Biomarkers in Autism Spectrum Disorder PI: James McPartland, Ph.D. - PowerPoint PPT Presentation

Biomarkers in Autism Spectrum Disorder PI: James McPartland, Ph.D. Yale Child Study Center

Overview ■State of biomarker science in autism ■Rationale for ABC-CT ■Study design ■Preliminary results ■Ongoing activities The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 2

Autism spectrum disorder (ASD) ■ ASD is a behaviorally defined neurodevelopmental condition of unknown etiology ■ Social-communicative deficits ■ Restricted, repetitive behavior or interests ■ Heterogeneity in clinical phenotype ■ Core social features ■ Associated features (e.g., cognitive function) ■ Gold standard for quantifying symptoms (clinical, research) ■ Clinician-rated behavioral assessment and parent interview ■ Caregiver and self-report questionnaires ■ No established biomarkers for any context of use The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 3

State of the Science: ASD Biomarkers ■ Promise of EEG and eye-tracking ■ Viable in population ■ Economical, accessible ■ Multiple candidate markers ■ Mechanism ■ Symptom domain ■ Suggestive evidence ■ Sensitivity to diagnostic status ■ Association with symptoms ■ Limited evidence ■ Test-retest reliability ■ Stability over development ■ Sensitivity to clinical change ■ Influence of methodological variation The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 4

Autism Biomarkers Consortium for Clinical Trials ■ Test well-evidenced biomarkers ■ Acquired via practical assays ■ Large sample (including TD) ■ Deep phenotyping ■ Longitudinal design ■ Methodological rigor The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 5

ABC-CT Objectives 1. Evaluate candidate biomarkers for clinical trials ■ Feasibility of implementation ■ Reliability across sites ■ Construct validity ■ Discrimination between ASD and TD ■ Stratification within ASD ■ Developmental stability/Sensitivity to change ■ Predictive of course 2. Compare to conventional clinician and caregiver assessments 3. Create a community resource spanning genetics, biomarkers, and clinical and behavioral information 4. Develop infrastructure viable for clinical trials The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 6 6

ABC-CT Study Design ■ Multi-site, naturalistic study ■ Administrative Core: Yale Center for Clinical Investigation ■ Sites : Duke, UCLA, UW, Boston Children’s Hospital, Yale ■ Data Coordinating Core : YCCI/YC Analytical Sciences, Prometheus ■ Data Acquisition and Analysis Core : SCRI, SiStat, Duke, Yale, BCH, Penn ■ Feasibility study: 25 children with ASD and 25 with typical development ■ Main study: 200 children with ASD and 75 with TD ■ Three time points (Baseline, 6 weeks, 24 weeks) ■ Biomarkers of social-communicative function ■ Harmonized with EU-AIMS consortium ■ Commonly used clinician and caregiver assessments ■ Blood draw for participants with ASD and biological parents ■ Integrative governance (U19 mechanism) The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 7

ABC-CT Study Design ■ Sample characteristics ■ Eye-tracking ■ Age 6-11 ■ Activity monitoring ■ IQ 60-150 ■ Interactive social task ■ Medication stable 8 weeks ■ Static social scenes* ■ EEG ■ Biological motion* ■ Resting EEG ■ Pupillary light reflex* ■ Visual evoked potentials ■ Blood draw ■ Biological motion ■ Probands, biological ■ N170 ERP to faces* parents * EU-AIMS paradigm The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 8 8

ABC-CT Study Design ■ Clinician administered ■ Caregiver report ■ Autism Diagnostic ■ Aberrant Behavior Checklist Observation Schedule ■ Autism Impact Measure ■ Autism Diagnostic ■ Pervasive Developmental Disorder Interview – Revised Behavior Inventory ■ Vineland Adaptive ■ Social Responsiveness Scale Behavior Scales ■ Child and Adolescent Symptom ■ Differential Ability Scales Inventory ■ Clinical Global ■ ACE Family/Medical History Impression Scale ■ Intervention/Medication History ■ Demographics/Screening The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 9 9

ABC-CT Rigor ■ Weekly calls within and across cores ■ Biomarker data ■ Identical biomarker acquisition hardware and protocols at sites ■ DAAC staff performed on-site setup and training ■ Manuals of Procedures ■ Biomarker acquisition, room setup, behavioral management ■ QC and feedback to data collection sites within 72 hours ■ Centralized processing and analysis ■ Regulatory ■ Administered according to Good Clinical Practice guidelines ■ Statistical ■ Pre-designated directional hypothesis for primary DV from primary assay within each data modality The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 10

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org ABC-CT Enrollment ■ Completion: N = 374 (ASD = 260, TD = 114) ■ Enrollment: N = 399 (ASD = 280, TD = 119) 100 200 300 400 500 600 700 800 900 0 9/26/2016 10/10/2016 10/24/2016 11/3/2016 11/11/2016 Pre-Screened 11/28/2016 12/5/2016 12/20/2016 1/1/2017 1/15/2017 52 wks 1/30/2017 2/13/2017 2/27/2017 3/13/2017 Screened at T1 3/27/2017 4/10/2017 4/24/2017 5/8/2017 5/22/2017 6/5/2017 6/19/2017 6/30/2017 7/17/2017 Screen Failure 7/27/2017 8/14/2017 8/28/2017 9/4/2017 9/18/2017 10/2/2017 10/15/2017 10/30/2017 Enrolled 11/13/2017 11/27/2017 12/11/2017 1/2/2018 1/15/2018 1/29/2018 2/12/2018 Discontinued 2/26/2018 3/12/2018 3/28/2018 4/9/2018 4/23/2018 5/7/2018 5/21/2018 6/4/2018 Completed 6/18/2018 7/2/2018 7/16/2018 7/30/2018 8/13/2018 8/27/2018 9/10/2018 Target for Screened at T1 9/24/2018 ENROLLMENT 10/8/2018 END OF 10/31/2018 11/9/2018 11/30/2018 12/10/2018 1/2/2019 1/21/2019 2/4/2019 2/18/2019 3/4/2018 3/18/2019 4/22/2019 374 399 510 822 5/6/2019 38 98 11

ABC-CT Biomarker Acquisition ■ EEG neural response to faces (N170) ■ ASD: 74% across time points ■ TD: 92-94% across time points ■ Eye-tracking composite ■ ASD: 97-99% across time points ■ TD: 98-100% across time points ■ Blood draw ■ Probands: 76.8% ■ One or both parents: 85.0% 52 wks The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 12

Primary EEG Biomarker: N170 Latency ■ N170 event-related potential ■ Neural index of early stage face processing ■ Activity in superior temporal sulcus, fusiform gyrus ■ Delayed in children through adults with ASD ■ Experiment ■ Faces, inverted faces, houses ■ EU-AIMS harmonized assay ■ Prediction ■ Increased N170 latency to upright faces at 52 wks right posterior temporal electrode cluster 13 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 13

Primary EEG Biomarker: N170 Latency Whole sample TD ASD Test (N=179) (N=59) (N=120) TD vs ASD p Mean 204.8 194.3 209.2 F(1,201)=10.7 <.01 SD 30.2 26.8 30.6 N170 Latency to Upright Faces 52 wks Faster l atency 14 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 14

Primary EEG Biomarker: N170 Latency Time 1 (Baseline) Time 2 (6 weeks) Time 3 (6 months) ASD TD ASD TD ASD TD Faster latency Frequency Frequency Frequency Frequency Frequency Frequency The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 15

Primary EEG Biomarker: N170 Latency ICC All ASD TD T1,T2,T3 .62 .53 .75 T1,T2 .68 .67 .67 T1,T3 .58 .45 .78 T2,T3 .62 .49 .78 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 16

Primary ET Biomarker: Social Composite ■ Eye-tracking social composite ■ Visual attention to onscreen faces and heads ■ Modulated by amygdala and superior temporal sulcus ■ Reduced attention to faces in ASD ■ Experiments ■ Two classes of videos ■ Images of social interactions ■ Prediction ■ Reduced proportion of looking time to faces in ASD Activity Monitoring Social Interactive Static Scenes 17 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 17

Primary ET Biomarker: Social Composite Whole sample TD ASD Test (N=222) (N=64) (N=158) TD vs ASD p Mean .236 .290 .214 F(1,220)=51.5 <.01 SD .079 .073 .070 ET Composite # TD Participants Less looking at social information # ASD Participants 18 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 18

Primary ET Biomarker: Social Composite Time 1 (Baseline) Time 2 (6 weeks) Time 3 (6 months) ASD TD ASD TD ASD TD Less looking at social information Frequency Frequency Frequency Frequency Frequency Frequency The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 19

Primary ET Biomarker: Social Composite ICC All ASD TD T1,T2,T3 .83 .80 .78 T1,T2 .83 .79 .82 T1,T3 .83 .80 .77 T2,T3 .83 .81 .75 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 20