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Sex differences in the association between infant markers and later autistic traits


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Background: Although it is well established that the prevalence of autism spectrum disorder (ASD) is higher in males than females, there is relatively little understanding of the underlying mechanisms and their developmental time course. Sex-specific protective or risk factors have often been invoked to explain these differences, but such factors are yet to be identified. Methods: We take a developmental approach, using a prospective sample of 104 infants at high and low familial risk for ASD, to characterise sex differences in infant markers known to predict emerging autism symptoms. We examine three markers previously shown to be associated with later autistic social-communication symptoms: the Autism Observation Scale for Infants (AOSI) total score, attention disengagement speed and gaze following behaviour. Our aim was to test whether sex differences were already present in these markers at 1 year of age, which would suggest sex-specific mechanisms of risk or protection. Results: While no sex differences were found in any of the three markers investigated, we found sex differences in their relationship to 3-year autism traits; all three markers significantly predicted later autism traits only in the boys. Conclusions: Previously identified 'early autism markers' were associated with later autism symptoms only in boys. This suggests that there may be additional moderating risk or protective factors which remain to be identified. Our findings have important implications for prospective studies in terms of directly testing for the moderating effect of sex on emerging autistic traits.
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R E S E A R C H Open Access
Sex differences in the association between
infant markers and later autistic traits
Rachael Bedford
, Emily J. H. Jones
, Mark H. Johnson
, Andrew Pickles
, Tony Charman
and Teodora Gliga
Background: Although it is well established that the prevalence of autism spectrum disorder (ASD) is higher in
males than females, there is relatively little understanding of the underlying mechanisms and their developmental
time course. Sex-specific protective or risk factors have often been invoked to explain these differences, but such
factors are yet to be identified.
Methods: We take a developmental approach, using a prospective sample of 104 infants at high and low familial
risk for ASD, to characterise sex differences in infant markers known to predict emerging autism symptoms. We
examine three markers previously shown to be associated with later autistic social-communication symptoms: the
Autism Observation Scale for Infants (AOSI) total score, attention disengagement speed and gaze following
behaviour. Our aim was to test whether sex differences were already present in these markers at 1 year of age,
which would suggest sex-specific mechanisms of risk or protection.
Results: While no sex differences were found in any of the three markers investigated, we found sex differences in
their relationship to 3-year autism traits; all three markers significantly predicted later autism traits only in the boys.
Conclusions: Previously identified early autism markerswere associated with later autism symptoms only in boys.
This suggests that there may be additional moderating risk or protective factors which remain to be identified. Our
findings have important implications for prospective studies in terms of directly testing for the moderating effect of
sex on emerging autistic traits.
Keywords: Sex difference, Infants, Autism, High risk, Differential liability
It is well established that autism spectrum disorder
(ASD) is more prevalent in males than in females, with
1:42 boys and 1:189 girls meeting ASD criteria [1]. Des-
pite this being a topic of great interest (see recent special
issue in Molecular Autism, vol. 6), the mechanisms
underlying sex differences in the prevalence of autism,
as well as in other childhood-onset psychiatric condi-
tions, are still poorly understood [2]. In order to charac-
terise sex differences in infant markers previously shown
to predict emerging symptoms of autism, we take a de-
velopmental approach using a prospective sample of in-
fants at high risk for ASD. The aim of the current paper
is to assess whether sex differences are apparent in
known early autism markers or in the relationships be-
tween early markers and later autistic traits.
According to a prominent hypothesis, the differential
liability model [3], boys are more susceptible than girls
because they are subject to boy-specific risk factors or
because girls benefit from protective factors. To under-
stand the underlying mechanisms, we can examine two
types of evidence [2]: direct evidence for sex differences in
the risk/protective factors themselves (Fig. 1a), or indirect
evidence, in the form of differential relationships between
risk/protective factors and the disorder, suggesting the
presence of additional sex-specific moderating factors
(Fig. 1b). Indirect evidence for girl-specific protective
factors comes from studies showing that a higher load of
genetic/phenotypic risk is needed for girls to eventually ex-
press autistic traits [3]. As a consequence of this, siblings
of girls with autism show a higher incidence of autism than
siblings of boys with autism [4], although see [5, 6] for no
difference in incidence between these groups.
* Correspondence:
Centre for Brain and Cognitive Development, Birkbeck College, University of
London, London, UK
Full list of author information is available at the end of the article
© 2016 Bedford et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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Bedford et al. Molecular Autism (2016) 7:21
DOI 10.1186/s13229-016-0081-0
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Phenotypic differences between males and females
with autism may also reflect the moderating role of sex-
specific factors, although evidence for sex differences is
mixed. One commonly reported finding is that females
with autism have lower IQ than males ([7, 8], although
see [9]), which is consistent with the idea of sex differ-
ences in the liability threshold. Language has often been
suggested as a protective factor, since girls lead in lan-
guage skills from early in development (e.g. [10]). How-
ever, evidence suggests that autistic girls with better
language also have better cognitive and adaptive skills,
which is not consistent with the idea of protection (e.g.
[11, 12]). Evidence from earlier in development is less
clear still, with Carter et al. [13] showing significantly
better language and fine motor skills in autistic toddler
boys but greater visual reception abilities in girls on the
Mullen Scales of Early Learning (MSEL; [14]). Other
studies find no sex difference in the adaptive and behav-
ioural functioning of toddlers with autism [15, 16]. Dif-
ferences between studies in the age groups tested, in
functional level and in potential diagnostic and sampling
biases may cloud the evidence for the differential liability
model in autism.
Longitudinal prospective designs of high-risk popula-
tions deal with some of these methodological issues,
avoiding ascertainment bias and including a typically de-
veloping control group. In addition, they allow us to
look for sex differences early on in development. Given
the evidence for differential genetic liability (e.g. [17])
and the fact that sex differences in prenatal hormones
like testosterone have been linked to later autism symp-
tomatology [2], it is plausible that sex-specific risk fac-
tors act even before birth, in which case their effects
would be apparent in infancy. Messinger et al. [5] and
Zwaigenbaum et al. [18] have utilised a prospective longitu-
dinal design with infants at high risk for autism (owing to
an older sibling with a diagnosis) to investigate sex differ-
ences in the MSEL. Both studies found increased MSEL
scores in girls compared to boys across both the high- and
low-risk groups. Similarly, Charwarska et al. [19] found that
high-risk girls (as compared to both high-risk boys and all
low-risk controls) show increased attention to social stim-
uli. This suggests that autism risk may be differentially
expressed in males and females, conferring protection in
the girls. As well as allowing the investigation of sex-
specific effects very early in development, these studies also
have the advantage of a typically developing comparison
group, which enables the specificity of sex differences in
the development of autism to be directly tested.
Among familial high-risk infants, approximately 20 %
go on to an autism diagnosis [20] with a further 20 %
showing sub-threshold symptoms [21] and a variety of
early markersfor autism outcome have been described
from 6 months of age (see [22]). We define an early
marker as a particular aspect of cognition, behaviour or
neural response, measured in infancy, which is associ-
ated with later traits of autism. The current study exam-
ines the impact of sex on three early markers, which
span the domains of social and non-social attention and
are known to relate to emerging autistic symptomatol-
ogy: the Autism Observation Scale for Infants (AOSI;
[23, 24]), gaze following behaviour [25] and disengage-
ment latency in the gap-overlap task [26, 27].
The AOSI is an observational assessment of emerging
autism-like atypicality measuring, for example, anticipa-
tion of social interaction, imitation and motor skills. The
second early marker, looking time to the gazed-at object
during a gaze following task, is a measure of social at-
tention. Gaze following behaviour can be decomposed
into first look (did the infant correctly follow gaze) and
looking time (how long did they then spend looking at
the object). Looking time is thought to index a more in-
depth understanding of the referential meaning of eye-
gaze (e.g. [28]) and is the measure which relates to sub-
sequent social-communication abilities [25]. The final
marker, disengagement latency from the gap-overlap
task, measures infantsability to shift attention from a
centrally presented stimulus to a peripheral one.
If particular early markers are expressed differently
in infant boys and girls, they may act as sex-specific
risk or protective factors (Fig. 1a). For example, high-
risk girls show greater social attention than high-risk
boysa sex difference in the early marker itself
[25]. Alternatively, if no differences are measured in
expressed early markers, then sex differences may appear
in the relationship between early markers and later
traits (Fig. 1b). Differences in the relationship (i.e. the
Fig. 1 Sex differences can appear in the expression of early autism
markers or in the relationship between marker and outcome. aThe
marker differentiates between the boys and girls, but relates to later
symptoms in the same way in both sexes; here, having lower levels
of this marker is protective in girls. bThe early marker is similarly
expressed in boys and girls but only relates to later symptoms in
boys; this is due to additional moderating factors (which are likely to
be type of marker described in a) decreasing the impact of this
marker in girls. A combination of the two models is also possible
Bedford et al. Molecular Autism (2016) 7:21 Page 2 of 11
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slope) between the marker and autism traits would
point to differential liability effects. A significant rela-
tionship in boys but not in girls would be consistent
with the existence of additional sex-specific factors;
these putative factors may confer protection in girls or
increase risk in boys.
For all three markers (AOSI, gaze following, disen-
gagement), we first ask whether there are sex differences
at 14 months, the age at which these measures have
been previously linked with autistic traits in the same
cohort of children [25, 26, 23]. More particularly, we ask
whether girls show lower AOSI scores, increased atten-
tion to the jointly attended object and faster disengage-
ment latencies compared to boys. Second, we test
whether the relationship between these infant markers
and later autism traits (i.e. Autism Diagnostic Observa-
tional Schedule (ADOS) scores) is similar across males
and females, predicting a stronger magnitude of relation-
ship between risk and outcome in boys than girls. The
ADOS was chosen as the primary outcome because it is
both a gold standard measure of autism traits and a con-
tinuous outcome measure. This is consistent with the
emphasis shift from categorical to more continuous ap-
proaches in characterising psychopathology (Diagnostic
and Statistical Manual 5th edition (DSM-5) [29]).
Ethical approval was given by the National Health Ser-
vice, National Research Ethics Service London Research
Ethics Committee (08/H0718/76), and parents gave in-
formed consent.
As part of the British Autism Study of Infant Siblings
(BASIS:, 104 infants (54
high-risk, 21 males; 50 low-risk, 21 males) took part in a
battery of assessments at approximately 7 months,
14 months, 2 years and 3 years. At the time of enrol-
ment (<5 months of age), none of the infants had been
diagnosed with any medical or developmental condition.
Data presented in the current paper come from the 14-
month infant visit (mean 13.79 months, SD 1.46; males
mean 13.84, SD 1.08; females mean 13.76, SD 1.65) and
3-year outcome visit (mean 37.93 months, SD 3.02;
males mean 38.13, SD 3.36; females mean 37.81, SD
2.82). For the high-risk group, consensus ICD-10 [30]
ASD diagnoses (ASD-sibs; childhood autism; atypical
autism, other pervasive developmental disorder
(PDD)) were achieved using all available information
from all visits by experienced researchers. Seventeen
of the high-risk children met ASD criteria (11 males).
Different numbers of infants contributed data to the
three early autism markers:
Autism Observational Scale for Infants (AOSI) (see [23]):
53 high-risk (21 males) and 48 low-risk (17 males) infants
completed the AOSI assessment (see Table 1).
Gaze following task (see [25]): The same 32 high-risk
(13 males) and 37 low-risk (10 males) siblings from the
Bedford et al. [25] analysis were included in the current
Gap-overlap task (see [26]): Data from 52 high-risk
siblings (21 males) and 46 low-risk controls (16 males)
were included from the gap-overlap task.
Autism Diagnostic Observational Schedule-Generic
(ADOS-G); 3-year ADOS assessments were conducted
with 53 high-risk (21 males) and 48 low-risk (17 males)
Social Communication Questionnaire Lifetime (SCQ-L);
Questionnaires were completed for 52 high-risk (21
males) and 48 low-risk (17 males) toddlers.
All the 14-month measures have previously been re-
ported in separate paperssee Gammer et al. [23],
Elsabbagh et al. [26] and Bedford et al. [25] for full de-
scription of the method.
Fourteen-month measures
Autism Observation Scale for Infants
The Autism Observation Scale for Infants (AOSI; [31];
revised version used in this study [32]) is a semi-
structured observational assessment of ASD-related be-
havioural markers in infancy. A 19-item version of the
AOSI was used (see [32]) which gives a total score (sum
of all codes; max score 44), with higher scores indexing
greater atypicality. The majority of assessments were
double coded with excellent reliability (n= 85, intraclass
correlation coefficient = 0.95).
Gaze following task
Infants were seated on their parents lap at a distance of
50 cm from the 17-in. flat screen monitor and looking be-
haviour was recorded using a Tobii 1750 eye-tracker.
Stimuli were presented using ClearView software, and
gaze data were recorded at 50 Hz. Each trial began with
two objects on a table and a female model looking down
(3 s), then looking up—‘direct gaze(2 s)and then turn-
ing her head to look at one of the objects—‘shift(6 s).
The object looked at by the model during shiftis the con-
gruent object, and the other, non-gazed-at object, is the in-
congruent object. There were 12 trials, and six different
pairs of objects counterbalanced across trials.
Trial exclusion criteria were as follows: (1) no looking
to the face during direct gazeand (2) looking away
from the computer screen for the entire shiftphase.
Three high-risk children (none of whom were diagnosed
with autism at 3 years) had <3 valid trials and were
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excluded. Looking time to the congruent object was calcu-
lated as a proportion (out of total looking time to the
slide) during the shiftphase. A 2*2 ANOVA showed no
significant difference in the number of valid trials by
group (high- versus low-risk infants: F(1, 65) = 1.13, p=
0.29), sex (boys versus girls: F(1, 65) = 0.001, p= 0.98) or
group*sex interaction: F(1, 65) = 0.09, p= 0.77.
Gap-overlap task
Infants were seated on their parents lap 60 cm from the
46-in. LCD computer screen. A video camera was used
to record looking behaviour and trial presentation was
controlled by the experimenter. A central stimulus ap-
peared (subtending 13.8° × 18.0°) followed by a periph-
eral target green balloon (subtending 6.3° × 6.3°) which
appeared randomly on the left or right. The target
remained on the screen until either (1) the infant looked
at it or (2) the maximum time of 2.5 s passed. An animal
reward stimulus (elephant, lion, seal, etc.) then appeared
in the place of the green balloon. Up to 70 trials were
presented depending on infantsattentiveness. There were
two trial types analysed in this study: baseline and overlap.
In the baseline condition, the central stimulus disappeared
at the same time as the peripheral target appeared,
whereas in the overlap condition, the central stimulus
remained present while the target stimulus appeared in
the periphery.
Data were video coded frame-by-frame by two raters
(reliability of >0.9 Cohens K for trial validity). Invalid
trials were those in which the infant (1) looked away
from the screen; (2) did not look at the central stimulus
immediately before the onset of the peripheral stimulus
and (3) looked away or blinked during the onset of the
peripheral stimulus. A 2*2 ANOVA showed that there
was no significant difference in the number of valid tri-
als by group (high- versus low-risk infants: F(1, 94) =
1.77, p= 0.19), a marginal effect of sex (boys versus girls:
F(1, 65) = 3.97, p= 0.05) and no group*sex interaction:
F(1, 65) = 0.06, p= 0.81. Because the effect of sex ap-
proached significance, with more valid trials for girls, the
number of valid trials was included as a covariate in the
analyses for disengagement. Saccadic reaction times
were analysed from all valid trials in which the infants
oriented towards the peripheral stimulus 1001200 ms
after its onset. If the infant did not look towards the
stimulus in this time, the trial was called failure to
Table 1 Descriptive statistics split by sex and risk group for the 14-month early markers (AOSI, gaze following, disengagement) and
3-year autistic trait measures (ADOS, SCQ)
AOSI GF Disengagement ADOS SCQ
14 months 14 months 14 months 3 years 3 years
M (SD) M (SD) M (SD) M (SD) M (SD)
Low risk
Overall 3.17 (3.25) 0.31 (0.14) 138.15 (105.81) 5.52 (4.33) 3.00 (2.40)
N=48 N=37 N=46 N=48 N=48
Males 3.59 (3.02) 0.27 (0.08) 148.34 (104.77) 6.41 (5.36) 2.88 (2.12)
N=17 N=10 N=16 N=17 N=17
Females 2.94 (3.40) 0.32 (0.16) 132.71 (107.73) 5.03 (3.65) 3.06 (2.57)
N=31 N=27 N=30 N=31 N=31
High risk
Overall 4.64 (4.47) 0.26 (0.10) 179.55 (152.91) 8.25 (5.34) 6.37 (7.12)
N=53 N=32 N=52 N=53 N=52
Males 5.19 (5.72) 0.25 (0.12) 196.91 (203.30) 9.24 (5.42) 6.00 (5.33)
N=21 N=13 N=21 N=21 N=21
Females 4.28 (3.48) 0.26 (0.08) 167.78 (108.81) 7.59 (5.26) 6.61 (8.20)
N=32 N=19 N=31 N=32 N=31
Risk group F= 3.26 F= 1.86 F= 2.36 F= 7.19** F= 8.75**
Sex F= 0.92 F= 1.11 F= 0.77 F= 2.26 F= 0.12
Risk*sex F= 0.03 F= 0.35 F= 0.05 F= 0.02 F= 0.04
AOSI Autism Observation Scale for Infants, GF gaze following, disengagement overlapbaseline saccadic reaction time in gap-overlap task, ADOS Autism Diagnostic
Observation Schedule total social communication score, SCQ Social Communication Questionnaire
**p< 0.01
Bedford et al. Molecular Autism (2016) 7:21 Page 4 of 11
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disengageand reaction time was not analysed. Disen-
gagement was calculated as reaction time in overlap tri-
alsbaseline trials.
Three-year measures
Autism Diagnostic Observational Schedule [33]
The ADOS-G is a semi-structured observational assess-
ment used in the diagnosis of ASD, which involves as-
sessment of social interaction with an examiner through
play or conversation (depending on the age of the child),
and a range of different behaviours, including language,
gestures, eye contact, play and creativity, and stereo-
typed behaviours are coded. The codes are 0, 1, and 2
(and in some cases 3) with a higher score indicating a
greater level of autistic-like atypicality. Certain item
scores make up the final algorithmscores, which are
split into subsections: social, communication, creativity
and repetitive and stereotyped behaviours. Ninety-eight
children did module 2 and three children completed
module 1. At the time the data were collected and first
published, the ADOS-G social-communication algo-
rithm was the standard way of computing ADOS scores,
and thus we used the social and communication algorithm
as a measure of autism traits at 3 years. However, analyses
using the new ADOS-2 calibrated social affective severity
scores are presented in Additional file 1.
Social Communication Questionnaire Lifetime
The Social Communication Questionnaire (SCQ) is a
parent-completed questionnaire with questions devel-
oped from the Autism Diagnostic Interview-Revised
(ADI-R; [34]).
Statistical analyses
The infant markers were not significantly correlated with
one another in the overall sample (AOSI and gaze follow-
ing: r=0.17, p= 0.17; AOSI and disengagement: r=0.09,
p= 0.37; gaze following and disengagement: r=0.12, p=
0.33). To address our first questionare there sex differ-
ences in the early markers, we first ran a 2*2 ANOVA with
sex (boys versus girls), group (high-risk versus low-risk)
and sex*group interaction for each early marker separately
(see Table 1).
To test for sex differences in the relationship between
early markers and later ADOS outcome, we first ex-
plored lowess curves (smoothed lines through the points
on the scatterplot) to check that there was overlap in the
data between boys and girls. Based on visual inspection
of the plots, any extreme non-overlapping values were
trimmed to one point above the next highest score [35].
The relationship between the predictor and outcome
can differ along the predictors scale (i.e. a non-linear re-
lationship). Restricting the analysis to the region where
the predictors overlap in boys and girls ensures that any
sex differences in the relationships between early
markers and later autism traits are not due to the groups
spanning different portions of the predictor scale (see
[36] for discussion of this issue). Analyses followed the
same procedure for each early marker: (1) linear regres-
sion with ADOS social and communication algorithm
score as the outcome and early marker, and sex and
early marker*sex interaction as predictors; (2) planned
sex comparisons: linear regression of ADOS score on
predictor split by sex.
Autism Observation Scale for Infants total score
A 2*2 ANOVA showed no significant main effect of sex
on total AOSI score at 14 months: F(1, 97) = 0.92, p=
0.34, ηp
= 0.01 (see Table 1). The risk group effect was
marginally significant F(1, 97) = 3.26, p= 0.07, ηp
= 0.03,
and there was no group*sex interaction F(1, 97) = 0.03,
p= 0.88, ηp
< 0.001.
A smoothed lowess curve indicated good overlap
between males and females across the range of scores
(see Fig. 2). A linear regression showed a significant
relationship between AOSI and ADOS score (β= 0.527,
p< 0.001) and a significant sex*AOSI interaction
(β=0.44, p= 0.005). When this was broken down by
sex, AOSI was a significant predictor of ADOS in males
(β= 0.57, p< 0.001) but not in females (β=0.015,
p= 0.905). Results were similar across high- and low-risk
groups with significant effects in males (high risk:
β= 0.588, p= 0.005; low risk: β= 0.542, p= 0.03) but not
in females (high risk: β=0.29, p= 0.113; low risk:
β= 0.059, p= 0.75). Significance levels remained un-
changed when Mullen Scales of Early Learning (MSEL)
verbal and non-verbal tscores were added as covariates
(see Additional file 1).
Gaze following
Results from a 2*2 ANOVA showed that there was no
significant effect of sex on correct looking time from a
gaze following task: F(1, 65) = 1.11, p= 0.30, ηp
= 0.02
(see Table 1). The risk group effect (F(1, 65) = 1.86,
p= 0.18, ηp
= 0.03) and group*sex interaction (F(1, 65)
= 0.35, p= 0.56, ηp
= 0.005) were also not significant.
Examination of the lowess curves (see Fig. 3a) showed
that at high levels of gaze time there were no data for
males due to an outlier, a female with particularly long
looking time. For the following analysis, this point was
trimmed back to 0.61 (the value one point above the
highest non-outlier score, see [35]).
Gaze time significantly predicted ADOS score (β=
0.567, p= 0.012), while the effect of sex (β=0.64, p=
0.053) and the sex*gaze time interaction time (β= 0.689,
p= 0.086) were marginally significant. When we ran sep-
arate simple linear regressions for males and females,
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gaze time predicted later ADOS in males (β=0.46;
F(1,21) = 5.64, p= 0.027; R
= 0.21) but not in females
(β=0.13, p= 0.39). We did not look at this analysis split
by risk group owing to the very small sample size for the
males (n= 10 low risk, n= 13 high risk). Results remained
substantively similar when MSEL scores were added as
covariates (see Additional file 1).
For disengagement, number of valid trials was included as
a covariate in the analysis, to account for the marginally
significant sex effect. As for the other infant markers, no
significant sex difference in disengagement was found
F(1, 93) = 0.77, p= 0.38, ηp
= 0.008 in an ANOVA.
The main effect of risk group F(1, 93) = 2.36, p= 0.13,
= 0.03 and the group*sex interaction were also non-
significant F(1, 93) = 0.05, p=0.82, ηp
= 0.001. There was
no effect of the number of valid trials (F(1, 93) = 0.23,
p=0.64, ηp
Similarly to the gaze time measure, examination of the
lowess curve suggested a region of no overlap between
male and female disengagement scores at very slow RTs,
owing to a single unmatched point. For the following
analysis, this point was trimmed to a value of 479 ms
(see Fig. 4).
When entered into a regression model, disengagement
reaction time was a significant predictor of subsequent
ADOS score (β= 0.38, p= 0.007). There was no effect of
valid disengagement trials (β=0.05, p= 0.66). The
interaction between sex and disengagement was
Fig. 2 aThe relationship between infant AOSI and 3-year ADOS outcome with smoothed lowess curves for males and females. bThe relationship
between infant AOSI and 3-year ADOS outcome with linear fit for males and females
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marginally significant (β=0.36, p= 0.05), and when
this was broken down into two separate regressions,
again the relationship between disengagement and
ADOS score was significant for males (β=0.41, p=
0.013) but not for females (β=0.02, p=0.86). When
split by risk group, the βvalues remained very similar
with the effect of disengagement on ADOS in males
becoming marginally significant in the high-risk group
(β= 0.43, p= 0.06) and non-significant for the low-risk
group (β=0.39, p=0.18).Neithergroupshowedasig-
nificant effect in females (pvalues >0.66). Again, results
remained similar after controlling for MSEL scores (see
Additional file 1).
Social Communication Questionnaire analysis
To confirm that our results were not due to some spe-
cific measurement issue related to the ADOS, we also
assessed the relationship between risk factors and
parent-reported SCQ score. As the data were skewed, a
square root transformation was also applied to the SCQ
and both transformed and untransformed results are
presented. Results remained similar, with the AOSI
scores significantly predicting SCQ scores in males (β=
0.35, p= 0.04; although this became a trend only for the
transformed scores β= 0.26, p= 0.12) but not in females
(β= 0.07, p= 0.61; transformed β= 0.08, p= 0.53). Gaze
following behaviour was marginally significant in males
Fig. 3 aThe relationship between infant looking time in the gaze following task and 3-year ADOS outcome with smoothed lowess curves for
males and females. For further analysis, the outlier was trimmed back to one point above the next highest value. bThe relationship between
infant looking time in the gaze following task and 3-year ADOS outcome with linear fit for males and females
Bedford et al. Molecular Autism (2016) 7:21 Page 7 of 11
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(β=0.38, p= 0.08; transformed β=0.37, p= 0.08) and
not significant in females (β= 0.08, p= 0.59; transformed
β= 0.12, p= 0.44), and disengagement latency signifi-
cantly predicted SCQ in males (β= 0.35, p= 0.04; trans-
formed β= 0.32, p= 0.06) but not in females (β= 0.14,
p= 0.32 transformed β=0.13, p= 0.33).
The aim of this paper was to investigate sex differences
in three documented early autism markers, which are
known to associate with the severity of autistic social-
communication symptomatology, at 3 years of age. We
found no evidence for sex differences in the AOSI sever-
ity scores, gaze following and attentional disengagement,
when infants were 14 months of age. However, these
measures appeared to act as early markers in boys only,
with all three significantly relating to later 3-year ADOS
social communication and SCQ scores in males but not
in females.
Our results show that so-called early autism markers,
previously shown to be associated with later autistic
symptomatology [25, 26, 23], are actually only effective
markers in the boys. However, since there are no sex
differences in the expression of these behaviours at
14 months, this suggests the existence of additional
moderating factors. One line of evidence which could
help to determine whether boys have additional risk fac-
tors, or girls additional protective factors, comes from
Fig. 4 aThe relationship between infant disengagement in the gap-overlap task and 3-year ADOS outcome with smoothed lowess curves for
males and females. For further analysis, the outlier was trimmed back to one point above the next highest value. bThe relationship between
infant disengagement in the gap-overlap task and 3-year ADOS outcome with linear fit for males and females
Bedford et al. Molecular Autism (2016) 7:21 Page 8 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
looking at the risk group effects. If the there is a main
effect of risk group (where high-risk boys and girls show
increased early markers compared to low-risk boys and
girls), this would suggest that perhaps the females re-
cover from risk, i.e. they benefit from protective factors.
Alternatively, if the groups show similar levels of these
early markers, this suggests that the boys have additional
risk factors. Our results show no significant risk group
effects for the three markers, although, as there are
trend effects for each measure, this cannot be used as
strong evidence to tease apart increased risk versus pro-
tection. What we can conclude is that there must be
additional sex-specific factors which moderate the devel-
opmental effects of the early markers.
Genetic susceptibility effects have often been described
in psychopathology, where particular gene variants con-
fer more or less susceptibility to the effects of other
genes (e.g. [37]) or particular environments [38]. Given
the variety of the early markers we examined, which
span the social and non-social domains of the early aut-
ism phenotype, any moderating factors that might in-
crease the impact of these traits on emerging pathology
in boys (or that decrease their impact in girls) will need
to have a broad scope. Messinger et al. [5] found sex dif-
ferences in Mullen Scales for Early Learning (MSEL)
scores in both low-risk and high-risk participants. From
18 months (the earliest age included in analysis), girls
outperformed boys, across the subscales (expressive and
receptive language, visual reception, fine motor). Faster
general development could protect girls against the ef-
fect of other risk factors. However, despite replicating
these sex differences in our cohort, covarying for MSEL
scores did not alter the differential relationship between
early markers and outcomes. Other potential moderating
factors will have to be explored in the future. For ex-
ample, one recent hypothesis proposes that sex differ-
ences in synaptic and regional plasticity could explain
differences in autism prevalence rates [39].
It is also possible that interactions occur between the
markers under investigation, i.e. that a combination of
higher AOSI scores, reduced gaze following and slower
disengagement is necessary for girls to manifest autism
symptoms. Indeed, it was shown that gaze following and
attention disengagement act additively in predicting later
autism outcome (e.g. [40]). It could be that girls need
multiple hits across several different factors, consistent
with the existence of additional protective factors in
girls, whereas boys are more susceptible to a single-hit
pathway [41]. Future studies with larger sample sizes will
be important to test for interactive developmental effects.
Given that we found no early sex differences in early
markers at 14 months, i.e. quite late in development,
one interesting possibility is that some sex-specific mod-
erating factors may be environmental. In typical infants,
differences in maternal social interaction with boys and
girls have been documented, with different styles of sen-
sitive responding (e.g. [42]), and increased parent-infant
communication in response to infant girls than boys,
even in the absence of behavioural differences between
the infants themselves [43, 44]. Parent-child interaction
is known to be important in the development of socio-
communication abilities, including in autism [45], al-
though it remains unknown whether the above sex
differences in parental interaction are consequential for
development. However, protracted expression of intrin-
sic moderating factors is also possible. For example,
while sex differences in neural gene expression peak pre-
natally, the effects of certain genes continue on after
birth into early childhood [46].
Our results were similar across high-risk and low-risk
groups indicating that the link with later social-
communication abilities is not specific to those at risk
for autism. This suggests that our markers reflect com-
mon variation as proposed by recent genetic models of
autism [47]. The results are consistent with Messinger
et al.s [5] study, who found that sex differences in tod-
dlers with autism reflect typically occurring sex differences
also seen in low-risk controls. Other neurodevelopmental
disorders such as ADHD and early onset antisocial behav-
iour disorder also show an increased prevalence in males
[2], and future research will be required to study sex dif-
ferences in the broader context of psychopathology and
development, since it is unlikely that sex-specific mecha-
nisms are disorder-specific. There is evidence, for ex-
ample, of sex differences in the relationship between
sensitive parenting during infancy and the subsequent de-
velopment of callous unemotional (CU) traits (e.g. [48,
49]) with increased maternal sensitivity associated with
lower CU traits most strongly in girls.
A clear strength of the current paper is the use of a
prospective infant sibling design. This allows us to test
for sex differences without the male ascertainment bias
faced by studies with diagnosed individuals [5]. However,
given our modest sample size, there is a clear need for
replication. While we specifically use two clinical tools,
the ADOS and SCQ, to deal with tool-specific lack of
sensitivity, it remains possible that neither of these in-
struments capture autistic traits in girls at 3 years of age,
when they were administered. Future work assessing
symptoms of autism measured later in childhood should
establish whether these sex-specific relationships are
time dependent. In addition, a larger sample would en-
able the relationships with categorical autism diagnostic
outcomes to be assessed.
The results of the current study draw attention to the
need to routinely examine sex differences in the predic-
tion of later autistic symptoms. It is plausible that factors
which have previously been found to be non-significant
Bedford et al. Molecular Autism (2016) 7:21 Page 9 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
in the prediction of autism symptoms may in fact be as-
sociated in the boys, but the overall effect is masked by
the presence of girls. However, although we find that
three different measures previously described as early
markers for autism are only really markers of later autis-
tic traits in boys, this should not encourage research to
selectively study this sex. While investigating only boys
will increase prediction [50], studying girls is crucial not
only for tailoring diagnosis and intervention to this
smaller but by no means negligible group but also for
unveiling potential important protection that could be
used to improve outcomes for both boys and girls.
In conclusion, although we found no evidence for early
sex differences in markers previously shown to relate to
emerging autistic symptoms, we did find sex-specific re-
lationships with later autistic traits, with prediction to
outcome in males but not in females. These data suggest
that so-called early autism markers may only act as
markers in boys. This implies the existence of additional
sex-specific intervening factors, yet to be identified,
which confer risk in boys or protection in girls. Our re-
sults emphasise the importance of testing for a moderat-
ing effect of sex on emerging autism traits. Characterising
sex differences in the developmental trajectory leading to
autism has important potential implications for differen-
tial early identification of autism in boys and girls.
Additional file
Additional file 1: Supplementary information. (DOCX 31 kb)
ADI-R: Autism Diagnostic Interview-Revised; ADOS: Autism Diagnostic
Observational Schedule; AOSI: Autism Observation Scale for Infants;
ASD: autism spectrum disorder; BASIS: British Autism Study of Infant Siblings;
DSM-5: Diagnostic and Statistical Manual 5th edition; MSEL: Mullen Scales of
Early Learning; SCQ: Social Communication Questionnaire.
Competing interests
The authors declare that they have no competing interests.
RB contributed to design of the study, collected and analysed data, wrote
and edited the manuscript; EJ contributed to the design of the study and
helped to draft the manuscript; MJ conceived of the study and helped to
draft the manuscript; AP conceived of the study and helped to draft the
manuscript; TC conceived of the study and helped to draft the manuscript;
TG conceived of the study, collected data, wrote and edited the manuscript.
All authors read and approved the manuscript.
We are very grateful for the important contributions BASIS families have
made towards this study. The research was supported by the BASIS funding
consortium led by Autistica (, a UK Medical
Research Council Programme Grant (G0701484) to M.H. Johnson and a
European Project TRIGGER (Transforming Institutions by Gendering Contents
and Gaining Equality in Research) Grant agreement no. 611034. R. Bedford is
supported by a Sir Henry Wellcome Postdoctoral Fellowship, T. Charman by
the COST Action BM1004 and E. Jones, M. Johnson and T. Charman have
received support from the Innovative Medicines Initiative Joint Undertaking
under grant agreement no. 115300, resources of which are composed of
financial contribution from the European Unions Seventh Framework
Programme (FP7/20072013) and EFPIA companiesin kind contribution.
This work was additionally supported by the National Institute for Health
Research (NIHR) Mental Health Biomedical Research Centre at South London
and Maudsley NHS Foundation Trust and Kings College London. The views
expressed are those of the author(s) and not necessarily those of the NHS,
the NIHR or the Department of Health.
Author details
Biostatistics Department, Institute of Psychiatry, Psychology & Neuroscience,
Kings College London, London, UK.
Centre for Brain and Cognitive
Development, Birkbeck College, University of London, London, UK.
Psychology Department, Institute of Psychiatry, Psychology & Neuroscience,
Kings College London, London, UK.
Received: 13 October 2015 Accepted: 24 February 2016
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... Pineal dysfunction has been implicated based on the common observation of low melatonin levels and sleep disorders associated with autism. Abnormal neuroplasticity may be explained by hyperactivity of endogenous N, N-dimethyltryptamine (DMT) produced in pineal gland, according to some authors [16]. ...
... The objective of this study was to evaluate if there is any association between the presence of pineal cysts in MRI and children diagnosed with ASD in order to find some correlation between pineal gland and ASD as suggested by some authors [16]. Through the analyses of the results, there are differences when comparing the presence of pineal cysts between children with ASD and the control group (statistically significant, with p=0.041). ...
... Some authors relate this malfunction with sleep disorders and some immune deregulation in autism [22]. Another hypothesis is that the dysfunction of pineal gland may be related with abnormal metabolism of N-dimethyltryptamine which could explain abnormal neuroplasticity and neuronal distribution that can be found in some cases of autism [16]. ...
... The research protocol was approved by Human Investigations Committees at Yale and Emory University Schools of Medicine, as well as and Children's Healthcare of Atlanta, and all parents and/ or legal guardians gave written informed consent. We have limited analyses in the current study, in both TD and ASD samples, to males since the low number of females with ASD who enrolled in the study (N = 5) left us unable to address potential sex-based differences either in language acquisition (Wallentin 2008) or in social visual engagement in children with ASD (Bedford et al. 2016;Chawarska et al. 2016). A total of 84 males (28 TD, 56 ASD) completed the experimental (eye-tracking) protocol, as well as diagnostic/ developmental characterization, and 82 (28 TD, 54 ASD) were included in the final analysis. ...
... These conclusions nonetheless respect limitations of the current study design. Replication with a sufficient sample of female toddlers with ASD (and an age-matched cohort of TD females) will be necessary in order to determine whether these findings hold across sex, or whether established sexbased differences in language development (Wallentin 2008) and social visual engagement (Bedford et al. 2016;Chawarska et al. 2016) result in patterns of association and interactions unique to females. Additionally, it is important to note the possibility that some toddlers in this sample (particularly those with a score of 3 on item 11 of the expressive language subtest of the Mullen) may already be entering the "word explosion" phase of language development. ...
Full-text available
Infants show shifting patterns of visual engagement to faces over the first years of life. To explore the adaptive implications of this engagement, we collected eye-tracking measures on cross-sectional samples of 10–25-month-old typically developing toddlers (TD;N = 28) and those with autism spectrum disorder (ASD;N = 54). Concurrent language assessments were conducted and relationships between visual engagement and expressive and receptive language were analyzed between groups, and within ASD subgroups. TD and ASD toddlers exhibited greater mouth- than eye-looking, with TD exhibiting higher levels of mouth-looking than ASD. Mouth-looking was positively associated with expressive language in TD toddlers, and in ASD toddlers who had acquired first words. Mouth-looking was unrelated to expressive language in ASD toddlers who had not yet acquired first words.
... Furthermore, Filliter et al. (2015) provided additional support that HR-ASD infants at 12 months showed lower rates of smiling and positive affect compared to the HR-no ASD and LR groups and by 14 months of age HR-ASD showed marginally less engagement of attention and orientation to name than HR-no ASD during specific AOSI presses (Gammer et al. 2015). However, when examining HR-ASD behavior markers, more specifically total AOSI score, disengagement of attention and gaze following at 12 months, Bedford et al. (2016) reported these markers to reliably predict autism at 36 months in boys only but not in girls. ...
... Other key findings of the present SLR corroborate previous findings that delayed motor skills, or atypical stereotyped or repetitive motor skills are indicators of ASD (Choi et al 2018;Elison et al. 2014;Lebarton & Landa 2019;Sacrey et al. 2015;Samango-Sprouse et al. 2015;Wolff et al. 2014). Additionally, social communicative behaviors such as the use of gestures, eye gaze, social smiling, anticipatory smiling, responding to name, and various forms of imitation continue to make up the bulk of the research regarding the earliest symptoms, however often times these behaviors are still present in the HR-ASD population but reported as less frequently occurring than in HR-no ASD and LR comparison groups (Bedford et al. 2016;Filliter et al. 2015;Gammer et al. 2015;Gangi et al. 2014;Gangi, Schwichtenberg et al.2018;Gordon & Watson 2015;Nichols et al. 2014;Rowberry et al. 2015;Sanefuji & Yamamoto 2014). The understanding that the majority of social communicative early symptoms appear as deficits or are observed less frequently contributes to the difficulty of early identification of ASD symptoms, as infants who will later go on to receive a diagnosis are engaging in social communicative behaviors but often less frequently than typically developing children, making it difficult to the untrained eye to identify them. ...
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Pre-diagnostic intervention for autism spectrum disorder (ASD) allows symptoms to be addressed as they emerge, often between six to 18 months, rather than after the full onset of the disorder. A systematic literature review, spanning the previous six years was conducted in order to provide an updated review looking at the earliest behavior symptoms of ASD. All included studies used a prospective experimental design, reported on symptoms that emerged before 18-months of age, exclusively in children who would later receive a diagnosis, and were assessed for quality. This review is the first to address this research question through the use of a systematic research design and extends the literature by following up on recommendations for future research from previous findings.
... Social attention − dynamic engagement with other people − has been a leading candidate neurocognitive marker of autistic neurodevelopment. Several studies have found that social attention is decreased in autistic people (Frazier et al., 2017) and altered prior to formal clinical diagnosis (Bedford et al., 2016;Chawarska, Macari, Powell, DiNicola, & Shic, 2016). However, interpretation and generalisation have been partly limited by low female representation (Frazier et al., 2017). ...
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Background: Social attention affords learning opportunities across development and may contribute to individual differences in developmental trajectories, such as between male and female individuals, and in neurodevelopmental conditions, such as autism. Methods: Using eye-tracking, we measured social attention in a large cohort of autistic (n = 123) and nonautistic females (n = 107), and autistic (n = 330) and nonautistic males (n = 204), aged 6-30 years. Using mixed Growth Curve Analysis, we modelled sex and diagnostic effects on the temporal dynamics of proportional looking time to three types of social stimuli (lean-static, naturalistic-static, and naturalistic-dynamic) and examined the link between individual differences and dimensional social and nonsocial autistic traits in autistic females and males. Results: In the lean-static stimulus, average face-looking was higher in females than in males of both autistic and nonautistic groups. Differences in the dynamic pattern of face-looking were seen in autistic vs. nonautistic females, but not males, with face-looking peaking later in the trial in autistic females. In the naturalistic-dynamic stimulus, average face-looking was higher in females than in males of both groups; changes in the dynamic pattern of face looking were seen in autistic vs. nonautistic males, but not in females, with a steeper peak in nonautistic males. Lower average face-looking was associated with higher observer-measured autistic characteristics in autistic females, but not in males. Conclusions: Overall, we found stronger social attention in females to a similar degree in both autistic and nonautistic groups. Nonetheless, the dynamic profiles of social attention differed in different ways in autistic females and males compared to their nonautistic peers, and autistic traits predicted trends of average face-looking in autistic females. These findings support the role of social attention in the emergence of sex-related differences in autistic characteristics, suggesting an avenue to phenotypic stratification.
... Many studies in this review conducted post-hoc examination of symptom associations for regions showing differences in their primary categorical analyses of sex-by-diagnosis effects. However, only a handful of studies examined both categorical and dimensional associations with brain features in their primary whole-brain analyses of sex differences in ASD (Bedford et al., 2016;Kozhemiako et al., 2020Kozhemiako et al., , 2019Moessnang et al., 2020;Oldehinkel et al., 2019). In terms of morphometry, one study showed more widespread ASD-related effects in females using dimensional vs. categorical measures of symptom severity (Bedford et al., 2019). ...
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Females with autism spectrum disorder (ASD) have been long overlooked in neuroscience research, but emerging evidence suggests they show distinct phenotypic trajectories and age-related brain differences. Sex-related biological factors (e.g., hormones, genes) may play a role in ASD etiology and have been shown to influence neurodevelopmental trajectories. Thus, a lifespan approach is warranted to understand brain-based sex differences in ASD. This systematic review on MRI-based sex differences in ASD was conducted to elucidate variations across the lifespan and inform biomarker discovery of ASD in females We identified articles through two database searches. Fifty studies met criteria and underwent integrative review. We found that regions expressing replicable sex-by-diagnosis differences across studies overlapped with regions showing sex differences in neurotypical cohorts. Furthermore, studies investigating age-related brain differences across a broad age-span suggest distinct neurodevelopmental patterns in females with ASD. Qualitative comparison across youth and adult studies also supported this hypothesis. However, many studies collapsed across age, which may mask differences. Furthermore, accumulating evidence supports the female protective effect in ASD, although only one study examined brain circuits implicated in “protection.” When synthesized with the broader literature, brain-based sex differences in ASD may come from various sources, including genetic and endocrine processes involved in brain “masculinization” and “feminization” across early development, puberty, and other lifespan windows of hormonal transition. Furthermore, sex-related biology may interact with peripheral processes, in particular the stress axis and brain arousal system, to produce distinct neurodevelopmental patterns in males and females with ASD. Future research on neuroimaging-based sex differences in ASD would benefit from a lifespan approach in well-controlled and multivariate studies. Possible relationships between behavior, sex hormones, and brain development in ASD remain largely unexamined.
... The resulting clinical sign of sleep disorder is often associated with ASD. Dysfunction of the pineal gland is also related to abnormal metabolism of N-dimethyltryptamine, which could explain the abnormal neuroplasticity and neuronal distribution that are present in some cases of autism (Bedford et al., 2016). Subependymal cysts were found to be closely associated with developmental delay and developmental disability, ADHD and ASD in particular, while the higher the extent of subependymal cysts, the higher the risk of neurodevelopmental delay (Chang et al., 2018). ...
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The aim of the present research has been to determine whether there is a relationship between brain abnormalities found on magnetic resonance imaging (MRI) and autistic psychopathology. A retrospective analysis covering a period between 1998 and 2015 included 489 children with autism (404 boys, 85 girls; average age 8.0 ± 4.2 years) who underwent an MRI of the brain. For clinical diagnosis of autism, the International Classification of Diseases, 10th revision (ICD-10), was used. Autistic psychopathology was evaluated by means of the Autism Diagnostic Interview - Revised. The Spearman nonparametric correlation analysis and chi-square test were used to examine the possible relationships between variables. The group of autistic children did not manifest a statistically significant correlation between the parameters examined on MRI and autistic psychopathology. A correlation between other cysts and repetitive behavior was significant only at trend level (P = 0.054). Gliosis of the brain was significantly more frequent in autistic children with mental retardation than in children without mental retardation (14.1% vs. 7.4%; P = 0.028). Nonmyelinated areas in the brain were significantly more frequent in autistic children with autistic regression than in children without autistic regression (29.9% vs. 15.7%; P = 0.008). Mental retardation was significantly more frequent in autistic children with autistic regression than in children without regression (73.2% vs. 52.5%; P = 0.002). Our research study did not reveal a statistically significant correlation of brain abnormalities on MRI with autistic psychopathology.
... Here too, sex differences converge where females and males become indistinguishable over the course of the first years of life. Considering that there is a lower prevalence of ASD in females, and that sex differences appear during early development in both typically and atypically developing infants across a range of domains (Messinger et al., 2015), these findings may signal underlying processes that promote better than expected outcomes in terms of ASD diagnosis in female infants at risk for ASD (Bedford et al., 2016;Elsabbagh, 2020). Additional research into the development of female infants at risk for ASD is needed. ...
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Autism spectrum disorder (ASD) has its origins in the atypical development of brain networks. Infants who are at high familial risk for, and later diagnosed with ASD, show atypical activity in multiple electroencephalography (EEG) oscillatory measures. However, infant‐sibling studies are often constrained by small sample sizes. We used the International Infant EEG Data Integration Platform, a multi‐site dataset with 432 participants, including 222 at high‐risk for ASD, from whom repeated measurements of EEG were collected between the ages of 3–36 months. We applied a latent growth curve model to test whether familial risk status predicts developmental trajectories of spectral power across the first 3 years of life, and whether these trajectories predict ASD outcome. Change in spectral EEG power in all frequency bands occurred during the first 3 years of life. Familial risk, but not a later diagnosis of ASD, was associated with reduced power at 3 months, and a steeper developmental change between 3 and 36 months in nearly all absolute power bands. ASD outcome was not associated with absolute power intercept or slope. No associations were found between risk or outcome and relative power. This study applied an analytic approach not used in previous prospective biomarker studies of ASD, which was modeled to reflect the temporal relationship between genetic susceptibility, brain development, and ASD diagnosis. Trajectories of spectral power appear to be predicted by familial risk; however, spectral power does not predict diagnostic outcome above and beyond familial risk status. Discrepancies between current results and previous studies are discussed. Lay Summary Infants with an older sibling who is diagnosed with ASD are at increased risk of developing ASD themselves. This article tested whether EEG spectral power in the first year of life can predict whether these infants did or did not develop ASD.
... Rather, the decrease in predictive validity of some sensorimotor factors may be indicative of the emerging influence of other systems in the second year of life. Indeed, there have already been empirical demonstrations for significant moderation in developmental trajectories to ASD by sex (Bedford et al., 2016) and effortful control (Bedford et al., 2019). A range of evidence converges to point to the action of protective, resilience or other modifying factors on developmental trajectories to ASD (Chawarska, Macari, Powell, DiNicola, & Shic, 2016;Harrop et al., 2018;Klin et al., 2020;Robinson, Lichtenstein, Anckars€ ater, Happ e, & Ronald, 2013). ...
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We present the Anterior Modifiers in the Emergence of Neurodevelopmental Disorders (AMEND) framework, designed to reframe the field of prospective studies of neurodevelopmental disorders. In AMEND we propose conceptual, statistical and methodological approaches to separating markers of early-stage perturbations from later developmental modifiers. We describe the evidence for, and features of, these interacting components before outlining analytical approaches to studying how different profiles of early perturbations and later modifiers interact to produce phenotypic outcomes. We suggest this approach could both advance our theoretical understanding and clinical approach to the emergence of developmental psychopathology in early childhood.
To date, a deficit-oriented approach dominates autism spectrum disorder (ASD) research, including studies of infant siblings of children with ASD at high risk (HR) for the disabilities associated with this disorder. Despite scientific advances regarding early ASD-related risk, there remains little systematic investigation of positive development, limiting the scope of research and quite possibly a deeper understanding of pathways toward and away from ASD-related impairments. In this paper, we argue that integrating a resilience framework into early ASD research has the potential to enhance knowledge on prodromal course, phenotypic heterogeneity, and developmental processes of risk and adaptation. We delineate a developmental systems resilience framework with particular reference to HR infants. To illustrate the utility of a resilience perspective, we consider the “female protective effect” and other evidence of adaptation in the face of ASD-related risk. We suggest that a resilience framework invites focal questions about the nature, timing, levels, interactions, and mechanisms by which positive adaptation occurs in relation to risk and developmental pathways toward and away from ASD-related difficulties. We conclude with recommendations for future research, including more focus on adaptive development and multisystem processes, pathways away from disorder, and reconsideration of extant evidence within an integrated risk-and-resilience framework.
Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter‐individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver‐reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. Lay Summary In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.
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Objective: Sexual dimorphism in autism spectrum disorders (ASD) is a well-recognized but poorly understood phenomenon. Females are four times less likely to be diagnosed with ASD than males and, when diagnosed, are more likely to exhibit comorbid anxiety symptoms. One of the key phenotypic features of ASD is atypical attention to socially relevant stimuli. Eye-tracking studies indicate atypical patterns of spontaneous social orienting during the prodromal and early syndromic stages of ASD. However, there have been no studies evaluating sex differences in early social orienting and their potential contribution to later outcomes. Method: We examined sex differences in social orienting in 6-, 9-, and 12-month-old infants at high genetic risk for ASD (n = 101) and in low-risk controls (n = 61), focusing on neurobehavioral measures of function across a spectrum of autism risk. Results: Results suggest that, between 6 and 12 months of age, a period highly consequential for the development of nonverbal social engagement competencies, high-risk females show enhanced attention to social targets, including faces, compared to both high-risk males and low-risk males and females. Greater attention to social targets in high-risk infants was associated with less severe social impairments at 2 years. Conclusion: The results suggest an alternative expression of autism risk in females, which manifests in infancy as increased attention toward socially relevant stimuli. This increased attention may serve as a female protective factor against ASD by providing increased access to social experiences in early development.
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This study investigated the differences in clinical symptoms between females and males with autism spectrum disorder (ASD) across three verbal ability groups (nonverbal, phrase and fluent speech), based on which Autism Diagnostic Observation Schedule module was administered to 5723 individuals in four research datasets. In the Simons Simplex Collection and Autism Treatment Network, females with ASD and phrase or fluent speech had lower cognitive, adaptive, and social abilities than males. In the Autism Genetics Resource Exchange and the Autism Consortium, females with phrase or fluent speech had similar or better adaptive and social abilities than males. Females who were nonverbal had similar cognitive, adaptive, and social abilities as males. Population-based longitudinal studies of verbally fluent females with ASD are needed.
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The increased male prevalence of autism spectrum disorder (ASD) may be mirrored by the early emergence of sex differences in ASD symptoms and cognitive functioning. The female protective effect hypothesis posits that ASD recurrence and symptoms will be higher among relatives of female probands. This study examined sex differences and sex of proband differences in ASD outcome and in the development of ASD symptoms and cognitive functioning among the high-risk younger siblings of ASD probands and low-risk children. Prior to 18 months of age, 1824 infants (1241 high-risk siblings, 583 low-risk) from 15 sites were recruited. Hierarchical generalized linear model (HGLM) analyses of younger sibling and proband sex differences in ASD recurrence among high-risk siblings were followed by HGLM analyses of sex differences and group differences (high-risk ASD, high-risk non-ASD, and low-risk) on the Mullen Scales of Early Learning (MSEL) subscales (Expressive and Receptive Language, Fine Motor, and Visual Reception) at 18, 24, and 36 months and Autism Diagnostic Observation Schedule (ADOS) domain scores (social affect (SA) and restricted and repetitive behaviors (RRB)) at 24 and 36 months. Of 1241 high-risk siblings, 252 had ASD outcomes. Male recurrence was 26.7 % and female recurrence 10.3 %, with a 3.18 odds ratio. The HR-ASD group had lower MSEL subscale scores and higher RRB and SA scores than the HR non-ASD group, which had lower MSEL subscale scores and higher RRB scores than the LR group. Regardless of group, males obtained lower MSEL subscale scores, and higher ADOS RRB scores, than females. There were, however, no significant interactions between sex and group on either the MSEL or ADOS. Proband sex did not affect ASD outcome, MSEL subscale, or ADOS domain scores. A 3.2:1 male:female odds ratio emerged among a large sample of prospectively followed high-risk siblings. Sex differences in cognitive performance and repetitive behaviors were apparent not only in high-risk children with ASD, but also in high-risk children without ASD and in low-risk children. Sex differences in young children with ASD do not appear to be ASD-specific but instead reflect typically occurring sex differences seen in children without ASD. Results did not support a female protective effect hypothesis.
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Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (e.g. traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. Autism onset mechanism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most plastic, sexually dimorphic brain regions. The sex ratio bias in autism may arise from males’ lower threshold to develop this plastic reaction following a genetic or environmental event.
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Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model. We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)). Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e-08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e-09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families. By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.
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We investigated early behavioural markers of autism spectrum disorder (ASD) using the Autism Observational Scale for Infants (AOSI) in a prospective familial high-risk (HR) sample of infant siblings (N=54) and low-risk (LR) controls (N=50). The AOSI was completed at 7 and 14 month infant visits and children were seen again at age 24 and 36 months. Diagnostic outcome of ASD (HR-ASD) versus no ASD (HR-No ASD) was determined for the HR sample at the latter timepoint. The HR group scored higher than the LR group at 7 months and marginally but non-significantly higher than the LR group at 14 months, although these differences did not remain when verbal and nonverbal developmental level were covaried. The HR-ASD outcome group had higher AOSI scores than the LR group at 14 months but not 7 months, even when developmental level was taken into account. The HR-No ASD outcome group had scores intermediate between the HR-ASD and LR groups. At both timepoints a few individual items were higher in the HR-ASD and HR-No ASD outcome groups compared to the LR group and these included both social (e.g. orienting to name) and non-social (e.g. visual tracking) behaviours. AOSI scores at 14 months but not at 7 months were moderately correlated with later scores on the autism diagnostic observation schedule (ADOS) suggesting continuity of autistic-like behavioural atypicality but only from the second and not first year of life. The scores of HR siblings who did not go on to have ASD were intermediate between the HR-ASD outcome and LR groups, consistent with the notion of a broader autism phenotype. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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Epidemiological studies have highlighted a strong male bias in autism spectrum disorder (ASD), however few studies have examined gender differences in autism symptoms, and available findings are inconsistent. The aim of the present study is to investigate the longitudinal gender differences in developmental profiles of 30 female and 30 male age-matched preschool children with ASD. All the children underwent a comprehensive evaluation at T0 and at T1. Our results have shown no significant interaction between time and gender for predicting autism symptoms, developmental quotient, parental stress, children's adaptive skills and behavior problems. Shedding light on the developmental trajectories in ASD could help clinicians to recognize children with ASD at an earlier age and contribute to the development of appropriate treatments.
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Objectives: To evaluate the verbal interactions of parents with their infants in the first months of life and to test the hypothesis that reciprocal vocalizations of mother-infant dyads would be more frequent than those of father-infant dyads. Methods: This prospective cohort study included 33 late preterm and term infants. Sixteen-hour language recordings during the birth hospitalization and in the home at 44 weeks' postmenstrual age (PMA) and 7 months were analyzed for adult word count, infant vocalizations, and conversational exchanges. Results: Infants were exposed to more female adult speech than male adult speech from birth through 7 months (P < .0001). Compared with male adults, female adults responded more frequently to their infant's vocalizations from birth through 7 months (P < .0001). Infants preferentially responded to female adult speech compared with male adult speech (P = .01 at birth, P < .0001 at 44 weeks PMA and 7 months). Mothers responded preferentially to girls versus boys at birth (P = .04) and 44 weeks PMA (P = .0003) with a trend at 7 months (P = .15), and there were trends for fathers to respond preferentially to boys at 44 weeks PMA (P = .10) and 7 months (P = .15). Conclusions: Mothers provide the majority of language input and respond more readily to their infant's vocal cues than fathers; infants show a preferential vocal response to their mothers in the first months. Findings also suggest that parents may also respond preferentially to infants based on gender. Informing parents of the power of early talking with their young infants is recommended.
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Background Children with callous unemotional (CU) traits, a proposed precursor to adult psychopathy, are characterised by impaired emotion recognition, reduced responsiveness to others’ distress and a lack of guilt or empathy. Reduced attention to faces, and more specifically the eye region, has been proposed to underlie these difficulties, although this has never been tested longitudinally from infancy. Attention to faces occurs within the context of dyadic caregiver interactions, and early environment such as parenting characteristics have also been associated with CU traits. The present study tested whether infants’ preferential tracking of a face with direct gaze and levels of maternal sensitivity predict later CU traits. Methods Data were analysed from a stratified random sample of 213 participants drawn from a population-based sample of 1233 first-time mothers. Infants’ 5-week preferential face tracking and 29-week maternal sensitivity were entered into a weighted linear regression as predictors of CU traits at 2.5 years. Results Controlling for a range of confounders (e.g. deprivation) lower preferential face tracking predicted higher CU traits (p = 0.001). Higher maternal sensitivity predicted lower CU traits in girls (p = 0.009) but not boys. No significant interaction between face tracking and maternal sensitivity was found. Conclusions This is the first study to show that attention to social features during infancy, as well as early sensitive parenting, predict the subsequent development of CU traits. Identifying such early atypicalities offers the potential for developing parent-mediated interventions in children at-risk for developing CU traits.