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RISK OF AUTISM SPECTRUM DISORDER
Risk of Autism Spectrum Disorder
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A lot of concern has risen due to rise in cases of children born with Autism Spectrum
Disorder (ASD) in the United States over the decades. In the article, “Advanced Parental Age
and the Risk of Autism Spectrum Disorder”, Durkin et al. (2008) sought to examine the
association between prevalence of ASD with older parental age. The study was based on data
from ten US study sites with a birth cohort of 253,347 children in the year 1994. The cases were
1,251 children who had complete parental information aged 8 years. The researchers noted that
autism had become common in children of older parents and confirming such an association
would shed the light to the diagnosis of a group of neurodevelopmental disorder to the public
health, which is still misunderstood and termed to be multifactorial and complex. The study was
guided by the research question; does the prevalence of ASD in children of older parents explain
the relationship between paternal and maternal age while controlling other variables such as
gestational age, birth order, and ethnicity?
Study design
For the study, the researchers used the birth cohort of children with ASD living in the
study area in 2002 who met the criteria for pervasive developmental disorders, Asperger’s
disorder, or autistic disorders such as atypical autism. The complete cohort included 326, 785
live births but only a cohort of 253,347 live births was used to serve as a comparison group since
73,438 had been excluded for missing parental information. The Autism and Developmental
Disabilities Monitoring Network found 2,142 ASD cases of children aged 8 years in the study
areas. This number was further restricted to 1,251 representing cases where gestational age, both
parents’ age, and birth order information was available. Out of this cases, 80.7% were
determined to meet the criteria for autistic disorder. I found the exposure and outcome clearly
defined with the researchers providing clear estimations in terms of percentages.
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The researchers used two data sources to develop the cohort: deidentified birth records of
1994 provided by Wisconsin Department of Health and Family Services for the Wisconsin study
area, and data files from the National Centre for Health Statistics for the remaining sites.
Information from sparsely populated areas was obtained through aggregate information on the
total number of births on the county level in 1994 where a stratified random sample was created
with their distribution variables. The researchers employed a case-cohort, population-based
design to carry out the study. This design was essential for the study since it was based on a
similar study hence the covariates were easy to compare and adjust. I found these methods of
collecting data to be appropriate as they were records from government databases hence some
degree of accuracy.
Analysis
The researchers used chi-square tests for analysis of variance for continuous variables
and categorical variables to evaluate the statistical significance of the study. Potential site-to-site
variability was adjusted by inclusion of bogus variables in sites in all multivariable models. The
researchers also used stratified analyses to evaluate modifying effects or interaction of ASD
subtypes and of each covariate on the associations between ASD and paternal age. Regression
models were used to test for interaction terms for paternal age and maternal age and three-way
and two-way interaction terms for each parent’s age by other covariates. This analyses were
essential to determine an association between autism risk and parental age across the study sites.
To determine the potential for confounding effects of gender, birth order and other
multiple variables, adjusted associations between independent variables for paternal and
maternal age and each potential cofounder were first examined together with the dependent
variable, ASD. If the variables were associated with both ASD and parental age then they were
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considered to be confounding factors. The magnitude of these interactions was achieved by
computing unadjusted odd ratios with confidence intervals while 95% confidence intervals and
adjusted odd ratios were estimated by unconditional logistic regression models.
Results and conclusions
The researchers noted significant results in the study. Mean paternal age and mean
maternal age were found to be significantly higher for ASD cases than the birth cohort in the
unadjusted analyses. This was across categories of maternal education, birth order, gestational
age, ethnicity, birth weight regarding gestational age, and multiple birth. The study also found
out that in developing ASD, the odds increased significantly from paternal age > 40 and maternal
age > 35 and reduced for parental age < 20 years. After adjustments were made for the covariates
and other parent’s age, the prevalence of ASD associated with paternal age > 40 and maternal
age > 35 were slightly reduced. Other results showed that there was a decline in ASD risk as a
result of birth order in adjusted analyses as compared to unadjusted analyses. The researchers
also found that the maternal education effect in increase of ASD risk was mainly due to the
correlation with parental age. These conclusions are justifiable with the study revealing that there
was a 30% increase in ASD risk with each 10-year increase in paternal age and an increase of
20% in ASD risk with each 10-year increase in maternal age. The risk of ASD was found to be
highest for firstborns which significantly reduced with the third and later-born children of fathers
aged <40 and mothers aged 20-34 years.
To determine if the epidemiologic associations of the covariates are casual, I will use the
nine viewpoints of Sir Austin Bradford Hill. Using the first criteria of strength of association, it
is evident that the association between ASD and maternal and paternal age is casual. The
researchers reported odd ratios ranging from 1.2-1.4 for the strength of the independent
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associations between the two variables, which was modest. Causality of the association is
supported by the second criteria of Hill, consistency. The findings of the study were consistent
with the study from California Health Maintenance Organization with even identical odd ratios.
This association is further supported by the third criteria of specificity. The researchers pointed
to a casual of gene mutations that increase with men’s age contributing to the paternal age effect.
Hill suggested in the fourth criteria of temporality that for a relationship to be casual, the onset of
the disease should be preceded by exposure. The researchers noted that exposure to assisted
reproductive technologies and tendency of parents to not have subsequent children could explain
the birth order defects in autism cases. Using the fifth criteria of Hill, presence of biological
gradient, a causal relationship can be established between ASD and parental age since exposure
of offspring to potentially fat-soluble, neurotoxic chemicals present in maternal tissues leads to
risk of ASD. This risk increases over the years since the neurotoxins continue to accumulate.
The casual relationship can also be determined using plausibility, the sixth criteria.
Epidemiology for ASD has been attributed to biological factors and this has been revealed in
many studies that have been conducted thus suggesting a casual relationship. With the results
that have been found over the years, ASD and parental age satisfy Hill’s seventh criteria of
coherence. This is because the cause-and-effect story regarding the covariates in the studies are
similar in many occasions. The eighth criteria, experiment, is evident by the changes that were
found when unadjusted and adjusted analyses were done. The risk of ASD with regard to levels
of maternal education was seen to reduce when adjusted analyses were done in comparison to
unadjusted analyses. The study also satisfies the last criteria of Hill’s exposure-response
associations, analogy. The researchers noted that observations made in the study regarding the
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high risk of developing ASD for firstborns and decline with birth order was a similar pattern
observed in other childhood disorders such as Atopy and Type I Diabetes.
Validity
The researchers made significant strides in establishing the relationship between parental
age and risk of ASD. However, there was some information bias that was present in the study.
The researcher did not provide enough information to justify the hypothesis of the birth-order
effects. Selection bias is also evident in the study since the researchers excluded all the births
that had missing paternal age information. To limit this biasness, the researcher made exclusions
to both the comparison group and ASD cases to achieve relevant estimates. Another limitation of
the study was the comparison group included postnatal deaths of children in the birth cohort. In
addition, there was also an unknown number of children who had relocated from the study areas
from birth to 8 years making the estimation of cumulative incidence of ASD difficult to
determine.
The study information was also limited since when comparing parental ages, older
parents tend to have more awareness on developmental abnormalities than younger parents.
Based on the results from the study, the prevalence of ASD in 8 year olds could be generalized
on Non-Hispanic white people in the United States, with boys having a higher chance of
developing the disorder.
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References
Durkin, M., Maenner, M., Newschaffer, C., Lee, L., Cunniff, C., & Daniels, J. et al. (2008).
Advanced Parental Age and the Risk of Autism Spectrum Disorder. American Journal Of
Epidemiology, 168(11), 1268-1276. https://doi.org/10.1093/aje/kwn250