Biomarkers in Autism Spectrum Disorder - ISCTMThe Autism Biomarkers Consortium for Clinical Trials l...

Biomarkers in Autism Spectrum Disorder

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

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


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


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


Autism Biomarkers Consortium for Clinical Trials

■ Test well-evidenced biomarkers■ Acquired via practical assays■ Large sample (including TD)■ Deep phenotyping■ Longitudinal design■ Methodological rigor

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

ABC-CT Objectives1. 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 assessments3. Create a community resource spanning genetics, biomarkers,

and clinical and behavioral information4. Develop infrastructure viable for clinical trials


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)


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


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


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


52 wks

ABC-CT Enrollment

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

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

END OF ENROLLMENT


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%


52 wks

Primary EEG Biomarker: N170 Latency

13

■ 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


52 wks

Primary EEG Biomarker: N170 LatencyWhole 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 <.01SD 30.2 26.8 30.6

14

Faster latency

N170 Latency to Upright Faces


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


Faster latency

TDASD TDASD TDASD

FrequencyFrequency FrequencyFrequency FrequencyFrequency


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 ET Biomarker: Social Composite

17

■ 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


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 <.01SD .079 .073 .070

Less looking at social information



Less looking at social information


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

TDASD TDASD TDASD

FrequencyFrequency FrequencyFrequency FrequencyFrequency


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



52 wks

N170 Latency: Biomarker Qualification

21

■ 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


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

Overall PIJames McPartland, Ph.D.

Administrative CorePI: 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.; ChairEvdokia 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

DukePD: Geraldine Dawson, Ph.D.; Co-Director, Clinical Workgroup

Boston Children’sPD: Charles Nelson, Ph.D.;

Co-Director, EEG Workgroup

UCLAPD: Shafali Jeste, M.D.;

Co-Director, EEG WorkgroupCo-I: Scott Johnson, Ph.D.;Co-Director, ET Workgroup

UWPD: Raphael Bernier, Ph.D.;

Co-Director, Clinical Workgroup

YalePD: James McPartland, Ph.D.PD: Kasia Chawarska, Ph.D.

Data Coordinating CorePD: 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-TrackingFred Shic, Ph.D.;

Co-Director, ET WorkgroupMichael Platt, Ph.D.Adam Naples, Ph.D.

EEGSara Webb, Ph.D.April Levin, M.D.

StatisticalCatherine Sugar, Ph.D.;

Director, AnalyticsDamla Senturk, Ph.D.

Gerhard Helleman, Ph.D.

BehavioralMichael Murias, Ph.D.;

Director; Lab-based Behavioral Assessment

Workgroup

Data

Monitoring

Oversight

Hardware set-upAcquisition protocols

QA/QC

Data

Autism Biomarkers Consortium for Clinical TrialsFNIH Biomarkers Consortium

Project Team

James McPartland, Ph.D.; Co-chairLinda Brady, Ph.D; Co-chairGeraldine 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

Version D_1

Autism Biomarkers Consortium for Clinical Trials

Autism BiomarkersConsortium forClinical Trials

Biomarkers in Autism Spectrum Disorder - ISCTMThe Autism Biomarkers Consortium for Clinical Trials l...

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