What We know, What We Dont Know : Natural History Studies in Infants with Autism Spectrum Disorder

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What We know, What We Dont Know Natural
History Studies in Infants with Autism Spectrum
Disorder

• Wendy Roberts, MD,FRCPC
• Developmental Paediatrician
• Bloorview Kids Rehab
• Autism Research Unit,SickKids
• Professor of Paediatrics
• University of Toronto

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Objectives

• To understand the current evidence for reliable
  early detection of autism
• To think together about translation of early
  signs into active intervention
• To learn, through prospective monitoring, the
  different trajectories different signs at
  different stages of development and in varying
  environments

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The Autism Spectrum

• Qualitative vs Quantitative Impairment

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What is Autism?

• Social communication impairment
• Verbal and non verbal delays and deficits
• Delayed talking
• Apraxia
• Interest / skills in social interaction
• Behaviour
• Insistence on samenessanxiety, obsessions
• Repetitive motor and sensory interests and
  behaviours

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Is Autism Increasing?

• 6/1000 stable in Midlands, UK.1996-98 99-03
• (Chakrabarti and Fombonne,
• Amer.J.Psych, 2005
• 162pp1133-1141)

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Numbers based on 2001 Census data Prevalence rate
of 60/10,000 (1/165) 2004 estimate about 48,000
children Modified from CAIRN Review Vol 1, No.2
April 2004
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Conclusions drawn from existing research...

• Signs often present by age two years (80-90 of
  cases)
• Early signs of autism may involve a range of
  developmental domains
• Some children may show signs in early infancy
  others not until 2nd year

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Age of diagnosis in recent studies
Blaxill, 2004
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Early detection of autism

• Most of what is known about early signs of ASD
  comes from retrospective studies (i.e., parents
  reports and home videos)
• Behavioral extremes
• Decreased social responses
• Atypical communication and play behaviors
• Poor eye contact, not looking at faces
• Repetitive behaviors, atypical motor development

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• Population screening
• Wetherby et al. (2004) followed 13-24-month-olds
  who screened positive on CSBS
• Several features differed between children with
  ASD, language delay, and typical development
• Eye gaze coordinate gaze/ gestures, joyful
  expression
• Lack of babbling (consonant sounds) unusual
  prosody
• Lack of showing, sharing of enjoyment
• Lack of response to name
• Repetitive movements, repetitive actions with
  toys
• Limitations Selected based on particular
  features, follow-up period limited by timing of
  screen

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Canadian Baby Sibs Study

• Current participants
• 230 siblings of children with ASD
• 100 comparison infants (no family history of ASD)
• Assessed every 6 months to age 24 months, then
  independent diagnostic assessment at 36 months
• 102 siblings and 46 controls followed to 36
  months
• Measures of early behavioral signs, language and
  cognitive skill development

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Study Team

• McMaster University
• Lonnie Zwaigenbaum MD
• Peter Szatmari MD
• Tracy Vaillancourt PhD
• Michelle Pawliw MA
• Magda Doris MSc
• Ann Thompson MSc
• Dalhousie University
• Susan Bryson PhD
• Isabel Smith PhD
• Theresa McCormick MSc

• University of Toronto
• Wendy Roberts MD
• Jessica Brian PhD
• Catherine McDermott MSc
• Bonnie McKinnon BSc
• Shelley Mitchell MSc SLP

Supported by Canadian Institutes of Health
Research National Alliance for Autism
Research National Institutes of Child Health and
Development Many children and families!
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Study Protocol
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Autism Observation Scale for Infants(Bryson et
al., in press)

• Standardized, interactive, play-based measure of
  early signs of autism, 16-item scale
• Covers several developmental domains
• Attention (e.g., tracking)
• Communication (e.g., social babbling)
• Social responses (e.g., peek-a-boo)
• Play (e.g., imitation)
• Motor control
• Atypical behaviors (e.g., visual fixations)

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Autism Observation Scale for Infants

• Visual tracking
• Disengagement of attention
• Response to name
• Social babbling
• Eye contact
• Social smiling
• Social anticipation (peek-a-boo)
• Social interest and affect
• Response to change in facial emotion

• Imitation
• Coordination of eye gaze and action
• Reactivity
• Transitions between activities
• Motor behavior
• Atypical motor behaviours
• Atypical sensory behaviours

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AOSI Scores over time in Siblings with ASD,
Non-ASD Siblings and Controls
__

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Children with Autism Features at 6 Months

• Subtle differences
• Visual tracking1
• Anticipatory responses1
• Motor control1,2
• Many typical social behaviors
• Eye contact (100)
• Reciprocal social smiling (88)
• Social interest and affect (88)

1Sibs-ASDgtcontrols 2Sibs-ASDgtSibs-N plt.01
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Children with autism features at 12 months

• Poor visual tracking
• Quiet, lack social babbling
• Decreased social behaviors (smiling, response to
  game of peek-a-boo, interest and affect)
• Lack basic imitation skills
• Extreme reactivity
• Atypical sensory-oriented behaviors

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Camerons Story

• Seen first at 2 years 5 months due to language
  delay
• Uneventful pregnancy and delivery 39 wks, birth
  weight 9 lbs
• 2 days of age, readmitted due to
  hyperbilirubinemia, ABO incompatibility-gt UV
  light for 3 days

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Camerons Story

• Passive baby - frequent nursing normal growth
• Frequent otitis media from 12 months onwards, no
  tubes
• 2 head injuries as a toddler, first with hairline
  fracture
• Never a good sleeper
• Very picky eater - no fruit or vegetable

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Camerons Developmental Story

• Smile 2 months, good attention to mothers face
• Very little babbling or gestures until one year,
  then few words, counting to 10
• Words lost by 18 months
• High pitched Brrr sound to request or when
  upsetby 20 months learned sign for more, but
  very little social interest
• Did not respond to name or learn to point

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Which Trajectory?

• Autism Spectrum of Disorders
• Asperger Syndrome
• High functioning autism
• Autistic Disorder
• PDD-NOS
• Pathways to Better Outcomes, Szatmari CIHR
  2005-10

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Regression or Trajectory?

• Lord et al 2004. J.Child Psych Psych. 455 pp
  936-955
• n112
• 21controls, 21 DD
• Loss of words or vocalizations social skills
• 19 lost words, 7 fluctuating, 12 vocalizns-16
  mos.
• 25 lost words in second year of life-specific to
  ASD
• Nonspecific vocalization loss related to delay,
  not ASD - poor cognitive outcome

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Findings McArthur CDI(Mitchell et al., in press)
Sibs with ASD lt non-ASD sibs, controls
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AOSI items at 12 months compared to asst at
36-48 months
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AOSI items at 12 months compared to asst at
36-48 months
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Communication

• Attention to voice Response to name (Stone, 07)
• Attention to faces shifts to objects
• Gestures (Mitchell et al, 2006)
• Vocalization
• Effortful processing imitation
• Reciprocal communication

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Language Disorder ASD

• Not communicatively impaired
• Use language that they have
• Compensate for language deficits using gestures,
  e/c,vocal.
• Potential play delay eg. if cognitive delay

• Communication impairment
• language delay
• Dont use known words
• Limited commun. gestures
• Arms up
• Shaking head no
• greeting
• Limited play gestures
• Stirring with spoon

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Importance of Play

• Dearth of evidence arena for social, language,
  emotion regulation, attention, motor
  developmental rehearsal!
• Emergence of imaginative play parallels language
  development.Happe, 95,
• Affects language development
• ASD - few gestures /symbolic play. Mitchell,06
• Play based intervention (Floortime, Greenspan
  RDI,Gutstein)

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Reactivity

• Temperament and Emotion RegulationRothbart
• Behaviour Inhibition
• Threat
• Danger
• Behaviour Activation
• Novelty
• Stimulation and reward

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Components of TemperamentRothbart

• Fear
• Frustration
• Negative affect
• Extraversion
• Orienteering, perceptual sensitivity
• Effortful control

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Pearls re infancy from decade 95-05

• Biology and environment hard to separate!!
  (Jaffee 05)
• More able to orient (by self or with help),
  distress diminishes
• 10-13 months self-soothing
• High and very low levels of fearmore prone to
  pathology some fear promotes adaptation!
• Higher soothability..lower negative
  affectlong-term anxiety lower

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Summary of initial findings

• Behaviors markers for ASD at 12 months
• Visual tracking, eye contact, response to name,
  social smile, babbling, social interest and
  affect, imitation, sensory behaviors
• Markers may emerge between 6 and 12 m
• Language development
• Delayed expressive and receptive language
  (Mullen) and gestures (McArthur) at 12 months
• Language delays more severe by 24 months

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Initial findings from our Infant Sib project
(Inter. J Dev. Neurosci. April 2005)

• Early behavioral markers cover several
  developmental domains
• attention
• imitation
• communication
• social responses
• reactivity
• Markers emerge between 6 and 12 months
• Language and cognitive delays detectable at 12
  months, but become increasingly severe

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NAAR-NICHD High-Risk/Baby Sibs Research
Consortium

• Collaboration of several research groups
  committed to identifying and gaining a better
  understanding of the earliest signs of autism.
• Research workshops 2003-2006
• Working towards common research protocol to
  ensure the highest quality of assessment, and
  largest possible sample of infants.

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Head Circumference in ASD Courchesne 01, 03
Hazlett Piven, 05 Lainhart,06

• More rapid brain growth in first 14 months
• MRI retrospective studies
• Increased HC 6-14 months
• White gt grey matter, cerebral and cerebellar vols
  Increased at 2-4 y both decreased by
  adolescence (Courchesne)
• Enlarged cerebral white and grey matter by 2
  years..suggest change in latter part of first
  year (Piven)

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High-Risk/Baby Sibs Research ConsortiumStudy of
early head growth in autism (PI L. Zwaigenbaum)

• First joint project of the Consortium, the
  largest prospective head circumference study of
  children with autism.
• Evaluate early patterns of head growth as a
  possible risk marker for autism.
• Correlate early head growth with other early
  features of autism.

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Phenotype Leading to Elusive Genes ?

• Head circumference
• Regression (Rogers, 04, Luyster, 05)
• Epilepsy (Clarke, 05)
• Language development - with or without apraxia
  (Mitchell, 05)
• Dysmorphic features, cognition (Miles, 05)
• Gender, parental age.

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Diagnostic dilemmas

• Interpreting behaviour without detailed history
• Engaging the silent child in assessment
• Social anxiety and ASD - each most communicative
  with parents / familiar people/ 11
• Language delay or selective mutism
• Role of intervention - impact on diagnostic
  formulations. Do children move off spectrum?

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Assessing ASD in 18-24 month olds

• Some cases are very clear diagnostic measures
  agree with clinical judgement
• Some cases are less straightforward
• Lower specificity of diagnostic measures
• Children with developmental delays or difficult
  behavioral styles (e.g. anxiety or intensity)

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18-month assessment

• With current practice guidelines emphasizing the
  importance of early identification, some toddlers
  as young as 18 months are being referred
• Available measures such as the ADOS have not been
  formally evaluated in this age group.
• The stability of clinical ASD diagnoses has been
  established at age 2 years but not younger.
• Longitudinal baby sibs study provides a unique
  opportunity to assess the stability of diagnostic
  classification of ASD from 18 months to 3 years.

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Objectives

• To assess, in high risk infants (baby sibs),
  the agreement between assessment for ASD at 18
  months using ADOS and independent clinical
  diagnostic assessment at 3 years.
• Within the group initially classified as having
  an ASD, to compare behavioral symptoms and
  language skills at 18 months in children with and
  without confirmed diagnoses at 3 years.

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What is the agreement between the ADOS at 18
months and clinical diagnosis at 3 years?
3-year clinical diagnosis
18-month ADOS
kappa .31 p .001
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Agreement between ADOS at 18 mo. and clinical
diagnosis at 3 years

• Fair agreement between ADOS classification at 18
  months and clinical diagnosis at 3 years (?.31
  95 CI .15-.46).
• If autism and ASD are collapsed into a single
  category, agreement is still only fair (?.40)
• Of the 39 children with positive ADOS at 18 mo.,
  16 had diagnosis at 3 years and 23 did not.
• How do these two groups differ?

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Sensitivity and specificity of 18-mo. ADOS

• 18-mo ADOS algorithm (autism cut-off) identified
• Nine of 20 children with a clinical diagnosis at
  3 years (sensitivity 45), and 6 of 81 children
  who do not (specificity 93).
• 18-mo ADOS algorithm (ASD cut-off) identified
• 16 of 20 children with a clinical diagnosis at 3
  years (sensitivity 80) and 23 of 81 children
  who do not (specificity 72).
• Alternatively, the relative risk of a clinical
  diagnosis at 3 years given an ADOS score above
  the ASD cut-off at 18 months, is 6.4 (95 CI
  2.4, 18).

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Clinical Implications

• The ADOS is informative at 18-months. Scoring
  score above the ASD cut-off is predictive of a
  clinical diagnosis at 3 years.
• However, perhaps even more so than in older
  children, ADOS scores must be interpreted in the
  context of an overall clinical assessment.
• The ASD cut-off has high sensitivity, but
  specificity is too low for a confirmatory test on
  its own. The autism cut-off at 18-months has
  higher specificity, but misses more than 50 of
  the children with diagnoses at 3 years.

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False negatives at 18 months

• There were four children with clinical diagnoses
  at 3 years who scored below the ASD cut-off at 18
  months, including two with scores of 0 and 1.
  
• One child deteriorated markedly by 24 months
  (ADOS score 18) and was diagnosed with autism.
  He had social impairments at 12 months.
• The second child had more slowly progressing
  impairments between 18 and 36 months. His ADOS
  score at 24 months was below the ASD cut-off.

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• Sources of disagreement between 18-month ADOS and
  3-year diagnostic assessment?
• Measurement issues versus true changes in
  clinical status due to variable time course of
  ASD.

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Implications for Surveillance and Screening

• Majority of children with autistic disorder at
  two years continue to have AD at 3 y.
• Some children have major improvement in social
  skills and imaginative play as develop language
• Some children fit criteria for social anxiety
  disorder but go on to Asperger Disorder

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Implications for Surveillance and Screening

• Avoid dogmatic ruling in or out of ASD under 3
  yrs may overinclude in DD (Vig, 99)
• Particular attention to 20 of parents who will
  not express concerns (Glascoe)
• Use clinical assessment with ADOS as important
  physical exam equivalent which may change over
  time, most notably in high functioning children

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Recurrence Rate

• 13 of 100 (13), which is high relative to
  published rates (5-8)
• Strict criteria (ADI, ADOS and clinical)
• 9 sibs with autistic disorder (9)
• Wide 95 confidence interval (6.4-19.6)
• Possible participation bias
• Although similar recurrence among siblings
  recruited at 6 months versus 12 months

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What can we do?

• Be vigilant for early behavioral markers
• Listen to parents concerns and ask about early
  communication, social and play skills
• Initiate intervention based on identified
  concerns, even when ultimate diagnosis is
  uncertain

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References

• Lord,C. et al Regression and word loss in ASDs.
  J. Child Psychology and Psychiatry
  455(2004),pp936-955
• Rogers,S. Developmental Regression in ASDs. MR
  and DD.Research Reviews10139-143(2004)
• Howlin, P. (2003). Can early interventions alter
  the course of autism? Novartis Foundation
  Symposium
• Smalley, S., McCracken, J. Tanguay, P. (1995).
  Autism, affective disorders and social phobia. Am
  J Med Gen, 60, 19-26.
• Standards and Guidelines for the Assesst and
  Diagnosis of Young Children with ASD in BC
  www.healthservices.gov.bc.ca/CPA/publications/asd
• Koegel,L, LaZebnik,C...Overcoming Autism.
  Penguin, 2004
• A Mind Apart. Understanding Children with Autism
  and Asp. Syn
• Guilford press 2004

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References

• Can. J Psychiatry, ed. Fombonne, E. September
  2003
• Bryson S, Zwaigenbaum L, Roberts W The Early
  Detection of Autism in Clinical Practice.
  Paediatrics Child Health 9, No 4219 pp
  219-221.
• Zwaigenbaum L, Bryson S, Rogers T, Roberts W,
  Brian J, Szatmari, P. Behavioral manifestations
  of autism in the first year of life. Int J
  Devel. Neurosci. 2005 23 143-152
• Lauritsen, B. et al Effects of familial risk
  factors and place of birth on the risk of autism
  a nationwide register-based survey. J of Child
  Psychology and Psychiatry 2004
• Szatmari P, Perspectives on the Classification of
  AS , In Klin, Volkmar, Sparrow. Asperger
  Syndrome. pp 403-417