10 - ASD, Lord 2018

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Nat Rev Dis Primers. Author manuscript; available in PMC 2022 March 07.
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Published in final edited form as:

Nat Rev Dis Primers. ; 6(1): 5. doi:10.1038/s41572-019-0138-4.
Autism spectrum disorder

Catherine Lord1,*, Traolach S. Brugha2, Tony Charman3, James Cusack4, Guillaume
Dumas5, Thomas Frazier6, Emily J. H. Jones7, Rebecca M. Jones8,9, Andrew Pickles3,
Matthew W. State10, Julie Lounds Taylor11, Jeremy Veenstra-VanderWeele12
1Departments of Psychiatry and School of Education, University of California, Los Angeles, Los
Angeles, CA, USA.
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2Department of Health Sciences, University of Leicester, Leicester, UK.

3Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.
4Autistica, London, UK.
5Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France.
6Autism Speaks, New York, NY, USA.
7Centre for Brain & Cognitive Development, University of London, London, UK.
8The Sackler Institute for Developmental Psychobiology, New York, NY, USA.
9The Center for Autism and the Developing Brain, White Plains, NY, USA.
10Departmentof Psychiatry, Langley Porter Psychiatric Institute and Weill Institute for
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Neurosciences, University of California, San Francisco, CA, USA.

11Department of Pediatrics and Vanderbilt Kennedy Center, Vanderbilt University Medical Center,
Nashville, TN, USA.
12Department of Psychiatry, Columbia University, New York, NY, USA.
Abstract
Autism spectrum disorder is a construct used to describe individuals with a specific combination
of impairments in social communication and repetitive behaviours, highly restricted interests
and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just
under 1%, but estimates are higher in high-income countries. Although gross brain pathology is
not characteristic of autism, subtle anatomical and functional differences have been observed in
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post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate
measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic
findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial
interventions in children can improve specific behaviours, such as joint attention, language and
social engagement, that may affect further development and could reduce symptom severity.
*
[email protected] .
Author Contributions
All authors read and edited the full document. Introduction (C.L.), Epidemiology (T.S.B.), Mechanisms/pathophysiology (M.W.S.,
G.D., R.M.J., T.C. and E.J.H.J.), Diagnosis, screening and prevention (T.C., E.J.H.J. and T.S.B.), Management (T.S.B., T.C., E.J.H.J.,
J.L.T. and J.V.-V.), Quality of life (J.L.T., J.C. and T.F.), Outlook (C.L. and A.P.), Overview of Primer (C.L.).
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However, further research is necessary to identify the long-term needs of people with autism,
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and treatments and the mechanisms behind them that could result in improved independence
and quality of life over time. Families are often the major source of support for people with
autism throughout much of life and need to be considered, along with the perspectives of autistic
individuals, in both research and practice.
Autism spectrum disorder (ASD), also known as autism, is a common, highly heritable
and heterogeneous neurodevelopmental disorder that has underlying cognitive features and
commonly co-occurs with other conditions. The behaviours, strengths and challenges of
people with autism have attracted the attention of scientists and clinicians for at least 500
years (FIG. 1). Autism is a heterogeneous disorder and, reflecting this heterogeneity, the
term autism has been used in various ways to describe both a broader presentation as well as
a specific diagnosis following its consideration as a subgroup within the general diagnostic
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category of ‘pervasive developmental disorders’ (PDDs). PDDs are a group of disorders

introduced in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition
(DSM-III) in 1980 to convey the idea of a broader spectrum of social communication
deficits. Owing to a lack of clear borders between the PDDs and difficulties in reliably
distinguishing them, the most recent diagnostic systems, the International Classification of
Diseases 11th Revision (ICD-11) and DSM-5 use the umbrella term ‘ASD’, and differentiate
individuals using additional clinical specifiers and modifiers. In this Primer, we use the term
‘autism’ to refer to ASD in general, both for brevity and out of respect for the preferences of
self-advocates.
Manifestations of autism include impairments in social communication and interaction,

sensory anomalies, repetitive behaviours and varying levels of intellectual disability (BOX
1). Together with these core symptoms, co-occurring psychiatric or neurological disorders
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are common in people with autism, of which hyperactivity and attention disorders (such
as attention-deficit/hyperactivity disorder (ADHD)), anxiety, depression and epilepsy are
fairly prevalent. A diagnosis of autism is reached after obtaining a detailed developmental
history, often from the parents, and observation of the individual interacting with parents
or other individuals1,2. Early intervention for children with autism is key owing to
common difficulties in communication. The types of interventions used change throughout
life and include parent-mediated interventions and/or therapist-delivered interventions
in childhood, and school-based strategies and techniques to promote independence in
adulthood. Pharmacological therapies can be used to treat some of the associated symptoms
of autism, such as irritability, and comorbidities, such as anxiety.
This Primer discusses the epidemiology and mechanisms of autism, together with the
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diagnosis and treatment of people with this condition. Three themes are addressed:
mechanisms of causality and change over time, heterogeneity within and between
individuals with autism, and outcomes across the lifespan.
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Epidemiology
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Prevalence
Epidemiological administrative and community-based studies have suggested that autism
is more common in males than in females, with reported ratios ranging from 2:1 to 5:1,
with an estimate of 4:1 in the 2010 Global Burden of Disease study3,4. The sex ratio is
slightly lower in studies that use population-wide testing to find community cases within a
population than in the more common passive case-finding studies that review administrative
data (for example, medical or special educational records), which may result in less
plausible associations and may, therefore, artificially increase prevalence estimates5. Active
case-finding that does not rely on administrative records has demonstrated an equivalent
community rate of autism in men and women with moderate-to-profound intellectual
disability4. Thus, even the most widely accepted tenet of our understanding of factors
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associated with autism is far from straightforward.
Estimates of the prevalence of autism in various populations and settings differ according to
the method of ascertainment used in the study, including definition, sampling and the extent
of independent population case assessment in contrast to administratively based sources.
Of note, the Global Burden of Disease study uses all known data from administrative
and community survey sources on a disease or disorder to model associations (particularly
with time) to examine trends. In the 2010 Global Burden of Disease study, an estimated
52 million people had autism globally, equating to a prevalence of 1 in 132 individuals6.
Worldwide, little interpretable variation in the prevalence of autism between regions,
ethnicities or services and resource provision has been reported. Indeed, one systematic
review did not find a strong effect of ethnic, cultural or socioeconomic factors on the
prevalence of autism7. However, statistical power to detect any effects was limited in
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the available data sets, particularly in low-income countries. An increased prevalence of

autism has been reported in migrant groups in some studies8, with few clear factors that
might contribute to a greater prevalence in an Afro-Caribbean population in higher-income
countries9–11 in the absence of any evidence of geographical variation7. However, a survey
of adults in the general population has shown that rates of autism in black and minority
ethnic groups may be lower than in the rest of the population12; data from indigenous and
Aboriginal cultures are very limited.
Many individuals and groups presume that rates of autism are increasing over time, but
this supposition is based on data from administrative records rather than community-based
studies. Indeed, after accounting for methodological variations between studies, there was
no clear evidence of a change in the prevalence of autism in the community between 1990
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and 2010 (REF.13). In addition, general population and systematic case-finding community-
based surveys (including testing of representative populations) have also confirmed the
lack of significant change in prevalence rates in childhood14 and adulthood15 over time.
No significant evidence is available supporting that autism is rarer in older people, which
provides further evidence against the suggestion that autism is increasing in prevalence over
time4. Even in high-income countries with strong autism public health policies, there is
evidence that autism in adults goes largely unrecognized, whereas administratively recorded
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diagnoses in children increase year by year16. This finding highlights the importance of
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obtaining information on autism rates in settings where professionals may be able to

improve its recognition. The prevalence of autism in mental health inpatient settings is
estimated to be far higher than in the general population, ranging from 4% to 9.9%17.
Environmental factors
One review of systematic reviews and meta-analyses of environmental risk factors for autism
included a comprehensive coverage of the literature, a discussion of the limitations of
research and the need for long-term prospective cohort-based studies to begin to address
these limitations18 (FIG. 2). This review and other studies identified environmental risk
factors for autism as advanced parental age19 and birth trauma, particularly if due to
proxies of hypoxia18. Moreover, maternal obesity, a short interval between pregnancies,
gestational diabetes mellitus and valproate use during pregnancy have all been associated
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with increased risk of autism (FIG. 2). However, it should be noted that these factors cannot
be considered causal, but could be reactive, independent or contributory for autism. Studies
evaluating risk factors for autism that have reported an absence of association are equally,
if not more, important to note, including clear evidence that autism is not associated with
vaccination20. Other negative associations include prolonged labour, delivery by caesarean
section or assisted vaginal delivery, premature rupture of membranes and the use of
assisted reproductive technologies, among other factors (FIG. 2). Environmental risk factors
could trigger the risk of autism through several complex underlying mechanisms such as
genetic and epigenetic effects (see Mechanisms/pathophysiology, below), inflammation and
oxidative stress, or hypoxic and ischaemic damage18.
Mechanisms/pathophysiology
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Many cognitive theories have been suggested to underlie the behavioural and developmental
manifestations of autism, although the prominence and the consensus on the potential
explanatory value of these theories have declined in the past decade. These theories
range from ‘social first’ theories, such as the theory of mind (or mentalizing) and social
motivational deficit theories, to global processing deficit theories, including attentional
control, executive dysfunction and weak central coherence or enhanced perceptual
processing theories21,22. Although many of these theories had a useful descriptive role and
provide potential insights into differences in how autistic individuals might process and
experience the world around them, the theories pertain to neurodevelopmental disorders in
general and lack specificity for autism, they are largely non-developmental, applying only
to a single point in time, and lack evidence as explanatory models. Nevertheless, they have
been useful in clinical practice and underlie some recently proposed interventions, such as
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cognitive behavioural therapy (CBT)-oriented treatments for anxiety23.
Following cohorts of infants from gestation or birth to 2 or 3 years of age (that is, to
an age when a diagnosis of autism can be established) enables the study of the brain
and behavioural manifestations of autism as they emerge24. Indeed, prospective studies of
infants with a relative with autism have yielded several insights into the mechanisms of
this disorder. For example, infants who develop autism later in childhood have substantially
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typical profiles of interest in faces25 and eyes26 at 6 months of age, which have cast
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doubt on social orienting theories in which autism originates from a primary deficit in
innate patterns of subcortically mediated social orienting27. In addition, subtle but diffuse
differences in electroencephalography (EEG) and other measures of brain function have
been demonstrated in autistic people (see Findings from electrophysiological studies,
below), which could represent alternative pathways to a common end-state phenotype or to
whole-brain alterations in synaptic signalling pathways that have effects on development28.
Such considerations highlight the limitations of deterministic models of autism, in which
a genetic change leads to a synaptic change that relates to a canonical symptom29. Rather,
there is probably a complex set of developmental interactions in which the child’s emerging
brain activity and behaviour have bidirectional relationships to synaptic signalling and gene
expression30.
Genetics
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Twin and family studies consistently demonstrate that autism has a particularly large genetic
contribution, with estimated heritability ranging from ~40% to 90%31,32. In addition,
one analysis demonstrated that autism is among the most heritable common medical
conditions33. More than 100 genes and genomic regions have now been confidently
associated with autism34,35, mostly based on the study of heterozygous, germline, de novo
mutations. These genetic changes range in size from a single base (or nucleotide)36–38
to submicroscopic segments of DNA of thousands to millions of bases (also known as
copy number variations (CNVs))39,40. Whether these genetic changes lead to alterations
in the sequence of DNA or in the structure of the chromosome, changes that have a
functional effect on protein-coding regions of the genome have the strongest and most
reliable association with autism risk. Collectively, these de novo heterozygous mutations are
rare and confer relatively large risks of autism41. With genetic studies now including cohorts
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of up to tens of thousands of individuals and the associated increase in statistical power,

common, transmitted alleles of modest effect size, mostly corresponding to the non-coding
regions of the genome, have begun to be identified42.
Studies of the genetics of autism contrast broadly with those of adult-onset psychiatric
disorders in which most successful gene discovery has emerged from genome-wide
association studies assessing common alleles of small effect size. Indeed, the earliest
successes in autism presaged a more general finding that the contribution of rare, de novo
mutations in coding regions of the genome is relatively greater among a range of early-onset
disorders43–45 than for typically later-onset common conditions such as schizophrenia and
bipolar disorder, although there is also a surprising degree of overlap in genetic risk for
overtly disparate neuropsychiatric phenotypes that remains to be further elucidated31.
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The extent to which rare, high effect size mutations account for autism risk raises some
important definitional issues. Considering the overall population, the contribution of de novo
mutations to autism risk is quite small (~3%)32. Indeed, most individuals who harbour a
genetic risk for a common condition, particularly those with variants of small effect size,
will never develop symptoms or need clinical attention. By contrast, there is a marked
enrichment of individuals with rare and de novo mutations in the clinical autism population.
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Conservative estimates are that 10–20% of people with autism harbour a de novo rare
point mutation or CNV contributing to their presentation34,46,47. If the clinical population is
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constrained to those with autism who have a combination of factors, including being female,
having intellectual disability, multiple unaffected siblings, or seizures, ~20–30% have a rare
de novo mutation; if an individual has several of these risk factors, the yield of de novo
sequence and structural mutations would be expected to be even higher34.
However, irrespective of the precise proportion of risk conveyed by these mutations, their
most substantial contribution to the understanding of autism is likely to be in elaborating
the mechanisms of this disorder48,49. In autism, a single de novo germline heterozygous
loss-of-function point mutation can convey more risk than the cumulative effect of the top
decile of polygenic risk for schizophrenia47,50. Unfortunately, although manifestly more
tractable than modelling hundreds of alleles simultaneously, addressing a single autism
mutation at a time is not synonymous with an easy avenue to clinical care of most people
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with autism.
Molecular pathophysiology.—Over the past decade, there have been many studies using
model systems to recapitulate so-called single gene (or monogenic) versions of autism, such
as fragile X syndrome and tuberous sclerosis complex, which are cumulatively estimated
to account for <10% of clinical cases of autism51. In addition, more recent studies have
modelled the effects of rare and de novo mutations identified in idiopathic autism. This
literature is too vast to review comprehensively here52,53. Although the study of autism
risk genes in model systems has revealed a great deal about general biology, how these
findings relate to the pathophysiology of autism is less clear48,49. In general, autism risk
genes tend to have a role in multiple functions in many brain regions that unfold in a
spatiotemporally defined manner across development. Consequently, although manipulation
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of a single risk gene in a model system may lead to interesting phenotypes, including
social-behavioural phenotypes in evolutionarily distant organisms, it does not necessarily
illuminate its contribution to human social disability. Moreover, although a single mutation
can confer a several-fold increase in the risk of autism, these variants do not demonstrate
the type of causal clarity that is associated with classic monogenic neurodevelopmental
disorders such as fragile X syndrome, Angelman syndrome, Rett syndrome or tuberous
sclerosis complex. In addition, the well-established sexual dimorphism of social disability
adds yet another dimension to the expansive search space that exists between risk genes and
human behaviour48. The challenges of disentangling the spatiotemporal dynamics of risk
gene expression and protein function are made even more difficult by the reality that these
may play out differently in males and females.
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Owing to these challenges, multiple approaches have emerged focusing on

convergence38,40,54–57, that is, searching for points of commonality across different autism
risk genes, with the reasoning that this approach could identify shared pathological
mechanisms. In fact, the earliest successes in gene discovery quickly revealed important
general properties that have held up well over time, including that, prima facie, most
proteins encoded by autism risk genes are involved in either synaptic structure and
function or chromatin modification and regulation of gene expression38,46,47,58 (FIG. 3).
More recently, there has been an additional focus on spatiotemporal convergence and
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several studies have supported a nexus in mid-fetal, glutamatergic neurons during cortical
development, with modestly divergent findings regarding deep56 versus superficial54 cortical
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layers. With improvements in technology, additional regions, including the striatum, have
also begun to emerge as points of potential risk convergence for autism59.
The ability to constrain future experiments to examine mutations in specific risk-associated

regional, cellular and developmental contexts should allow narrowing in on relevant
mechanisms. Of note, one study used single-cell technologies to examine specific cell types
and developmental stages using brain tissue from people with autism60, and demonstrated
changes in transcription in multiple cell types, including upper-layer cortical neurons.
These types of post-mortem studies ask important but somewhat broader questions from
the approaches described above regarding the underlying pathology and how the brain
changes and responds to pathology over time. In these studies, similar to any cross-sectional
study, it can be challenging to differentiate cause from effect. Consequently, the pursuit
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and intersection of studies that seek to define convergence early in development and those
that examine subsequent molecular, cellular and circuit level changes will be critical to
illuminating pathological mechanisms.
Indeed, given the success and US FDA approval of gene therapy for early-onset neurological
disorders, particularly spinal muscular atrophy type 1 (REFS61,62), targeting single genes
of large effect in both idiopathic and monogenic autism is being viewed as increasingly
plausible. As rare syndromes such as fragile X syndrome, Angelman syndrome and Rett
syndrome have offered some of the earliest insights into autism biology, these disorders are
also likely to lead the way in illuminating the practical and important ethical challenges that
will attend such efforts for idiopathic autism. Efforts aimed at the highest confidence risk
genes identified in idiopathic autism, such as SCN2A and CHD8 (REFS34,35), are almost
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certain to soon follow on attempts at gene therapy for monogenic neurodevelopmental

disorders in light of the growing list of well-defined large-effect targets, the increasing
options for addressing haploinsufficiency63, the ability to manipulate gene products without
leaving a DNA ‘scar’ (REFS63,64) and the increasing ability to readily detect mutations —
and intervene — in utero and very early in postnatal development.
Neurobiology
Findings from MRI studies.—MRI can facilitate understanding of how the brain
structurally and functionally develops differently in people with autism, although, to date,
MRI results in autism are not definitive. Although neuroimaging is typically more expensive
than EEG and studies are limited by issues of replication (sometimes this is related to head
motion occurring during the scan, which can erode signal65), structural studies including
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those using diffusion tensor imaging66 and functional MRI (fMRI)67 have accelerated our
understanding of how altered neural circuits relate to clinical symptoms of autism68,69.
Studying circuitry in childhood that is specifically associated with the social brain (a
network of brain areas involved with processing social information), including visual areas,
areas of the prefrontal cortex, sub-cortex and areas integrating information (such as temporal
parietal function and superior temporal sulcus), could also offer insight into the neural
mechanisms of autism70. In addition, MRI may facilitate understanding of the heterogeneity
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of autism, demonstrating subgroups of individuals with specific neurobiological alterations

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that could account for their symptomology. The summary of MRI studies in this section
focuses on 0–2 years of age and addresses biomarkers for autism. Prospective study designs
are largely covered as they represent a substantial portion of MRI research in autism.
The first MRI studies of autism focused on cerebral and cerebellar grey matter and white
matter volumes in young children71,72, although these studies were limited by studying
toddlers and children aged ≥18 months, missing the opportunity to detect biomarkers of
autism in the first year of life. More recently, longitudinal studies have obtained multiple
brain MRIs of infants at high risk of developing autism (that is, those with a sibling with
autism; known as baby sibling studies) during their first 2 years of life and assessed these
children for autism at this age. In these studies, detectable differences in brain structure were
observed at 6 months of age in the fractional anisotropy trajectories for 12 of 15 neural
fibre tracts in the brain in children diagnosed with autism at 2 years of age compared with
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children not diagnosed73. Furthermore, abnormal growth in the cortical surface between 6
and 12 months of age and greater brain volume between 12 and 24 months of age were seen
in children who were later diagnosed with autism, compared with those not diagnosed with
autism74 (FIG. 4). In addition, white matter integrity in the genu pathway at 6 months of
age predicted the presence of restricted and repetitive behaviours at 2 years of age75 and
computational work demonstrated that whole-brain functional connectivity at 6 months of
age predicted a diagnosis of autism at 2 years of age76. Collectively, these studies suggest
the presence of disrupted neural pathways before the emergence of behavioural symptoms
in children with autism and might provide clues about the underlying neural mechanisms of
autism. Although data from MRI studies have revealed differences in neurobiology between
young children diagnosed with autism and those without autism77, given that replication has
been particularly difficult in these studies, more work is required before MRI can be used as
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a reliable biomarker of autism78.
Task-based fMRI studies investigate circuits that are responsible for core challenges in
autism, such as language production and comprehension79, and have demonstrated hyper-
activation of the superior temporal gyrus and inferior frontal gyrus as well as hypoactivation
of the bilateral middle temporal gyrus76. In addition, these studies have demonstrated
challenges in processing emotions in faces and the ‘social brain’ (REF.78) and deficits
in attention79. Studies have also demonstrated greater sensitivity to sensory information.
Increased connectivity between the anterior insula and sensorimotor areas, and the anterior
insula and amygdala, together was associated with greater sensitivity to slightly aversive
sounds and tactile information80. Although this area of research has revealed similarities
or differences in people with autism in relation to comparison groups, it has been limited
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by averaging data across many individuals, which can mask heterogeneity and differences
across age groups. In addition, the work has been limited by small sample sizes and
problems with replication probably caused by the many challenges with MRI data collection
in people with autism, such as differences in data processing, inter-subject variability
and data quality80. Longitudinal imaging81 as well as associating neuroimaging data with
longitudinal behavioural outcomes82 can address some of these limitations characterizing
differences within participants.
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Resting state functional connectivity MRI studies that require participants to look at a
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blank screen with no task demands have been used to study intrinsic connections in the
human brain. Large data sets, such as the Autism Brain Imaging Date Exchange (ABIDE)83,
have enabled researchers to pool data to allow more highly powered studies to address
known limitations of small sample sizes, and many data sets have relied on resting state
studies to study neural connectivity in autism. In these studies, evidence has emerged of
both hyper-connectivity and hypo-connectivity in short-range and long-range connections
throughout the brain84,85. Differences in results between studies could be due to the age
of the participants86, sex differences, heterogeneity, methodological concerns87 or that both
connectivity states exist in autism.
In future, MRI could be well suited to categorize subgroups of autism88 as well as parsing
out commonalities and distinctions among other developmental disorders89. Using MRI
to better understand the differences between boys and girls on the spectrum90, such as
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differences in whole-brain connectivity90 or the social brain91 — a field in its infancy — or

as a marker of biological change due to treatment, has growing interest92.
Findings from electrophysiological studies.—EEG has historically been used for the
diagnosis of comorbid epilepsy in people with autism93, although it can also be used to
study the mechanisms of autism. Compared with MRI, EEG is more economical, easier
to use and less invasive, which is particularly important for paediatric populations, while
granting access to brain dynamics at millisecond timescales. Magnetoencephalography
(MEG), although more expensive, provides higher spatial resolution than EEG.
Since the early recordings, the first focus of quantitative EEG was to study people with
autism in task-free conditions. Pioneering studies have revealed alterations in oscillatory
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activity during resting state in people with autism, with more slow waves and less alpha
waves as well as less intra-hemispheric and inter-hemispheric asymmetry than in people
without autism94. More recent work has demonstrated the presence of developmental
trajectories as revealed through increasingly sophisticated spatiospectral analyses, and has
shown how differences in the trajectories of EEG power in high-risk infants may represent
endophenotypes of autism95,96.
In terms of mechanisms, other studies have started to focus on the task-based modulation of
cognitive function such as low-level perceptual anomalies and action observation that relate
to the autism phenotype. One theory proposing a specific failure in autism of the ability of
the brain to ‘mirror’ observed actions of another person (thereby named the ‘broken mirror’
theory) was based on altered mu wave suppression in autism97 but was later questioned
both theoretically98,99 and empirically100,101, pointing towards a more complex picture
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of dysfunctional executive functions and visual attention102. Other studies, particularly

those assessing event-related potentials, have demonstrated the modulation of sensory
processing in people with autism, with observed changes in sensitivities and latency103.
Differences in auditory and visual processing could have a role in the development of core
features of autism, such as language delay and difficulty in emotion recognition, although
this hypothesis requires further study. Although perceptual processes appear different in
people with autism, the electrophysiological underpinning is still far from clear regarding
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the main event-related potentials such as mismatch negativity104 or the N170 (REF.105).
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Although data from meta-analyses have suggested smaller mismatch negativity amplitudes
and delayed N170 latencies, on average, in people with autism compared with typically
developing controls, additional studies are required that account for the large heterogeneity
of this disorder by moving away from averaging the data to focus either on specific
subgroups106 or refined modelling strategies that can capture individual differences in
developmental trajectories95. Although this avenue of research has not yet been fully
explored, interactive tasks that encompass real-time social interaction could allow the study
of brain activity in experimental contexts that are more relevant for core autism symptoms,
rather than the more passive tasks that are used in most functional imaging studies107.
Experiments focusing on human–human interaction108 and human–machine interaction109
have been under-taken but, so far, no study has ever made explicit use of such methods to
study the electrophysiology of autism.
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In a further search for mechanisms of autism, prospective baby sibling studies have
suggested that the gradual emergence of behavioural symptoms of autism is preceded by
earlier subtle alterations in the activity of regions and networks of the social brain24.
For example, early work on a small group of 5–6-month-old infants who later developed
autism observed faster but less prolonged neural activation and delayed sensitization
responses to faces compared with infants who did not develop autism110, and one report
demonstrated that newborns with an increased familial likelihood of autism showed higher
signal homogeneity within core social brain networks (the right fusiform and left parietal
cortex111). By comparison, reduced frontal power, particularly in the high-alpha band,
during quiet play at 3 months of age112 and cortical hyperexcitability in the right tempo-
parietal region during auditory repetition of pure tones at 9–10 months of age have been
found in babies at familial risk for autism113, suggesting that atypical patterns occur in
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brain regions other than those involved in social processing. Such alterations could have
a cascading effect on social learning and contribute to the later emergence of behavioural
symptoms of autism, although a causal link remains to be demonstrated. Replications across
different research centres are needed because many of these studies had small sample sizes,
different definitions of groups, and varied measures and time points.
Interestingly, results from MEG and EEG studies jointly point towards two physiological
mechanisms of autism: excitation/inhibition imbalance and alteration of large-scale
functional interactions of brain systems as quantified through connectivity analysis114. An
excitation/inhibition imbalance is supported by results from computational modelling of how
reductions in the amount of inhibition can account for the previously observed perceptual
consequences of autism115 and by transcranial magnetic stimulation studies demonstrating
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a neurophysiological deficit in γ-aminobutyric acid (GABA) receptor-mediated function in

people with autism116. In parallel, decreased long-range functional connectivity has also
crystalized as a consistent mechanism117. MEG studies have suggested a complex functional
connectivity pattern in the somatosensory cortex with reductions in the feedback (top-down)
direction but increased in the feedforward (bottom-up) direction118. Clarifying the extent
to which this pattern is a methodological artefact that could result from the predominant
average-brain approach, as suggested by fMRI studies, is critical119.
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Beyond use to understand the pathophysiology of autism, the scalability and accessibility
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of EEG suggest that this technique could be an ideal candidate for use as a brain-based
biomarker. Measures from information theory have already provided promising case–control
classification120, but developing generalizable biomarkers may require a combination of
multiple EEG measures supported by robust machine learning methods121. Against the
background of the current reproducibility crisis that characterizes many studies122 as well
as the defining heterogeneity of autism, the next breakthrough will certainly demand large-
scale collaboration between researchers and clinicians.
Diagnosis, screening and prevention

Diagnosis of autism is made on the basis of behavioural presentation. Although substantial
heterogeneity exists between and within individuals across development, a set of core
diagnostic features of autism (covering social interaction, communication, and restricted,
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repetitive or sensory behaviours) can be reliably identified by trained clinicians123,124.
Diagnostic criteria
The reformulation of the diagnostic criteria for ASD in DSM-5 (REF.125) (BOX 1), which is
similar to the criteria in ICD-11 (REF.126), contains several changes from previous editions
that were based on good empirical and clinical evidence127. First, the subclassification of
‘Asperger’s disorder’ was subsumed under the unitary term ASD as the diagnosis was
inconsistently applied even by expert groups128. This change is controversial, yet the
evidence supporting the inclusion of Asperger’s disorder as a separate condition is very
weak129. The important issues are how to better consider the factors that characterize
differences among autistic individuals and ensuring that these differences are measured and
addressed using neurobiological and clinical research, rather than contained within very
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poorly defined categories of Asperger’s and PDD not otherwise specified (NOS), as defined
in DSM-IV130. In addition, some individuals with social communication problems but not
restricted and repetitive behaviours who would previously have fallen into the now-removed
subcategory of PDD-NOS now receive a different diagnosis of social communication
disorder, which is not yet well validated. Although these changes have led to concerns
that the DSM-5 ASD criteria are more restrictive than those in DSM-IV, many clinicians
feel that the changes better reflect clinical consensus and practice. Second, the social
and communication domains of the diagnostic criteria were unified to reflect the factor
structure of symptomatology. Third, sensory anomalies (hypersensory and hyposensory
responsiveness and sensation-seeking) in DSM-5 were included under the ‘restricted,
repetitive behaviours and interests’ domain to reflect their pervasiveness131. Fourth, the
DSM-IV criteria required symptoms to be present in the first 3 years of life, but criteria
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in DSM-5 recognize symptom onset during the early developmental period with the caveat
that symptoms might not fully manifest until social demands exceed limited capacities. This
change recognizes the developmental nature of autism, wherein for some individuals, clear
manifestation of autism might not be apparent until mid-childhood, adolescence or even
adulthood. In addition, late diagnosis (that is, diagnosis beyond early childhood) can occur
even in those who received intensive early monitoring132. The DSM-5 criteria support the
use of specifiers that can denote those with dual diagnoses such as individuals with ASD
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and ADHD or other psychiatric disorders as well as with genetic conditions such as fragile
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X syndrome or Down syndrome. Beyond the clinic, these changes have implications for
large-scale data pooling efforts, in considering domains of behaviour to be modelled, and
in identifying shared and distinct developmental pathways to conditions such as autism and
ADHD.
Diagnosis and screening in children

The two core elements of the diagnostic process of autism in children are a detailed
developmental history that is usually obtained from parents, covering first concerns and
early history to the present day, and an observation of the child’s interactions with their
parents and with unfamiliar adults during a combination of structured and unstructured
assessments. Ideally, observations of the young person in peer-group settings such as school
or nursery would also form part of the diagnostic process. Of note, in one population-
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based study in the UK, girls with similar levels of symptom expression to boys were
less likely to receive a diagnosis of autism from clinical services133. This finding might
reflect sociocultural factors in the application of the diagnostic criteria, greater resilience or
protective factors in girls that reduce the need for clinical services at a given symptom level,
or the need for the revision of instruments used to identify symptoms to more fully cover
female autistic traits127.
A number of structured diagnostic interviews and observational assessments for autism

exist, but only a limited number have been rigorously tested for diagnostic accuracy
relative to the gold standard of expert clinician judgement. Although these interviews
and assessments have reasonably robust sensitivity, specificity and reliability (see134 for
a review) and are widely used in some services in communities135, there are also challenges
to the widespread adoption of the best validated instruments: the Autism Diagnostic
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Interview-Revised (ADI-R)136 and the Autism Diagnostic Observation Schedule-2nd

Edition (ADOS-2)123. These challenges include the cost of the instruments and training, the
time required to complete them and the need for substantial training to use them reliably137.
Although expert clinical judgement was previously believed to be more reliable than reliance
on instrument scores alone for the diagnosis of autism138, more recent evidence suggests
that this may not be true at least in toddlers and preschool children139. The need to take a
global perspective on autism is driving attempts to develop more scalable tools but this work
is currently in its infancy140 (BOX 2).
The stability of a diagnosis of autism from the preschool years to mid-childhood is relatively
high1. However, although diagnostic systems currently pre-suppose that autism is a lifelong
condition, there is a growing recognition that autism has a heterogeneous developmental
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time course141. Indeed, subgroups of individuals with autism and improving or worsening
symptoms over time can be identified142,143. Such developmental trajectories might be
a more meaningful phenotype on which to map aetiological mechanisms than a static
case–control dichotomy74,144,145. Some individuals diagnosed as children have no clinically
meaningful (or even detectable) impairment later in life (so-called optimal outcome146,147);
one critical question in identifying mechanisms is whether this profile is associated with the
successful effects of early intervention or is an aetiologically distinct subtype of autism.
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Screening and early identification.—The potential for early testing to prospectively

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identify children with autism at a young age has considerable interest and several
studies have evaluated the performance of parent-report instruments between 14 and 24
months of age such as the Modified Checklist for Autism in Toddlers (M-CHAT) and
the Early Screening of Autistic Traits (ESAT)134,148,149. However, there are contrasting
views on the strength of the evidence for universal population-wide testing, also known
colloquially as screening150,151. Of note, research is lacking on the effectiveness of
therapeutic interventions in those identified with autism through universal screening. In
addition, although it is possible to identify some children with autism before parents or
professionals have identified concerns, diagnosis is missed in many children152, and most
tested cohorts have not been systematically followed up to identify later-onset autism
in children who initially tested negatively153. Screening also often identifies children
with broader developmental difficulties as well as those with autism154. In general, such
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instruments could be more useful for identifying possible signs and symptoms of autism
in high-risk populations, for example, in young children with older siblings with autism155
or in those referred for speech or other developmental concerns to community paediatric
services156. In addition, population-wide testing may also have a role in improving
awareness and recognition of the early signs and symptoms of autism of both professionals
and the general public, which alongside ongoing developmental surveillance pathways in
community services, could help to bring down the age of recognition and diagnosis. These
principles also apply in low-income and middle-income countries in which testing for autism
and other neurodevelopmental disabilities has only just begun to be implemented154. Very
little research has been devoted to cultural and ethnic differences in either child early
presentation and parents’ understanding or the experience of autism, which may affect how
screening instruments work and, therefore, affect parents and families as much as autistic
individuals.
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Early developmental profiles.—Understanding of onset patterns of autism has

dramatically expanded over the past 10 years through work on infants with a first-degree
relative with autism who, due to the high heritability of the condition, have a 20% chance of
developing autism themselves25. Symptoms of autism have a gradual developmental onset.
Indeed, although the average age of autism diagnosis remains at ~4–5 years of age157,
parents typically report first concerns to health professionals at ~2 years of age158. In
many individuals, symptoms emerge during the second and third year of life (although,
as per the DSM-5 onset criteria above, in others, onset might not be noticed until the
child reaches school-age or later), whereas in others, symptoms become apparent after
a seeming period of typical development, including a period of regression or stasis. To
this end, conceptualization of what has been called ‘regression’ prior to 2 years of age
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has been reconsidered159,160. Over the first 2 years of life, a substantial proportion of
infants who later receive autism diagnoses show gradually accumulating delays across
social, communication and language domains, suggesting that ‘regression’ represents a
spectrum ranging from frank loss of acquired skills, to a gradual erosion (or ‘plateauing’) of
developmental potential to individuals in whom these skills never emerge161.
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Diagnosis and screening in adults

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Information on diagnostic methods to identify autism in adulthood is in its infancy,

with little methodologically acceptable evaluation of interview methods or screening
questionnaires (including self-completion questionnaires). Clinical approaches rely heavily
on extending methods developed for use in childhood to adulthood. These methods tend
to rely on childhood developmental data, although validation research from adult general
population-wide testing suggests good specificity and sensitivity for the observationally
based ADOS Module 4 (REF.162). However, typically, much research has depended
on the judgement of expert clinicians and on standardized data collection of early
child development that is unlikely to be obtainable for many older adults. Given that
(undiagnosed) autistic adults presenting for an autism assessment are also more likely to
have co-occurring adult mental health disorders, any method of assessment must be capable
of differentiating such abnormalities in symptoms and behaviour from abnormalities due to
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autism. This point has led to the suggestion that clinical examination methods to identify
adult psychopathology could be extended to include autism in addition to depression,
anxiety and psychosis, among other disorders163. Semi-structured adult psychopathology
interviewing has been fruitful in the assessment of closely related neurodevelopmental
disorders in adults, most notably ADHD164. Given that most people in the world who
are autistic are adults, and as many of these individuals have not received a diagnosis of
autism4,15, the development and evaluation of such adult assessment approaches is an urgent
research priority.
Co-occurring disorders
In addition to the core features of autism, co-occurring difficulties or disorders (FIG. 5)
are much more widely recognized in research165,166, although they are not necessarily
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adequately addressed in clinical practice167. For preschool children with autism, language
delays, motor problems, epilepsy, difficulties with sleep and eating, and high levels of
activity are most commonly observed168,169. By comparison, ADHD, anxiety, obsessive–
compulsive disorder (OCD), intellectual disability, academic challenges, irritability and
disruptive behaviours become more apparent in school-aged children170. The proportion
of individuals with depressive symptoms becomes higher in adolescents and adults171,
whereas other issues often remain. Moreover, growing evidence (although it is reliant
on administrative case-finding data) suggests that people with autism have premature
mortality172,173 and increased risk of self-harm and possibly suicide, although the
mechanisms involved have yet to be elucidated. Studies using electronic health records have
demonstrated that adults with autism are more likely to be diagnosed with many physical
health conditions, such as immune conditions, sleep disorders and obesity, than adults in the
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general population167.
Collectively, these difficulties and disorders contribute to autism severity174 as well as

independence and well-being at each age175. However, it is important to note, in the
context of heterogeneity, that the prevalence of each of these co-occurring conditions varies
considerably with the context of the sample (such as from psychiatry referrals, neurological
referrals or schools) and the methodology used (administrative, self-report or assessed) as
well as with age, level of cognitive function and perhaps region166. As many of these
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conditions are treatable, they are very important as clinical considerations but are also more
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complex than sometimes conveyed.
Management
Early intervention
Early intervention is seen as a priority because many young children with autism struggle
to communicate and interact with others, restricting their opportunities to learn and affecting
their parents, who can find their child’s behaviour perplexing and challenging to manage.
Thus, outcomes of such interventions include changes in the individual’s availability for
learning and increased parent understanding. Intervention delivered in the preschool years at
an age when there is increased brain plasticity might lead to additional benefit, although this
theory has not yet been empirically supported.
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The primary models of psychological intervention for preschool children with autism
are developmental and behavioural. Although some consensus has been reached on
the interventions that have more supporting evidence (termed naturalistic developmental
behavioural interventions176), there is some uncertainty and disagreement about the
strength of evidence for different approaches, with almost no direct comparisons of
treatments or studies to assess which child should receive what treatment or the treatment
intensity. Indeed, clinical trials in autism are limited by cost, time, placebo effects and
limited outcome measures, and are far behind much other research. This gap leaves
parents and practitioners with no options other than what is available and sometimes
marketed in their region. Indeed, access to early intervention services is variable in
most communities, including in high-income countries, and is mostly carried out by non-
specialists supervised by specially trained professionals. In low-income and middle-income
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countries, most children and young people with autism — similar to those with intellectual
and developmental disabilities — will not receive specialized services177, although a number
of groups have begun to test community delivery of early intervention in such settings178.
Many current interventions build on the original applied behavioural analysis (ABA)179 and
have shifted to more natural, child-initiated developmentally appropriate strategies and tasks
instead of dependence on repeated ‘discrete trials’ (known as discrete trial training (DTT)).
In addition, considerable variation exists between different intervention models in terms
of mode of delivery (for example, parent mediated versus therapist implemented), length
(12-week versus 2-year programmes), intensity (from a few hours a week to ~15 hours per
week) and the balance between the developmental or dyadic versus behavioural components.
Lower-intensity approaches include parent-mediated interventions whereby parents are

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coached to become more attuned to their child’s communication signals and style (which
are considered an intermediate child outcome) and to facilitate more joint engagement in
play and everyday activities designed to increase social and communication skills in the
child180. Some studies, such as the 12-week Joint Attention Symbolic Play Engagement
and Regulation (JASPER) programme, both when delivered by parents in the home181
and by teaching assistants in school182, have demonstrated enhanced joint engagement and
joint attention (which are considered important intermediate child outcomes) with these
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lower-intensity approaches in preschool children compared with a control group. However,

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other lower-intensity, time-limited parent-mediated interventions, such as focus playtime

intervention (FPI)183, have not improved child outcomes (such as social orienting and
joint attention), although some interventions have increased parental responsiveness184.
A longer programme (Preschool Autism Communication Trial (PACT)), which consists
of fortnightly parent–therapist sessions for 6 months, then monthly sessions for another
6 months, demonstrated improvements in parent and child dyadic behaviours such as
parental synchrony and child initiations when interacting with each other (those close to
the intervention target) but not symptom reduction at immediate follow-up185. A subsequent
6-year follow-up to mid-childhood at age 7–11 years identified modest reductions in overall
autism symptoms using the ADOS over the whole course of the study; these reductions
were not detectable at the immediate end point, suggesting that a longer-term perspective is
critical in considering outcomes186.
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A higher intensity, more comprehensive approach is the Early Start Denver Model (ESDM),
which combines behavioural and developmental or dyadic approaches. The ESDM is
delivered by therapists for ~15 hours per week, and as part of this programme, parents
are trained to improve social communication and interaction with their child. A small-scale
trial demonstrated improvements in child developmental and adaptive outcomes, primarily
in the language and communication domains, following 2 years of ESDM compared with
treatment as usual187. One larger multi-site trial found attenuated benefits with improvement
in language outcomes at two of the three trial sites, but no differences between the treatment
as usual and ESDM groups in overall developmental ability, adaptive behaviour or autism
severity188,189.
Many of these early intervention approaches are based on models of typical development.
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Increasingly, studies are using a combination of methods to define treatment outcomes and
to better understand the mechanisms and models of change of interventions. These methods
include analysis of the degree to which changes in the direct target of the intervention
(for example, parent behaviour) mediate later changes in child behaviour186 and the use of
experimental methods such as EEG to examine whether there are accompanying changes in
relevant brain networks190. Many parents seek complementary medical approaches, which,
to date, have not been supported and are sometimes dangerous191. A note of general caution
is that, even in the context of significant treatment differences between groups, individual
outcomes are very variable, and some children do not improve, although reliable predictors
of response to treatment have not been demonstrated in rigorous, randomized controlled
trials. As autism is a heterogeneous developmental condition, different interventions may
be required at diverse stages throughout life and different individuals might benefit
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from different interventions. One area that many consider to hold much promise —
neurobiologically or biomarker ‘informed’ psychological intervention — is on the horizon
but such targeted therapies have not yet been developed.
School-age children and adolescents

Many children and young people with autism can also benefit from interventions at later
ages. A number of programmes and approaches are available that focus on the core social
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communication difficulties of autism, for example, social skills training programmes, for
which moderate evidence of benefit exists192,193. In addition, non-verbal young people
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with autism can benefit from the use of augmentative communication systems such
as the Picture Exchange Communication System (PECS) and more-sophisticated speech
generating devices that use picture symbols and behavioural training methods to allow
children to request and make choices194 or of other technology-based augmentative
communication systems. Increasingly, more generic interventions that target co-occurring
emotional and behavioural problems are being adapted for youths with autism, with initial
studies suggesting moderate benefits195. These interventions include modified CBT for
anxiety (modified, for example, to include parents, increase the duration of sessions, use
more visual materials and specific work on understanding one’s own emotional states)196
and parent-mediated interventions for disruptive behaviour and ADHD197. More recently,
there have been efforts to develop and test interventions that target aspects of parental
wellbeing, such as parental stress and self-efficacy198. Increasingly, interventions for
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school-age children and young people with autism are being delivered within the school
environment, rather than the clinic, which has natural advantages for programmes that
consist of groups or peer-to-peer interactions with an emphasis on social skills. Indeed, it is
hoped that this approach may facilitate generalization of the skills learned199,200.
Adult services
As individuals with autism progress into and through adulthood, the focus of management
shifts from treating the core symptoms of autism to addressing associated symptoms or
behaviours and promoting independence. However, there are few intervention studies to
guide treatment options in adulthood. Indeed, a 2012 systematic review identified only 32
studies published between 1980 and 2010 that evaluated treatment studies for adolescents
and young adults with autism201. A more recent review identified 41 studies of interventions
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targeting social functioning in adults over a 37-year period202.
Despite the low number of treatment studies, there is some evidence supporting treatment
efficacy for a limited number of symptoms, behaviours and functional outcomes such as
employment, social skills and anxiety; however, in general, the evidence base is weak201,202.
For example, only three randomized controlled trials (all of which included small cohort
sizes) that tested job interviewing skills curricula have been published. Social skills
interventions have a somewhat more robust literature base (see202 for review), but most
of these studies had very small sample sizes and were not well controlled. In addition,
it is unclear whether social skills interventions can be generalized to other social settings
and situations, that is, whether skills learned in the treatment context are used by the
participants in other settings such as with peers or at work. There is some evidence for
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the use of CBT for effectively treating anxiety in people with autism who have sufficient
cognitive and language skills to participate in current programmes203. However, nearly all
of the existing research has been conducted with children and adolescents rather than with
adults202, and individuals with substantial communication challenges are excluded from
CBT studies. Furthermore, in contrast to the general population, CBT has not yet been
shown to be effective for the treatment of depression in individuals with autism. Given this
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weak evidence base, it may be fruitful to explore therapies and treatments tested in other
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groups that may benefit those with autism.
Formal service systems and social care can help fill in the treatment gaps. Indeed, although
many adults with autism do not receive adequate services and support204, their receipt can
improve outcomes across a number of domains163. For example, transportation services can
allow adults with autism to engage in employment and access therapies and programmes in
the community. In addition, comprehensive job support services can promote finding and
maintaining employment, particularly for adults with more severe impairments205. Public
health insurance can increase access to psychiatric care for those with co-occurring mental
health problems and income support can reduce dependence on families.
Medications
All medications that have evidence of benefit for autism treat the associated symptoms
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or co-occurring diagnoses, rather than the symptoms of autism directly (including social
communication or repetitive behaviours). As mentioned earlier, autism is an extremely
heterogeneous disorder, and individuals with autism can have a number of common co-
occurring disorders that can also vary in severity.
Risperidone and aripiprazole (both of which are often termed ‘atypical antipsychotics’) are
approved in the USA to treat irritability and agitation, including aggression, self-injury
and tantrums, in children and adolescents with autism206–208. However, both treatments
are associated with adverse events, including sedation, risk of movement disorders and
weight gain, which limit their use to people with severe irritability with agitation208. The
anti-diabetic drug metformin has been shown to limit weight gain from these medications,
possibly broadening their safe use209.
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As mentioned previously (see Co-occurring disorders, above), co-occurring mental

health conditions are common in people with autism. Methylphenidate, atomoxetine and
guanfacine are beneficial for ADHD symptoms in people with autism210–212 (TABLE 1).
Although serotonin reuptake inhibitors, such as fluoxetine and citalopram, are used for the
treatment of depression, anxiety and OCD in the general population, their efficacy in people
with autism is less well established. Indeed, although fluoxetine improves symptoms of
OCD in adults with autism213, citalopram has demonstrated poor tolerability and no benefit
for repetitive behaviour in children with autism214. Medications for depression or anxiety
have not been tested in people with autism.
Some excitement has accompanied the recent studies of medications targeting the
neurohormonal oxytocin or vasopressin systems, both of which modulate social behaviour
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across species. Underpowered studies of intranasal oxytocin have demonstrated mixed

results that are overall not supportive of a large effect size215,216, with results from
adequately powered studies (NCT01944046) still pending. In addition, a pilot study of
intranasal vasopressin suggested possible benefit in people with autism, although this study
was underpowered217. A large trial of balovaptan, a vasopressin AVPR1A antagonist, in
adults with autism showed negative results on its primary outcome (a general rating of
autism symptoms), with suggestive results on a key secondary parent report measure of
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adaptive behaviour, including social and communication behaviour218. A few studies have
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also focused on the hypothesis that, at the level of neural circuits, autism may result from
excessive excitation or insufficient inhibition219, with some promising but inconclusive
results for medicines that target the GABAergic system220. Medications targeting genetic
syndromes that can cause autism have not yet yielded consistent improvement221,222, but
there is much hope for a precision medicine approach that links genetic subgroups with
neurobiology-based treatments.
Quality of life
Objective and subjective measures
Several aspects of intervention research speak straight to the heart of current debates within
the clinical field and broader autism community, including how a good outcome is defined
for an individual with autism as well as who should decide what outcomes are used in
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intervention studies223. This point is aligned both with the debates about medical versus
social models of disability but also with a more general shift in medicine away from
focusing on symptom reduction to improving the wellbeing and quality of life (QOL) of
patients. QOL research in adults with autism has focused on two aspects: objective and
subjective QOL. Objective QOL encompasses social achievements such as employment,
adequate living conditions, supportive relationships, and good physical and mental health224,
whereas subjective QOL focuses on individuals’ perceptions and subjective assessments of
their own lives225. Both subjective and objective QOL are often related but not synonymous,
and both are important to take into account when considering outcomes for individuals with
autism (TABLE 2).
Objective QOL.—Adults with autism tend to have poor objective QOL. Unemployment
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is high in this population, and even among those employed, individuals are often working
below their skills and abilities226,227. Moreover, independent living can be a challenge, and
adults often lack meaningful relationships with peers228. When aggregating across these
domains of life, many adults with autism have ‘poor’ or ‘very poor’ outcomes229,230.
Autism is a highly heterogeneous condition and several factors have been associated
with higher versus lower objective QOL. Most of the studied factors associated with
higher objective QOL have been characteristics of the individuals (versus families, service
system or communities), and consistent predictors of higher objective QOL include
better early language development, higher IQ and adaptive behaviour scores, less severe
autism symptoms and fewer challenging behaviours231. In addition, more recent research
suggests that women with autism may have a more difficult time maintaining employment
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positions232, and are more likely to ‘camouflage’ their autism symptoms than men, which
can lead to mental health challenges233.
Subjective QOL.—Meta-analyses have suggested that, across the lifespan, subjective

QOL tends to be lower among individuals with autism than among typically developing
peers234 but is often more positive than indicators of objective QOL229,235. Predictors of
subjective QOL tend to be inconsistent across studies, except for perceived stress and
support, the latter of which encompasses services, family and social support236–238.
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Self-advocate perspective
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It is clear that autism has heterogeneous outcomes and biological underpinnings; what is less
clearcut are the differing and nuanced views of autistic people regarding how autism should
be approached and researched (BOX 3, Autistica239, see also Ontario Brain Institute240).
Indeed, some people with a diagnosis see autism as being a fundamental part of their
identity, whereas other people do not. In addition, many people feel that social change is
required241, whereas others want therapies to meet a range of their needs242. The key is
respect for a variety of views and ultimately respect for autistic people. Researchers can
demonstrate respect by considering how autism as a topic is distinct from, for example,
cancer. To this end, terms such as ‘disease’ are inappropriate and are scientifically inaccurate
when referring to autism. Ultimately, active participation in the design, implementation
and interpretation of research studies, clear consideration of research ethics, and the
consequences of research involvement and broad consultation of autistic people in research
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is key to authentically addressing the substantial inequalities that autistic people face as a
group and ensuring that they live long, healthy and happy lives.
Family perspectives
Families of people with autism are also heterogeneous, yet, as a group, they experience
lower QOL than families with a member with other neurodevelopmental conditions, even
before receiving the formal diagnosis243. Thus, it is essential that parents, other family
members, clinicians, educators and the entire external support system coalesce around
common goals for outcomes while accessing and maximizing resources for the betterment
of the child and family. Parents are typically at the centre of this support network and
carry much of the responsibility of direct care, coordination and advocacy, over and above
typical parental responsibilities244,245. The exact parental roles are dependent on the child’s
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strengths and challenges, and frequently shift over time (FIG. 6). During this process, it is
important that parents maintain motivation by setting realistic goals and tracking progress to
experience the many achievements that their loved one with autism can attain.
Effective parents often work closely with experienced providers who can track the
development of the child with autism and can provide guidance on next actions246. Early
in childhood, this role includes identifying and engaging with early and school-based
interventions. It is never too early for parents to begin planning for the adult transition
process, including (dependent on the capacity of the person with autism) promoting self-
advocacy, preparation for life after secondary education, vocational training and employment
support, living needs, community participation and long-term financial considerations.
During adulthood, for cognitively able adults, parental roles might shift to more traditional
relationships247, whereas for those with cognitive disability, parental caregiving often
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continues and culminates in planning for late life needs248. Although the journey can be
challenging, for many parents, it can be incredibly rewarding and a source of life meaning.
Many parents recognize the need to give back to the community through research.
Accordingly, it is crucial that researchers foster this desire carefully, communicating with
parents to ensure that any potential immediate or future risks or benefits are clear. Even if
the study period is brief, in many cases, the goal should be to develop a positive longer-term
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relationship, as this can lead to parents and people with autism continually re-engaging in
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and developing positive feelings about the research process.
Outlook
Autism research has substantially expanded in the past 50 years, and particularly in the
past 20 years, as reflected in the websites listed in BOX 4. Although it seems unlikely that
the incidence of autism is truly rising at the rate suggested in administrative prevalence
studies, these data have increased the awareness and the numbers of diagnosed children
in schools and clinics, although adult services and recognition run far behind. The lives
of people with autism diagnoses have improved at least in some high-income countries,
with a greater proportion of children using some language249, more adults with educational
qualifications and less institutionalization249, although the changing nature of diagnoses
has to be considered when interpreting historical trends. Some risk factors for autism have
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been identified, which has implications at least for more careful follow-up. In addition,
the genetics of autism has yielded surprising discoveries, with substantial implications
for heritable neurodevelopmental disorders such as ADHD, language delay and named
syndromes associated with profound intellectual disability. The perceived value of routine
genetic screening for autism diagnosis is disputed, with American medical academies
strongly in favour, whereas those in other countries are much more selective. Studies of
brain structure and function have added similarly intriguing findings that are just beginning
to be integrated into both developmental and more mechanistic models of behaviour with
possible targets or markers for change. Despite the intellectual contribution of these studies
to research, at this point, neither EEG nor imaging are recommended as part of standard
practice for the diagnosis of autism but can be used for other neurological indicators (such as
if there are concerns beyond autism symptoms that merit an EEG or imaging). In this field,
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replication of findings across sites and even within individuals as well as larger samples
through collaboration are the promise of the future.
One way of bringing the three themes of mechanisms, heterogeneity and outcomes of
autism together is to consider the trajectories of this disorder over time (FIG. 7), how
knowledge of these trajectories can contribute to investigations of the biological and
cognitive underpinnings of autism, and how treatments and supports could make the lives of
children and adults with autism more positive.
In terms of mechanisms, despite earlier hopes for simple genetic explanations of autism, we
have instead identified many single-gene, germline loss-of-function point mutations yielding
some initial models of disruption in very basic molecular patterns as well as common
genes with small effects that are just beginning to emerge29. Attempts to study genes
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first have shown heterogeneity even within highly specific CNVs, with a few exceptions.
In addition, hope exists that genetically based interventions for autism may be possible,
although this will probably involve much further research. Data from genetic approaches
that might yield targeted genetic interventions may be most relevant to rare and severe
neurodevelopmental difficulties in general rather than autism as a specific entity. With
more information about the differing developmental trajectories of autism, more continuous
measures of symptoms and measures of language and intellectual function, behavioural
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phenotypes and changes over time can be quantified across different neurobiologically
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defined subgroups. This approach could potentially identify different ‘routes’ to different
outcomes, whether autism or not, and could have a practical benefit in terms of selecting
and monitoring appropriate treatments. In addition, with the heterogeneity of autism, our
growing understanding of mechanisms, be they causal or mechanisms for change, needs
to be linked to trajectories in development and not considered as static250. Researchers
modelling autism in other species might find the incorporation of early developmental
manifestations, such as regressions or motor delays, more tractable than the current focus
on autism-related social communication symptoms seen in humans. With collaborations
and studies of sufficient sample sizes, investigators have begun to focus on findings within
different developmental periods that could provide insight into trajectories and targets for
intervention. Thus, more study of the development of autism, both in studies of human
behaviours and in animal models, might influence the identification and treatment of autism
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as a neurodevelopmental disorder. Prospective studies, including epidemiological and direct

behavioural work across developmental periods, moving beyond very young children to later
childhood, adolescence and adulthood are needed.
Similarly, limited findings about adult development and patterns that lead into autism
(FIGS 5,7) call for measurement of different outcomes that respect individual differences
in autistic people and in families (BOX 3). By young adulthood, available supports for
places to live, employment and mental health services are needed for individuals who have
a range of skill levels, with supports not always well matched to the needs of individuals;
however, comparisons of treatments or treatment intensities have not historically been made,
even though they are continually called for. The types and specific goals of treatments
differ greatly for autistic people who are verbally fluent versus those who have difficulty
speaking for themselves, such that alternative systems need to be in place that consider co-
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occurring conditions, strengths, preferences and challenges. More studies of well-defined,

more homogeneous subgroups of autistic children and adults over time would provide
different and more useful information about real-life issues (TABLE 2) than large-scale
surveys of very heterogeneous samples251.
Progress in the biology of more generally defined neurodevelopmental disorders may have
the greatest yield for children with autism in their early years. Clinical trials that compare
known treatments (both psychosocial and biological) with new ones and treatment-as-usual
would allow us to build on previous findings in a more meaningful way and begin to
address the priorities listed in BOX 3, which, strikingly, are seldom priorities in autism
research. To move from science to practice, including evaluation and treatment, autism
researchers need to find a way to select and fund studies of more mundane, but critical
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evidence gaps in understanding heterogeneity, mechanisms of change and outcomes that

affect practice in any circumstance, not just internationally, within academic systems that
reward creativity and novelty. Unique methodologies, including the baby sibling studies,
accumulation of large data sets (such as ABIDE and the Simons Simplex Collection (SSC)),
prospective epidemiological studies and mechanistic studies of intermediate biomarkers
may begin to bring together information from molecular to pathophysiological to cognitive
and behavioural levels. However, for now, as for other neurodevelopmental and psychiatric
disorders including schizophrenia252, the distance between science and practice remains
Lord et al. Page 23
great, and the amount of research that attempts to address solvable problems for autistic
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people alive today and their families remains modest.
Acknowledgements
The authors thank J. McCauley, S. Gaspar, K. Byrne and A. Holbrook from UCLA for help with manuscript
preparation. S. Tromans is thanked for his updated review of the epidemiology literature. We recognize the many
investigators who contributed research that we cannot cite due to space limitations. C.L. is supported by the Eunice
Kennedy Shriver National Institute of Child Health and Human Development (NICHHD; R01 HD081199), the
National Institute of Mental Health (NIMH; R01MH081873-01A1) and the Simons Foundation. T.S.B. is supported
by grants from the Health and Social Care Information Centre, Leeds, and the National Institute for Health
Research (NIHR HTA; grant ref. NIHR127337). T.C. is supported by grants from Innovative Medicines Initiative 2
(no. 777394), the Medical Research Council (MRC; grants MR/K021389/1) and the NIHR (grant 13/119/18). J.C.
is funded by Autistica. G.D. is supported by the Institut Pasteur. T.F. is supported by the Autism Speaks Foundation.
E.J.H.J. is supported by grants from the Economic and Social Research Council (ESRC; ES/R009368/1), the
Innovative Medicines Initiative 2 (no. 777394), the MRC (MR/K021389/1) and the Simons Foundation (609081).
R.M.J. acknowledges the Mortimer D. Sackler Family and the NIMH (R01MH114999). J.L.T. is supported by
grants from the FAR fund and the NIMH (R34 MH104428, R03 MH 112783 and R01 MH116058). A.P. is partially
Author Manuscript
supported by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s
College London and the NIHR (NF-SI-0617-10120). M.W.S. is supported by the National Institutes of Health
(NIH; MH106934, MH109901, MH110928, MH116487 MH102342, MH111662, MH105575 and MH115747), the
Overlook International Foundation and the Simons Foundation. J.V.-V. is supported by the NIH (MH016434 and
MH094604), the Simons Foundation and the New York State Psychiatric Institute. The views expressed are those of
the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.
Competing Interests
C.L. acknowledges the receipt of royalties from Western Psychological Services for the sale of the Autism
Diagnostic Interview-Revised (ADIR), the Autism Diagnostic Observation Schedule (ADOS) and the Social
Communication Questionnaire (SCQ). T.S.B. has received royalties from Cambridge University Press and Oxford
University Press. T.C. has served as a consultant to F. Hoffmann-La Roche. and has received royalties from
Guilford Publications and Sage Publications. T.F. has received federal funding research support from, acted as a
consultant to, received travel support from, and/or received a speaker’s honorarium from the Brain and Behaviour
Research Foundation, Bristol-Myers Squibb, the Cole Family Research Fund, EcoEos, Forest Laboratories, Ingalls
Foundation, IntegraGen, Kugona LLC, the National Institutes of Health, Roche Pharma, Shire Development and the
Author Manuscript
Simons Foundation. J.L.T. receives compensation from Sage Publishers for editorial work. A.P. receives royalties
from Imperial College Press, Oxford University Press and Western Psychological Services. M.W.S. serves on the
scientific advisory boards and has stock or stock options for Arett Pharmaceuticals and BlackThorn Therapeutics.
J.V.-V. has consulted or served on an advisory board for Novartis, Roche Pharmaceuticals and SynapDx, has
received research funding from Forest, Novartis, Roche Pharmaceuticals, Seaside Therapeutics, SynapDx, and has
received an editorial stipend from Springer and Wiley. All other authors declare no competing interests.
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Box 1 |
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ASD as defined in DSM-5a

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria for autism spectrum disorder (ASD) comprise five symptom clusters (A–E).
A. Social communication and social interaction
• Must have evidence across multiple contexts of all of the following

three subdomains currently or by history:
– Social reciprocity
– Non-verbal communication
– Developing, maintaining and understanding relationships

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B. Restricted, repetitive behaviours and interests
• Must have evidence of two of four of the following subdomains

currently or by history:
– Stereotyped, repetitive behaviours
– Insistence on sameness
– Highly restricted, fixed interests
– Hypersensitivity or hyposensitivity or interest in sensory

inputs
C. Symptoms must be present in early development but may not fully manifest
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until later or may be masked later in life by learned strategies
D. Symptoms must cause clinically significant impairment in current functioning
E. Not better explained by intellectual disability or global developmental delay
Note: previously established DSM-IV diagnoses of any pervasive developmental

disorder, including Asperger’s disorder, should be assumed to be equivalent to
DSM-5 ASD. ASD may co-occur with many other disorders, including attention-deficit/
hyperactivity disorder, intellectual disability, language delay and genetic syndromes.
a Adapted from REF.125.
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Lord et al. Page 39
Box 2 |
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Global challenges in autism research

Recently, there have been calls for more attention to global issues in autism
research251 (Global Research on Developmental Disabilities Collaboration – Lancet
Global Health, 2016), including a number of related issues with somewhat different
potential solutions. For example, broader populations should be included in autism
research, including individuals from low-income and middle-income countries, but also
inclusive representation of the ethnic, linguistic and socioeconomic diversity of many
high-income countries and people whose autism is unrecognized. Moreover, there should
be the creation of opportunities to carry out research in low-income and middle-income
countries253. Open source and shared databanks, including autism-specific resources such
as the Simons Simplex Collection and Autism Brain Imaging Data Exchange (ABIDE),
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as well as broader collaborations, such as PsychENCODE, could assist in promoting

international research. In addition, the science of autism should be disseminated in ways
that are useful for practice in all countries but with particular attention to the needs of
communities and families with fewer resources254,255. More immediately, searches for
scalable methods of identification, and perhaps intervention, with children and adults
with autism140,256 have begun. However, the need to develop scalable global practices
highlights how little is known about when we need population-wide testing for autism
versus broader neurodevelopmental disorders, the minimal intensity and duration needed
for effective interventions, behavioural mechanisms behind changes in behaviour, and
which treatments work with which children, adults and families, all of which have
a bearing on interventions locally and globally. In addition, global issues of stigma,
governance and paucity of resources also have to be considered253.
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Box 3 |
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Top questions for autism research from autistic people, families and
professionalsa
1. Which interventions improve mental health or reduce mental health problems
in people with autism? How should mental health interventions be adapted for
the needs of people with autism?
2. Which interventions are effective in the development of communication and

language skills in autism?
3. What are the most effective ways to support or provide social care for autistic
adults?
4. Which interventions reduce anxiety in autistic people?

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5. Which environment supports are most appropriate in terms of achieving the

best education, life and social skills outcomes in autistic people?
6. How can parents and family members be supported and/or educated to care
for and better understand an autistic relative?
7. How can autism diagnostic criteria be made more relevant for the adult
population? And how do we ensure that autistic adults are appropriately
assessed and diagnosed?
8. How can we encourage employers to apply person-centred interventions and

support to help autistic people maximize their potential and performance in
the workplace?
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9. How can sensory processing in autism be better understood?
10. How should service delivery for autistic people be improved and adapted in
order to meet their needs?
aBased on REF.239.
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Box 4 |
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Examples of autism websites

Sites for health-care professionals or research scientists
• American Academy of Paediatrics: https://www.aap.org/en-us/advocacy-and-
policy/aap-health-initiatives/Pages/autism-initiatives.aspx
• International Society for Autism Research: https://www.autism-insar.org
• National Autistic Society: https://www.autism.org.uk
• Royal College of General Practitioners: https://www.rcgp.org.uk/clinical-and-

research/resources/toolkits/asd-toolkit.aspx
Information about treatment, research and advocacy for people with autism and
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their families
• Autism Canada: https://autismcanada.org
• Research Autism: http://www.researchautism.net/
• Autism Europe: https://www.autismeurope.org/
• Autism India: http://www.autism-india.org
• WHO: https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-
disorders
• Autism Spain: http://www.autismo.org.es
• Autism Speaks: www.autismspeaks.org

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• Autismus Deutschland: https://www.autismus.de
• Autistica: https://www.autistica.org.uk
Information about research funding and up-to-date information for people with
autism and families
• Simons Foundation: https://www.sfari.org
• US NIH: https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-
asd/index.shtml
• Autism Science Foundation: https://autismsciencefoundation.org
Epidemiological and surveillance information

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• US CDC: https://www.cdc.gov/ncbddd/autism/index.html
• Adult Population Autism

Surveys, England: https://digital.nhs.uk/data-and-information/
publications/statistical/adult-psychiatric-morbidity-survey/adult-psychiatric-
morbidity-survey-survey-of-mental-health-and-wellbeing-england-2014
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• Mental Health of Children and Young People (including autism)

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in England, 2017: https://digital.nhs.uk/data-and-information/publications/

statistical/mental-health-of-children-and-young-people-in-england/2017/2017
• The University of Queensland, Queensland Centre for Mental Health

Research: Global Burden of Disease Programme (autism): https://
www.uq.edu.au/news/article/2014/08/autism-rates-steady-two-decades
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Fig. 1 |. Theories and findings regarding autism mechanisms, outcomes and heterogeneity.
Original descriptions of the cardinal features of autism were attributed to a range of
causes, including being raised by wolves (the Wild Boy of Aveyron), inborn limitations
in affective contact and unfeeling parenting (such as ‘refrigerator mothers’), and holy
people (such as Fools for Christ)257. Conceptualizations of autism as a common highly
heritable neurodevelopmental disorder with underlying cognitive features began with the
recognition of differences in brain function and cognition in the 1960s258–261 and the
first twin study in the 1970s262. Other proposed mechanisms include maturational lags in
neurophysiology94 and cognitive mechanisms such as joint engagement176,263. With the
search for pathways to and sometimes out of autism on many levels, conceptualization
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of positive outcomes has been more recent but has also varied markedly. In the 1970s,
autism societies and collaborative clinical programmes focused on community integration
and de-institutionalization (such as National Autistic Society (NAS) and National Society
for Autistic Children (NSAC))264. Priorities shifted in the 1980s and 1990s, with still
unreplicated claims of ‘recovery’ in children who participated in intensive behavioural
interventions179, new advocacy groups focusing on biomedical discoveries to yield potential
biological treatments and even ‘cures’ (such as National Alliance for Autism Research
(NAAR) and Cure Autism Now257), and the neurodiversity movement265, which rejected
Lord et al. Page 44
‘cures’ and called for adaptation of environments to support autistic people, using
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terminology preferred by self-advocates and community participation. Recognition of the

marked heterogeneity within autism began in the 1970s, with the triad of impairments
in language, play and social interaction characterizing many children with intellectual
disabilities (ID) or those with classical autism266. The first twin study demonstrated
that monozygotic twin pairs, although concordant for difficulties associated with autism,
differed in specific characteristics and co-occurring conditions, including ID262. More
recently, phenotypic heterogeneity has been the rule in most, although not all, gene-first
phenotypic studies267. Thus, developmental aspects of differences in strengths, difficulties
and trajectories as well as biological factors require highly personalized conceptualizations
of the needs of autistic individuals and their families. ABA, applied behaviour analysis;
AGRE, Autism Genetic Resource Exchange; ASD, autism spectrum disorder; DSM,
Diagnostic and Statistical Manual of Mental Disorders; EEG, electroencephalography;
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GRASP, Global and Regional Asperger Syndrome Partnership; IDEA, Individuals with
Disabilities Education Act; MECP2, the gene associated with Rett syndrome; PACT,
Preschool Autism Communication Trial; PDD, pervasive developmental disorder; RCT,
randomized controlled trial; SNAP, Special Needs and Autism Project; SPARK, Simons
Foundation Powering Autism Research for Knowledge; TEACCH, Treatment and Education
of Autistic and Related Communication-handicapped Children.
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Fig. 2 |. Environmental risk factors for autism.

Data from studies aiming to identify risk factors for autism can be broadly split into
three categories: those with evidence supporting an association (a), those with inconclusive
evidence (b) and, importantly, those with no supporting evidence (c). Bars represent ranges.
aRepresents recurrence risk. Figure adapted from REF.18 with added findings from select
reviews and empirical papers: neonatal hypoxia estimate268, childhood vaccines20, valproate
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use during pregnancy269, parent age estimates270, preterm birth estimate271,272, maternal
obesity estimate273, folic acid intake estimate274, siblings estimate275,276, interpregnancy
interval estimate277, assisted reproductive technologies estimate278,279, pesticide and air
pollution estimate280, and caesarean section estimate281. Adapted from REF.18, CC-BY-4.0
(https://creativecommons.org/licenses/by/4.0/).
Lord et al. Page 46
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Fig. 3 |. Encoded proteins associated with autism risk.

Simplified schematic of the major cellular components of a neural circuit in the cerebral
cortex, with a focus on pyramid-shaped glutamatergic excitatory projection neurons.
Proteins encoded by selected high-confidence (false discovery rate < 0.1) autism risk
genes34 and proteins encoded by selected syndromic autism genes have a role in these
neurons during development. These proteins have a diverse intracellular distribution: those at
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the synapse have roles in cell adhesion, scaffolding and signalling. In addition, some of these
proteins are localized to the nucleus and have been shown, broadly, to mediate chromatin
modification and transcriptional control. Syndromic autism genes include FMR1 (encoding
fragile X mental retardation protein; fragile X syndrome), UBE3A (encoding ubiquitin-
protein ligase E3A; Angelman syndrome), TSC1 and TSC2 (encoding hamartin and tuberin;
tuberous sclerosis complex), PTEN (encoding phosphatase and tensin homologue) and
Lord et al. Page 47
MECP2 (encoding methyl-CpG-binding protein 2; Rett syndrome). GABA, γ-aminobutyric

acid; Ub; ubiquitin. Adapted with permission from REF.48, Elsevier.
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Fig. 4 |. Longitudinal trajectories of total brain volume, surface area and cortical thickness in
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autism.
Brain trajectories from 6 to 24 months of age for total brain volume (a), total surface area
(b) and total cortical thickness (c). Toddlers diagnosed with autism spectrum disorder (ASD)
had significantly greater surface area growth from 6 to 12 months than infants who were
high risk for ASD but did not receive a diagnosis as well as than typically developing
infants. Differences in surface area growth became more pronounced from 12 to 24 months
of age for toddlers who received an ASD diagnosis. Corrected age refers to the age corrected
by length (body size). Adapted from REF.74, Springer Nature Limited.
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Fig. 5 |. Co-occurring disorders.

Primary and secondary disorders and disadvantage can accumulate through development in
people with autism. These disorders can form additional targets for treatment and policy.
Prevalence estimates are preliminary, derived from QUEST282, SNAP138,283 and EDX147
cohorts, but are limited by the fact that many are based on clinical populations or data that
are inherently biased (such as US Medicaid data, in which billing for treatment is contingent
on having a non-autism diagnosis) and few well-designed population studies exist. ADHD,
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attention-deficit/hyperactivity disorder; OCD, obsessive–compulsive disorder.

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Fig. 6 |. Major parental milestones in advocating and supporting their child with autism.
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Families of children and adults with autism have many decisions and expectations across
the lifespan of their children, from seeking initial diagnostic evaluation and intervention
to preparing for ageing-related services. These decisions vary across different cultures,
regions and countries, and depend on many factors, including the resources and services
available. However, several decisions are common across all regions, including low-income
and middle-income countries, such as choices about who will care for their child if the
parents are temporarily unable, the amount of time parents and other family members can
spend with the child with autism versus meeting other needs, ways to modify their home
environment to ensure the safety and independence of the individual with autism and the
kinds of behavioural expectations that are most helpful for their child or adult. Of note, for
many families, these choices and responsibilities are lifelong and are relevant for children,
adolescents, adults and elders with autism.
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Fig. 7 |. Changes in daily living scores as predicted by IQ scores and autistic symptoms.
Changes in independent daily living skills can be observed in people with autism over
time. This sample consists of ~100 young adults with autism with a mean age of 26
years, who were evaluated at 2, 3 and 9 years of age and followed up to 26 years of age.
Daily living scores are very diverse, ranging from age-appropriate levels of independence
at adulthood (represented by a daily living score of 100, assessed using Vineland II284)
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to very limited skills (represented by a score of <30). Increasing divergence shows where
measurement after 2 years of age is additionally predictive, with the line thickness indicating
the proportion of early referred children that followed each trajectory. Heterogeneity
in intellectual functioning and severity of autistic symptoms (social communication and
restricted, repetitive, sensory behaviours) can be observed. In addition, improvements and
worsening of autistic symptoms and intellectual functioning can occur over time. a,b |
Referred children had verbal IQs predominantly <50 (over 3 standard deviations below
average) but could show improvement in daily living standard scores from 2 to 3 years
of age that were indicative of eventual greater independence in adulthood. Relatively less
early change in non-verbal IQ is seen but, like verbal IQ, by adulthood the association
with eventual adult daily living skills is strong. c,d | Variation in autism symptom severity
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in social communication (CSS refers to the Autism Diagnostic Observation Schedule,

Second Edition (ADOS-2) comparison scores) showed a stronger association with adult
independence than restricted, repetitive behaviours and continued to change over the lifespan
following more divergent pathways than intellectual functioning. Data from the EDX cohort
compiled from REFS1,147,285.
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Table 1 |
Evidence-based medication in autism
Medication FDA or EMA, indication and age Effect size (d)286 Common adverse effects
Lord et al.
Typically used for ADHD symptoms

Methylphenidate FDA and EMA approval for ADHD (not specific for autism) in those ≥6 years of age d = 0.78 (teacher rated) Sleep disruption and decreased appetite
Atomoxetine FDA and individual country approval for ADHD (not specific for autism) in those ≥6 years of age d = −0.68 to 0.084 Decreased appetite, nausea and irritability
Guanfacine FDA and EMA approval for ADHD (not specific for autism) in those 6–17 years of age d = 1.67 Fatigue, sedation, and decreased pulse and
blood pressure
Typically used to treat agitation and irritability

Risperidone FDA approval for irritability associated with autism and EMA approval only for other indications in d = 0.94 Increased appetite, sedation and weight gain
those 5–17 years of age
Aripiprazole FDA approval for irritability associated with autism and EMA approval only for other indications in d = 0.87 Nausea and weight gain
those 6–17 years of age
ADHD, attention-deficit/hyperactivity disorder; EMA, European Medicines Agency.
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Table 2 |
Factors that affect QOL
Type of QOL Factor Description

Lord et al.
Objective QOL Early language Follow-up studies of adults with autism who were diagnosed as children have examined the amount of spoken language during early childhood. Individuals
with autism who had fluent speech are more likely to have higher levels of objective QOL in adulthood than those with phrase speech or those with no speech
or who spoke in single words
Indicators of Studies examining IQ scores using standardized IQ tests administered in both early childhood and adulthood find that individuals with autism and higher IQ
intelligence scores have higher levels of objective QOL than those with lower IQ scores. Other, less-standardized measures of intelligence (such as those used in large
cohort studies) have similar findings
Adaptive behaviour Higher levels of adaptive behaviour — and particularly more activities of daily living — are associated with better objective QOL in people with autism.
Adaptive behaviour is a challenge for many individuals with autism, who have scores below what would be expected based on IQ287. Adaptive behaviour is
changeable, making it a promising avenue for interventions to improve objective QOL
Autism symptom Individuals with more severe autism symptoms tend to have lower objective QOL in adulthood
severity
Challenging Higher levels of challenging behaviours in people with autism, which can include both internalizing problems and externalizing problems, are related to lower
behaviours objective QOL
Sex or gender Sex or gender associations with objective QOL have been demonstrated in terms of employment or post-secondary education; indeed, women with autism
obtain employment and post-secondary educational positions at the same rate as men with autism but have a more difficult time maintaining those positions
over time
Subjective QOL Perceived stress Many adults with autism perceive high levels of stress in their own lives; these perceptions are related to lower subjective QOL
Supports Several different types of supports have been related to subjective QOL, including formal services, support from family members (most often parents) and
more general social support from others
QOL, quality of life.
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Autism spectrum disorder

2Department of Health Sciences, University of Leicester, Leicester, UK.

Neurosciences, University of California, San Francisco, CA, USA.

category of ‘pervasive developmental disorders’ (PDDs). PDDs are a group of disorders

Manifestations of autism include impairments in social communication and interaction,

associated with autism is far from straightforward.

the available data sets, particularly in low-income countries. An increased prevalence of

obtaining information on autism rates in settings where professionals may be able to

cognitive behavioural therapy (CBT)-oriented treatments for anxiety23.

of up to tens of thousands of individuals and the associated increase in statistical power,

Owing to these challenges, multiple approaches have emerged focusing on

The ability to constrain future experiments to examine mutations in specific risk-associated

certain to soon follow on attempts at gene therapy for monogenic neurodevelopmental

of autism, demonstrating subgroups of individuals with specific neurobiological alterations

a reliable biomarker of autism78.

differences in whole-brain connectivity90 or the social brain91 — a field in its infancy — or

of dysfunctional executive functions and visual attention102. Other studies, particularly

a neurophysiological deficit in γ-aminobutyric acid (GABA) receptor-mediated function in

Diagnosis, screening and prevention

repetitive or sensory behaviours) can be reliably identified by trained clinicians123,124.

Diagnosis and screening in children

A number of structured diagnostic interviews and observational assessments for autism

Interview-Revised (ADI-R)136 and the Autism Diagnostic Observation Schedule-2nd

Screening and early identification.—The potential for early testing to prospectively

Early developmental profiles.—Understanding of onset patterns of autism has

Diagnosis and screening in adults

Information on diagnostic methods to identify autism in adulthood is in its infancy,

Collectively, these difficulties and disorders contribute to autism severity174 as well as

complex than sometimes conveyed.

Lower-intensity approaches include parent-mediated interventions whereby parents are

lower-intensity approaches in preschool children compared with a control group. However,

other lower-intensity, time-limited parent-mediated interventions, such as focus playtime

School-age children and adolescents

targeting social functioning in adults over a 37-year period202.

groups that may benefit those with autism.

As mentioned previously (see Co-occurring disorders, above), co-occurring mental

across species. Underpowered studies of intranasal oxytocin have demonstrated mixed

Subjective QOL.—Meta-analyses have suggested that, across the lifespan, subjective

and developing positive feelings about the research process.

as a neurodevelopmental disorder. Prospective studies, including epidemiological and direct

occurring conditions, strengths, preferences and challenges. More studies of well-defined,

evidence gaps in understanding heterogeneity, mechanisms of change and outcomes that

people alive today and their families remains modest.

haploinsufficiency. Science 363, eaau0629 (2019). [PubMed: 30545847]

autism. Biol. Psychiatry 76, 405–411 (2014). [PubMed: 24090791]

processing in autism spectrum disorders: a meta-analysis of neuroimaging studies. Autism Res 9,

11, 1002–1016 (2016). [PubMed: 26989195]

(2011). [PubMed: 21641861]

Autism Dev. Disord 49, 1837–1852 (2019). [PubMed: 30617550]

176. Schreibman L et al. Naturalistic developmental behavioral interventions: empirically validated

(2018). [PubMed: 29946699]

239. Autistica. Your questions shaping future autism research. https://www.autistica.org.uk/downloads/

autism and ASD over the years.

12, 316–327 (2019). [PubMed: 30575327]

Health Dev 42, 486–493 (2016). [PubMed: 27126521]

ASD as defined in DSM-5a

A. Social communication and social interaction