Overview of studies in ASD - internal presentation to staff at Ron Joyce Children's Health Centre

1. Olaf Kraus de Camargo
@DevPeds
Update on ASD Research
April 25th 2016
1

2. Disclaimer
This is a biased selection based on my
non-systematic readings, clinical
practice and small involvement in some
of the studies without any financial gains
2

3. First: some definitions!
• Statistically Significant: usually means that the chance that an observed effect is related to an
intervention is at least 95% - it does not tell if this effect is big or small!
• Clinically Significant: describes how meaningful is the effect
• Evidence level: refers to the type of studies done to describe a certain effect and the likelihood that
the results can be trusted.
• Randomized: it is a lottery to determine which child gets which treatment
• Double-blind: neither patient/caregiver nor experimenter knows who is being treated
3

4. 4
Causes for ASD
Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE:
The third Birgit Olsson lecture. Nord. J. Psychiatry 9488, 1–9.
doi:10.3109/08039488.2015.1042519
Genetic: 600 -700 candidate genetic
alterations
“The recent advances in genomics have
demonstrated that an identical genetic
variant may increase the risk for a wide
range of diagnoses formerly thought of as
distinct”

5. 5
ASD & Genes
Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE:
The third Birgit Olsson lecture. Nord. J. Psychiatry 9488, 1–9.
doi:10.3109/08039488.2015.1042519

6. 6
ASD & Genes &…...
Zhao, Y., Castellanos, F.X., 2016. Annual Research Review: Discovery science strategies in studies of the pathophysiology of child
and adolescent psychiatric disorders: promises and limitations. J. Child Psychol. Psychiatry n/a–n/a. doi:10.1111/jcpp.12503

7. 7
ASD & Prematurity

8. 8
ASD & Prematurity

9. 9
International Classification of
Functioning, Disability and Health (WHO)

10. 10
Research Domain Criteria (NIH)
Domain Genes Cells Circuits Physiology Behaviour SelfReport Paradigm
Negative
Valence
Systems
Positive
Valence
Systems
Cognitive
Systems
Systems for
Social
Processes
Arousal and
Regulatory
Systems
Environment
Development
https://www.nimh.nih.gov/research-priorities/rdoc/index.shtml
Body Functions and Body Structures
Activities and
Participation
Environmental
Factors

11. Omega-3-fatty acid
supplementation
“To date there is no high quality
evidence that omega-3 fatty acids
supplementation is effective for
improving core and associated
symptoms of ASD.”
Two double-blind randomized trials - 37 patients
2011
11

12. Gluten-free, Casein-free Diet
“Evidence to date on the effectiveness of
gfcf-d for children with ASD has been
inconclusive due to methodologic
limitations. Preliminary data suggest there
may be a subgroup of children with ASD
who respond to a gfcf-d.”
Many low quality studies, only two
double-blind randomized trials
12

13. Social Groups
“There is some evidence that
social skills groups can
improve social competence
for some children and
adolescents with ASD.”
Five randomized controlled studies, only
children and adolescents with IQ > 70
(196 participants)
13

14. Risperidone
“There is some limited evidence of
efficacy of risperidone reducing
aggression and conduct problems in
children aged 5 to 18 with disruptive
behaviour disorders in the short term.
For aggression, the difference in scores
of 6.49 points on the ABC Irritability
subscale (range 0 to 45) may be
clinically significant. For conduct
problems, the difference in scores of
8.61 points on the NCBRF-CP (range 0
to 48) is likely to be clinically
significant.”Eight randomized controlled trials, over 200 patients
14

15. Melatonin
“Melatonin administration in
ASD is associated with
improved sleep parameters,
better daytime behavior, and
minimal side effects.”
Five randomized double-blind studies
15

16. IBI
“We found that children receiving
the EIBI treatment performed
better than children in the
comparison groups after about
two years of treatment on tests of
adaptive behavior (behaviors that
increase independence and the
ability to adapt to one’s
environment), intelligence, social
skills, communication and
language, autism symptoms, and
quality of life. The evidence
supports the use of EIBI for some
children with ASD. However, the
quality of this evidence is low as
only a small number of children
were involved in the studies and
only one study randomly assigned
children to groups.”
One randomized trial, four non-
randomized trials, 203 children
16

17. Joint Attention
17
• Analyzed 16 studies
• About 750 children
• Different approaches were analyzed
(behavioural and developmental)
• No RCT’s

18. Joint Attention
18
• The results of this meta-analysis provide strong support for explicit
joint attention interventions for young children with ASD with most
comparisons showing a statistically significant 2/3 standard
deviation treatment effect increase for the experimental group
compared with the control/comparison group.
• No specific type of approach was superior

19. Research at Mac & HHS
19
• Riluzole: is a substance that reduces the action
of glutamate on synapses in the brain
• Has been proposed in ALS, Alzheimer,
Depression, Anxiety
• Has been used in a multi-site trial in adolescents
with ASD
• Data collection is finished, Analysis is in
progress

20. Research at Mac & HHS
20
• Tideglusib: is a substance that reduces the
action of an enzyme (GSK-3β) identified as
modulating pathways and reversing symptoms
in animal models of fragile-X and congenital
myotonic dystrophy
• Recruitment is ongoing (multi-site trial): 12-17
years old with ASD
• Double-blind, placebo-controlled, randomized
study

21. Research at Mac & HHS
21

22. Research at Mac & HHS
22
• Why is this important?
• Is a meaningful concept for ASD as it
focusses on a core symptom (not IQ)
• Better description of level of functioning
• Opens the possibility to compare data from
different studies
• Will help to identify what works for which
children and what does not work!

23. 23
Conclusion
• Different types of lesions and exposures to the
brain can result in similar behavioural
manifestations
• Despite decades of high level basic research we
still lack effective treatments for the majority of
children with ASD
• ASD is an example for a spectrum condition -
case-control studies are difficult to replicate –
need for better description of study populations

24. 24
Conclusion
• Understanding complex systems requires
“explorative science” (Big Data)
• Effective treatment of spectrum conditions
requires a personalized approach
• Future developments will depend on close
cooperations between basic sciences, clinical
research, clinical practice and patients with their
families
macautism.ca

25. 25
References
1.Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture. Nord. J. Psychiatry 9488,
1–9. doi:10.3109/08039488.2015.1042519
2.Zhao, Y., Castellanos, F.X., 2016. Annual Research Review: Discovery science strategies in studies of the pathophysiology
of child and adolescent psychiatric disorders: promises and limitations. J. Child Psychol. Psychiatry n/a–n/a.
doi:10.1111/jcpp.12503
3.Kuzniewicz, M.W., Wi, S., Qian, Y., Walsh, E.M., Armstrong, M.A., Croen, L. a., 2014. Prevalence and neonatal factors
associated with autism spectrum disorders in preterm infants. J. Pediatr. 164, 20–25. doi:10.1016/j.jpeds.2013.09.021
4.Webb, S.J., 2014. Neonatal factors associated with autism spectrum disorders in infants. Evid. Based. Ment. Health 17, 106–
106. doi:10.1136/eb-2014-101763
5.James, S., Montgomery, P., Williams, K., 2011. Omega-3 fatty acids supplementation for autism spectrum disorders (ASD).
Cochrane Database Syst Rev Cd007992. doi:10.1002/14651858.CD007992.pub2
6.Reichow, B., Barton, E.E., Boyd, B.A., Hume, K., 2012. Early intensive behavioral intervention (EIBI) for young children with
autism spectrum disorders (ASD). Cochrane Database Syst Rev 10, Cd009260. doi:10.1002/14651858.CD009260.pub2
7.Dosman, C., Adams, D., Wudel, B., Vogels, L., Turner, J., Vohra, S., 2013. Complementary, holistic, and integrative medicine:
autism spectrum disorder and gluten- and casein-free diet. Pediatr Rev 34, e36–41. doi:10.1542/pir.34-10-e36
8.Reichow, B., Steiner, A.M., Volkmar, F., 2013. Cochrane review: social skills groups for people aged 6 to 21 with autism
spectrum disorders (ASD). Evid Based Child Heal. 8, 266–315. doi:10.1002/ebch.1903
9.Reichow, B., Barton, E.E., Boyd, B.A., Hume, K., 2012. Early intensive behavioral intervention (EIBI) for young children with
autism spectrum disorders (ASD). Cochrane Database Syst Rev 10, Cd009260. doi:10.1002/14651858.CD009260.pub2
10.Loy, J.H., Merry, S.N., Hetrick, S.E., Stasiak, K., 2012. Atypical antipsychotics for disruptive behaviour disorders in children
and youths. Cochrane Database Syst Rev 9, Cd008559. doi:10.1002/14651858.CD008559.pub2
11.Rossignol, D.A., Frye, R.E., 2011. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med
Child Neurol 53, 783–792. doi:10.1111/j.1469-8749.2011.03980.x
12.Wainer, A.L., Hepburn, S. & McMahon Griffith, E., 2016. Remembering Parents in Parent-Mediated Early Intervention:
An Approach to Examining Impact on Parents and Families. Autism, March 7(Online), pp.1–13.
13.Murza, K.A. et al., 2016. Joint attention interventions for children with autism spectrum disorder: a systematic review and
meta-analysis. International Journal of Language & Communication Disorders, p.n/a–n/a.
Collection of ASD papers: https://www.mendeley.com/groups/8628801/asd/