CME Author: Vicki Brower
Study Authors: Meghan Miller, Erica D. Musser, et al.
Target Audience and Goal Statement:
Pediatricians, family medicine physicians, pediatric psychiatrists, and psychologists
To understand whether later-born siblings of those with autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) have an elevated risk of being diagnosed with either condition.
Questions Addressed by this Study:
What is the degree of family aggregation in ASD and ADHD? What is the recurring risk of ASD among later-born siblings of children with ASD, and does it replicate other studies? What is the recurrence risk of ADHD among later-born siblings of children with ADHD and is it possible to provide the first estimates of familial cross-aggregation of recurrence of both disorders among later-born siblings?
Study Synopsis and Perspective:
In this study using 2 sets of population-based medical records, researchers found that children whose older brother or sister had autism were 30 times more likely to receive the same diagnosis and 3.7 times more likely to be diagnosed with ADHD than children whose older sibling did not have either disorder.
Led by Meghan Miller, PhD, of the University of California, Davis MIND Institute, the team discovered that similarly, children with an older sibling who had ADHD were 13 times more likely to receive an ADHD diagnosis and 4.4 times more likely to be diagnosed with autism than children in the control group, they wrote in JAMA Pediatrics.
For their research, Miller and team extracted data from medical records of children born or seen during 1995 and 2013 in two large health care systems: one in the Upper Midwest region of the U.S., and the other in Oregon and Washington. Both systems identified siblings by their mother.
The data included 730 younger siblings of children with ADHD, 158 younger siblings of children with autism, and 14,287 younger siblings of children with no known diagnosis of either disorder. If a child was identified as having both autism and ADHD, the autism diagnosis was considered primary. Only families who had at least one younger child after a diagnosed child were included in the study, and children under age 5 were excluded.
Across all children in the sample — later-born children and their older siblings — the incidence of autism was 0.8%, and of ADHD was 3.3%, considerably less than the CDC estimates of autism or ADHD in the U.S. These lower levels may be due to conservative definitions of ADHD and autism, the researchers noted: cases were counted as positive only if identified at two or more points.
The analyses showed the following absolute percentages and ORs, compared with younger siblings of children who had neither autism nor ADHD:
- 12.03% of younger siblings of children with autism had a diagnosis of autism; OR 30.38, 95% CI 17.73-52.06
- 3.8% of younger siblings of children with autism had an ADHD diagnosis; OR 3.70, 95% CI 1.67-8.21
- 12.47% of younger siblings of children with ADHD had a diagnosis of ADHD; OR 13.05, 95% CI, 9.86-17.27
- 1.92% of younger siblings of children with ADHD had an autism diagnosis; OR 4.35, 95% CI 2.43-7.79
A new finding the team discovered is the cross-aggregation rates of later-born siblings. “This finding is consistent with numerous studies using genetically informed methods that have suggested shared genetic influences on both ASD and ADHD traits and diagnoses, and several that have highlighted shared copy number variants, although other studies have not identified genetic overlap,” they wrote.
In addition, maternal age had an additive effect and interacted with familial risk status: as the mothers age increased from 20 to 50 years, the probability of ADHD diagnosis decreased in the no-known-risk group (from 2.8% to 0.25%) and ADHD-risk group (from 18.5% to 13.3%), but increased in the ASD-risk group (from 4.0% to 10.4%). There was no association with gestational age.
This study gives support to the idea of shared familial mechanisms underlying ASD and ADHD, which researchers believe could be helpful for future genetic and prospective developmental studies, researchers wrote.
JAMA Pediatrics, Dec. 10, 2018; DOI:10.1001/jamapediatrics.2018.4076
Study Highlights: Explanation of Findings:
Researchers expected to find higher rates of ASD recurrence in later-born siblings of children with ASD, and this confirms earlier research: 12.03% of later-born siblings of children with ASD were diagnosed with ASD versus 0.45% of the later-born siblings of non-diagnosed older siblings. They also expected to find that later-born siblings of children with ADHD to be at higher risk for developing ADHD. Researchers of this study may be the first group to report rates of ADHD among later-born siblings of children with ADHD. “These findings suggest the potential utility of prospective family risk designs to ADHD, while also providing more useful estimates of recurrence rates for genetic counseling,” they wrote.
“We’ve known for quite some time that risk for autism is elevated among younger siblings of children with autism, that ADHD is highly heritable, and that autism and ADHD frequently co-occur,” Miller told MedPage Today. “But we didn’t have good data on recurrence risk for ADHD specifically among younger siblings of children with ADHD, nor did we know much about how these conditions aggregate across families,” she said. These 2 conditions are common and understood to be “highly heritable neurodevelopmental disorders, but data about their shared heritability is “mixed,” the authors wrote. “It remains unclear how related these disorders are etiologically,” they observed. Measuring recurrence risk is one accepted method of measuring “shared genetic contributions.”
Miller and colleagues set out to avoid one important confounder of previous studies, namely estimates based on total number of children in a family rather than limiting their research to later-born siblings, which means that their data cannot be influenced by “reproductive stoppage” (if families decide to have fewer children after 1 child with an ASD or ADHD diagnosis in an older child).
While ADHD and autism may have shared familial mechanisms, Miller reassured parents of a child with autism or ADHD: “Although risk is increased among these younger siblings, most do not develop autism or ADHD,” she said. Indeed, the risk was about one in eight.
The authors also noted that “the fact that ASD was more common than ADHD in the siblings of ASD probands and ADHD was more common than ASD in the siblings of ADHD probands supports the distinction between these disorders. Conversely, the excess cross-aggregation in siblings indicates shared etiologic (familial) factors.” This is, they wrote, consistent with other studies using genetic methods that have indicated shared genetic influences on both disorders, with several highlighting shared copy number variants. However, other studies have not found such genetic overlap.
“These within- and cross-condition recurrence figures are of important clinical usefulness in terms of informing discussions with parents about the need for enhanced developmental surveillance for neurodevelopmental conditions, such as ASD and ADHD, in their younger children,” observed Tony Charman, PhD, of King’s College London, England, and Emily J.H. Jones, PhD, of the University of London, in an accompanying editorial. These commentators suggest that proactive monitoring of younger children in these families for signs of ASD and ADHD could be useful, but also warn that “it might be best not to impart this information at the initial feedback from the diagnostic consultation but instead at a later review…” They add that identifying underlying mechanisms of co-occurrence between neurodevelopmental conditions such as ASD and ADHD is important not just for understanding the causes of these conditions, but also to guide early intervention.
The data should be interpreted cautiously — the sample sizes were modest and the confidence intervals of the elevated ORs were wide, “and this imprecision should add caution to how this information is conveyed to parents, although it is clear that the later-born siblings are at a considerably elevated likelihood of developing ASD and ADHD,” Charman and Jones wrote.
Miller and co-authors noted several limitations to their study. It was based on a population sample. The researchers had no information about full- versus half-sibling status, nor data about parental psychopathology, comorbidities, or other potential confounders. Data came from general medical records and diagnostic procedures were unknown, but the relatively low incidence of autism and ADHD in this study (because two or more instances of a given diagnosis were required) suggests there was not much over-identification, they noted.
Judy George wrote the original story for MedPage Today.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner