Bringing science to the community: A new system of healthcare delivery for infants & toddlers with autism spectrum disorders

Bringing science to the community: A new system of healthcare delivery for infants & toddlers with autism spectrum disorders Ami Klin, PhD Director, Marcus Autism Center, Children s Healthcare of Atlanta GRA Eminent Scholar Professor & Chief, Division of Autism, Department of Pediatrics, Emory University School of Medicine Emory Center for Translational Social Neuroscience

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 Marcus Autism Center 2

Conflicts of Interest No conflicts of interest associated with this presentation Marcus Autism Center 3

Marcus Autism Center 4

Marcus Autism Center at a glance: Strategic Plan 214-219 Transla;on Impact Clinical Resources Science Faculty Advancement Research Resources Excellence CENTER- BASED MODEL PROGRAM COMMUNITY- VIABLE OUTREACH MODEL The Science of Clinical Care

Research Enterprise Strategic Plan 214-219 CAUSES TREATMENT COMMUNITY- VIABLE SOLUTIONS VALUE PROPOSITION RESEARCH INITIATIVES RESEARCH INFRASTRUCTURE Strategy for Reseach Enterprise 13 RESEARCH CORES 9 INTERNAL, 4 COLLABORATIVE RESEARCH ADMINISTRATION INFORMATICS DATA MANAGEMENT & ANALYSIS Diagnosis Concept Psychopharmacology Social Neuroscience Animal Models Neurobiology Genetics Marcus Autism Center 6

Marcus Autism Center, An NIH Autism Center of Excellence Social Visual Engagement in Infants( to 36 months) Social Vocal Engagement in Infants ( to 36 months) Treatment in Infants & Toddlers (beginning at 12 months) Social Visual Engagement & Brain Development in a Model System $ 8.8 m total 7

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 CDC, 214; Mandell et al., 213; 214 Marcus Autism Center is an affiliate of Children s Healthcare of Atlanta. 212 Children s Healthcare of Atlanta Inc. All rights reserved. Marcus Autism Center 8

Challenges and Opportunities: Reducing Age of Diagnosis & Improving Acess to Care 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 9

GENETIC MECHANISMS OF SOCIALIZATION BEHAVIORAL LIABILITY SYMPTOMS First 2 years of life Jones et al. (28). Arch Gen Psy, 65(8), 946-54. Klin et al. (29). Nature, 459, 257-61. Jones & Klin (29). J Am Acad of Child Psy, 48(5): 471-3.

Our mission is to transform au;sm diagnosis and treatment to alter the life course of kids with au;sm FUTURE Age of Diagnosis (Phase II) FUTURE Age of Diagnosis (Phase I) Average Age of Diagnosis TODAY FUTURE Independent, College, Working, Rela;onships Posi2ve Outcome Window of Opportunity to Change Au2sm BEST SCENARIO NOW Not independent, Medium level of Supports TYPICAL NOW Disabled, High level of Supports PREVENT AUTISM ALLEVIATE AUTISM PROMOTE LANGUAGE REDUCE ASSOCIATED DISABILITIES (language, intellectual, behavioral, medical) 1 yr 2 yrs 3 yrs 4 yrs 5 yrs Development (Age) 6 yrs + Marcus Autism Center

Redefining Autism: Preventing costly impact 12 Marcus Autism Center is an affiliate of Children s Healthcare of Atlanta. 26 Children s Healthcare of Atlanta Inc. All rights reserved.

Developmental Trajectories

Au;sm Disrupts the Plaeorm for Brain Development MH Johnson PhD birth AGE (in months) 18 months White Ma)er Development The Brain Becomes Who We Are... JE LeDoux PhD H-J Park PhD 15

Attention to Biological Motion not significantly different from chance, p Non-verbal mental-age matched control Verbal mental-age match Klin & Jones (28). Developmental Science 11(1),4-6.

Two-year-olds with autism do not exhibit preferential attention to biological motion Autism Group N = 21 Typically-Developing Group, N = 39 Developmentally- Delayed Group, N = 16 Klin, Lin, Gorrindo, Ramsay, & Jones (29). Nature, 459, 257-261.

But during Pat-a-Cake... Autism Group N = 21 Typically-Developing Group, N = 39 Developmentally- Delayed Group, N = 16 Klin, Lin, Gorrindo, Ramsay, & Jones (29). Nature, 459, 257-261.

Exploring Audiovisual Synchrony Autism Group N = 21 A pat-a-cake finding led to the hypothesis that children s visual behavior was being guided by physical, not social contingencies.

Audiovisual Synchrony Quantification Change in Motion * Change in Sound = Audiovisual Synchrony CHANGE IN MOTION CHANGE IN SOUND AUDIOVISUAL SYNCHRONY Time

Cumulative Audiovisual Synchrony in Point- Light Animations Relative Audio-Visual Synchrony = Normalized Peak Difference Clap Location Max Synchrony Pat-a-cake Upright Inverted Feeding No Synchrony Inverted Upright

Klin, Lin, Gorrindo, Ramsay, & Jones (29). Nature, 459, 257-261.

Patterns of visual fixation to approaching caregiver Jones, Carr, Klin (28). Archives of General Psychiatry. 65(8):946-54.

How do 2-year-olds with autism watch the face of a caregiver? Eye: F 2,63 = 12.87, p<.1 d = 1.56 Mouth: F 2,63 = 5.599, p<.6 d = 1.4 Jones, Carr, Klin (28). 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 Jennings Xu ASD TD

Growth Charts of Social Engagement 3

Strategic Plan Diagnosis & Treatment Psychopharmacology & Clinical Trials Behavioral Neuroscience Animal Models Neurobiology Genetics Marcus Autism Center 31

Marcus Autism Center, An NIH Autism Center of Excellence Social Visual Engagement in Infants( to 36 months) Social Vocal Engagement in Infants ( to 36 months) Treatment in Infants & Toddlers (beginning at 12 months) Social Visual Engagement & Brain Development in a Model System 32

Infants

Growth Charts of Social Visual Engagement (Typically-Developing Children) 8 7 percent fixation percent fixation 6 5 4 3 2 1 eyes mouth body object 2 3 4 5 6 9 12 15 18 24 month age (months) Jones & Klin (213). Nature, 54, 427-431. TD mean +/- 1 SD

Eye Fixation Children with ASD relative to Typically-Developing Norms 7 percent fixation 6 5 4 3 2 TD eyes ASD eyes 1 2 3 4 5 6 9 12 15 18 24 TD, N=25, male, 1637 trials ASD, N=11, male, 747 trials age (months) mean 95% CI

7 6 Eye Fixation, and Rate of Change in Eye Fixation percent fixation 5 4 3 2 eyes D t fixation 1 4 2 2 2 3 4 5 6 9 12 15 18 24 age (months) mean 95% CI D eyes t 4 2 3 4 5 6 9 12 15 18 24

7 6 Eye Fixation, and Rate of Change in Eye Fixation percent fixation 5 4 3 2 TD eyes ASD eyes D t fixation 1 4 2 2 F1,34 = 11.9, p =.2 2 3 4 5 6 9 12 15 18 24 age (months) mean 95% CI D TD eyes t D ASD eyes t 4 2 3 4 5 6 9 12 15 18 24

35 3 Body Fixation Children with ASD relative to Typically-Developing Norms percent fixation 25 2 15 1 ASD body TD body 5 2 F1,34 = 1.6, p =.3 2 3 4 5 6 9 12 15 18 24 mean 95% CI D t fixation 1 1 2 2 3 4 5 6 9 12 15 18 24 D t ASD body D t TD body

35 3 Object Fixation Children with ASD relative to Typically-Developing Norms percent fixation 25 2 15 1 ASD object TD object 5 2 F1,34 = 12.8, p =.2 2 3 4 5 6 9 12 15 18 24 mean 95% CI D t fixation 1 1 2 2 3 4 5 6 9 12 15 18 24 D t ASD object D t TD object

Decline in Eye Fixation Predicts Severity of Outcome A Fixation Time, Eyes (%) C 7 6 5 4 3 2 1 mean ASD fixation on eyes direction of individual trajectories with positive PC1 scores direction of individual trajectories with negative PC1 scores 2 3 4 5 6 9 12 15 18 24 Age (in months) B Outcome at 24 Months (ADOS Social Affect) 2 15 1 5 15 1 5 5 1 15 PC1 Score r =.75 p =.7

7 6 Growth Charts of Social Engagement to Enable Early Diagnosis percent fixation 5 4 3 2 TD eyes ASD eyes D t fixation 1 4 2 2 2 3 4 5 6 9 12 15 18 24 age (months) mean 95% CI D TD eyes t D ASD eyes t 4 2 3 4 5 6 9 12 15 18 24

Differences Present within the First 6 Months of Life eyes A B C Fixation Time, Eyes (%) 1 9 8 7 6 5 4 3 2 Fixation Time, Eyes (%) 1 9 8 7 6 5 4 3 2 Fixation Time, Eyes (%) 1 9 8 7 6 5 4 3 2 TD ASD 1 1 1 2 3 4 5 6 2 3 4 5 6 Age (in months) Age (in months) D E F 1 1 8 2 3 4 5 6 Age (in months) body Fixation Time, Body (%) 9 8 7 6 5 4 3 2 1 Fixation Time, Body (%) 9 8 7 6 5 4 3 2 1 Fixation Time, Body (%) 7 6 5 4 3 2 1 2 3 4 5 6 Age (in months) 2 3 4 5 6 Age (in months) 2 3 4 5 6 Age (in months) G H 1 ASD Eyes Correlation Age months).5.5 1 24 18 15 12 9 6 4 2 Age months) 2 4 6 9 12 15 18 24

Internal Validation eyes body 1 Known Dx LOOCV Known Dx LOOCV E F G H 1 1 1 8 8 8 8 Fixation Time (%) 6 4 Fixation Time (%) 6 4 Fixation Time (%) 6 4 Fixation Time (%) 6 4 2 2 2 2 2 3 4 5 6 2 3 4 5 6 2 3 4 5 6 2 3 4 5 6 Rate of Change 1 5 Rate of Change 1 5 Rate of Change 1 5 Rate of Change 1 5 2 3 4 5 6 Age (in months) 2 3 4 5 6 Age (in months) 2 3 4 5 6 Age (in months) 2 3 4 5 6 Age (in months) I J K L True positive rate 1.8.6.4.2 True positive rate 1.8.6.4.2 True positive rate 1.8.6.4.2 True positive rate 1.8.6.4.2.2.4.6.8 1 False positive rate.2.4.6.8 1 False positive rate.2.4.6.8 1 False positive rate.2.4.6.8 1 False positive rate

External Validation M 1 O 1 6 Independent Test Cases Change in Eye Fixation (%) 5 TD ASD 5 Change in Body Fixation (%) 5 Change in Eye Fixation (%) 5 5 Change in Body Fixation (%)

Translational Opportunities 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 48

Screening devices in primary care offices? Marcus Autism Center 49

Developmental Instantiation of a Spectrum of Social Disability: A GLIMPSE INTO SIBLING RESILIENCE (eye fixation) Fixation Time, Eyes (%) 7 6 5 4 3 2 1 Fixation Time, Eyes (%) 7 6 5 4 3 2 1 Outcome x Time: F = 6.95, p <.1 2 3 4 25 36 4 5 69 912 1215 1518 18 24 24 Age (in Age months) (in months) TD (N = 29) HR-ASD_No-Dx (N = 18) HR-ASD_BAP (N = 1) ASD (N = 13) F Fixation Time (%) Change Rate-of-Change 7 6 4 3 2 1 4 2 No Eye Decline in First 6 Months, Unaffected Outcome (N = 16) 2 3 4 6 9 12 18 24 2 3 4 6 9 12 18 24 2 3 4 6 9 12 18 24 Age (in months) G TD (N = 29) ASD (N = 13) 7 6 4 3 2 1 4 2 Eye Decline in First 6 Months, Resilient Outcome (N = 12) 2 3 4 6 9 12 18 24 2 3 4 6 9 12 18 24 2 3 4 6 9 12 18 24 Age (in months) 5

New Scientific Hypotheses 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 51

Eye Fixation Are we wrong? Not one but in fact two curves? Reflexive Experience Expectant 7 Subcortically controlled Interactional, Reward-Driven Experience Dependent Cortically controlled percent fixation 6 5 4 3 2 TD eyes ASD eyes 1 2 3 4 5 6 9 12 15 18 24 age (months) mean 95% CI

New Scientific Hypotheses Human Developmental Neuroimaging Specific developmental timing of corticalsubcortical connectivity Non-Human Primate Developmental Neuroimaging 53

Toddlers

Au;sm Disrupts the Plaeorm for Brain Development MH Johnson PhD birth AGE (in months) 18 months White Ma)er Development The Brain Becomes Who We Are... JE LeDoux PhD H-J Park PhD 55

Improving Access to Early Interven;on.from 5 years to 2 years ALLEVIATE AUTISM (Na3onal Research Council, 21) 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? Less than 2% of children with Autism in the US are identified before the age of 3 years 56

Augmen;ng Access to Early Treatment Family Primary Care Physician Amy Wetherby, PhD Early Intervention Provider Jennifer Stapel- Wax, PsyD

the Community: Families, Pediatricians, Early Intervention Providers Marcus Autism Center 58

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Teaching Strategies & Supports to Promote Active Engagement Supports for better skills w Model and expand language and play skills w Extend activity, child s roles, & transitions w Balance demands and supports Supports for social reciprocity w Natural reinforcers w Waiting for initiation and balance of turns w Clear message to ensure comprehension Supports for a common agenda w Positioning w Follow child s attentional focus w Motivating activity with clear roles & turns Marcus Autism Center

Goals for Early Treatment: Every wakeful hour in the home and in the community Child Behaviors ACTIVE ENGAGEMENT 1. Emotional Regulation 2. Productivity 3. Social Connectedness 4. Gaze to Face 5. Response to Verbal Bids 6. Directed Communication 7. Flexibility 8. Generative Ideas Parent Behaviors TRANSACTIONAL SUPPORTS 1. Participation & Role 2. Make Activity Predictable 3. Follow Child s Attention 4. Promote Initiations 5. Balance of Turns 6. Support Comprehension 7. Modeling 8. Expectations & Demands Marcus Autism Center 62

Our ultimate goal To make au;sm an issue of diversity, not of disability Marcus Autism Center 63