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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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