Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis

Abstract

Importance: Presence of developmental delays in autism is well established, yet few studies have characterized variability in developmental milestone attainment in this population.

Objective: To characterize variability in the age at which autistic individuals attain key developmental milestones based on co-occurring intellectual disability (ID), presence of a rare disruptive genetic variant associated with neurodevelopmental disorders (NDD), age at autism diagnosis, and research cohort membership.

Design: The study team harmonized data from 4 cross-sectional autism cohorts: the Autism Genetics Research Exchange (n = 3284; 1997-2015), The Autism Simplex Collection (n = 694; 2008-2011), the Simons Simplex Collection (n = 2753; 2008-2011), and the Simons Foundation Powering Autism Research for Knowledge (n = 10 367; 2016-present). The last sample further included 4145 siblings without an autism diagnosis or ID.

Participants: Convenience sample of 21 243 autistic individuals or their siblings without an autism diagnosis aged 4 to 17 years.

Main outcomes and measures: Parents reported ages at which participants attained key milestones including smiling, sitting upright, crawling, walking, spoon-feeding self, speaking words, speaking phrases, and acquiring bladder and bowel control. A total of 5295 autistic individuals, and their biological parents, were genetically characterized to identify de novo variants in NDD-associated genes. The study team conducted time-to-event analyses to estimate and compare percentiles in time with milestone attainment across autistic individuals, subgroups of autistic individuals, and the sibling sample.

Results: Seventeen thousand ninety-eight autistic individuals (mean age, 9.15 years; 80.8% male) compared with 4145 siblings without autism or ID (mean age, 10.2 years; 50.2% female) showed delays in milestone attainment, with median (IQR) delays ranging from 0.7 (0.3-1.6) to 19.7 (11.4-32.2) months. More severe and more variable delays in autism were associated with the presence of co-occurring ID, carrying an NDD-associated rare genetic variant, and being diagnosed with autism by age 5 years. More severe and more variable delays were also associated with membership in earlier study cohorts, consistent with autism’s diagnostic and ascertainment expansion over the last 30 years.

Conclusions and relevance: As the largest summary to date of developmental milestone attainment in autism, to our knowledge, this study demonstrates substantial developmental variability across different conditions and provides important context for understanding the phenotypic and etiological heterogeneity of autism.

Group social skills interventions (GSSIs) are among the most commonly used treatments for improving social competence in youth with ASD, however, results remain variable. The current study examined predictors of treatment response to an empirically-supported GSSI for youth with ASD delivered in the community (Ntotal=75). Participants completed a computer-based emotion recognition task and their parents completed measures of broad psychopathology, ASD symptomatology, and social skills. We utilized generalized estimating equations in an ANCOVA-of-change framework to account for nesting. Results indicate differential improvements in emotion recognition by sex as well as ADHD-specific improvements in adaptive functioning. Youth with both co-occurring anxiety and ADHD experienced iatrogenic effects, suggesting that SDARI may be most effective for youth with ASD without multiple co-occurring issues. Findings provide important directions for addressing variability in treatment outcomes for youth with ASD.

Keywords: ASD; Community; GSSI; Intervention; Social Skills; Treatment predictors.

Autism Spectrum Disorder (ASD) is diagnosed three to four times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common inherited genetic risk for ASD are less studied, particularly within families. Leveraging the Danish iPSYCH resource, we found siblings of female ASD cases (n = 1,707) had higher rates of ASD than siblings of male ASD cases (n = 6,270; p < 1.0 × 10−10). In the Simons Simplex and SPARK collections, mothers of ASD cases (n = 7,436) carried more polygenic risk for ASD than fathers of ASD cases (n = 5,926; 0.08 polygenic risk score [PRS] SD; p = 7.0 × 10−7). Further, male unaffected siblings under-inherited polygenic risk (n = 1,519; p = 0.03). Using both epidemiologic and genetic approaches, our findings strongly support an FPE against ASD’s common inherited influences.

This week’s #ASFpodcast highlights a few articles from the Journal of Autism and Developmental Disorders this week which examined the tolerability and efficacy of online diagnostic procedures and interventions, from the perspective of both parents and clinicians. They seem to work about the same, although there were some caveats. For many reasons, online and Telehealth options are here to stay, and more needs to be done to improve their accuracy, acceptability, feasibility and effectiveness. These early studies are promising though, and lead the way to even more improvements to help make them a viable option for families in the future. Listen to the podcast here.

https://link.springer.com/article/10.1007/s10803-022-05435-z

https://link.springer.com/article/10.1007/s10803-022-05576-1

https://link.springer.com/article/10.1007/s10803-022-05554-7

https://link.springer.com/article/10.1007/s10803-022-05580-5

https://link.springer.com/article/10.1007/s10803-022-05607-x

This week’s podcast explores the question about whether or not it is beneficial or just confusing to teach your child with autism multiple languages, or suppress the use of more than one language at home. Turns out, being bilingual helps with executive functioning (or those with preserved executive functioning can be bilingual), language, and provides benefits in verbal IQ depending on SES. In other words, it’s not harmful, it can be helpful, and those who choose to speak two languages at home should continue to do so if they feel that it is enhancing their child’s learning. Listen to the podcast here and find more information in the links below:

https://pubmed.ncbi.nlm.nih.gov/35102760/

https://pubmed.ncbi.nlm.nih.gov/34813032/

https://pubmed.ncbi.nlm.nih.gov/36222993/

More and more, psychiatrists are looking to psychedelic medication to help individuals who are resistant to other types of therapies. These include seizures, PTSD and depression. But can they help individuals with autism or ease autism-related problems or improve cognition? Two new studies on cannabis and one on ketamine are summarized in this week’s ASFpodcast. Promising, interesting, but not definitive. It’s a short podcast this week. You can listen to it here.

https://pubmed.ncbi.nlm.nih.gov/36085294/

https://pubmed.ncbi.nlm.nih.gov/35617670/

https://www.sciencedirect.com/science/article/pii/S2666247722000549?via%3Dihub

Fieri said “Cooking with kids is not just about ingredients, recipes, and cooking. It’s about harnessing imagination, empowerment, and creativity.” This week’s podcast produced by ASF intern Mia Kotikovski from Stony Brook University explores how cooking can be not just fun for autistic individuals, but how it can build healthy habits in everyone. She discusses the scientific literature on why cooking improves eating habits and builds confidence. Listen to the podcast here.

Anxiety is common in people with autism – but is is different than other types of anxiety or similar? Is it part of the autism phenotype? When does it start and what triggers it? Two new studies which use a longitudinal design and examine the links between autism features, anxiety symptoms and brain development are summarized this week. It shows that the amygdala is important, that some features of anxiety are core to ASD and some are separate, and it is related to autism features like insistence on sameness. This has implications for how anxiety is diagnosed and treated in those with ASD. Listen to the podcast here.

https://pubmed.ncbi.nlm.nih.gov/35871413/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116934/?report=printable

We’ve heard a lot about social robots – do they help? One or two studies are not going to answer this, but a systematic review and meta analysis will! It turns out when you combined all the data, they do help in social abilities, but not other areas. This is how technology can help those with autism, especially technology which can be adapted to address the heterogeneity across the spectrum. And what about more subtle changes in the environment like light, sound, the built environment in classrooms and the home? Are there things that can be done that should be taken into account when these things are being built or modified? Again, a review article can help decipher all of the little studies that have been published over the year. Listen here for specific recommendations for builders, architects, and even you as you make your home more autism friendly.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0269800

https://journals.sagepub.com/doi/10.1177/13623613221102753?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

https://lukerosen212.medium.com/the-supreme-courts-decision-impact-on-the-rare-genetic-disease-community-f9ac22bd1411

This week is a pharmacopeia of inflation. The #ASFpodcast talks debilitating gastrointestinal issues and new efforts to understand and treat them (including the CANDID meeting www.candidgi.com), a new method to understand adverse events in those that cannot report them on their own, and new news on Celexa, which is used to treat anxiety. Listen to the podcast here.

www.candidgi.com

https://www.theautismstudy.com

https://pubmed.ncbi.nlm.nih.gov/35165451/

https://pubmed.ncbi.nlm.nih.gov/35501967/

https://pubmed.ncbi.nlm.nih.gov/34652075/

At this year’s International Society of Autism Research meeting in Austin, TX, there was a variety of themes explored. From early development and milestones, to intervention and supports, to different features like sensory issues, treatment, and how to solve the problem of heterogeneity. It comes down to this: Autism means different things to different people. This is just a small subset of everything that was presented at INSAR 2022 and I hope that if you want to see more, you advocate to have the presentations posted online or even have the program book made available publicly. In the meantime, enjoy the 30 minute summary here.

www.autism-insar.org

This week, the #ASFpodcast explores different types of interventions for which the core autism features are not necessarily the target, but those that enhance quality of life and provide help for irritability and emotional dysregulation. They include cooking, music therapies and antipsychotic medications. While they may not be effective in core autism features, they may help in other ways. Listen to the podcast here.

https://www.jaacap.org/article/S0890-8567(22)00198-8/fulltext

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004381.pub4/full

https://www.sciencedirect.com/science/article/abs/pii/S0891422222000890?via%3Dihub