Developmental Course of Phenotypes in Preschool Children with ASD

Peter Szatmari MDChief of the Child and Youth Mental Health

CollaborativeHospital for Sick Children, Centre for Addiction and Mental Health, and University of TorontoPatsy and Jamie Anderson in Child and Youth

Mental Health

Financial Disclosure

– The Canadian Institutes of Health Research – Autism Speaks– Sinneave Family Foundation– Ontario Research Fund– Genome Canada – Royalties from Guildford Press– No other sources of funding (stocks, industry, Big Pharma)

Background

• ASD is seen as a heterogeneous disorder at multiple levels

• Heterogeneity at the clinical level reflects the co-variation of multiple phenotypes

• While we know something of the natural history of ASD, we know little of the developmental trajectories of more specific phenotypes

Breaking Down the ASD Phenotype

• Is course heterogeneous or homogeneous?• Are different phenotypes “yoked” or

“coupled” during development?• If yoked, what is the nature of the

relationship? Do they influence each other?• How can we model those influences over

time?

Pathways in ASD Study

• Phenotypes on interest;– Adaptive functioning– Autism symptom severity– Social competence– Structural language ability

• Use several different methods of modeling change over time

Context• Several longitudinal studies of ASD symptoms

– Focus on change in ADOS severity and classification

• Adaptive functioning is also an important domain associated with outcome in ASD

• Most published studies consider these two to be– homogenous domains

– highly correlated may be correlated at one given point

• BUT no studies investigated the degree of overlap in their developmental trajectories

Objectives

• To investigate the developmental course of ASD symptom severity and adaptive functioning in preschool children with ASD

• Is it heterogeneous or homogenous?

• To describe the degree of overlap of the trajectories of these two domains

Pathways in ASD Study

• Longitudinal study of developmental trajectories • Inception cohort of newly diagnosed children• Data from 5 Canadian sites• Multi-method• Multi-informant

Parent interviewsParent report questionnairesDirect child observation

Descriptive statisticsn %

Gender Male 355 84.3 Female 66 15.7Site Halifax 56 13.3 Montreal 134 31.8 Hamilton 68 16.2 Vancouver 93 22.1 Edmonton 70 16.6

Mean SDAge at diagnosis 38.2 8.8Age at study enrolment 39.9 9.0M-P-R developmental index standard score 57.2 26.2PLS-4 total language standard score 65.2 19.2

T1Diagnosis

T26 months

T312 months

T4age 6

ADOS severity metric √ √ √VABS II adaptive functioning √ √ √ √

• ASD symptom severity: ADOS severity metric

• Adaptive Functioning: VABS II composite (standard) score

Measures for trajectory analysis

Statistical Analysis• PROC TRAJ semi-parametric group based modeling of

longitudinal data to identify distinct trajectories of ASD symptom severity and adaptive functioning

– Best fitting model selected based on parsimony and fit indices

• Cross-tabulation examine cross-trajectory group membership

40 45 50 55 60 65 70 75 800

1

2

3

4

5

6

7

8

9

10

Group 1 (11.4%: low & improving) Group 2 (88.6%: high & stable)

age (months)

ADO

S Se

verit

y M

etric

Developmental trajectories of ASD symptoms

40 45 50 55 60 65 70 75 800

10

20

30

40

50

60

70

80

90

100

Group 1 (29.2%: low & declining)Group 2 (49.9%: medium & slightly improving)Group 3 (20.9 %: high & improving)

age (months)

VABS

II A

dapti

ve C

ompo

site

Developmental trajectories of adaptive functioning

Results• Two developmental trajectories of symptom severity

• Group 1 (11%): low & improving• Group 2 (89%): high & stable

• Three developmental trajectories of adaptive functioning• Group 1 (29%): low & declining• Group 2 (50%): medium & slightly improving• Group 3 (21%): high & improving

1 (11%: low & improving) 2 (89%: high & stable)ADOS severity

12.5%

31.4%

62.5%

48.3%

25.0%20.4%

Adaptive Functioning 1 (29%: low & declining)Adaptive Functioning 2 (49.9%: medium & slightly improving)Adaptive Functioning 3 (21%: high & improving)

Cross-trajectory group membership

Summary• Different children with ASD follow different

developmental trajectories in – ASD symptom severity

– Adaptive functioning

• Heterogeneity within domains increases over time

• Some degree of overlap but heterogeneity across domains increases over time

• Trajectories appear to have “construct” validity:– different predictor variables (at baseline)– different outcomes (at age 6)

Implications• Need for a suite of interventions to focus on

– different domain trajectories

– for different children

– at different time periods

• Little evidence of “yoking” of domains developmentally– decline in ASD symptom severity may still be accompanied by

significant difficulties in adaptive functioning– Children with “severe” autism can improve in adaptive

functioning

• What about other phenotypes? Language and socialization

How do Social and Language Skills influence each other over time?

• Typical development: reciprocal interactions between emerging social competence (VABS) and language (PLS)

• Developmental disabilities: “developmental coupling”

• Are social competence and language abilities reciprocally related over time in preschoolers with ASD?

How to Model Cascade Effects?• ….Cross-domain intrapersonal effects…

– Discriminant validity of measures– Measurement invariance: multi-group– Adequate coverage of developmental constructs

• …Unique relations…– Control for stability of domains– Control for within-time correlations– Control for covariates

• ….Over time…– Measurement invariance: temporal– Appropriate time intervals

» (Borenstein et al., 2010)

LANGLANG

SOC SOCSOCβ=0.47**

β=0.78**

β=0.79**

β=0.80**

β=0.37** β=0.16

β=0.13* β=.14*r=0.74**

LANG

r=0.35**r=0.16

Implications

• Relative abilities in social competence and language domains are largely stable by time of diagnosis in young children with ASD

• Reciprocal effects between domains are small • Social competence and language trajectories

resemble specialist pathways • Post-diagnosis window may not capture

period of largest cross-domain cascades

The Relationship between Baseline and Trajectory

• How are initial levels and growth (or slope) of SOC and LANG related?

• Do children in this sample vary with respect to initial levels and rate of change across domains

• Do children with and without comorbid cognitive impairment differ?

– Initial abilities and rate of change

Intercept SC(Mean T1 Score)

Intercept LANG(Mean T1 Score)

Slope SC(Rate of Change)

Slope LANG(Rate of Change)

β=-0.49*

β=0.77*

β=0.51*

β=0.28, p=0.07

β=0.51*

*p<0.01; β= standardized regression coefficient

GOODNESS OF FIT = EXCELLENTCFI=0.99-1.0TLI=0.98-0.99RMSEA=0.04-0.6

Summary of Results

• Notable growth in SC and LANG in first year post-diagnosis of ASD

• Early SC and its growth more strongly predictive of LANG growth than the converse

• Children with higher cognitive abilities developed more quickly with respect to language ability only

• Pattern may differ for children with different baseline cognitive abilities

Clinical Implications

• Some ASD phenotypes are only weakly yoked• Other phenotypes are more strongly related;

social competence and language• Social competence as an important

component of early language intervention • Should dx be the intervention gatekeeper?• Multiple ASD phenotypes – multiple tailored,

developmentally sequenced therapies

Limitations

• Small developmental window• Censorship of language data• Inability to covary for service use and other

variables• Absence of multiple methods and informants

– Trade-offs: multiple measures vs. response burden• “It’s just a model”– need replication in other

samples and through intervention research

Aknowledgements

• Stelios Georgiades, Eric Duku, Terry Bennett, Susan Bryson, Eric Fombonne, Pat Mirenda, Wendy Roberts, Isabel Smith, Tracy Vaillancourt, Joanne Volden, Charlotte Waddell, Lonnie Zwaigenbaum, Ann Thompson,

• Pathways in ASD Study Team

Thank you!Children/families participating in Pathways in ASD study

www.asdpathways.ca Our sponsors:

JOHN AND SUSAN MAYBERRY