Towards a blood based biomarker for autism?

By Matt Carey

When I attended IMFAR in 2011, the work of Eric Courchesne’s group at UCSD was highlited in the press conference . The main study highlighted was Abnormally Accelerated Development of Higher-Order Long-Distance Cerebral Tracts In ASD Infants and Toddlers, which was a structural (MRI) study of brains in autistic children.

Another study presented by Prof. Courchesne’s group at the conference was Blood-Based Transcriptomic Biomarker Profiles of Autistic Spectrum and Other Developmental Disorders. The results were intriguing: mRNA expression in the blood was different for autistics than either typically developing or developmentally disabled young children. The genes involved were related to mitotic cell cycle regulation as well as cerebral cortex development and other processes which might shed light on etiology. What was particularly intriguiing was the conclusion of the conference abstract:

[peripheral blood mononuclear cells] may serve as a useful tissue for deriving biomarker profiles of ASDs that are highly specific to particular neurodevelopmental disorders. Ongoing longitudinal analyses of these subjects will determine if these blood-based biomarker profiles fluctuate as symptom profiles change over time with intensive behavioral treatment.

In other words: these mRNA expressions might be specific enough to serve as a biomarker.

Blood-based gene expression signatures of infants and toddlers with autism.

Autism spectrum disorders (ASDs) are highly heritable neurodevelopmental disorders that onset clinically during the first years of life. ASD risk biomarkers expressed early in life could significantly impact diagnosis and treatment, but no transcriptome-wide biomarker classifiers derived from fresh blood samples from children with autism have yet emerged.
Using a community-based, prospective, longitudinal method, we identified 60 infants and toddlers at risk for ASDs (autistic disorder and pervasive developmental disorder), 34 at-risk for language delay, 17 at-risk for global developmental delay, and 68 typically developing comparison children. Diagnoses were confirmed via longitudinal follow-up. Each child’s mRNA expression profile in peripheral blood mononuclear cells was determined by microarray.
Potential ASD biomarkers were discovered in one-half of the sample and used to build a classifier, with high diagnostic accuracy in the remaining half of the sample.
The mRNA expression abnormalities reliably observed in peripheral blood mononuclear cells, which are safely and easily assayed in infants, offer the first potential peripheral blood-based, early biomarker panel of risk for autism in infants and toddlers. Future work should verify these biomarkers and evaluate whether they may also serve as indirect indices of deviant molecular neural mechanisms in autism.

The published study follows the conservative approach of the IMFAR abstract: the title is not focused on the potential for this discovery to be used as a biomarker, but the conclusions point out that this is a possibility. Had I not been watching for published studies such as this from Prof. Courchesne’s group, I might have passed over this abstract after reading the title.

Autism is currently diagnosed based on behaviors. Because of this many autistics are missed. For example, the CDC autism prevalence estimates identify individuals who previously were undiagnosed, and the median age of diagnosis in the recent study from Sweden was 8 years old. A blood based biomarker would be very helpful in helping to provide therapies and supports to autistics from an early age.

Prof Courchesne has worked as a grant reviewer for the Autism Science Foundation.

Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity

By Matt Carey

The prevalence of autim spectrum disorders in Sweden is estimated at about 1% (1.15%) based on a study just released using the Stockholm Youth Cohort. This prevalence is consistent with current estimates in the U.S. and the U.K., and with a subset of the population from a previous Swedish study. Autism prevalence is relatively flat with age, especially for children born in the 1990’s.

Most autism prevalence data is from Europe and the United States, with the U.S. as the largest source of data. CDC prevalence estimates are reported every two years. CDC estimates use a record-review methodology. While this methodology has its own limitations, including likely underestimating autism prevalence, relying upon administrative registries (such as the California Department of Developmental Services datasets or medical registries) are likely to give an even greater underestimation of autism prevalence. A whole-population approach, such as that used in a recent study of autism prevalence in Korea, should give the most accurate estimates, but are more costly to perform and typically limited to the number of study subjects.

The recent study presents autism prevalence in Sweden, using the Stockholm Youth Cohort (a medical registry). The paper, Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity, is in the journal PLoS ONE, which means the full article is available online.

A previous report, from 2006, gave the prevalence of autistic disorder in Sweden (from data in 2001) at 20.5 per 10,000, with other ASD’s at 32.9 per 10,000. This for a population born from 1977-1994. The prevalence in the youngest population in the study (7-12 years old at time of the study) was 1.23%. Yes, 1.23% for kids born in 1989-1994. That’s a prevalence comparable to the recent CDC estimate for U.S. kids born in 2000.

Back to the present Sweden study. The authors note the potential problem with using medical registries:

Furthermore, Scandinavian studies have frequently ascertained ASD cases via health care registries [8], [9], [10], [11]. This approach may underestimate the prevalence of ASD, since affected children require social and educational interventions more often than health care.

Stockholm county has a very active surveillance program:

All ASD related services, including diagnosis and follow-up health, special educational and social care are provided by services run by, or contracted with the Stockholm County Council and available free of charge. Referrals for diagnostic evaluation of suspected ASD are commonly made by child healthcare centres, whose health- and developmental surveillance program engages 99.8% of all preschool children [15]. Developmental surveillance is performed by specially trained child healthcare centre nurses at regular intervals (1, 2, 6, 10–12, 18, 36, 48 and 60 months of age), with examination by a paediatrician at key ages (2, 6, 10–12 months) and in case of developmental deviation or according to need at other age intervals. Speech abilities and language comprehension are evaluated by nurses at 36 and 48 months, and examination of sight and hearing is made at 48 months.

Interestingly, even with this tight surveillance effort, the median age of diagnosis is 8. Children with intellectual disability were identified as autistic earlier. Girls were identified later.

Where such information was available (n = 148), the median age at diagnosis was 8.0 years for ASD overall (range 1–19, interquartile range [IQR] 8.0). For cases without and with intellectual disability (n = 80 and 68), the corresponding ages were 11.5 (range 4–19, IQR 6.0) and 6.0 (range 1–17, IQR 4.0) years. Girls (n = 48) were older than boys (n = 100) at diagnostic assessment (median age 11.0 as compared to 8.0 years).

The authors were able to test the validity of the diagnoses by checking on a subset of autistic children (starting from a sample of 100 with and 100 without intellectual disability). The researchers were able to check records on 85% of this subset, and 96% of the records checked were consistent with a diagnosis of ASD.

Unlike U.S. CDC prevalence estimates, this study gives prevalence estimates for a range of ages. The graph below (and larger here) is part of Figure 1 from the study:

The prevalence is given for children born between 1983 and 2003, with a peak ASD prevalence of about 1.5% for children born between 1990 and 1997. Lower autism prevalence for younger children is likely due to underdiagnosis: the average age of diagnosis being about 8. The lower prevalence for older autistics is possibly due to “key registers used for case ascertainment only being started in 1997 and 2001, respectively, may have deflated the observed ASD prevalence among older children.”

For those interested in how this ties into the failed notion of thimerosal causing an autism epidemic: Swedish children had low exposures to thimerosal in the 1980’s and it was phased out in 1993. The flat prevalence though the 1990’s speaks strongly against the notion. In fact, the data, especially for autistics without intellectual disability, speaks against a strong rise in autism prevalence, especially during the 1990’s.

The prevalence of ASD without intellectual disability is higher than that with ID throughout the entire age range of the study. The Male:Female ratio (not shown in the graph above) changes with age. It is often about 4-5 to 1, with males predominant. For the older individuals, the ratio decreased from 5.1:1 at age 8 to 1.9:1 at age 18.

What’s most important is that this is only the first report on the autistics in the Stockholm Youth Cohort. The researchers now have a cross section of ages to work with to look at outcomes, risk factors and other studies.

Here is the abstract for the study:

Reports of rising prevalence of autism spectrum disorders (ASD), along with their profound personal and societal burden, emphasize the need of methodologically sound studies to explore their causes and consequences. We here present the design of a large intergenerational resource for ASD research, along with population-based prevalence estimates of ASD and their diagnostic validity.

The Stockholm Youth Cohort is a record-linkage study comprising all individuals aged 0–17 years, ever resident in Stockholm County in 2001–2007 (N = 589,114). ASD cases (N = 5,100) were identified using a multisource approach, involving registers covering all pathways to ASD diagnosis and care, and categorized according to co-morbid intellectual disability. Prospectively recorded information on potential determinants and consequences of ASD were retrieved from national and regional health and administrative registers. Case ascertainment was validated through case-note review, and cross validation with co-existing cases in a national twin study.

The 2007 year prevalence of ASD in all children and young people was 11.5 per 1,000 (95% confidence interval 11.2–11.8), with a co-morbid intellectual disability recorded in 42.6% (41.0–44.2) of cases. We found 96.0% (92.0–98.4) of reviewed case-notes being consistent with a diagnosis of ASD, and confirmed ASD in 85.2% (66.2–95.8) of affected twins.

Findings from this contemporary study accords with recently reported prevalence estimates from Western countries at around 1%, based on valid case ascertainment. The Stockholm Youth Cohort, in light of the availability of extensive information from Sweden’s registers, constitutes an important resource for ASD research. On-going work, including collection of biological samples, will enrich the study further.

Grants will fund pre- and post-doctoral autism research fellowships

Today we opened our applications process for the 2013 Pre- and Post-doctoral Training Awards for graduate students, medical students and postdoctoral fellows interested in pursuing careers in basic and clinical research relevant to autism spectrum disorders. In the past three years, ASF has funded over $700,000 in pre- and post-doctoral grants.

“Pre- and post-doctoral fellowships not only build our knowledge about what causes autism and how best to treat it, but also build our future by encouraging outstanding young investigators to dedicate their careers to autism research,” said Alison Singer, president of ASF.

“We are so grateful to all our donors and volunteers who have come together to support autism research and who make these grants possible,” said Karen London, co-founder of ASF.

The proposed training must be scientifically linked to autism. ASF will consider for training purposes all areas of related basic and clinical research including but not limited to:

  • Human behavior across the lifespan (language, learning, communication, social function, epilepsy, sleep, repetitive disorders)
  • Neurobiology (anatomy, development, neuro-imaging)
  • Pharmacology
  • Neuropathology
  • Human genetics/genomics
  • Immunology
  • Molecular and cellular mechanisms
  • Studies employing model organisms and systems
  • Studies of treatment and service delivery

Applications must be received by November 16, 2012. Additional information about the RFA can be found at

Grant applications will be reviewed by members of ASF’s Science Advisory Board (SAB) and other highly qualified reviewers. Current SAB members include Dr. Joseph Buxbaum (Mt. Sinai School of Medicine); Dr. Emanuel DiCicco-Bloom (UMDNJ-Robert Wood Johnson Medical School); Dr. Sharon Humiston (University of Rochester); Dr. Bryan King (University of Washington, Seattle); Dr. Ami Klin (Emory University); Dr. Harold Koplewicz (The Child Mind Institute); Dr. Eric London (New York Institute for Basic Research); Dr. Catherine Lord (New York Center for Autism and the Developing Brain); Dr. David Mandell (University of Pennsylvania/CHOP); Dr. Kevin Pelphrey (Yale Child Study Center) and Dr. Matthew State (Yale Medical School).

To learn more about the ASF’s grant programs, and to read about projects funded through this mechanism in prior years, visit

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