Three EU funded Multi-Centre Studies focused on
Child & Adolescent Psychiatry
• TACTICS – Compulsivity in ASD & OCD• EU-AIMS – European Autism Interventions
A Multicentre Study for Developing New Medications
• MATRICS – Multidisciplinary Approaches to Translational Research In Conduct Syndromes
The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278948
TACTICS
EU FP7 consortium focused on compulsivity in:
• Obsessive Compulsive Disorder• Autism Spectrum Disorders• Matched Controls
• Coordinatoring team: • Prof. Jan Buitelaar / Dr. Jeffrey Glennon• Donders Institute, Radboud University Medical Centre,
Nijmegen, The Netherlands.
2
The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278948
11 partners across 8 countries
3
Radboud University Nijmegen (Medical Center)
King’s College London
Zentralinstitut fur seelische Gesundheit
University Medical Center Utrecht
Tel Aviv University
University College Cork
Massachusetts General Hospital
GenOway S.A.
University of Cambridge
Concentris research management GmbH
H. Lundbeck A/S
1H PRESS MRS Results from Anterior Cingulate Cortex
• Voxel Dimensions = 2 cm x 2 cm x 2cm• Prescribed from a “classic” ADNI-2/GO volume scan• Also used to determine WM/GM/CSF contribution• TE = 30 ms• TR = 3000 ms• NEX = 96• Total Acquisition Time ~ 6 mins• No of successful spectra from ACCASD = 51 (out of 68); OCD = 29 (out of 34); HC= 53 (out of 61)
Voxel Positions
Superposition on the MNI152 template of: (A) all ACC and (B) left dorsal striatum voxelsLondon(blue), Mannheim (red), Nijmegen (yellow), and Utrecht (green)
Marcel Zwiers (Donders)
“Typical” example from Anterior Cingulate
NAA
ChomI
Cr
Cr
glnglu
Dave Lythgoe (King’s College London)
Voxel composition and glutamate concentrations
ASD OCD HC F statistic p-value
Mean SD Mean SD Mean SD
ACC
% grey matter 67.8 8.6 68 10 67 11 0.98 0.91
% white matter 11.6 2.9 11.23 4.5 12.5 4.2 1.17 0.32
% CSF 20.5 9.0 20.9 10.5 20.5 9.9 0.20 0.98
Glutamate (i.u.) 12.4 3.1 11.5 3.2 11.3 2.4 3.62 0.019*
Striatum
% grey matter 56.0 7.7 57.3 10.5 58.0 9.0 0.54 0.59
% white matter 43.3 8.1 42.3 10.8 41.0 9.1 0.70 0.50
% CSF 0.66 0.97 0.44 0.52 0.99 1.8 1.51 0.22
Glutamate (i.u.) 7.3 1.7 7.1 1.3 7.1 1.3 1.26 0.310
Sig at p < 0.05 corrected for multiple comparisons and co-varying for 4 sites, 3 scanner manufactures
Jill Naaijen (Donders)
Forward – translation
Clinical Trial of Memantine
Well tolerated NMDA antagonist Reduces cerebral glutamate
Correlation between ACC glutamate and compulsivity(r=0.24, p=0.03 - derived from the Repetitive Behaviours Scale)
Back - translation
Rodent models linking a tangible psychiatric symptom/behaviour to brain chemistry
Ralf Dittmann (Donders)
10
SVM - training
Input Output
Volumes from group 1
Volumes from group 2
…
… Map: Discriminating regions between group 1 and group 2
Pattern recognition approach: Multivariate Analysis
SVM - test Prediction: group 1 or group 2New example
Applying Machine Learning Methods to Brain Images
Automated “Diagnosis” of Adult Autism
90% Accuracy
Ecker C et al, Describing the brain in autism in five dimensions, The Journal of Neuroscience 2010 30(32),: 10612-10623.
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
The Consortium
12
Eva Loth
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Project Structure
13
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI) 14
http://www.eu-aims.eu/
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Primary Study Objectives
● To identify biomarkers and methodologies that can be used to stratify individuals with ASD into more (biologically) homogeneous subgroups and that predict clinical outcome
● To examine how the clinical ASD phenotype and biomarker profile develop over time
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Why we need biomarkers?**Objective measure of a quantifiable process
● Risk/ diagnostic biomarker: predicts which child will develop ASD, detect ASD as early as possible
● Stratification biomarker: groups patients into biologically (more homogeneous) subtypes
● Prognostic biomarker: predicts the progression of symptoms and ‘outcome’ in adulthood
● Predictive biomarker: Estimates a patient’s treatment response ● Biomarker as surrogate outcome measure: predicts clinical
outcome and can be used as a substitute for a clinical end-point
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Multi-modal assessment
• King’s College London• Cambridge• Nijmegen• Utrecht• Mannheim• Rome• Karolinska Institute
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Qualification Advice from EMA
18
Priorities to be considered in the core analysis plan:• Define cut-offs for clinically
meaningful changes in primary outcome measures and surrogate outcome measures
• Cut-offs for stratification biomarkers
• Establishing sensitivity and specificity of any biomarker
• Independent replication, in particular to validate a biomarker as a surrogate outcome measure
• Test-retest reliabilityLoth, Spooren et al., Nature Reviews Drug Discovery, 2015
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
EU-AIMS LEAP Study Recruitment
19
0 11 23 3459
91127
169211
253
311
369
433
497
561
625
689695701708
714721727733740746753759765
0 16 26 4567
97132
171208
247277
320
374419
468
529577
636674689
718740756765779794
0.0
100.0
200.0
300.0
400.0
500.0
600.0
700.0
800.0
900.0
Feb-
14
Mar
-14
Apr-
14
May
-14
Jun-
14
Jul-1
4
Aug-
14
Sep-
14
Oct
-14
Nov
-14
Dec-
14
Jan-
15
Feb-
15
Mar
-15
Apr-
15
May
-15
Jun-
15
Jul-1
5
Aug-
15
Sep-
15
Oct
-15
Nov
-15
Dec-
15
Jan-
16
Feb-
16
Mar
-16
Apr-
16
May
-16
Jun-
16
End of March 2016
Target
Actual
Recr
uitm
ent c
ompl
etes
for a
ll sit
es e
xcep
t KI
Original recruitment completion deadline for all sites except KI.
Target: 600: 350 ASD, 250 TD
Caroline Wooldridge
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Data Cleaning
20
Banksy
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
Stratification by participant characteristics
• Age• Sex • Comorbidities• IQ
21
Loth, Spooren et al., 2015, Nat Rev Drug Discovery
EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)
II. Stratification by …
22
Brain anatomy, function, cognitive profile: Cluster analysis, functional data analysis, Multivariate pattern recognition
Genetic-molecular profile:Network-based stratification
The research leading to these results has received funding from the European Community’sSeventh Framework Programme (FP7/2007– 2013) under grant agreement n° 603016
Aggression!
Reactive Aggression (Frustration)
Proactive aggression (Planned act)
Hot blooded
Coldblooded