Co-morbidly of Autism and SLI: Kinds, Kin or Confounds?

1. Co-morbidly of Autism and SLI: Kinds, Kin or Confounds? Bruce Tomblin, Ph.D. Department of Communication Sciences and Disorders University of Iowa Research Supported by Grant R01 NIH-DC-19-90 from the NIDCD

2. The Issue • Is there an excess of specific language impairment (SLI) among children with autism? • If so why?

3. Early Perspectives on Autism and Language Impairment • “central language deficits related to those found in children with developmental aphasia, but more severe, may be the necessary and sufficient cause of behavior which marks children as autistic” (Churchill, 1972). • “It is concluded that the autistic child's language deviance is not just a reflection of language impairment” (Cantwell, Baker & Rutter, 1978)

4. The Relationship Re-stated and Rebutted • The Shot Heard Round the World • SLI is co-morbid with Autism (Kjelgaard & Tager-Flusberg, 2001) • There is a subgroup of children with Autism plus SLI (Tager-Flusberg) • The British Respond • There is no excess of SLI in autism. • Language problems of children with autism do not represent cases of SLI (Whitehouse, Barry & Bishop, 2008; Williams, Botting & Boucher, 2008)

5. Goals of Talk • Review autism and the place of communication problems within autism. • Summarize models on the relationship of language impairment in autism with SLI • Examine key pieces evidence for and against there being a group of children with both autism and SLI. • Where does the solution lie? • A re-conceptualization of SLI • An alignment of SLI with a model of autism

6. Communication as Multidimensional Language Gesture Pragmatics • Communication is accomplished by the use of conventionalized gestures to convey messages that accomplish social acts. • Gesture=Speech or sign (how communication is accomplished) • Messages= comprise symbols (words) and symbol arrangements (grammar) to convey and interpret meaning (Language) • Social Acts=Pragmatics (why the message is expressed)

7. Autism • DSM-IV Perspective • Triad of Qualitative Autism Symptoms • Impaired social interactions • restricted and repetitive interests and activities • Qualitative impairments in communication • Abnormal use of language as a social tool • Etiologic core comprised of a single etiology underlying all features. • Autism represents a “natural kind” of developmental disorder. • “Natural kind” “entities possessing properties bound by natural law” (Quine, 1969) Rigidity Communication Function Social Deficits

8. Spared and Impaired Communication in Autism • Communication function (pragmatics) is universally impaired • Speech sound production is spared in many children • Language is highly variable • 20+% normal or above language • 40+% poor language • 40+% or more have no usable language X Language X X Gesture Pragmatics Autism normal language (A0) Autism + LI (ALI)

9. ALI = Autism plus SLI “The language phenotype of the ALI subtype is the same as the phenotype for SLI.” (Tager-Flusberg, 2006)

10. SLI Conceptualized • SLI constitutes a “natural kind” of language learner • It posses features that are shared uniquely by all other children with SLI. • These children present with distinctive language and cognitive markers that differentiate them from other poor language learners • High rates of co-morbidity with SSD • Predominance of expressive problems • Extraordinary difficulties with grammar (omission of INFL) • Poor Non-word Repetition (Phonological Processing/Memory) • Heritability suggests a genetic aetiology

11. Models of Overlap between SLI and Autism • ALI represents the co-morbidity of SLI and Autism • Separate causal systems that are themselves correlated. • The ALI overlap is due to causal factors for SLI being associated with those causing Autism. • The same causal factor yielding different diseases (Pleiotropy) • Autism and SLI are phenotypic variants of the same set of genes (Bishop, 2003) • Should expect overlap in both directions Autism ALI SLI A B Autism ALI SLI A B C

12. ALI SLI Models of Overlap between SLI and Autism • ALI is a Phenocopy of SLI • ALI mimics many of the surface features of SLI but does not represent the same condition. • Those factors the cause ALI are distinct from those that cause SLI. • Many of these features may arise from the core features of autism. Autism X Y Z A B C

13. Domains of Evidence for Overlap between SLI and Autism • Language Profiles and Markers • Cognitive Endophenotypes • Brain Structure • Familial Aggregation • Genetics

14. Vocabulary Grammar The SLI Language Features in ALI • ALI • Language profile on standardized tests reveal depressed grammar scores relative to vocabulary. • Sentence repetition similar to SLI group • Particular difficulties with tense and number agreement in elicited sentence tasks marked by bare stems. (He walk_) • The language phenotype of the ALI subtype is the same as the phenotype for SLI.” (Tager-Flusberg, 2006) Kjelgaard & Tager-Flusberg, 2001 Joseph & Tager-Flusberg, 2003 Roberts, Rice & Tager-Flusberg, 2004 Rapin & Dunn, 2003 Botting & Conti-Ramsden, 2003 Whitehouse, Barry & Bishop, 2008

15. Non-SLI Features in ALI • But unlike SLI • Few expressive only children. • Preserved speech production • Agreement bare stem errors were not different between groups (A0, ALI) and there was a high rate of non-morphological errors. (Williams, Botting & Boucher, 2009) • Better sentence repetition in ALI than SLI (Whitehouse, Barry & Bishop, 2008) • Presence of differences and the possibility that similarities are phenocopies suggest that ALI is not the same as SLI.

16. Why Might ALI not Look Like SLI? • Children with SLI are typically sampled from clinical service units for children with communication impairments. • Children with autism are sampled from service units for children with autism. • Does the referral pattern influence the phenotype?

17. Is SSD Prominent in SLI? Rates of SSD and SLI in Clinically Served Children Prevalence of SSD

18. Percent of Children 40 33 35 28 30 20 10 4 0 Neither Expressive Only Receptive Only Both Rates of Expressive Receptive Subtypes in SLI 100 80.6 80 60 40 20 10.65 6.48 2.31 0 Expressive Only Receptive Only Neither Both • Within a Population Sample • Expressive only problems are not the predominant subtype of SLI. • The rate of subtypes is dependent on how they are computed.

19. Endophenotypes of SLINon-Word Repetition • Co-morbidity in ALI • ALI children were less able to repeat nonwords accurately than A0 children. • ALI children were similar to SLI children on overall accuracy of non-word repetition. Kjelgaard & Tager-Flusberg, 2001 Botting & Conti-Ramsden, 2003 Whitehouse, Barry & Bishop, 2008

20. Phonological Memory Endophenotype of SLI • Phenocopy(Whitehouse, Barry & Bishop, 2008) • The effect of word length (# of syllables) was different in SLI than ALI. • ALI children with poor NWR were also more likely to have more severe autism symptoms. • Many of the LI symptoms of ALI children are caused by the autism symptoms.

21. Brain Imaging of Language Areas in Children with Autism and SLI • Brain Structure Similarities • Overall brain size larger • Language areas (inferior frontal, superior temporal gyrus) • Greater rates of reduced or reversed hemispheric asymmetry in Broca’s area • Right=>left • Mixed finding regarding greater than normal asymmetry (L>R) for SLI and ALI in posterior regions. Superior Temporal G. Inferior Frontal Herbert et al., 2001; 2002; 2005 DeFosse et al., 2004 Joseph & Tager-Flusberg, 2003

22. Language Status of SLI and Autism Family Members of • Bishop et al. (2006) observed that in the BAP studies language and communication were not distinguished. • A parent questionnaire (CCC-2) distinguishing between language and communication was with siblings of children with ASD. • The siblings showed elevated rates of BOTH language and communication deficits. • Whitehouse et al. (2007) tested parents of probands with ASD or SLI or TD children • ASD parents were similar to TD parents on language measures, but SLI parents were poorer. • ASD parents were poorer than TD and SLI parents on pragmatics.

23. Language Status of SLI and Autism Family Members of • Ruser et al. (2007) compared parents of ASD, SLI or Down Syndrome on communication and language from spontaneous language samples. • ASD & SLI parents were poorer than DS parents in both communication and language. • Language features in parents were more associated with SLI in children • Communication features were associated with ASD in children. • Lindgren et al. (2008) compared language, phonological processing and reading test performance in sibs and parents of SLI, ALI and A0 • Relatives of SLI children were generally poorer than the relatives of the ALI or A0. • “the hypothesis that ALI and SLI families share similar genetic loading for language is not strongly supported”

24. Is There a Genetic Link? Autism linked to regions on 7q (Alarcon et al., 2002: 2005; Wassink et al. , 2001) with linkage improvedwhenlanguageisincorporatedintophenotype. FOXP2 (7q31) associatedwith speech and language (Lai et al., 2001) in isolated families, but mutations in FOXP2 are not often associated with autism or SLI. Association of LI to 7q31 regionoutside of FOXP2 (O’Brien et al. 2003)

25. CNTNAP2 FOXP2 CNTNAP2 • CNTNAP2 is telomeric to FOXP2 on ch 7 and is regulated by FOXP2 • CNTNAP2 has been found to be associated with autism and especially those with language impairment (Alercon et al. 2008). • CNTNAP2 is associated with Phonological Memory (non-word rep.) in children with SLI (Vernes, et al. 2009)

26. rs17236239 rs2710117 Iowa Replication in 484 Children (Mueller, in prep)

27. Summary of ALI/SLI Co-Morbidity • Language Phenotype • Similarities in profiles and grammatical morpheme markers, but some features are missing • Perhaps due to phenocopy • Perhaps due to ascertainment. • Phonological Memory • Deficits in both groups, but some differences • Perhaps due phenocopy • Brain Structure • Similarities in general size and anterior L-R (a)symmetries. • Co-Familiality • Increased liability of language/communication deficits, but language deficits are less likely to be found in relatives of ASD children but more so in SLI families. • Genetics • Association of ASD and SLI at CNTNAP2.

28. Current Status of Issue • The data are not completely in favor of one or the other position. • Overlap is most robust when we look at the children (phenotype, brains, genes) • Less overlap in family members. • Is there a way forward?

29. Toward a Resolution: Reconceptulizing SLI (and Autism)

30. SLI is not a natural kind of language learner abcde a b c d e Language emerges out of multiple interactive neuro-cognitive systems that are highly responsive to the biological and experiential environment. These multiple systems are influenced by many factors including genes The same systems that give rise to “normal” variation contribute to “abnormal.” This results in traits that are continuous from exceptionally high to exceptionally low (Multifactorial trait)

31. SLI as Region of Individual Differences Language • SLI represents a region of low language ability that shares the same etiologic factors as those that contribute to normal variation. • There is no unique causation for SLI, but rather it is a constellation (conspiracy) of common factors. • Poor language arises out of the number of risk factors and nature of their interactions. • Some children with very good language may carry the CNTNAP2 risk allele, but this allele is more likely in children with poor language.

32. Where does the convergence come from? • Standard Model (co-morbidity) • Liability factors are themselves correlated if not shared (plieotropy). • Convergence as an outgrowth of help seeking • Illness represents the complaints of patients (Englehardt) • When children present with troubling development, parents seek help. • Certain combinations of developmental difficulty are more troubling than others. • This results in convergence of symptoms in the clinic. (Skuse, 2007) • Language impairment is likely to follow this pattern.

33. A Possible Resolution • The triad of symptoms of autism and to a lesser degree the poor language skills (SLI) arise from somewhat different causes. • Phenotypic interaction remains likely. • Among children with ASD, there is likely to an excess of children with poor language abilities (SLI) as an outgrowth of the added burden of worry.

34. Conclusion We need to avoid thinking of children with disabilities as natural kinds distinct from “normal” Individual differences among children across domains of ability are usually multifactorial. We need to acknowledge that clinical populations are formed by help seeking and that the causes for this are not the same as those that generate individual differences in the population. Population based research is needed to ensure that we identify artificial co-morbidity.

35. Complex Variation Emerges via Multilevel Pathways • Language emerges from complex interactions within and between levels of brain and cognitive systems. • Genetic processes contribute to this emergence. • The nonlinear interactions within one level give rise to emergent properties at another level. • Language emerges out of multiple layers of causal systems. Causal relationships are not deterministic across levels. like cat be flight flower Environmental