Presymptomatic Detection and

Intervention for Autism

Spectrum Disorder
Katherine E. MacDuffie, PhD,a,b Annette M. Estes, PhD,a Lucas T. Harrington, PsyD,a Holly L. Peay, PhD,c Joseph Piven, MD, PhD,d
John R. Pruett, Jr, MD, PhD,e Jason J. Wolff, PhD,f Benjamin S. Wilfond, MDb,g

Universal screening for autism spectrum disorder (ASD) is recommended abstract

during pediatric primary care visits in the first 2 years of life. However, many
children are missed by initial screening and not diagnosed with ASD until
years later. Research efforts are underway to develop and evaluate new Departments of aSpeech and Hearing Sciences and
g
Pediatrics, University of Washington, Seattle, Washington;
objective measures of risk for ASD that can be used in infancy, before b
Treuman Katz Center for Pediatric Bioethics, Seattle
symptoms emerge. Initial studies with these tests, particularly MRI-based Children’s Research Institute, Seattle, Washington;
c
Research Triangle Institute International, Research
screening for infants at high familial risk, have shown promise but have Triangle Park, North Carolina; dCarolina Institute for
not yet been evaluated in clinical trials. We present the study design for Developmental Disabilities, University of North Carolina
Chapel Hill, Chapel Hill, North Carolina; eSchool of Medicine,
a hypothetical clinical trial that would combine presymptomatic detection Washington University, St Louis, Missouri; and fDepartment
and intervention for ASD and consider, through commentaries from diverse of Educational Psychology, University of Minnesota,
Minneapolis, Minnesota
perspectives, the ethical issues that should be anticipated in advance of
beginning such trials. Commentators Drs Pruett and Piven address the social Drs MacDuffie and Wilfond conceptualized the overall
value of the proposed research and importance of researcher-bioethicist manuscript, conceptualized and drafted their
commentary, and reviewed and revised the overall
collaborations. Drs Estes and Wolff discuss the clinical potential and manuscript; Drs Estes, Harringon, Peay, Piven, Pruett,
challenges of developing presymptomatic interventions for infants at risk for and Wolff contributed to conceptualizing, drafting,
ASD. Dr Harrington takes a neurodiversity view of presymptomatic prediction and revising their respective commentaries; and all
authors approved the final manuscript as submitted
and intervention and their implications for autistic identity and quality of life. and agree to be accountable for all aspects of
Finally, Drs MacDuffie, Peay and Wilfond consider the potential risks and the work.
benefits that must be evaluated and weighed in the next phases of research on DOI: https://doi.org/10.1542/peds.2020-032250
presymptomatic detection and intervention for ASD. Accepted for publication Feb 8, 2021
Address correspondence to Katherine E. MacDuffie,
PhD, University of Washington Autism Center, 1701 NE
Columbia Rd, Box 357920, Seattle, WA 98195.
In the 13 years since the American diagnosis. Some have the goal of E-mail: kmacd@uw.edu
Academy of Pediatrics recommended detecting ASD in the first year of life, PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
that all children be screened for autism before the emergence of observable 1098-4275).
spectrum disorder (ASD) at 18- and 24- symptoms. If validated, screening tests Copyright © 2021 by the American Academy of
month well-child visits,1 pediatrician that enable accurate presymptomatic Pediatrics
offices have become the primary site detection will be poised to alter FINANCIAL DISCLOSURE: The authors have indicated
for ASD screening in the United States. dramatically the landscape of ASD they have no financial relationships relevant to this
screening in pediatric primary care. article to disclose.
Unfortunately, the most widely used
parent-report screening test (the FUNDING: Supported by National Institute of Mental
The focus with this Ethics Rounds is Health grant F32MH118689 (to Dr MacDuffie) and
Modified Checklist for Autism in phenotypic tests under development National Institute of Mental Health grant R01
Toddlers) has only modest positive that could identify infants at risk for MH118362 (to Drs Pruett and Piven). Funded by the
predictive values (15%–18%)2 and ASD before the onset of symptoms. This National Institutes of Health (NIH)
misses the majority of children who are is in contrast to genetic testing
eventually diagnosed with ASD. approaches to identify genetic To cite: MacDuffie KE, Estes AM, Harrington LT,
Research efforts are underway to syndromes frequently associated with et al. Presymptomatic Detection and Intervention
for Autism Spectrum Disorder. Pediatrics. 2021;
develop new screening approaches that ASD like tuberous sclerosis complex or
147(5):e2020032250
could lower the average age of Fragile X. Current research efforts apply

PEDIATRICS Volume 147, number 5, May 2021:e2020032250 ETHICS ROUNDS

Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
 methods like eye-tracking, EEG, and
MRI to detect developmental
alterations in the first year of life that
can predict later ASD diagnosis, even
for children with no identified or
suspected genetic syndrome.3 In one
recent example, the Infant Brain
Imaging Study Network
demonstrated that brain
characteristics detectable on MRI as
early as 6 months of age can predict
later diagnoses of ASD in infants with
an older affected sibling.4,5 The Infant
Brain Imaging Study network is
currently working to replicate their
initial results, with the eventual goal
of using MRI to detect high-risk
infants for entry into a randomized
controlled trial (RCT) of
a presymptomatic intervention. In
this article, we present a hypothetical
study design to anticipate the ethical
issues that should be considered
when designing such a trial.
THE CASE
Infants with an older sibling with ASD
will be recruited at 6 months of age to
participate in an MRI scan conducted
during natural sleep (no sedation
required). A machine-learning
algorithm applied to the MRI data is
expected to yield a predictive result
(positive predictive value $80%) for
ASD in ∼20% of the infants. These
infants will then be recruited into an
RCT, in which they will receive either
a novel behavioral intervention or
usual care. The behavioral
intervention will use play-based
techniques to encourage the
development of social communication
and improve parent–child
interactions. During the consent
process, parents will be informed that
there is limited evidence to date
supporting the efficacy of the
intervention for this age group.
Primary outcomes at 24 months will
include whether infants meet
diagnostic criteria for ASD, the
severity of autism symptoms, and
measures of language and social
communication abilities.
2 MACDUFFIE et al
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
This study will be the first to combine
predictive testing and delivery of
presymptomatic intervention to
infants before the consolidation of
symptoms that define ASD. Given the
complexity and novelty of this
approach, what ethical issues are
raised by such a trial?
DRS PRUETT AND PIVEN,
PSYCHIATRISTS/NEUROSCIENTISTS,
COMMENT
This case prompts consideration of
the potential social value and ethical
challenges associated with prediction
and intervention for later developing
ASD. We are co–principal
investigators of a new project (the
inspiration for this case report) to
replicate and extend findings
predicting ASD from MRI scans in the
first year of life.4,5 The
presymptomatic detection of, and
intervention for, those infants
classified as ultrahigh risk for ASD is
a worthy goal for ASD research, as
long as we carefully consider the
challenges inherent in treating risk
(not disorder) and take into account
the tremendous heterogeneity
associated with ASD and the nature of
ASD-associated behaviors that can be
egosyntonic (ie, compatible with an
individual’s values and beliefs about
themselves).
Facilitating Efficient Presymptomatic
Intervention Trials
Although data are limited,
researchers suggest that early ASD
intervention is better than later.6
Presymptomatic intervention might
be even more powerful, coming at
a time when the brain is most
malleable and before the
consolidation of brain changes and
behaviors that further complicate
treatment. Treating risk before
disorder is a well-worn path in
medicine (eg, treating hypertension
reduces the chance of a later heart
attack). However, this approach is
novel for ASD. Without accurate
presymptomatic prediction, all high-
familial-risk children must be
enrolled in presymptomatic
intervention trials, although the
majority (80%) will not develop ASD.
Our current work may, therefore,
enable highly efficient trials of
potentially efficacious
presymptomatic interventions by
enrolling children at ultrahigh risk for
developing ASD. Although our current
prediction algorithms reference
a diagnostic category associated with
significant impairment (ie, ASD),
future clinical trials might predict
more dimensional aspects of behavior
that are related to ASD. These trials
might include children with a range of
impairment in the behaviors that
define ASD (social communication
and interaction deficits, restricted and
repetitive behavior) and associated
comorbidities (eg, aggression or
language disorder). If we succeed in
predicting quantitatively defined
levels of impairment, referrals would
then be possible for clinical trials of
interventions for specific patterns
and profiles of behavioral challenges,
rather than serving only those
children who are predicted to meet
a dichotomous threshold for ASD.
Treating Impairment, Not Eliminating
Diversity
The tremendous phenotypic
heterogeneity in ASD is well known.
Individuals with ASD are often
classified as either “high-” or “low-
functioning” and have various
combinations of other-defining
behaviors and associated comorbid
conditions, including language
deficits, motor coordination
problems, self-injury, aggression,
intellectual disability, anxiety,
attention-deficit/hyperactivity
disorder, and epilepsy. Few would
question treating depression or
hallucinations, because these cause
great pain and discomfort. With ASD,
however, there is a question about
changing enduring traits that are
more akin to personality and may be
seen as defining who an individual is.
Our goal is to mitigate the
 development of significantly
impairing ASD phenotypes and not to
limit the wonderful diversity of
human expression, subjective
experience, and achievement inherent
in those individuals who find these
characteristics syntonic with their
view of themselves. We do not want
to change behavioral characteristics
for individuals with symptoms that
are manageable and who are able to
succeed in life in a way that meets
their personal goals. However, just as
there is no question that we should
treat learning disabilities and
depression, those ASD-associated
behaviors that result in significant
morbidity and impairment should be
considered legitimate targets for
intervention.
Collecting Social Science Data to
Guide Future Research and
Implementation
In our society, we allow parents
considerable discretion to make
treatment decisions for their children.
Accurate presymptomatic prediction
would give parents more power with
respect to these decisions, but there is
an urgent need to generate
a knowledge base about the
implications and various ways to best
use this information regarding risk
most effectively. It is essential to
develop a program of ethical, legal,
and social implications research
parallel to research on predictive
biomarkers and presymptomatic
clinical trials, to ensure ethical
conduct of this science and its future
clinical translation. Bioethicists must
collaborate with researchers studying
risk and contribute to our
understanding of the implications of
this research. Researchers must listen
to the broad array of stakeholders
with an interest in predicting ASD
outcome, including autistic
individuals, their parents, providers,
health economists, third party payers,
and clinicians. And finally, we must
commit to revising our scientific and
clinical objectives on the basis of this
feedback and the data generated in
PEDIATRICS Volume 147, number 5, May 2021
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
rigorously conducted ethical, legal,
and social implication studies of
presymptomatic detection and
intervention for ASD.
DRS ESTES AND WOLFF, CHILD CLINICAL
AND EDUCATIONAL PSYCHOLOGIST,
COMMENT
Current diagnostic practice for ASD
depends on recognition of core
behavioral signs in the domains of
social communication and restricted
and repetitive behaviors.7 However,
research has revealed behavioral and
neurobiological markers that are
present before core symptoms.4,5,8,9
Thus, as described in this case, it is
conceivable that it may soon be
possible to identify children who have
a high likelihood of developing ASD in
infancy. Current ASD interventions
are designed to address delays,
deficits, and behaviors that have
already consolidated into the
symptoms of ASD. There are not yet
guidelines for usual care of infants at
high familial risk. Pioneering ASD
intervention research was based on
children age 5 to 7 years10; much has
been done to extend and adapt such
interventions to younger children, as
early as toddlerhood.11,12 But,
because it is not yet possible to
reliably identify infants
presymptomatically in a clinical
setting, interventions have not yet
been designed or tested for infants
before symptom emergence. As
researchers involved with
understanding early development
and behavioral intervention for ASD,
we recognize some of the unique
opportunities (and potential
challenges) that presymptomatic
intervention presents.
Building Effective Presymptomatic
Interventions
Presymptomatic intervention would,
by definition, not target autistic
features directly. Existing
interventions for ASD could not
simply be adapted for infants.
Instead, presymptomatic intervention
would need to target behavioral
precursors of defining features of
autism, such as visual orienting to
promote the development of joint
attention and expressive language.
The process of intervention would
also differ, with procedures deftly
responsive to change to ensure
infants reach developmental
milestones across multiple domains.
New interventions might also include
targets not necessarily distinct to
autism but with known pervasive
positive effects on child development,
such as supporting parent–infant
interaction, as proposed in this case
example. However, it is unlikely that
improving parent–infant interaction
alone would significantly reduce the
prevalence of ASD or attenuate its
most severe cognitive and adaptive
outcomes because the parent–infant
relationship is not a causal factor.
Indeed, implicating parent behavior
as mechanistic in the development of
ASD recalls long discredited
psychogenic theory and underscores
why a careful, evidence-based
approach is essential. A strong
parent–infant relationship may
improve quality of life, an important
consideration for all interventions, or
may mediate longer-term
communication or social outcomes,
but should not be confused with
a primary target of presymptomatic
ASD intervention.
Potential Barriers to Implementation
Aside from whether an efficacious
presymptomatic approach can be
developed, the acceptability of
presymptomatic identification and
intervention and its potential impact
on families is poorly understood. It is
critical to incorporate diverse parent
perspectives on feasibility and
acceptability from the inception to
ensure effectiveness, not just efficacy.
Parents may find presymptomatic
intervention of lower priority than
other responsibilities; caring for an
infant is demanding even for the
“easiest” children. For some families,
it may come down to a choice
3
 between addressing clear
developmental needs in an older child
with autism versus taking action on
subtle alterations in a healthy baby
sibling. Although some parents feel
better prepared for a second child
with ASD, others experience
increased distress when faced with
the possibility that a younger sibling
may be developing ASD. Coupled with
the emotional impact of confronting
the likelihood of having a first or
second child with autism, this
calculus may result in the decision to
take a “wait and see” approach.13
Even if parents embrace
presymptomatic intervention, the
potential for iatrogenic effects and
the psychological and financial costs
of false-positives would need to be
considered. If intervention is
implemented without a holistic
approach, taking into consideration
family adaptive functioning, lasting
negative impacts are possible.
Clinically Promising, Structurally
Challenging
Despite current diagnostic
procedures that can identify ASD as
soon as symptoms consolidate,
usually by 24 months,14 and evidence
of cost effectiveness and long-term
efficacy of intervention,15 many
children are not identified until years
after their symptoms emerge and
many receive no ASD-specific,
evidence-based intervention.16,17
Even for families who do receive
early diagnosis, access challenges and
limited availability of trained
providers can result in long periods of
time spent on waitlists or otherwise
attempting to secure services. These
same structural challenges would
need to be addressed for
presymptomatic intervention to reach
its potential; if children are not
identified shortly after birth, the
window for presymptomatic
intervention will pass. Taking
advantage of the presymptomatic
window also requires that
interventions be immediately
available. These challenges are not
4 MACDUFFIE et al
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
insurmountable, but they require
significant investment and buy-in
from intervention scientists,
policymakers, and other stakeholders
from the outset.
The exciting potential of
presymptomatic intervention is
consistent with the maxim “an ounce
of prevention is worth a pound of
cure,” taking advantage of
neuroplasticity in the first years of
life and ensuring infants do not miss
the learning opportunities needed to
develop skills vital to achieving future
developmental milestones. Although
there are now a handful of
preliminary studies of
presymptomatic intervention (eg,
Green et al,18 Rogers et al19), issues
relevant to implementation, as well as
others such as content, timing, and
dosage, remain open to inquiry.
Caution and systematic evaluation are
imperative as we move forward, but
presymptomatic intervention
represents a potentially
transformative approach to
supporting children with autism.
DR HARRINGTON, CLINICAL
PSYCHOLOGIST/AUTISTIC
SELF-ADVOCATE, COMMENTS
This case proposes a new method for
identifying ASD in infancy, paired
with a novel behavioral intervention.
The previous commentary addressed
ethical ramifications if the proposed
intervention does not have the
intended outcome. As a licensed
psychologist who is also autistic, I
will address an issue that may not
occur to nonautistic researchers:
ethical concerns if the intervention
does have the intended outcome and
causes change in a child.
Intervening to Change Autistic Brain
and Behavior
Interventions that aim to change the
autistic brain to be more
“neurotypical” risk erasing a valuable
form of human diversity. Autism, once
conceptualized as a deficit, has been
reimagined by the autistic community
and researchers as a neurologic
variation associated with valued
strengths ranging from visual
processing20 to resistance of peer
pressure.21 Many autistic people take
deep joy in their distinctive interests,
values, and sensory experiences. The
autistic community compares the
desire to “cure” autism with past
efforts to “cure” homosexuality or
gender nonconformity,22 which often
had similarly caring but misguided
goals of alleviating a patient’s
suffering in an unsupportive world.
Interventions that aim to mold
autistic behavior toward neurotypical
norms can create an illusion of
“normality” but can leave a child
struggling with unrealistic
expectations and insufficient support.
Behavioral intervention has often
taught autistic children to ignore their
own needs and perceptions while
reinforcing desired compliance and
communication behaviors. For
example, increasing eye contact is
often a goal of treatment despite
autistic accounts of physical pain
from eye contact.23 “Treating” low
eye contact can be akin to “treating”
a sprained ankle by teaching the child
to walk on it without wincing. Known
as “masking” or “camouflaging,”24 the
suppression of natural autistic
behavior is associated with negative
outcomes such as suicidality.25
Conversely, feeling accepted as an
autistic person is associated with
improved mental health.26
Intervening to Meet the Goals of
Autistic Individuals
Identification during infancy is
advisable only if paired with an
intervention that will promote
flourishing rather than impose
normality. This is the primary goal of
the neurodiversity movement,
a political effort that overlaps with
the adult autistic community and
advocates for respecting and
accommodating diverse neurologies
rather than trying to “fix” them.27 The
movement is sometimes criticized as
 overlooking autistic people with
intense support needs such as
intellectual disability and destructive
behavior. It is true that many autistic
people and their families currently
experience significant challenges and
suffer from lack of support. However,
the movement sees this as a failure of
society rather than the individual and
imagines a world of supports and
accommodations robust enough that
autistic people can be safe, happy, and
included regardless of their language
levels or cognitive scores.28
An example of an existing
intervention that would be consistent
with neurodiversity goals is the
collaborative and proactive solutions/
collaborative problem-solving (CPS)
model, an empirically supported
intervention for children with
oppositional behavior that can reduce
severe outcomes such as self-injury
and need for restraint.29 The CPS
model conceptualizes aggressive and
self-injurious behavior as an
indication of a mismatch between the
child’s needs and the environment.
Rather than reshaping a child’s
behavior to fit inflexible norms, CPS
aims to reduce or eliminate
destructive stress responses by
tailoring expectations to the child’s
current level of skill development.
The child is then included in problem-
solving at whatever level their
cognitive and communication skills
allow, by using a prescribed method
that promotes trust and respects
autonomy while building skills such
as flexibility and perspective-taking.
CPS is an example of the type of
intervention that could be fruitfully
combined with identification in
infancy. Through earlier
identification, parents could prepare
to have more flexible expectations for
their child. Psychoeducation around
neurodiversity and contact with
autistic adults could help dispel
myths and fears that parents hold
about autism and prepare them to
understand and appreciate their
child’s unique perspective. Parents
PEDIATRICS Volume 147, number 5, May 2021
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
could proactively implement
strategies like sensory
accommodation, visual supports, and
alternative communication tools (eg,
sign language and picture cards) and,
eventually, behavioral interventions
like CPS if needed. Improved
communication and reduction in
stress could then help the child be
more available for learning and able
to cope without destructive behavior.
Toward an Inclusive Future
Similar to the way LGBTQ1
acceptance and racial integration
seemed unimaginable only decades
ago, disability inclusion as advocated
by the neurodiversity movement will
be challenging but is not impossible.
Effective disability inclusion often
indirectly improves the environment
for nondisabled members of
communities as well.30,31 Researchers
studying early identification and
intervention can help make this
vision a reality by incorporating ways
to uplift diverse minds rather than
homogenizing then.
DRS MACDUFFIE, PEAY, AND WILFOND,
RESEARCH ETHICISTS, COMMENT
This case and the above
commentaries convey the complex
pragmatic and ethical challenges
confronting researchers seeking to
develop and test tools for
presymptomatic detection and
intervention for ASD. These
commentators have so far highlighted
the importance of 2 benchmarks of
ethical clinical research32,33: forming
collaborative partnerships with
relevant community members to
determine appropriate intervention
targets (ie, parents, autistic adults)
and maximizing the social value of
this research for children and
families. Here, we focus on a third
benchmark: achieving a favorable
risk/benefit ratio for families (and
not solely for infants) via careful
attention to specific aspects of the
study design.
Potential Benefits and Risks
The clinical benefits (if any) of the
proposed presymptomatic
intervention are unknown, and this
state of equipoise can justify
randomizing a subset of the sample to
receive usual care, assuming robust
informed consent. The potential for
direct benefit from the intervention
may not, however, be the only type of
benefit valued by parents. Enrolled
infants may benefit from periodic
evaluation and close surveillance for
non-ASD developmental delays
(which are more common for high-
risk siblings)34 and associated
referral for standard early
intervention services (ie, publicly-
funded services like speech or
occupational therapy). Parents who
receive a presymptomatic prediction
of later diagnosis may benefit from
more time to prepare emotionally,
financially, and logistically (eg, by
moving closer to extended family or
an academic medical center).35
Previous work with families of
children with Fragile X syndrome
suggests parents place great value on
learning health information about
their child even if it does not lead to
proven treatment.36 As investigators
with expertise in pediatric bioethics
and genetic counseling, we
hypothesize that the same will be true
for many parents of children likely to
develop ASD and that parents who
value these types of ancillary
research benefits will be more likely
to enroll their children in the
research.
That said, the disclosure of
presymptomatic predictive results
also has potential to cause harm.
Risks include the potential for false-
positive or false-negative results.
Parents of children with a positive
result who do not develop ASD (false-
positive) may expend substantial
time, financial resources, and effort
on interventions that are unnecessary
and supplant other developmentally
valuable experiences. Worth noting,
however, is that the risks associated
5
 with unnecessary behavioral
intervention are minimal; current
approaches for young children use
play-based techniques to teach social
communication skills and encourage
responsive 1:1 caregiver interactions
that could benefit any child. Infants
with a negative test result who do
develop ASD (false-negative) could be
delayed in receiving a diagnosis and
miss out entirely on the window for
early intervention. Given that false-
negatives may have a greater impact
on child outcomes, it therefore may
be appropriate to prioritize test
sensitivity over specificity.
Determining optimal testing
parameters will require empirical
data collected over time on the
impact of predictive results on
parents, parent–child interactions,
and child outcomes.
The proposed trial provides an
opportunity to closely monitor
families who receive a positive
predictive test result and who are
enrolled in either in the experimental
or usual care group. Research teams
should also follow families who
receive negative test results and are
not recruited for the intervention
phase. Research staff should be
trained in education and counseling
approaches informed by genetic
counseling, and longitudinal follow-
up visits for all families should be
implemented to monitor parent
wellbeing and family and child
outcomes. Finally, in light of
emerging data that many parents
choose not to enroll their high-risk
infants in presymptomatic
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
REFERENCES
1. Johnson CP, Myers SM; American Academy
of Pediatrics Council on Children With
Disabilities. Identification and evaluation of
children with autism spectrum disorders.
Pediatrics. 2007;120(5):1183–1215
2. Wallis KE, Guthrie W. Identifying autism
spectrum disorder in real-world health
6 MACDUFFIE et al
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
intervention when offered,13 the
research team should also follow
families who receive positive
results even if they are unable or
decline (for personal, logistic, or
other reasons) to continue their
participation into the intervention
phase. Longitudinal data collected on
all families who receive predictive
results from novel testing
modalities will allow calculation of
the risk/benefit ratio to guide future
research.
CONCLUSIONS
In coming years, new screening
approaches to predict ASD
presymptomatically (whether by
MRI, EEG, eye-tracking, or other
behavioral assays) are anticipated to
move into subsequent stages of
clinical translation and be tested in
RCTs in combination with novel
interventions. Here we have
considered one potential trial
design and explored, along with
commentators, steps that should be
taken to promote the ethical
conduct of such trials.
Unfortunately, the broader context
for this research is an inequitable
landscape for ASD screening,
diagnosis and intervention. In US
primary care settings, children of
color tend to be screened less often,
with less accurate results, and are
diagnosed with ASD later compared
to white children.37,38 Particular
attention must be paid to potential
inequities before, during, and after
presymptomatic detection and
care settings. Pediatrics. 2020;146(2):
e20201467
3. Wolff JJ, Piven J. Predicting autism risk
in infancy [published online ahead of
print October 31, 2020]. J Am Acad Child
Adolesc Psychiatry. doi:10.1016/
j.jaac.2020.07.910
intervention trials. An unfortunate
outcome would be the creation of
new and expensive methods for
predicting and mitigating symptoms
of ASD that exacerbate existing
health disparities. We believe this
outcome is not inevitable and must
be actively avoided. Investment of
federal and philanthropic research
funds in ASD services research
could improve current service
systems and prepare for the
necessary expansion to implement
presymptomatic testing and
intervention. Although some might
view services research related to
not-yet-validated predictive
biomarkers as premature, in
reality, the simultaneous
advancement of biomarker and
services research is essential for
new predictive approaches to
achieve their clinical potential and
to avoid further disadvantaging
children and families who
already face challenges accessing
diagnostic and intervention services
for ASD.
ACKNOWLEDGMENTS
The authors thank Don Bailey and
John Lantos for their helpful input on
the conceptualization of this
manuscript.
ABBREVIATIONS
ASD: autism spectrum disorder
CPS: collaborative problem-solving
RCT: randomized controlled trial
4. Emerson RW, Adams C, Nishino T, et al.;
Network. Functional neuroimaging of
high-risk 6-month-old infants predicts
a diagnosis of autism at 24 months of
age. Sci Transl Med. 2017;9(393):eaag2882
5. Hazlett HC, Gu H, Munsell BC, et al.; IBIS
Network; Clinical Sites; Data
 Coordinating Center; Image Processing
Core; Statistical Analysis. Early brain
development in infants at high risk for
autism spectrum disorder. Nature.
2017;542(7641):348–351
6. Vivanti G, Dissanayake C; Victorian
ASELCC Team. Outcome for children
receiving the early start denver
model before and after 48 months.
J Autism Dev Disord. 2016;46(7):
2441–2449
7. American Psychiatric Association.
Diagnostic and Statistical Manual of
Mental Disorders, 5th ed. Arlington,
VA: American Psychiatric Publishing;
2013
8. Gabard-Durnam LJ, Wilkinson C, Kapur
K, Tager-Flusberg H, Levin AR, Nelson CA.
Longitudinal EEG power in the first
postnatal year differentiates autism
outcomes. Nat Commun. 2019;10(1):
4188
9. Estes A, Zwaigenbaum L, Gu H, et al.;
IBIS Network. Behavioral, cognitive, and
adaptive development in infants with
autism spectrum disorder in the first
2 years of life. J Neurodev Disord. 2015;
7(1):24
10. Lovaas OI. Behavioral treatment and
normal educational and intellectual
functioning in young autistic children.
J Consult Clin Psychol. 1987;55(1):
3–9
11. Smith T, Eikeseth S, Klevstrand M,
Lovaas OI. Intensive behavioral
treatment for preschoolers with
severe mental retardation and
pervasive developmental disorder.
Am J Ment Retard. 1997;102(3):
238–249
12. Dawson G, Rogers S, Munson J, et al.
Randomized, controlled trial of an
intervention for toddlers with autism:
the Early Start Denver Model.
Pediatrics. 2010;125(1). Available at:
www.pediatrics.org/cgi/content/full/
125/1/e17
13. Bradshaw J, Trumbull A, Stapel-Wax J,
et al. Factors associated with
enrollment into a clinical trial of
caregiver-implemented intervention for
infants at risk for autism spectrum
disorder. Autism. 2020;24(7):1874–1884
14. Estes A, St John T, Dager SR. What to tell
a parent who worries a young child has
PEDIATRICS Volume 147, number 5, May 2021
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS
autism. JAMA Psychiatry. 2019;76(10):
1092–1093
15. Cidav Z, Munson J, Estes A, Dawson G,
Rogers S, Mandell D. Cost offset
associated with Early Start Denver
Model for children with autism. J Am
Acad Child Adolesc Psychiatry. 2017;
56(9):777–783
16. Xu G, Strathearn L, Liu B, et al.
Prevalence and treatment patterns of
autism spectrum disorder in the United
States, 2016. JAMA Pediatr. 2019;173(2):
153–159
17. Maenner MJ, Shaw KA, Baio J, et al.;
EdS1; PhD-7. Prevalence of autism
spectrum disorder among children
aged 8 years - autism and
developmental disabilities monitoring
network, 11 sites, United States, 2016.
MMWR Surveill Summ. 2020;69(4):
1–12
18. Green J, Pickles A, Pasco G, et al.;
British Autism Study of Infant Siblings
(BASIS) Team. Randomised trial of
a parent-mediated intervention for
infants at high risk for autism:
longitudinal outcomes to age 3 years.
J Child Psychol Psychiatry. 2017;58(12):
1330–1340
19. Rogers SJ, Vismara L, Wagner AL,
McCormick C, Young G, Ozonoff S.
Autism treatment in the first year of
life: a pilot study of infant start,
a parent-implemented intervention
for symptomatic infants. J Autism
Dev Disord. 2014;44(12):
2981–2995
20. Meilleur A-AS, Jelenic P, Mottron L.
Prevalence of clinically and empirically
defined talents and strengths in autism.
J Autism Dev Disord. 2015;45(5):
1354–1367
21. Yafai A-F, Verrier D, Reidy L. Social
conformity and autism spectrum
disorder: a child-friendly take on
a classic study. Autism. 2014;18(8):
1007–1013
22. Gibson MF, Douglas P. Disturbing
behaviours: Ole Ivar Lovaas and the
queer history of autism science.
Catalyst: Feminism, Theory,
Technoscience. 2018;4(2):1–28
23. Trevisan DA, Roberts N, Lin C,
Birmingham E. How do adults and teens
with self-declared Autism Spectrum
Disorder experience eye contact? A
qualitative analysis of first-hand
accounts. PLoS One. 2017;12(11):
e0188446
24. Russo F. The costs of camouflaging
autism. 2018. Available at: https://www.
spectrumnews.org/features/deep-dive/
costs-camouflaging-autism/. Accessed
March 11, 2021
25. Cassidy S, Bradley L, Shaw R, Baron-
Cohen S. Risk markers for suicidality in
autistic adults. Mol Autism. 2018;
9:42
26. Cage E, Di Monaco J, Newell V.
Experiences of autism acceptance and
mental health in autistic adults.
J Autism Dev Disord. 2018;48(2):
473–484
27. Walker N. What is neurodiversity?
Available at: https://autisticuk.org/
neurodiversity/. Accessed March 11,
2021
28. Bailin A. Clearing up some
misconceptions about neurodiversity.
Scientific American. June 6, 2019.
Available at: https://blogs.
scientificamerican.com/observations/
clearing-up-some-misconceptions-
about-neurodiversity/. Accessed March
11, 2021
29. Ercole-Fricke E, Fritz P, Hill LE, Snelders
J. Effects of a collaborative problem-
solving approach on an inpatient
adolescent psychiatric unit. J Child
Adolesc Psychiatr Nurs. 2016;29(3):
127–134
30. Autism Spectrum Australia. Employing
people with autism: the benefits as
seen by employers. Available at: www.
autismlaunchpad.org.au/autism-
employment-how-benefits-employers/.
Accessed September 24,
2020
31. Turnbull K. The Benefits of Inclusion for
Peers Without Disabilities [Master’s
thesis]. Athens, Ohio: Ohio University;
2010
32. Emanuel EJ, Wendler D, Grady C. What
makes clinical research ethical? JAMA.
2000;283(20):2701–2711
33. Emanuel EJ, Wendler D, Killen J, Grady
C. What makes clinical research in
developing countries ethical? The
benchmarks of ethical research.
J Infect Dis. 2004;189(5):
930–937
7
 34. Charman T, Young GS, Brian J, et al.
Non-ASD outcomes at 36 months in
siblings at familial risk for autism
spectrum disorder (ASD): a baby
siblings research consortium (BSRC)
study. Autism Res. 2017;10(1):169–178
35. MacDuffie KE, Turner-Brown L, Estes AM,
et al. “If he has it, we know what to
do”: parent perspectives on familial
risk for autism spectrum disorder.
J Pediatr Psychol. 2020;45(2):
121–130
36. Bailey DB Jr., Bishop E, Raspa M,
Skinner D. Caregiver opinions about
fragile X population screening. Genet
Med. 2012;14(1):115–121
37. Guthrie W, Wallis K, Bennett A, et al.
Accuracy of autism screening in a large
pediatric network. Pediatrics. 2019;
144(4):e20183963
38. Constantino JN, Abbacchi AM, Saulnier
C, et al. Timing of the diagnosis of
autism in African American children.
Pediatrics. 2020;146(3):e20193629

8 MACDUFFIE et al
Downloaded from http://publications.aap.org/pediatrics/article-pdf/147/5/e2020032250/1181788/peds_2020032250.pdf
by IOSUNE AIS