed to a range of causes including 1574 being raised by wolves (the Wild Boy of Aveyron)

, Thus, developmental aspects of differences in strengths, difficulties and trajectories, as well as biological 1596 factors, require highly personalized conceptualizations of the needs of autistic individuals and their 1597 families. ABA, applied behaviour analysis; AGRE, Autism Genetic Resource Exchange; CDC, US Centers 1598 for Disease Control and Prevention

, Diagnostic and Statistical Manual of Mental Disorders; EEG, 1599 electroencephalography; GRASP, Global and Regional Asperger Syndrome Partnership ;IDEA, Individuals 1600 with Disabilities Education Act; MCEP, the gene associated with Rett Syndrome; PACT, Preschool Autism 1601 Communication Trial; PDD, pervasive developmental disorder; SNAP, Special Needs and Autism Project; 1602 SPARK, Simons Foundation Powering Autism Research for Knowledge

, Figure 2. Environmental risk factors for autism

, 1607 those with evidence supporting an association (panel a), those with inconclusive evidence (panel b) and 1608 importantly, those with no supporting evidence (panel c). Bars represent ranges. *Represents 1609 recurrence risk. Figure adapted from 18 with added findings from select reviews and empirical papers: 1610 neonatal hypoxia estimate 267 , childhood vaccines 20 , valporate use during pregnancy 268 , parent age 1611 estimates 269 , preterm birth estimate 270,271 , maternal obesity estimate 272 , folic acid intake estimate 273 , 1612 siblings estimate 274, Data from studies aiming to identify risk factors for autism can be broadly split into three categories, vol.275

, Box 2. Global challenges in autism research

, Recently, there have been calls for more attention to, global issues in autism research, vol.251