Why do neurodevelopmental disorders co-occur?
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Why do neurodevelopmental disorders co-occur?



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

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? Why do neurodevelopmental disorders co-occur? Presentation Transcript

    • Neurodevelopmental disorders: Why do they co-occur? Dorothy Bishop Wellcome Principal Research Fellow Department of Experimental Psychology University of Oxford
    • 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 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
    • Distinct disorders?
    • 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.
    • 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
    • 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 Likelihood of referral
    • 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
    • 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
    • Motor impairment Reading impairment Motor impairment Reading impairment Factor X Motor impairment Reading impairment Q1: Why are disorders associated?
    • 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.
    • 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
    • Autism spectrum disorder (ASD) Autistic disorder: impairments in:  Communication  Social interaction  Behavioural repertoire 14
    • 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
    • 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
    • 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
    • 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 7% • ASD prevalence 1% • Predicts comorbid 7 per 10,000 19 ASD SLI
    • • 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
    • 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?
    • 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
    • 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),
    • 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
    • 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.
    • 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
    • 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
    • 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
    • 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)
    • 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.
    • 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: Autism spectrum disorder (ASD)  Neurologist: Developmental co-ordination disorder (DCD)  Paediatrician: ADHD
    • 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 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 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
    • 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
    • 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 Road, Oxford, OX1 3UD, England. dorothy.bishop@psy.ox.ac.uk @deevybee