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Bringing science to the community: A new system of healthcare delivery for infants & toddlers with autism spectrum disorders
Ami Klin, PhDDirector, Marcus Autism Center, Children’s Healthcare of AtlantaGRA Eminent Scholar Professor & Chief, Division of Autism, Department of Pediatrics, Emory University School of MedicineEmory Center for Translational Social Neuroscience
Marcus Autism Center
Thank You
• The children and families for their participation• Warren Jones, my colleagues & students• The National Institute of Mental Health• The National Institute of Child Health and Human Development• The Marcus Foundation• The Whitehead Foundation• The Woodruff Foundation• The Simons Foundation• The Autism Science Foundation• Autism Speaks
2
Marcus Autism Center
Conflicts of Interest
3
No conflicts of interest associated with this presentation
Marcus Autism Center
4
Marcus Autism Center at a glance: Strategic Plan 2014-2019
CENTER-‐BASED MODEL PROGRAM
COMMUNITY-‐VIABLEOUTREACH MODEL
• Transla;on• Impact• Clinical Resources
• Science• Faculty Advancement• Research Resources
The Science of Clinical Care
Excellence
Marcus Autism Center
Research EnterpriseStrategic Plan 2014-2019
6
• CAUSES• TREATMENT• COMMUNITY-‐VIABLE SOLUTIONS• “VALUE PROPOSITION”
• 13 RESEARCH CORES• 9 INTERNAL, 4 COLLABORATIVE• RESEARCH ADMINISTRATION• INFORMATICS• DATA MANAGEMENT & ANALYSIS
RESEARCH INITIATIVES
RESEARCH INFRASTRUCTURE
Social Neuroscience
Neurobiology
Genetics
Animal Models
Diagnosis
Psychopharmacology
Concept
Strategy for Reseach Enterprise
Marcus Autism Center, An NIH Autism Center of Excellence
Social Visual Engagement in Infants(0 to 36 months)
Social Vocal Engagement in Infants (0 to 36 months)
Treatment in Infants & Toddlers(beginning at 12 months)
Social Visual Engagement &Brain Development in a Model System
7$ 8.8 m total
Marcus Autism Center8
Marcus Autism Center is an affiliate of Children’s Healthcare of Atlanta. ©2012 Children’s Healthcare of Atlanta Inc. All rights reserved.
CDC, 2014; Mandell et al., 2013; 2014
Societal Impact of Au;sm
• Prevalence: 1 : 68 [1:42 in boys] • Community Dispari;es • Societal Cost/Year in the US: $ 136 billion• Life;me Cost of Care Per Child: $ 1.4 to 2.4 million
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•Brain disorder of gene;c origins•Adverse outcomes can be prevented•Importance of early diagnosis and interven;on for lifelong outcome and cost of care
•American Academy of Pediatrics– Screening (18 and 24 months), but s;ll low uptake
•Median age of diagnosis in US: 4-‐6 to 5.7 years•No Community-‐viable system of care•Reimbursement systems NOT in place
Challenges and Opportunities:Reducing Age of Diagnosis & Improving Acess to Care
Jones et al. (2008). Arch Gen Psy, 65(8), 946-54.Klin et al. (2009). Nature, 459, 257-61.
Jones & Klin (2009). J Am Acad of Child Psy, 48(5): 471-3.
GENETIC MECHANISMS OF SOCIALIZATION BEHAVIORAL LIABILITY SYMPTOMS
First 2 years of life
Marcus Autism Center
Our mission is to transform au;sm diagnosis and treatment to alter the life course of kids with au;sm
Development (Age)
2 yrs 3 yrs 4 yrs 5 yrs
Posi2v
e Outcome
1 yr
Average Age of Diagnosis TODAY
FUTUREIndependent,College, Working,Rela;onships
FUTURE Age of Diagnosis (Phase II)
Window of Opportunity to Change Au2sm
REDUCE ASSOCIATED DISABILITIES (language, intellectual, behavioral, medical)
BEST SCENARIO NOWNot independent, Medium level ofSupports
TYPICAL NOWDisabled,High level ofSupports
6 yrs +
FUTURE Age of Diagnosis (Phase I)
ALLEVIATE AUTISM
PROMOTE LANGUAGE
PREVENT AUTISM
Marcus Autism Center is an affiliate of Children’s Healthcare of Atlanta. ©2006 Children’s Healthcare of Atlanta Inc. All rights reserved.12
Redefining Autism:Preventing costly impact
Developmental Trajectories
Au;sm Disrupts the Plaeorm for Brain Development
AGE (in months)birth 18 months
15
The Brain Becomes Who We Are....
H-J Park PhD
MH Johnson PhD
JE LeDoux PhD
White Ma)er Development
Attention to Biological Motion
not significantly different from chance, p > .05
Non-verbal mental-agematched control Verbal mental-age match
Klin & Jones (2008). Developmental Science 11(1),40-6.
Two-year-olds with autism do not exhibit preferential attention to biological motion
Typically-Developing Group, N = 39
Developmentally-Delayed Group, N = 16
Autism Group N = 21
Klin, Lin, Gorrindo, Ramsay, & Jones (2009). Nature, 459, 257-261.
Autism Group N = 21
Typically-Developing Group, N = 39
Developmentally-Delayed Group, N = 16
Klin, Lin, Gorrindo, Ramsay, & Jones (2009). Nature, 459, 257-261.
But during ‘Pat-a-Cake’...
Exploring Audiovisual Synchrony
• A “pat-a-cake” finding led to the hypothesis that children’s visual behavior was being guided by physical, not social contingencies.
Autism Group N = 21
Audiovisual Synchrony QuantificationChange in Motion * Change in Sound = Audiovisual Synchrony
Time
CHANGE IN SOUND
AUDIOVISUAL SYNCHRONY
CHANGE IN MOTION
Cumulative Audiovisual Synchrony in Point-Light Animations
No Synchrony
Pat-a-cake
Feeding
Max Synchrony
Upright
Inverted
Upright
Inverted
Relative Audio-Visual Synchrony = Normalized Peak Difference
Clap Location
Klin, Lin, Gorrindo, Ramsay, & Jones (2009). Nature, 459, 257-261.
Patterns of visual fixation to approaching caregiver
Jones, Carr, Klin (2008). Archives of General Psychiatry. 65(8):946-54.
How do 2-year-olds with autism watch the face of a caregiver?
Eye: F2,63= 12.87, p<.001
Mouth: F2,63= 5.599, p<.006
d = 1.56
d = 1.40
Jones, Carr, Klin (2008). Arch Gen Psychiatry. 65(8):946-54.
Watching a face ... but seeing physical properties?
Fixation on Mouth and Eyes as a Function of Audiovisual Synchrony
ASD TD
JenningsXu
30
Growth Charts of Social Engagement
Marcus Autism Center
Strategic Plan
31
Behavioral Neuroscience
Neurobiology
Genetics
Animal Models
Diagnosis & Treatment
Psychopharmacology & Clinical Trials
Marcus Autism Center, An NIH Autism Center of Excellence
Social Visual Engagement in Infants(0 to 36 months)
Social Vocal Engagement in Infants (0 to 36 months)
Treatment in Infants & Toddlers(beginning at 12 months)
Social Visual Engagement &Brain Development in a Model System
32
Infants
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
80
month
perc
ent f
ixat
ion
age (months)
perc
ent
fixat
ion
eyesmouthbodyobject
TD mean+/- 1 SD
Growth Charts of Social Visual Engagement
(Typically-Developing Children)
Jones & Klin (2013). Nature, 504, 427-431.
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
Eye FixationChildren with ASD relative toTypically-Developing Norms
TD eyesASD eyes
perc
ent
fixat
ion
mean95% CI
age (months)
ASD, N=11, male, 747 trialsTD, N=25, male, 1637 trials
2 3 4 5 6 9 12 15 18 24−4
−2
0
2
4
6
8
10
12
month
Dt fi
xatio
nD
fixa
tion
t
D eyest
2 3 4 5 6 9 12 15 18 240
10
20
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40
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month
perc
ent fixation
TD−tooYoung unfiltered
age (months)
Eye Fixation, and Rate of Changein Eye Fixationpe
rcen
t fix
atio
n
eyes
mean95% CI
2 3 4 5 6 9 12 15 18 24−4
−2
0
2
4
6
8
10
12
month
Dt fi
xatio
n
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
age (months)
perc
ent
fixat
ion
mean95% CI
TD eyesASD eyes
D fi
xatio
nt
D TD eyest
D ASD eyest
F1,34 = 11.90, p =.002
Eye Fixation, and Rate of Changein Eye Fixation
2 3 4 5 6 9 12 15 18 24−2
−1
0
1
2
3
4
5
6
month
Dt fi
xatio
n 2 3 4 5 6 9 12 15 18 240
5
10
15
20
25
30
35
month
perc
ent f
ixat
ion
TD−tooYoung unfilteredpe
rcen
t fix
atio
n
mean95% CI
ASD bodyTD body
D fi
xatio
nt
D TD bodyt
D ASD bodyt
Body FixationChildren with ASD relative toTypically-Developing Norms
F1,34 = 10.60, p =.003
2 3 4 5 6 9 12 15 18 24−2
−1
0
1
2
3
4
5
6
month
Dt fi
xatio
n 2 3 4 5 6 9 12 15 18 240
5
10
15
20
25
30
35
month
perc
ent f
ixat
ion
TD−tooYoung unfilteredpe
rcen
t fix
atio
n
mean95% CI
D fi
xatio
nt
ASD objectTD object
D TD objectt
D ASD objectt
Object FixationChildren with ASD relative toTypically-Developing Norms
F1,34 = 12.08, p =.002
Decline in Eye Fixation Predicts Severity of Outcome
Outco
me a
t 24
Mont
hs(A
DOS
Socia
l Affe
ct)
2 3 4 5 6 9 12 15 18 240
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Age (in months)
Fixat
ion T
ime,
Eye
s (%
)
2 3 4 5 6 9 12 15 18 240
10
20
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2 3 4 5 6 9 12 15 18 240
10
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2 3 4 5 6 9 12 15 18 240
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2 3 4 5 6 9 12 15 18 240
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2 3 4 5 6 9 12 15 18 240
10
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A B
C
Figure 3. In children with ASD, growth curves of fixation to eyes during the first 2 years of life are strongly and significantly correlated with outcome measures of symptom severity. Functional Principal Component Analysis (FPCA) was used to extract growth curve components explaining variance in trajectory shape about the population mean. (A) Population mean for fixation to eyes in children with ASD (red line) plotted with lines indicating direction of individual trajectories having positive principal compenent one (PC1) scores (line marked by plus signs) or negative PC1 scores (line marked by minus signs). (B) Correlation of eyes PC1 score (as measure of decline in eye fixation) with ADOS social-affect cluster score at 24 months of age. (C) Correlation of eyes PC1 score relative to outcome for subsets of the available longitudinal data (2-6 mos vs. outcome at 24 mos; then 2-9 mos; 2-12 mos; etc.). Decline in eye fixation predicts outcome levels at trend levels by 2-9 months (p = 0.100), and is statistically significant thereafter (with r = -0.709, p = 0.015 for 2-12 months).
mean ASD fixation on eyesdirection of individual trajectories with positive PC1 scoresdirection of individual trajectories with negative PC1 scores
!50 0 50048
121620
PC1 Score,2-6 mos.
ADOS
, 24
mos. r = !0.415
p = 0.204
!50 0 50048
121620
PC1 Score,2-9 mos.
r = !0.521p = 0.100
!100 !50 0 50 100048
121620
PC1 Score,2-12 mos.
r = !0.708p = 0.015
!100 !50 0 50 100048
121620
PC1 Score,2-15 mos.
r = !0.659p = 0.027
!100 0 100048
121620
PC1 Score,2-18 mos.
r = !0.684p = 0.020
!150 !100 !50 0 50 100 1500
5
10
15
20
PC1 Score
r = !0.750p = 0.007
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
2 3 4 5 6 9 12 15 18 24−4
−2
0
2
4
6
8
10
12
month
Dt fi
xatio
n
age (months)
perc
ent
fixat
ion
D fi
xatio
nt
mean95% CI
TD eyesASD eyes
D TD eyest
D ASD eyest
Growth Chartsof Social Engagement to Enable
Early Diagnosis
Differences Present within the First 6 Months of Life
2 4 6 9 12 15 18 24246
912151824
!1!.5
0.51
TD Eyes
Corre
lation
2 3 4 5 60
10
20
30
40
50
60
70
80
90
100
Age (in months)
Fixat
ion T
ime,
Eye
s (%
)
2 3 4 5 60
10
20
30
40
50
60
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80
90
100
Age (in months)
Fixat
ion T
ime,
Eye
s (%
)
2 3 4 5 60
10
20
30
40
50
60
70
80
90
100
Age (in months)
Fixat
ion T
ime,
Eye
s (%
)
A B C
Figure 4. Developmental differences in visual fixation between 2 and 6 months of age. Boxplots and linear regression lines for eyes fixation (A-C) and mouth fixation (D-F) for typically-developing infants (in blue) and infants with autism (in red). Boxplot vertical lines and lightly shaded regions extend from minimum to maximum values in the data; boxplot boxes and more darkly shaded regions span the 25th to 75th percentiles of the data. When fitted with linear regressions (black lines), data for both ASD and TD groups show significant correlations with chronological age, but these correlations differ significantly between-groups for eyes and body fixations. (G-H) Bivariate correlation functions for eyes fixation in typically-developing infants (G) and infants with autism (H). Note the steep decline in month-to-month correlation in eyes fixation in infants with ASD: at 3 and 4 months of age, there is no longer any positive correlation in month-to-month eyes fixation, and the correlation becomes negative by months 5 and 6 and more negative by subsequent timepoints, indicating increased likelihood of declining eyes fixation. This can be contrasted with the eyes fixation correlation function for TD infants, which remains positively correlated throughout the first 2 years.
2 3 4 5 60
10
20
30
40
50
60
70
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100
Age (in months)
Fixat
ion T
ime,
Bod
y (%
)
2 3 4 5 60
10
20
30
40
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60
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90
100
Age (in months)
Fixat
ion T
ime,
Bod
y (%
)
2 3 4 5 60
10
20
30
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50
60
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80
Age (in months)
Fixat
ion T
ime,
Bod
y (%
)
D E F
G ASD Eyes
Age
Age (in months)
Age
Age (in months)
H
!1!.5
0.51
2 4 6 9 12 15 18 24246
912151824
ASDTD
eyes
body
2 3 4 5 60
20
40
60
80
100Fi
xatio
n Ti
me
(%)
2 3 4 5 6
�����
05
10
Age (in months)
Rat
e of
Cha
nge
2 3 4 5 60
20
40
60
80
100
Fixa
tion
Tim
e (%
)
2 3 4 5 6
�����
05
10
Rat
e of
Cha
nge
Age (in months)
2 3 4 5 60
20
40
60
80
100
Fixa
tion
Tim
e (%
)2 3 4 5 6
�����
05
10
Age (in months)R
ate
of C
hang
e
2 3 4 5 60
20
40
60
80
100
Fixa
tion
Tim
e (%
)
2 3 4 5 6
�����
05
10
Age (in months)
Rat
e of
Cha
nge
0 0.2 0.4 0.6 0.8 10
0.2
0.4
0.6
0.8
1
False positive rate
True
pos
itive
rate
0 0.2 0.4 0.6 0.8 10
0.2
0.4
0.6
0.8
1
False positive rate
True
pos
itive
rate
0 0.2 0.4 0.6 0.8 10
0.2
0.4
0.6
0.8
1
False positive rate
True
pos
itive
rate
0 0.2 0.4 0.6 0.8 10
0.2
0.4
0.6
0.8
1
False positive rate
True
pos
itive
rate
E F G H
I J K L
Known Dx LOOCV Known Dx LOOCV
Internal Validation
eyes body
��� �� 0 5���
���
��
0
5
10
Change in Body Fixation (%)
Cha
nge
in E
ye F
ixat
ion
(%)
TDASD
M N
External Validation
5Change in Body Fixation (%)
Cha
nge
in E
ye F
ixat
ion
(%)
��� �� 0 5���
���
��
0
5
10O
6 IndependentTest Cases
INFANT SIBLING STUDY
A National Institutes of Health Autism Center of Excellence
Translational Opportunities
48
•High-throughput, low-cost, deployment of universal screening in the community
•Early detection, early intervention, optimal outcome
•Prevention or attenuation of intellectual disability in ASD
Marcus Autism Center49
Screening devices in primary care offices?
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
Age (in months)
Fixati
on T
ime,
Eyes
(%)
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
Age (in months)
Fixati
on T
ime,
Eyes
(%)
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
Age (in months)
Fixati
on T
ime,
Eyes
(%)
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
Age (in months)
Fixati
on T
ime,
Eyes
(%)
Developmental Instantiation of a Spectrum of Social Disability:A GLIMPSE INTO SIBLING RESILIENCE (eye fixation)
50
HR-ASD_No-Dx (N = 18)TD (N = 29)
ASD (N = 13)HR-ASD_BAP (N = 10)
Age (in months)
Outcome x Time:
F = 6.95, p < 0.001
2 3 4 � 6 9 12 �� 18 24���
0�����
Age (in months)Rate
-of-C
hang
e 2 3 4 � 6 9 12 �� 18 24ï�ï�024
Chan
ge
2 3 4 � 6 9 12 �� 18 24010203040��6070
Fixa
tion
Tim
e (%
)
2 3 4 � 6 9 12 �� 18 24�����
0�������
Age (in months)
2 3 4 � 6 9 12 �� 18 24ï�ï�024
2 3 4 � 6 9 12 �� 18 24010203040��6070
No Eye Decline in First6 Months, UnaffectedOutcome (N = 16)
TD (N = 29) ASD (N = 13)Eye Decline in First6 Months, ResilientOutcome (N = 12)
F G
INFANT SIBLING STUDY
A National Institutes of Health Autism Center of Excellence New Scientific Hypotheses
51
•Genetics: gene expression and methylation studies
•Gene x Environment: alleles more plastic to environmental influences?
•Targeting onset of treatment at these “INFLECTIONABLE” points?
•WILLIAMS SYNDROME
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
2 3 4 5 6 9 12 15 18 240
10
20
30
40
50
60
70
month
perc
ent fixation
TD−tooYoung unfiltered
Eye FixationAre we wrong? Not one but in fact two curves?
TD eyesASD eyes
perc
ent
fixat
ion
mean95% CI
age (months)
•Reflexive•Experience Expectant•Subcortically controlled
• Interactional, Reward-Driven
•Experience Dependent
•Cortically controlled
INFANT SIBLING STUDY
A National Institutes of Health Autism Center of Excellence
53
•Human Developmental Neuroimaging
•Specific developmental timing of cortical-subcortical connectivity
•Non-Human Primate Developmental Neuroimaging
New Scientific Hypotheses
Toddlers
Au;sm Disrupts the Plaeorm for Brain Development
AGE (in months)birth 18 months
55
The Brain Becomes Who We Are....
H-J Park PhD
MH Johnson PhD
JE LeDoux PhD
White Ma)er Development
56
Improving Access to Early Interven;on….from 5 years to 2 years
ALLEVIATE AUTISM
…so how do we achieve 25 hours per week in which the child is engaged ac#vely and produc#vely in meaningful ac;vi;es?
(Na3onal Research Council, 2001)
“Less than 20% of children with Autism in the US are identified before the age of 3 years”
FamilyPrimary
Care Physician
Early Intervention
Provider
Augmen;ng Access to Early Treatment
Amy Wetherby, PhD
Jennifer Stapel-Wax, PsyD
Marcus Autism Center58
the Community: Families, Pediatricians, Early Intervention Providers
9292
Marcus Autism Center
Supports for better skillswModel and expand language and play skills wExtend activity, child’s roles, & transitions
wBalance demands and supports
Supports for a common agendawPositioning wFollow child’s attentional focus wMotivating activity with clear roles & turns
Supports for social reciprocitywNatural reinforcers wWaiting for initiation and balance of turns
wClear message to ensure comprehension
Teaching Strategies & Supports to Promote Active Engagement
Marcus Autism Center
Child BehaviorsACTIVE ENGAGEMENT
1. Emotional Regulation2. Productivity3. Social Connectedness4. Gaze to Face5. Response to Verbal Bids6. Directed Communication7. Flexibility8. Generative Ideas
Parent BehaviorsTRANSACTIONAL SUPPORTS
1. Participation & Role2. Make Activity Predictable3. Follow Child’s Attention4. Promote Initiations5. Balance of Turns6. Support Comprehension7. Modeling8. Expectations & Demands
Goals for Early Treatment:
Every wakeful hour in the home and in the community
62
Marcus Autism Center63
To make au;sm an issue of diversity, not of disability
Our ultimate goal
