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Neurodevelopmental disorders:
Why do they co-occur?
Dorothy Bishop
Wellcome Principal Research Fellow
Department of Experi...
2
Meanings of ‘neurodevelopmental
disorder’
 Neurological disorders with known prenatal
cause (genetic or acquired)
• e.g...
3
Common characteristics of
neurodevelopmental disorders
 Defined in terms of behaviour
 Often use medical terminology, ...
Distinct disorders?
Kaplan et al, 2001
Developmental co-ordination
disorder, 17%
ADHD, 65%
Dyslexia, 70%
“Comorbidity is the rule, not the exc...
Dyck, M. J., et al. (2011). The validity of psychiatric diagnoses: The case of 'specific'
developmental disorders. Researc...
Typical
Autism
MR
SLI
DCD
ADHD
Dyck et al: Discriminant function analysis
A non-causal explanation:
Ascertainment bias
Language
Motor
Population
sample
needed to
test if
association
is true
Likeli...
Genuine association:
Needs causal explanation
Reading
Motor
r = .25
e.g., Brookman, A., et al (2013). Fine motor deficits ...
Motor
impairment
Reading
impairment
Motor
impairment
Reading
impairment
Q1: Why are disorders associated?
• Generally, sim...
Motor
impairment
Reading
impairment
Motor
impairment
Reading
impairment
Factor
X
Motor
impairment
Reading
impairment
Q1: W...
12
Q2: At what level is the overlap?
Bishop, D., & Rutter, M. (2008). Neurodevelopmental disorders: conceptual issues. In ...
How to distinguish causal accounts?
 Better measures of phenotype – get at
common underlying cognitive processes
 Use fa...
Autism spectrum disorder (ASD)
Autistic disorder: impairments in:
 Communication
 Social interaction
 Behavioural reper...
Specific language impairment (SLI)
 Diagnosed in children when language
does not follow normal developmental
course
 Not...
Good ‘markers’ of SLI
Measures which are sensitive to SLI, and heritable
• Nonword repetition
Child listens to spoken nonw...
Evidence that aetiology is complex and
multifactorial in autism and SLI
i.e. Combined effect of many genes and
environment...
Traditional view: two separate disorders
risk
factors
Y
ASDSLI
-liability X
risk
factors
X
-liability Y
18
Predictions: independent disorders model
• Children with ASD and SLI together
should be vanishingly rare:
• SLI prevalence...
• Many children with ASD have language problems similar to SLI:
Kjelgaard & Tager-Flusberg (2003): poor nonword repetition...
Key question
ASD and LI can be dissociated
Yet they co-occur far more often than by chance
Conventional wisdom of independ...
Correlated risk factors
Some possible reasons for correlation:
• Same gene influences both liabilities (pleiotropy)
• Gene...
But nonword repetition shows
different pattern in relatives
• In SLI, nonword repetition deficit is
clearly familial (e.g....
Shared genetic risk? CNTNAP2
CNTNAP2 gene; polymorphic gene, neurexin, regulated
by FOXP2.
Common variant associated with ...
Alternative genetic
explanation
G x G interaction (epistasis)
25
25
Bishop, D. V. M. (2010). Overlaps between autism and l...
Overview of G x G model
• Common variant of gene such as CNTNAP2
creates mild risk for poor nonword repetition
• Other gen...
Evaluation of G x G model
• Predicts high frequency of comorbid ASD + LI
• Predicts lower rate of LI symptoms in relatives...
risk
factors
Y
-liability Y
ASDSLI
-liability X
risk
factors
X
Phenomimicry model
• Primary form of disorder, each with ow...
Evidence for phenomimicry
Different error patterns for ASD+LI cf. SLI on tests
of nonword repetition and verb inflection
2...
Remaining puzzle:
Why do only a subset of ASD have LI?
30
Not down to severity
Lindgren et al found language in ASD cases ...
The terminological jungle
Overlap in neurodevelopmental disorders
Clinical implications
ASD
SLI
Dyslexia
DCD ADHD
Same child, different diagnosis
 Educational psychologist: Dyslexia
 Speech and language therapist: SLI
 Psychiatrist: ...
Implications of terminological confusion
• Children’s needs may go unmet
• Arbitrary and unfair decisions about access to
...
35
Amount of research (1985-2009) and
prevalence of neurodevelopmental disorders
Condition
papers
/year
freq.
%
Tourette s...
36
NIH funding over time for
neurodevelopmental disorders
$K
0
100000
200000
300000
400000
500000
600000
700000
800000
900...
One alternative
 Broad category of ‘neurodevelopmental disability’ to
establish need for services
 ‘Disability’ emphasis...
Raising Awareness of Language Learning Impairments
http://www.youtube.com/RALLIcampaign
Dorothy Bishop
Oxford Study of Children’s
Communication Impairments,
Department of Experimental
Psychology,
South Parks Ro...
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Why do neurodevelopmental disorders co-occur?

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Slides from talk given at University of Leeds, Psychology Dept., Grand Research Challenge Series, 24th March 2014

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Transcript of "Why do neurodevelopmental disorders co-occur?"

  1. 1. Neurodevelopmental disorders: Why do they co-occur? Dorothy Bishop Wellcome Principal Research Fellow Department of Experimental Psychology University of Oxford
  2. 2. 2 Meanings of ‘neurodevelopmental disorder’  Neurological disorders with known prenatal cause (genetic or acquired) • e.g. Williams syndrome, fetal alcohol syndrome  Disorders where abnormal neurodevelopment is inferred: actual cause is complex or unknown • e.g. developmental dyslexia, autistic disorder, specific language impairment (SLI), developmental coordination disorder (DCD), developmental dyscalculia, ADHD
  3. 3. 3 Common characteristics of neurodevelopmental disorders  Defined in terms of behaviour  Often use medical terminology, drawing parallel with acquired disorders  Tend to run in families  No single biological cause  Male preponderance in most
  4. 4. Distinct disorders?
  5. 5. Kaplan et al, 2001 Developmental co-ordination disorder, 17% ADHD, 65% Dyslexia, 70% “Comorbidity is the rule, not the exception” (Gilger & Kaplan, 2001) • Sample of 179 children and families recruited from clinics, special schools • All had dyslexia and/or ADHD • Comprehensive assessment for ADHD, dyslexia, DCD, and psychiatric disorders Kaplan, B. J., et al (2001). The term comorbidity is of questionable value in reference to developmental disorders: data and theory. Journal of Learning Disabilities, 34, 555-565.
  6. 6. Dyck, M. J., et al. (2011). The validity of psychiatric diagnoses: The case of 'specific' developmental disorders. Research in Developmental Disabilities, 32(6), 2704-2713. 608 children aged 3 – 14 years  449 Typically-developing  30 Autism spectrum disorder (ASD)  24 Mental retardation (MR)  30 Receptive-expressive language disorder (SLI)  22 Developmental co-ordination disorder (DCD)  53 Attention deficit hyperactivity disorder (ADHD)  Assessments of IQ, language, motor, attention, social cognition, executive function Western Australian study Murray Dyck
  7. 7. Typical Autism MR SLI DCD ADHD Dyck et al: Discriminant function analysis
  8. 8. A non-causal explanation: Ascertainment bias Language Motor Population sample needed to test if association is true Likelihood of referral
  9. 9. Genuine association: Needs causal explanation Reading Motor r = .25 e.g., Brookman, A., et al (2013). Fine motor deficits in reading disability and language impairment: same or different? PeerJ. doi: 10.7717/peerj.217
  10. 10. Motor impairment Reading impairment Motor impairment Reading impairment Q1: Why are disorders associated? • Generally, simple causal model doesn’t work • Too many cases of dissociation • Also, in this case, implausible
  11. 11. Motor impairment Reading impairment Motor impairment Reading impairment Factor X Motor impairment Reading impairment Q1: Why are disorders associated?
  12. 12. 12 Q2: At what level is the overlap? Bishop, D., & Rutter, M. (2008). Neurodevelopmental disorders: conceptual issues. In M. Rutter et al (Eds.), Rutter's Child and Adolescent Psychiatry (pp. 32-41).Blackwell.
  13. 13. How to distinguish causal accounts?  Better measures of phenotype – get at common underlying cognitive processes  Use family data: can test whether disorders “breed true”  Training study Example: Autistic spectrum disorder and Specific Language Impairment
  14. 14. Autism spectrum disorder (ASD) Autistic disorder: impairments in:  Communication  Social interaction  Behavioural repertoire 14
  15. 15. Specific language impairment (SLI)  Diagnosed in children when language does not follow normal developmental course  Not due to hearing loss, physical abnormality, acquired brain damage  Normal development in other areas  Problems with language structure (phonology and syntax) common
  16. 16. Good ‘markers’ of SLI Measures which are sensitive to SLI, and heritable • Nonword repetition Child listens to spoken nonwords and repeats, e.g. 2 syllables: hampent 3 syllables: dopelate 4 syllables: confrantually 5 syllables: pristoractional • Verb inflectional morphology “Here’s a farmer. Tell me what a farmer does” Measures of language form, rather than content/use
  17. 17. Evidence that aetiology is complex and multifactorial in autism and SLI i.e. Combined effect of many genes and environmental risks  Disorders aggregate but do not segregate in families  Unaffected relatives of affected individuals may show mild or partial symptoms  High heritability in twin studies, yet genome scans have revealed few single gene causes  Relatively common disorders affecting reproductive success, yet persist in population 17
  18. 18. Traditional view: two separate disorders risk factors Y ASDSLI -liability X risk factors X -liability Y 18
  19. 19. Predictions: independent disorders model • Children with ASD and SLI together should be vanishingly rare: • SLI prevalence 7% • ASD prevalence 1% • Predicts comorbid 7 per 10,000 19 ASD SLI
  20. 20. • Many children with ASD have language problems similar to SLI: Kjelgaard & Tager-Flusberg (2003): poor nonword repetition and use of verb inflections; 76% ASD with LI Loucas et al (2008): epidemiological sample, cases with ASD and normal nonverbal IQ & impaired performance on a language battery: 57% (41 of 72) ASD with LI High comorbidity between ASD and language impairment (LI) 20 Kjelgaard, M. M., & Tager-Flusberg, H. (2001). An investigation of language impairment in autism: Implications for genetic subgroups. Language and Cognitive Processes, 16, 287-308. Loucas, T. et al. (2008). Autistic symptomatology and language ability in autism spectrum disorder and specific language impairment. [Article]. Journal of Child Psychology and Psychiatry, 49(11), 1184-1192. doi: 10.1111/j.1469-7610.2008.01951.x
  21. 21. Key question ASD and LI can be dissociated Yet they co-occur far more often than by chance Conventional wisdom of independent disorders seems wrong How to explain? 21?
  22. 22. Correlated risk factors Some possible reasons for correlation: • Same gene influences both liabilities (pleiotropy) • Genes close together on same chromosome (linkage) • Correlated environmental factors (e.g. poverty) • Non-random (assortative) mating risk factors Y ASDSLI -liability X risk factors X -liability Y r 22
  23. 23. But nonword repetition shows different pattern in relatives • In SLI, nonword repetition deficit is clearly familial (e.g. Barry et al, 2007) • In autism, where child is poor at nonword repetition, parents and sibs are not 23 Barry, J. G., Yasin, I., & Bishop, D. V. M. (2007). Heritable risk factors associated with language impairments. Genes, Brain and Behavior, 6, 66-76. Bishop, D. V. M., et al (2004). Are phonological processing deficits part of the broad autism phenotype? American Journal of Medical Genetics: Neuropsychiatric Genetics, 128B(54-60). Whitehouse, A. J. O., et al (2008). Further defining the language impairment of autism: Is there a specific language impairment subtype? Journal of Communication Disorders, 41, 319-336. Lindgren, K. A.,et al (2009). Language and reading abilities of children with autism spectrum disorders and specific language impairment and their first-degree relatives. Autism Research, 2(1),
  24. 24. Shared genetic risk? CNTNAP2 CNTNAP2 gene; polymorphic gene, neurexin, regulated by FOXP2. Common variant associated with risk of neurodevelopmental problems • Alarcon et al, 2008; assoc with late language in ASD • Vernes et al, 2008: assoc with nonword repetition in children with SLI • Li et al, 2010: autism association in Chinese Han • Steer et al, 2010; assoc with late lang acquisition • Whitehouse et al, 2011; assoc with delayed language milestones in gen pop. sample but NB very small effect sizes! 24Graham, S. A., & Fisher, S. E. (2013). Decoding the genetics of speech and language. Current Opinion in Neurobiology(0). doi: http://dx.doi.org/10.1016/j.conb.2012.11.006
  25. 25. Alternative genetic explanation G x G interaction (epistasis) 25 25 Bishop, D. V. M. (2010). Overlaps between autism and language impairment: phenomimicry or shared etiology. Behavior Genetics, 40, 618-629.
  26. 26. Overview of G x G model • Common variant of gene such as CNTNAP2 creates mild risk for poor nonword repetition • Other genes have risk variants that contribute to autism • If CNTNAP risk variant occurs together with certain ASD risk genes, effect on language much more severe 26
  27. 27. Evaluation of G x G model • Predicts high frequency of comorbid ASD + LI • Predicts lower rate of LI symptoms in relatives of ASD+LI than relatives of SLI • Fits with current move to look at gene networks rather than individual genes • Predicts molecular genetic overlaps 27
  28. 28. risk factors Y -liability Y ASDSLI -liability X risk factors X Phenomimicry model • Primary form of disorder, each with own cause, but also secondary form that mimics the other disorder. • Crucially, does NOT predict  SLI in relatives of those with ASD+LI 28 LI
  29. 29. Evidence for phenomimicry Different error patterns for ASD+LI cf. SLI on tests of nonword repetition and verb inflection 29 Williams, D., Botting, N., & Boucher, J. (2008). Language in autism and specific language impairment: Where are the links? Psychological Bulletin, 134(6), 944-963. doi: 10.1037/a0013743 From Whitehouse et al (2008)
  30. 30. Remaining puzzle: Why do only a subset of ASD have LI? 30 Not down to severity Lindgren et al found language in ASD cases was not correlated with ASD symptoms measured by ADI-R communication social repetitive normal language language impaired Lindgren, K. A., et al (2009). Language and reading abilities of children with autism spectrum disorders and specific language impairment and their first- degree relatives. Autism Research, 2(1), 22-38.
  31. 31. The terminological jungle
  32. 32. Overlap in neurodevelopmental disorders Clinical implications ASD SLI Dyslexia DCD ADHD
  33. 33. Same child, different diagnosis  Educational psychologist: Dyslexia  Speech and language therapist: SLI  Psychiatrist: Autism spectrum disorder (ASD)  Neurologist: Developmental co-ordination disorder (DCD)  Paediatrician: ADHD
  34. 34. Implications of terminological confusion • Children’s needs may go unmet • Arbitrary and unfair decisions about access to services • Lack of recognition of some conditions 34
  35. 35. 35 Amount of research (1985-2009) and prevalence of neurodevelopmental disorders Condition papers /year freq. % Tourette syndrome 83 0.5 Autistic spectrum disorder 643 0.7 Developmental dyscalculia 9 3.0 Attention deficit hyperactivity disorder 505 5.0 Developmental dyslexia 152 6.0 Developmental coordination disorder 16 6.5 Specific language impairment 46 7.4 Data from: Bishop, D. V. M. (2010). Which neurodevelopmental disorders get researched and why? PLOS One, 5(11), e15112. doi: 10.1371/journal.pone.0015112
  36. 36. 36 NIH funding over time for neurodevelopmental disorders $K 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 2000- 2001 2002- 2003 2004- 2005 2006- 2007 2008- 2009 Attention deficit hyperactivity disorder Autistic spectrum disorder Dyslexia/SLI/speech /dyscalc/DCD Data from: Bishop, D. V. M. (2010). Which neurodevelopmental disorders get researched and why? PLOS One, 5(11), e15112. doi: 10.1371/journal.pone.0015112
  37. 37. One alternative  Broad category of ‘neurodevelopmental disability’ to establish need for services  ‘Disability’ emphasises impact on individual  ‘Neurodevelopmental’ emphasises biological basis: not just poor teaching  Supplemented with assessment to establish profile of difficulties/strengths on different dimensions, and determine which services to prioritise http://deevybee.blogspot.com.au/2010/12/whats-in-name.html
  38. 38. Raising Awareness of Language Learning Impairments http://www.youtube.com/RALLIcampaign
  39. 39. Dorothy Bishop Oxford Study of Children’s Communication Impairments, Department of Experimental Psychology, South Parks Road, Oxford, OX1 3UD, England. dorothy.bishop@psy.ox.ac.uk @deevybee
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