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

▶

Jan 27, 2024 490 likes •739 views

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

SLIDE 1

Biomarkers in Autism Spectrum Disorder

PI: James McPartland, Ph.D. Yale Child Study Center

SLIDE 2

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 2

Overview

■State of biomarker science in autism ■Rationale for ABC-CT ■Study design ■Preliminary results ■Ongoing activities

SLIDE 3

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 3

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

SLIDE 4

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 4

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

SLIDE 5

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 5

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

SLIDE 6

6 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 6

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

SLIDE 7

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 7

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)

SLIDE 8

8 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 8

ABC-CT Study Design

■ Sample characteristics

■ Age 6-11 ■ IQ 60-150 ■ Medication stable 8 weeks

■ EEG

■ Resting EEG ■ Visual evoked potentials ■ Biological motion ■ N170 ERP to faces*

■ Eye-tracking

■ Activity monitoring ■ Interactive social task ■ Static social scenes* ■ Biological motion* ■ Pupillary light reflex*

■ Blood draw

■ Probands, biological

parents

* EU-AIMS paradigm

SLIDE 9

9 The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 9

ABC-CT Study Design

■ Clinician administered

■ Autism Diagnostic

Observation Schedule

■ Autism Diagnostic

Interview – Revised

■ Vineland Adaptive

Behavior Scales

■ Differential Ability Scales ■ Clinical Global

Impression Scale

■ Caregiver report

■ Aberrant Behavior Checklist ■ Autism Impact Measure ■ Pervasive Developmental Disorder

Behavior Inventory

■ Social Responsiveness Scale ■ Child and Adolescent Symptom

Inventory

■ ACE Family/Medical History ■ Intervention/Medication History ■ Demographics/Screening

SLIDE 10

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 10

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

SLIDE 11

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 11

52 wks

ABC-CT Enrollment

■ Enrollment: N = 399 (ASD = 280, TD = 119) ■ Completion: N = 374 (ASD = 260, TD = 114)

822 510 98 399 38 374

100 200 300 400 500 600 700 800 900 9/26/2016 10/10/2016 10/24/2016 11/3/2016 11/11/2016 11/28/2016 12/5/2016 12/20/2016 1/1/2017 1/15/2017 1/30/2017 2/13/2017 2/27/2017 3/13/2017 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 7/27/2017 8/14/2017 8/28/2017 9/4/2017 9/18/2017 10/2/2017 10/15/2017 10/30/2017 11/13/2017 11/27/2017 12/11/2017 1/2/2018 1/15/2018 1/29/2018 2/12/2018 2/26/2018 3/12/2018 3/28/2018 4/9/2018 4/23/2018 5/7/2018 5/21/2018 6/4/2018 6/18/2018 7/2/2018 7/16/2018 7/30/2018 8/13/2018 8/27/2018 9/10/2018 9/24/2018 10/8/2018 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 5/6/2019

Pre-Screened Screened at T1 Screen Failure Enrolled Discontinued Completed Target for Screened at T1

END OF ENROLLMENT

SLIDE 12

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 12

52 wks

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%

SLIDE 13

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 13

52 wks

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

right posterior temporal electrode cluster

SLIDE 14

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 14

52 wks

Primary EEG Biomarker: N170 Latency

Whole sample (N=179) TD (N=59) ASD (N=120) Test TD vs ASD p Mean 204.8 194.3 209.2 F(1,201)=10.7 <.01 SD 30.2 26.8 30.6

Faster latency N170 Latency to Upright Faces

SLIDE 15

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 15

Time 1 (Baseline) Time 2 (6 weeks) Time 3 (6 months)

Primary EEG Biomarker: N170 Latency

Faster latency

TD ASD TD ASD TD ASD Frequency Frequency Frequency Frequency Frequency Frequency

SLIDE 16

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 16

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

Primary EEG Biomarker: N170 Latency

SLIDE 17

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 17

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

SLIDE 18

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 18

ET Composite

# ASD Participants # TD Participants

Whole sample (N=222) TD (N=64) ASD (N=158) Test TD vs ASD p Mean .236 .290 .214 F(1,220)=51.5 <.01 SD .079 .073 .070

Less looking at social information

Primary ET Biomarker: Social Composite

SLIDE 19

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 19 Less looking at social information

Primary ET Biomarker: Social Composite

Time 1 (Baseline) Time 2 (6 weeks) Time 3 (6 months) TD ASD TD ASD TD ASD Frequency Frequency Frequency Frequency Frequency Frequency

SLIDE 20

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 20

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

Primary ET Biomarker: Social Composite

SLIDE 21

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 21

52 wks

N170 Latency: Biomarker Qualification

■ BQ LOI submitted November, 2018 ■ Accepted May, 2019 ■ Proposed context of use

■ Biologically homogeneous subgroup ■ Enrich clinical trials by reducing heterogeneity

■ Considerations

■ Refining COU ■ Determining cut point ■ Functional differentiation of subgroup ■ Processing and equipment ■ Development of BQP ongoing ■ FDA DDT grant awarded September, 2019

52 wks

Faster Latency N170 Latency to Upright Faces

SLIDE 22

The Autism Biomarkers Consortium for Clinical Trials l www.asdbiomarkers.org 22

52 wks

ABC-CT: Ongoing Work

■ ET LOI submission in preparation ■ Preparing data for final analyses

(NCE through June 2020)

■ Primary analyses

■ Relationship to clinical characteristics ■ Sensitivity to change in clinical status

■ Data-driven methods and composites

■ Scientific questions raised

■ Replicability ■ Age groups ■ IQ ranges ■ Measuring sensitivity to change

SLIDE 23

Overall PI James McPartland, Ph.D. Administrative Core PI: James McPartland, Ph.D. Project Manager: Helen Seow, Ph.D. Associate Project Manager: Julie Holub Scientific Coordinator: Nicole Wright, M.S. Multicenter Support: Rhoda Arzoomanian, R.N., M.S.M. Communications: Lisa Brophy Steering Committee (voting / non-voting) PI: James McPartland, Ph.D. Site Director: Geraldine Dawson, Ph.D. DCC: James Dziura, Ph.D. DAAC: Sara Webb, Ph.D. NIH Project Scientists: Lisa Gilotty, Ph.D. Alice Kau, Ph.D. Margaret Grabb, Ph.D. Adam Hartman, M.D. BCPT: Linda Brady, Ph.D. NIH Program Officer: Ann Wagner, Ph.D. External Advisory Board Robert Schultz, Ph.D.; Chair Evdokia Anagnostou, M.D. Daniel Geschwind, M.D., Ph.D. Ami Klin, Ph.D. James McCracken, M.D. John Elder Robison Mustafa Sahin, M.D., Ph.D. Alison Singer, M.B.A. Jeremy Veenstra-Vanderweele, M.D. Collaborating Implementation Sites Duke PD: Geraldine Dawson, Ph.D.; Co-Director, Clinical Workgroup Boston Children’s PD: Charles Nelson, Ph.D.; Co-Director, EEG Workgroup UCLA PD: Shafali Jeste, M.D.; Co-Director, EEG Workgroup Co-I: Scott Johnson, Ph.D.; Co-Director, ET Workgroup UW PD: Raphael Bernier, Ph.D.; Co-Director, Clinical Workgroup Yale PD: James McPartland, Ph.D. PD: Kasia Chawarska, Ph.D. Data Coordinating Core PD: James Dziura, Ph.D. PD: Cynthia Brandt, M.D., M.P.H. QA: Alyssa Gateman, M.P.H., C.C.R.P. Sub: Prometheus Research NDAR/ NIH/ NIMH Data Repositories SPARK/ NIMH Repository and Genomics Resource Data Acquisition and Analysis Core PD: Sara Webb, Ph.D. Co-PD: Fred Shic, Ph.D. Eye-Tracking Fred Shic, Ph.D.; Co-Director, ET Workgroup Michael Platt, Ph.D. Adam Naples, Ph.D. EEG Sara Webb, Ph.D. April Levin, M.D. Statistical Catherine Sugar, Ph.D.; Director, Analytics Damla Senturk, Ph.D. Gerhard Helleman, Ph.D. Behavioral Michael Murias, Ph.D.; Director; Lab-based Behavioral Assessment Workgroup

Data Monitoring Oversight Hardware set-up Acquisition protocols QA/QC Data

Autism Biomarkers Consortium for Clinical Trials

FNIH Biomarkers Consortium Project Team James McPartland, Ph.D.; Co-chair Linda Brady, Ph.D; Co-chair Geraldine Dawson, Ph.D. Sara Webb, Ph.D. James Dziura, Ph.D. Catherine Sugar, Ph.D. Ann Wagner, Ph.D. William Potter, M.D., Ph.D. Laurel Beckett, Ph.D. Wendy Chung, M.D. Gahan Pandina, Ph.D. Declan Murphy, Ph.D. Bernard Fischer, M.D. David Millis, M.D., Ph.D., M.B.A. Rosa Canet-Aviles, Ph.D. FNIH Biomarkers Consortium Executive Committee

Autism Biomarkers Consortium for Clinical Trials