Author: Sara Webb, PhD

Science with Sara: Biology Underlying ASD: Research Advances and Great Reviews

In this month’s Science with Sara blog entry, I’ve asked two researchers from the University of Washington & Seattle Children’s Research Institute — whose work falls under the broad area of the Biology Underlying ASD – to highlight an important or informative review or summary paper from their field.

Dr. Stephen Smith PhD is an Assistant Professor at the UW and Seattle Children’s Research Institute. His work focuses on how proteins located at the junctions between brain cells (called synapses) work or, in the case of neurodevelopmental disorders, why they might malfunction. Dr. Smith uses multiple animal models of ASD in order to understand how different genetic variants impact synapse function, and in turn, how this changes how a person learns and remembers.

Dr. Smith’s Pick:
• Sestan, N., & State, M. W. (2018). Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder. Neuron, 100(2), 406-423.

“This beast of a review paper is co-authored by Dr. Matthew State, who has been at the forefront of gene discovery in Autism for many years. I hesitate to recommend this paper for a non-specialist audience because it is so dense, but its depth and quality make it worth the effort. While it’s a bit heavy on the details of the genetics (Dr. State is a geneticist, after all), the main takeaway is that, after many years of gene discovery, we are beginning to understand the central pathways that are disrupted in autism- neuronal signaling, dynamic control of DNA translation, and how those processes play central roles in development. State and his co-author Dr. Nenad Sestan then discuss future efforts to understand how mutated genes lead to atypical behavior. Although this is clearly a difficult path, they outline a plausible route that many research groups, including mine, will be taking in the years ahead.“

You can find a full list of Dr. State’s work on

Dr. Smith’s website provides updates on the work in his lab.

Dr. Smita Yadav PhD is an Assistant Professor in Pharmacology at the UW. Her work focuses on neuronal networks (networks of brain cells) and specifically on how molecules regulate communication between brain cells. One focus of Dr. Yadav’s research is in the 16p11.2 genetic location – there are 29 genes that are in this region of our DNA, and structural changes to this area of our DNA are associated with both ASD and schizophrenia.

Dr. Yadav’s pick:
• Quesnel-Vallières, M., Weatheritt, R. J., Cordes, S. P., & Blencowe, B. J. (2018). Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nature Reviews Genetics, 1.

“The first one is a review about understanding the ~75% non-syndromic, idiopathic cases of autism. The authors argue that a common pathway is emerging from transcriptome analyses that implicates RNA processing in ASD. The evidence includes: (1) cortical patterning of gene expression is lost in autism; (2) mRNA, lncRNA, miRNA and other non-coding RNA programmes are disrupted in ASD; (3) subsets of mRNAs regulating neuronal processes are consistently downregulated in individuals with ASD; and (4) RNA splicing regulatory programmes disrupted in ASD are responsive to neuronal activity and, conversely, affect neuronal activity.”

• Amin, N. D., & Paşca, S. P. (2018). Building models of brain disorders with three-dimensional organoids. Neuron, 100(2), 389-405.

“The second paper is a review on using 3D brain organoids to model neuropsychiatric diseases. While this review is not specific to autism, in my view, this space is where a lot of the research on the biological basis of autism will be in the future. The different kinds of organoids and the questions that we can now ask are quite amazing. Some caveats of this technology remain.”

Additional References

IACC Office of Autism Research Coordination Summary of Advances in Autism Spectrum Disorder Research: Calendar Year 2017. Question 2: What is the Biology Underlying ASD?

IACC Office of Autism Research Coordination Strategic Plan For Autism Spectrum Disorder Research 2016-2017 Update. Question 2: What is the Biology Underlying ASD?

Science with Sara- Diagnosing ASD with the DSM-5

In this post, I discuss the study Mazurek et al. (2017). A Prospective Study of the Concordance of DSM-IV and DSM-5 Diagnostic Criteria for Autism Spectrum Disorder. I then chat with three of our clinical and research leaders at the Seattle Children’s Autism Center – Dr. Soo Kim, Dr. Raphael Bernier, and Dr. Gary Stobbe – about how the new criteria for Autism Spectrum Disorder in the DSM-5 have impacted clinical and research practices.

Background References: The Diagnostic and Statistical Manual of Mental Disorders

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is published by the American Psychiatric Association. For a brief history of the DSM: See the American Psychiatry Association Website (DSM History) or Shorter (2015). For a brief history of the DSM related to autism diagnosis, see King et al. (2014). The current DSM-5 criteria for Autism Spectrum Disorders can be found on the CDC website. Generally speaking, the DSM is meant to give clinicians and researchers concrete descriptions of behaviors and difficulties (which are called “diagnostic criteria”) for various diagnoses, so that they can apply those diagnoses in a more consistent and reliable way. Every so often, those diagnostic criteria are reviewed and updated by experts in the field using the knowledge that’s been gathered in recent years. There were four important changes that came about with the DSM-5 during the most recent update: First, the DSM-IV, under the heading of Pervasive Developmental Disorders, included the sub-categorization of Autistic Disorder (AD), Asperger’s Disorder (ASP), and Pervasive Disorder-Not Otherwise Specified (PDD-NOS). Thus, children with autism features were grouped into one of three different sub-categories based on symptom presentation and their development early in life (e.g., whether they’d had delays in language development). In the DSM-5, a single diagnosis of Autism Spectrum Disorder (ASD) is used.

Second, the criteria within the autism diagnosis changed from three domains ([1] social interaction, [2] communication & [3] restricted repetitive and stereotyped behaviors) to two domains ([1] social communication and social interaction; [2] restricted, repetitive behaviors). This change reflects an understanding that difficulties or unique use of language may be a key part of social communication but also can be part of the restricted or repetitive profile of children with autism.

Third, sensory difficulties were included in the restricted, repetitive behaviors domain. As reviewed in Robertson & Baron-Cohen (2017), sensory difficulties have been a significant issue for individuals with autism for a long time, but in the past were considered secondary to the social differences and weren’t included in the diagnostic criteria. As part of the DSM-5, sensory traits are considered a core or primary issue in autism.

Lastly, severity of symptoms is now specified in the DSM-5. Why? From a research perspective, findings from a decade of research had suggested significant behavioral overlap in the DSM-IV subcategories, poor predictive relation between early diagnostic category and later ability, and there was little relation to treatment approach or genetic etiology.

A Prospective Study of the Concordance of DSM-IV and DSM-5 Diagnostic Criteria for Autism Spectrum Disorder

In the Mazurek et al. study, the authors investigate how the criteria from the DSM-5 (published in 2013) versus the DSM-IV (published in 1994) impacts eventual diagnosis. To do this, across multiple clinical locations, the authors enrolled 439 children (aged 2 to 18 years) who were receiving a (first time) autism diagnostic evaluation. The clinicians used a standard protocol for diagnosis across sites, which included the ADOS (Autism Diagnostic Observation Schedule, a standardized clinician-child interaction) and cognitive and adaptive skills evaluations. After all clinical information was collected, the clinician evaluated the child’s behaviors using the DSM-IV and DSM-5 diagnostic criteria. For each patient, some clinicians filled out the DSM-5 first, and others filled out the DSM-IV first.

In 93% of the cases, there was agreement between both versions of the DSM about whether the individual did or did not have a clinical diagnosis of autism. More specifically, for 248 patients, there was an agreement in both systems that the individual had autism; and for 160 patients, there was an agreement that the individual did not have autism. For children who received a diagnosis of Autistic Disorder (via the DSM-IV), there was a strong likelihood of being given a diagnosis of ASD (via the DSM-5).

Table 1. Concordance / Discordance for the DSM-IV and DSM-5 checklists

Total Patients



YES- Diagnosis of AD, ASP or PDD-NOS


NO- Diagnosis of AD, ASP or PDD-NOS


YES- Diagnosis of ASD




NO- Diagnosis of ASD



However, there were 31 patients where the DSM-IV and the DSM-5 did not agree, most were individuals who were diagnosed with the DSM-IV but not the DSM-5 (n=30). Children who were discordant for diagnosis were more likely to be older, score higher on IQ tests, or be female. Of the 30 children who met criteria on the DSM-IV but not DSM-5, many received other diagnoses. Alternative diagnoses included ADHD, Anxiety Disorder, Social Communication Disorder, and Global Developmental Delay or Intellectual Disability. In summary, agreement was very high overall, but individuals who might have been diagnosed with ASP or PDD-NOS under the DSM-IV, were less likely to receive an ASD diagnosis with the DSM-5.

One benefit of the DSM-5 was consistency across clinicians and sites. Both the Mazurek et al. study and another multisite study (Lord et al., 2012) suggest that it was difficult for clinicians to reliably decide between DSM-IV subcategories. That is, even highly trained clinicians, using the same evaluation measures, did not provide the same DSM-IV sub-diagnosis. One interpretation is that the DSM-5 criteria and lack of sub-categories is more reliable across clinical communities.

Does the DSM-5 change the criteria for the diagnosis autism? The simple answer is yes. But each update of the DSM has changed the diagnostic criteria for autism, and there has been substantial change from the first published case studies in the 40s to our current criteria. Ideally, each set of changes improves how the DSM works for clinicians, researchers, individuals with ASD and families so that it captures ASD more and more accurately.

Implementing the DSM-5 at Seattle Children’s Autism Center.

To find out more about the impact of the DSM-5, I’ve asked 3 of our clinical/research leaders to weigh in on how this has impacted their clinical practice and research programs.

(1) In moving from DSM-4 criteria to DSM-5 criteria, what has changed in your clinical assessments?

“I would say one change when I do clinical evaluations is the consideration of sensory differences in category of repetitive behaviors/restricted interests. Most impactful, I think, is the better characterization of individuals – getting rid of Asperger’s/PDD-NOS and adding the inclusion of with or without co-occurring intellectual disability and language impairment has been useful in communicating to the family and to other providers.” – Dr. Gary Stobbe

 “I agree with Dr. Stobbe about DSM-5 vs. DSM-IV. While individuals with PDD-NOS were grandfathered into DSM-5 ASD diagnosis, PDD NOS was applied very differently based on the clinician and the clinic.” – Dr. Soo Kim

(2) What have been the biggest challenges for families or advocates related to the diagnostic criteria change? 

“I think, on the negative side, has been in accessing services through the Developmental Disabilities Administration (DDA). With DSM-5, the DDA is now also requiring IQ criteria to access DDA services, which can be challenging. Although in some ways, DSM-5 it is an improvement, as the DDA did not accept the DSM-IV subcategories of PDD-NOS or Asperger’s.” – Dr. Gary Stobbe

 “I’d agree that the biggest issue is that state servicing guidelines currently don’t directly follow along with the DSM-5 and at times that can result in additional steps that have to be taken to access services.” – Dr. Raphael Bernier

 (3) Has the DSM-5 changed the way you do research?

“I’m not sure it has changed my research at all. Most research continues to use the ADOS (a clinician – patient interaction) and ADI (a clinician – parent interview) to confirm diagnosis, so there has been consistency in the “gold standard” measurement of autism symptoms. But the change has set the stage to think about subgrouping based on biology instead of further searching for behaviorally defined subgroups.” –Dr. Raphael Bernier

“In regards to research, depending on the type of study, changes in diagnosis criteria definitely impact on inclusion/exclusion. Who gets into research will change if you require participants to have a clinical diagnosis before enrollment. — Dr. Soo Kim



Science with Sara: Gastrointestinal Related Problems in Children with ASD

For this blog, I invite Dr. Emily Neuhaus (who also blogs under “Ask Dr. Emily”) to join me in talking about her recent paper — Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents with Autism Spectrum Disorder.

With Dr. Raphe Bernier (Executive Director of the Seattle Children’s Autism Center) and Dr. See Wan Tham (Anesthesiologist and specialist in GI pain management), we examined the relation between GI problems and other problem behaviors in children with ASD. To do this, we used the large Simon’s Simplex Sample (SSC) data set– which is a data set of 2,800 4 to 18 year old children and adolescents  with ASD, and includes detailed information about the child’s symptoms, adaptive functioning (ability to handle everyday tasks like getting dressed, eating, grooming, etc.), medical concerns, and genetic events. The paper is available free through Frontiers in Psychiatry.

Why examine the relation between GI symptoms and psychiatric problems? The actual prevalence of GI problems in children with autism varies wildly across different reports – some estimates are relatively low, suggesting that 15-20% of children with autism experience GI difficulties, while other researchers have found rates of GI problems as high as 90% (see Neuhaus et al., 2018). While the links between GI problems and ASD is unclear, it is clear that children with ASD have elevated rates of GI problems.

Individuals with ASD are also at elevated risk for developing additional psychiatric problems across the lifespan with over 92% of children aged 4-14 with ASD reported as meeting criteria for attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety, or mood disorder (Brookman-Frazee et al., 2018).

Given that GI problems can cause significant pain and disruption of daily activities, might they also be playing a role in whether or not children develop other psychiatric problems?

What are GI problems?

In the SSC sample data set, 7 GI problems were included in our analyses– constipation, diarrhea, severe abdominal pain, gastro-esophageal reflux, vomiting, excessive gas, and bloating. We limited our analysis to symptoms that occurred after 36 months of age, were recurrent, not attributed to illness, and caused “significant bother”. We examined psychiatric problems via parent report of internalizing (anxiety and depression), externalizing (aggression and rule breaking) and self-injurious behavior (e.g., biting or hitting self). (We will focus on externalizing and self-injury in this blog.) In addition, we considered child characteristics such as race/ethnicity, sex, age, extent of ASD symptoms, IQ (verbal and non-verbal), and adaptive behavior; as well as family factors such as household income.


 Overall, 37.7% of the children with ASD were reported as having at least 1 GI problem, including constipation (24.1%), diarrhea (10.6%), and gas, reflux, and abdominal pain (~5-6% each). Moreover, 22.8% of the children had clinical levels of externalizing problems (aggression and rule breaking), suggesting that these were meaningful issues for those children and their families.

 What childhood characteristics were related to externalizing problems (aggression and rule breaking) and self-injury? In children aged 4-18 years, children with more ASD symptoms, better language, lower adaptive skills, lower household income, and more GI problems had more externalizing problems (aggression and rule breaking). Similarly, more self-injurious behavior was also related to more ASD symptoms, lower adaptive skills, and lower household income. In the younger group (4 to 9 years) (but not in the older group aged 10 to 18 years), more GI problems were also related to self-injury.

 Of note, a similar study by Rattaz et al. in 106 young adults with ASD found that more autism symptoms and more GI problems predicted the development of more stereotypy behaviors in adulthood.

 Thus, in children with ASD, GI problems may be contributing to the presence of externalizing behaviors in children with ASD, and self-injury in younger children with ASD. This is important to consider in providing mental health care to children and families with ASD, since addressing GI problems could be a helpful part of reducing behavior problems.

While we can’t determine if GI problems play a role in whether or not a child will develop other psychiatric problems – we would need a longitudinal study to do this– GI problems likely negatively impact daily living and quality of life.


Another resource for an update on GI issues in ASD is the recent ASF podcast by Alycia Halladay.


Brookman-Frazee L, Stadnick N, Chlebowski C, Baker-Ericzén M, Ganger W. Characterizing psychiatric comorbidity in children with autism spectrum disorder receiving publicly funded mental health services. Autism. SAGE PublicationsSage UK: London, England; 2018 Nov;22(8):938–952. PMID: 28914082.

Halladay, A. (2018, Nov). Scientist know in their gut how the GI symptoms are linked to autism.

Neuhaus E, Bernier RA, Tham SW, Webb SJ. (2018). Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. Frontiers in Psychiatry. 9:515. PMCID: PMC6204460.

Rattaz C, Michelon C, Munir K, Baghdadli A. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. Journal of Intellectual Disability Research. Wiley/Blackwell (10.1111); 2018 Jul;62(7):637–649. PMID: 29797498.









Science with Sara and Dimitri – Media Use in Young Children with ASD

Welcome to Dr. Dimitri Christakis who joins me in writing today’s blog. Dr. Christakis is a noted expert in the effects of media use on child development and author of The Elephant in The Living Room: Make Television Work for Your Kids.

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Science with Sara and Karen: Prevalence of Autism in Females

On Friday June 8th 2018, the UW Center on Human Development and Disability supported the Collaborative Research Area Biological Basis of Autism Seminar on Females with Autism Spectrum Disorder: Behavior, Brain and Genetics. Speakers included Karen Barnes PhD , Tychele Turner PhD , and myself . For this Blog, I invited Karen Barnes to join me to discuss the updated rates of autism in females as well as sex differences in autism. Read full post »