Phenotypic differences between female and male individuals with suspicion of autism spectrum disorder - Molecular Autism
Background Although autism spectrum disorder (ASD) is a common developmental disorder, our knowledge about a behavioral and neurobiological female phenotype is still scarce. As the conceptualization and understanding of ASD are mainly based on the investigation of male individuals, females with...
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Background
Autism spectrum disorder (ASD) is a common
developmental disorder with an onset within the first
years of life and early emerging atypicalities in social
attention and reciprocity [ 1]. Since the early days of
autism research, the condition has been understood to
predominantly affect males. Most epidemiological
studies report an approximately 4:1 male to female ratio
[2, 3], which has recently shifted toward a 3:1 ratio [ 4].
It has consistently been shown that the sex imbalance in
prevalence varies with cognitive ability, with a male to
female ratio of 2:1 among individuals with low cognitive
ability or co-occurring intellectual disability and a ratio
as high as 9:1 among individuals with average to above-
average IQ [2, 5]. Consequently, most research has
involved males, leading to a male-biased understanding
and conceptualization of ASD. Furthermore, although the
female ASD phenotype may present differently, current
defining diagnostic criteria are mainly based on male
characteristics, and diagnostic instruments may be
biased toward detecting ASD among male individuals,
with similar diagnostic thresholds for females and males
[6, 7].
Previous work suggests that ASD may be more difficult
to detect in females, as they tend to be diagnosed later
than males [ 8, 9] and seem to require a more significant
etiological load to manifest autistic behavioral
characteristics and autistic symptoms, or concurrent
impairments need to be more severe for the diagnosis
to be given [ 10]. It is argued that phenotypic sex
differences might lead to delayed or even missed
diagnoses in girls and women with ASD [ 11].
In the past decades, a wealth of investigations have
been conducted to examine the relationship between sex
and clinical profiles of individuals with ASD. Research
findings on differences between the sexes provide some
insight into why females might be more difficult to
detect and are diagnosed later in life than males.
However, knowledge about differences between the
sexes in terms of the phenotypic presentation of ASD
symptoms is still lacking, as the available studies
yielded inconsistent findings regarding symptom
severity across different age groups and different levels
of functioning. While some studies did not find sex
differences during a behavioral observation, e.g., [ 12,
13], others did report some differences [ 14].
It has been argued that females and males might meet
the diagnostic criteria for ASD differently, as a range of
different behaviors can be mapped onto each broad
criterion. For example, deficits in social-emotional
reciprocity may be composed of impairments in spoken
language, reduced joint attention, and reduced sharing
of interest, emotions, and affect. To meet the social-
emotional reciprocity criterion, an individual does not
need to present with all of these behaviors—rather, the
clinician needs to decide whether or not an individual
meets a particular criterion based on the available
information. Despite some work on a female autism
phenotype, little is known about how females and males
meet the diagnostic criteria.
Females with ASD appear to score lower than males on
measures of restricted and repetitive behavior (RRB),
they seem less likely to present with stereotyped use of
objects and show different types of restricted interests
than males [ 15]. Specific differences in social
communication deficits have not been consistently
observed. Some girls were more likely to show an ability
to integrate non-verbal and verbal behaviors, maintain
a reciprocal conversation, and be able to initiate, but
not maintain friendships [ 15] others showed more
impairment in communication [ 16] compared to boys.
Overall, results remain inconsistent (for reviews, see [ 5,
17, 18, 19 ]. If there are indeed different symptom
patterns in females and males, but diagnostic
instruments are biased toward the male ASD phenotype,
one solution to better recognize ASD in females would
be to revise the diagnostic criteria and the diagnostic
algorithms of standard diagnostic instruments.
The current study aimed to investigate an ASD specific
behavioral observation tool and explore whether there
are differences in how female and male individuals meet
the actual criteria for ASD. As females with ASD without
cognitive and language deficits are at risk of not being
identified until later in life, we investigated a sample of
individuals with fluent language and without profound
intellectual disabilities. Diagnoses at an older age have
been associated with increased comorbidity [ 20].
Moreover, the presentation of ASD symptoms can
significantly overlap with other mental disorders [ 21,
22]. Therefore, it is essential to investigate sex
differences in ASD symptom presentation not only in a
sample of individuals with ASD but also in those with
suspicion of ASD but no actual ASD diagnosis. The
present study thus aimed to extend previous research
on a female ASD phenotype, which focused on
differences in ASD symptoms between females and
males already diagnosed with ASD, by including a large
clinical sample comprising individuals without a
diagnosis of ASD but with a diagnosis of other mental
disorders. We aimed to identify those symptoms,
directly observed by trained specialists, which optimally
discriminate between ASD and non-ASD within a female
and a male sample, and to then compare these
discriminative features between the sexes. We thus aim
to facilitate the diagnostic identification of females by
highlighting potential nuanced differences between the
sexes. By using machine learning models, we sought to
identify the particular contributions of individual pieces
of diagnostic information (item codes from the ADOS)
for the diagnosis of female and male children and young
adolescents and for later diagnosis of older adolescents
and adults.
Differences in symptom severity
In the current study, females were older at the time of
the diagnostic appointment—an effect that was
pronounced in the older adolescent and adult sample . In
the young adolescent and adult group, males with ASD
scored higher in the RRB domain of the behavior
observation than females with ASD, but the effect size
was small. We observed no differences in social affect
between the sexes in the ASD samples of either age
group, but males scored higher on overall symptom
severity. These findings are in line with a meta-analysis
that reported few differences in communication and
social behavior between males and females and only in
the RRB domain did girls show fewer symptoms than
boys [ 18].
The present findings indicate, however, that as ASD
symptoms present differently across development, the
developmental aspect might be important with respect
to sex differences: In the older adolescent and adult
sample, we found fewer symptoms of RRB and lower
overall ASD severity (ADOS CSS total) in females than in
males. From the parental perspective (anamnestic data
from the ADI-R), females showed fewer symptoms in the
communication domain. In the child and young
adolescent sample, more parent-reported RRB were
observed in males compared to females, with moderate
effect sizes. Classification accuracy of the RF models
was similar to the diagnostic accuracy of the ADOS-2
algorithm in females as well as males. Interestingly, we
found more females than males who were diagnosed
with ASD while scoring below the ADOS autism spectrum
diagnostic cut-off (18.6% females vs. 13.5% males, i.e.,
false negative ADOS classifications). This suggests that
information from outside the standardized behavioral
observation may be of greater importance for the
diagnostic decision in females than in males, giving rise
to the question of which particular additional
information clinicians rely on in order to classify a
female as autistic. On the other hand, more males than
females did not receive an ASD diagnosis despite
exceeding the ADOS diagnostic threshold (6.4% females
vs. 14.2% males, i.e., false positive ADOS
classifications). This suggests that autistic traits in
males may be present during the behavioral observation
but are attributed to other underlying conditions or
symptoms of a differential diagnosis. However, our
female sample had more comorbid diagnoses (e.g.,
depression, social phobia), and particularly in females
with ASD, there is evidence that the presence of
depression and anxiety is associated with enhanced ASD
symptoms [ 30, 31, 32, 33 , 34, 35]. The considerable
symptom overlap of ASD with depressive and anxiety
disorders entails the risk of false-positive evaluations in
females. Although the ADOS-2 shows high sensitivity
(0.91; [ 23], p. 243) for detecting autism versus non-
spectrum cases, emerging research shows that it may be
less accurate in detecting ASD in individuals with
complex psychiatric presentations [ 36]. Moreover, the
observation in the current sample that the prevalence of
ASD diagnoses increases with age (45.9% of all
adolescent/ adult females, but only 33.8% of the
younger sample, received an ASD diagnosis) underlines
the need to carefully consider differential, potentially
overlapping diagnoses during the diagnostic process.
