Professional Documents
Culture Documents
Ares(2013)2786549 - 30/07/2013
THEME [HEALTH.2013.2.2.1-2]
[Development of effective imaging tools for diagnosis,
monitoring and management of mental disorders]
Grant agreement for: Collaborative project
Table of Contents
Part A
A.1 Project summary ...................................................................................................................................... 3
A.2 List of beneficiaries ..................................................................................................................................4
A.3 Overall budget breakdown for the project ............................................................................................... 5
Workplan Tables
WT1 List of work packages ............................................................................................................................1
WT2 List of deliverables .................................................................................................................................2
WT3 Work package descriptions ................................................................................................................... 7
Work package 1......................................................................................................................................7
Work package 2....................................................................................................................................10
Work package 3....................................................................................................................................12
Work package 4....................................................................................................................................15
Work package 5....................................................................................................................................18
Work package 6....................................................................................................................................21
Work package 7....................................................................................................................................24
Work package 8....................................................................................................................................27
WT4 List of milestones .................................................................................................................................30
WT5 Tentative schedule of project reviews ................................................................................................. 31
WT6 Project effort by beneficiaries and work package ................................................................................32
WT7 Project effort by activity type per beneficiary ...................................................................................... 33
WT8 Project efforts and costs ......................................................................................................................34
A1:
Project summary
Project Number
602478
Project Acronym
METSY
Starting date
01/09/2013
Duration in months
48
FP7-HEALTH-2013-INNOVATION-1
Free keywords
HEALTH.2013.2.2.1-2:
Development of effective
imaging tools for
diagnosis, monitoring and
management of mental
disorders
Positron emission tomography, magnetic resonance
imaging, systems biology, metabolomics, lipid
metabolism, endocannabinoids, obesity, psychosis,
schizophrenia
Abstract
The theme of this collaborative project is development and application of neuroimaging and bioinformatics
tools to study lipid metabolism as a common pathogenic link between psychotic disorders and its metabolic
co-morbidities. The overall objective is to identify, prioritize and evaluate multi-modal blood and neuroimaging
markers with diagnostic potential for prediction and monitoring of psychotic disorders and associated metabolic
co-morbidities. We aim to (1) optimise a multidisciplinary approach for combining positron emission tomography
(PET) and magnetic resonance imaging (MRI) with metabolomics approaches, (2) develop a PET-method for
exploring endocannabinoid pathways in early psychosis in longitudinal study setting, and (3) develop combined
PET-MRI biomarker methodology for psychiatric disorders by studying neurotransmitter interactions with multiple
PET scan and MRI sequences. The balance of two or more neurotransmitter systems may function as a novel
biomarker in these disorders. The expected impacts are (1) etiopathogenic understanding, (2) new validated
multi-modal markers for early disease detection and monitoring, (3) new tools for the identification of subjects
who may benefit from specific treatment (4) discovery of new avenues for disease prevention and therapy, and
(5) new tools and processes for applying brain imaging in personalised medicine. The consortium brings together
clinicians, researchers and industry partners in the domains of psychiatry, neuroimaging, metabolic research,
systems biology and bioinformatics.
A2:
List of Beneficiaries
Project Number
602478
Project Acronym
METSY
List of Beneficiaries
Name
Short name
Country
Project entry
10
month
Project exit
month
VTT
Finland
48
BIOMAX INFORMATICS AG
BIOMAX
Germany
48
SERMAS
Spain
48
TURUN YLIOPISTO
UTU
Finland
48
THL
Finland
48
PHILIPS
Germany
48
KCL
United Kingdom
48
No
A3:
Budget Breakdown
Project Number
602478
Project Acronym
METSY
Participant
number in
11
this project
Fund.
12
%
Ind. costs
13
RTD /
Innovation
(A)
Demonstration
(B)
Management
(C)
Other (D)
Total
A+B+C+D
Requested
EU
contribution
VTT
75.0
1,058,185.00
0.00
115,030.00
96,360.00
1,269,575.00
1,005,028.00
BIOMAX
75.0
799,200.00
0.00
1,600.00
72,360.00
873,160.00
673,360.00
SERMAS
75.0
571,267.20
0.00
2,500.00
0.00
573,767.20
430,950.00
UTU
75.0
723,062.40
0.00
2,000.00
0.00
725,062.40
544,296.00
THL
75.0
564,065.00
0.00
2,500.00
0.00
566,565.00
425,548.00
PHILIPS
50.0
1,183,904.00
0.00
5,000.00
0.00
1,188,904.00
596,952.00
KCL
75.0
724,900.00
0.00
3,500.00
10,560.00
738,960.00
557,735.00
5,624,583.60
0.00
132,130.00
179,280.00
5,935,993.60
4,233,869.00
Total
Note that the budget mentioned in this table is the total budget requested by the Beneficiary and associated Third Parties.
Workplan
Tables
Project number
602478
Project title
FP7-HEALTH-2013-INNOVATION-1
Funding scheme
Collaborative project
WT1
602478
Project Acronym
METSY
Type of
54
activity
WP Title
53
Lead
beneficiary
55
number
Person56
months
Start
month
End
month
57
58
WP 1
RTD
89.00
48
WP 2
RTD
42.40
48
WP 3
RTD
46.00
48
WP 4
RTD
52.00
48
WP 5
RTD
66.00
48
WP 6
RTD
64.00
18
48
WP 7
OTHER
9.00
48
WP 8
Management activities
MGT
5.00
48
Total
373.40
WT2:
List of Deliverables
Project Number
602478
Project Acronym
METSY
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
ciary number person53
months
Nature
62
Dissemination level
Delivery date
64
63
D1.1
Panel of
neuroimage
biomarker
candidates
associated
with patient
outcomes in
psychosis.
27.00 R
RE
18
D1.2
Baseline and
one-year
follow-up
evaluation of
250 first episode
schizophrenia
patients from
METSY cohorts
and their
controls.
42.00 R
RE
36
D1.3
Baseline and
one-year
follow-up
evaluation of
100 at-risk
patients and
their controls.
20.00 R
RE
36
D2.1
For a subgroup
of study
subjects: CB1
receptor PET
scans (as well as
sMRI and DTI) in
35 first-episode
patient with
psychosis, 35
individuals with
an at risk mental
state and 35
controls.
20.40 R
RE
36
D2.2
Circulating
concentrations
of endocannabinoids
in 35
first-episode
patient with
psychosis, 35
individuals with
an at risk mental
10.00 R
RE
36
WT2:
List of Deliverables
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
ciary number person53
months
Nature
62
Dissemination level
Delivery date
64
63
state and 35
controls.
D2.3
One-year
follow-up
neuroimage
and clinical
data (including
detailed data on
cannabis use).
12.00 R
RE
48
D3.1
Serum candidate
molecular
markers are
identified to
predict patient
outcomes in
psychosis as
well as metabolic
co-morbidities
after
treatment with
antipsychotics.
32.00 R
RE
24
D3.2
Dependency
networks are
constructed
based on
available
metabolomics,
neuroimage
and other data
in the context
of (risk of)
psychosis and
antipsychotic
medication use.
14.00 R
RE
36
D4.1
Optimised
PET/MR imaging
protocols for
psychiatric
disorders.
10.00 R
RE
12
D4.2
Software
prototype
to enable
combined 3D/4D
viewing of
dynamic PET
and MRI.
18.00 R
RE
24
D4.3
Software tools
for advanced
PET/MR image
24.00 R
RE
36
WT2:
List of Deliverables
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
ciary number person53
months
Nature
62
Dissemination level
Delivery date
64
63
processing and
image analysis.
D5.1
Prototype
software
implementation
of Disease
state index and
Disease state
fingerprint for
psychosis.
6.00 R
RE
24
D5.2
Network
inference
and machine
learning based
integrative
analysis of
imaging and
metabolic data.
26.00 R
PU
36
D5.3
Semantic model
as a tool for the
identification
of combined
neuroimage
metabolic
markers.
34.00 R
RE
48
D6.1
Validation results
for selected
biomarker
panel in the
context of patient
outcomes in
psychosis.
64.00 R
PU
48
D7.1
Establishment
of METSY web
page.
0.10 P
PU
D7.2
Establishment
of METSY
Foreground
Evaluation
Committee.
0.10 O
RE
D7.3
First major
collaborative
publication of
METSY findings.
1.00 R
PU
18
D7.4
First FEC
proposal
for METSY
technology
exploitation.
2.80 R
PU
18
WT2:
List of Deliverables
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
ciary number person53
months
Nature
62
Dissemination level
Delivery date
64
63
D7.5
First opinion
paper outlining
METSY
bioinformatics
platform.
5.00 P
PU
36
D8.1
Kick-off
consortium
meeting.
0.50 O
RE
D8.2
Signing of
consortium
agreement.
0.10 O
RE
D8.3
6-month
management
report.
0.30 O
RE
D8.4
Annual
consortium
meeting.
0.50 O
RE
12
D8.5
6-month
management
report.
0.30 O
RE
12
D8.6
0.30 O
RE
12
D8.7
Ethical
approvals,
protocols and
registrations
0.30 O
RE
12
D8.8
Annual
consortium
meeting.
0.50 O
RE
24
D8.9
Mid-term review.
0.30 O
RE
24
D8.10
6-month
management
report.
0.30 O
RE
24
D8.11
6-month
management
report.
0.30 O
RE
30
D8.12
Annual
consortium
meeting.
0.50 O
RE
36
D8.13
6-month
management
report.
0.30 O
RE
42
D8.14
Annual
consortium
meeting.
0.50 O
RE
48
WT2:
List of Deliverables
Deliverable
Number
61
Deliverable Title
Estimated
WP
Lead
benefiindicative
number
ciary number person53
months
Total
Nature
373.40
62
Dissemination level
63
Delivery date
64
WT3:
602478
Project Acronym
METSY
WP1
53
Type of activity
RTD
Start month
End month
48
54
55
3
Objectives
Main objective: To apply neuroimaging strategies to characterise structural and metabolic changes in the brain
during the first stages of psychosis.
Specific objectives
O1.1 To harmonize the data acquisition and processing protocols between the study centres.
O1.2 To analyse available neuroimaging data as a proof-of-concept of results of WPs 2, 3, 5.
O1.3 To evaluate 250 first episode psychosis patients at baseline and one-year follow-up.
O1.4 To evaluate 100 at-risk of psychosis patients.
Description of work and role of partners
WP leader: Carmen Moreno (P3)
Brief summary: This WP will pursue detailed multi-modal neuroimaging and neuropsychology characterisation
in longitudinal studies involving patients at-risk or with first episode of psychosis (as listed in Table 1.2a).
First-episode and at-risk subjects and matched healthy controls will be followed up simultaneously with
analogous methodology in order to extract neuroimaging information useful for characterization of the
development of psychosis and associated metabolic outcomes.
Task 1.1 Harmonization of the data acquisition and processing protocols [P3, P4, P5, P6, P7; task participants,
with lead participant underlined]
Multi-site neuroimaging and clinical studies may be criticised for lack of assessment tools that are harmonious
among sites. Such tools may overcome bias inherent to multiplicity of evaluators, sites and methodology for data
acquisition and processing. Efforts to harmonize data collection across independent imaging sites through the
use of a core phenotypic protocol are therefore mandatory. Biomax (P2) will provide expertise and infrastructure
for the between centres harmonisation of both already available and newly collected clinical data.
In keeping with this goal, all prospective studies will use Structured Clinical Interview for DSM Disorders
(SCID) or Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), depending on subjects age, and DSM-IV
criteria will be used to diagnose psychotic disorders. Symptom severity will be assessed using the 24-item
BPRS . Psychosis risk syndrome will be diagnosed using the Structured Interview for Prodromal Syndromes
. Functioning will be assessed using the Global Assessment of Functioning (GAF) and with the Social and
Occupational Functioning Assessment Scale (SOFAS). To assure consistency of the ratings across sites, raters
will undergo training on the clinical instruments used and a minimum inter-rater reliability (ICC 0.7) will be
established. In addition, a questionnaire assessing diet, exercise, smoking, alcohol and drug use as well as
antipsychotic side effects, including those related to appetite and weight gain, will be used. Comparativeness of
imaging data between sites will be controlled as suggested by Schnack et al. (H. G. Schnack et al., Hum Brain
Mapp 31, 1967 (2010)): The same six subjects are scanned twice during the same day at each centre, and the
intra-subject and inter-site variability is quantitatively controlled for in each voxel. In addition, scan sequence
parameters are matched between sites. For the metabolomic and lipidomic analyses, serum samples are
collected with standard procedure. Following centrifugation, the serum is apportioned into aliquots and stored at
80C. In addition, DNA samples are collected at baseline. Samples are taken in the morning after an overnight
fasting.
Task 1.2 Analysis of neuroimage data in early psychosis [P3, P4, P5, P7]
Brain images of existing datasets (FEP, at-risk of psychosis, and healthy controls) will be analysed in search
of a panel of biomarkers candidates for characterization of clinical progression and outcomes (together with
WT3:
10
11
2 BIOMAX
6.00
3 SERMAS
36.00
4 UTU
6.00
5 THL
32.00
6 PHILIPS
3.00
7 KCL
6.00
Total
89.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D1.1
27.00 R
RE
18
D1.2
42.00 R
RE
36
D1.3
20.00 R
RE
36
Total
89.00
Description of deliverables
D1.1) Panel of neuroimage biomarker candidates associated with patient outcomes in psychosis.: [month 18]
WT3:
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS1
MS4
18
Comments
WT3:
602478
Project Acronym
METSY
WP2
53
Type of activity
54
RTD
Start month
End month
48
55
Objectives
Main objective: To apply imaging strategies to characterise endocannabinoid functions in brain metabolism and
relate them to lipid molecular networks.
Specific objectives
O2.1 To characterise the brain CB1 receptors in at-risk state and first-episode psychosis.
O2.2 To characterise circulating endocannabinoids in at-risk state and first-episode psychosis.
Description of work and role of partners
WP leader: Jarmo Hietala (P4).
Brief summary: This WP builds on WP1 and will pursue detailed longitudinal PET neuroimaging and metabolic
studies of endocannabinoid pathways including synthesis and degradation systems. More accurate methods
for direct quantification of CB1 receptors have been recently developed. In collaboration with NIH a CB1 tracer
([18F]FMPEP-d2) was validated and will be used in this proposal in Turku (P4) and London (P7) with inter-center
methodology harmonization process.
Task 2.1 Quantification of brain CB1 receptors in at-risk state and first-episode psychosis [P4, P7]
35 FEP patients and 35 psychosis risk individuals and 35 controls will undergo a CB1 receptor PET scan at
baseline. An index of regional CB1 receptor density, distribution volume is the PET study primary outcome
as outlined above. Clinical outcomes are as in WP1. Data from 8 healthy volunteers suggest a coefficient of
variation of 18 % for the distribution volume of [18F]FMPEP-d2 in the frontal cortex which suggest that N=20
subjects in each group will allow for the detection of effects sizes greater than 0.9 (=0.05, =0.2) in other
words, percentual differences of >16 %. In addition, a previous study with [18F]FMPEP-d2 suggests that a 20 %
change in regional CB1 receptor binding in cannabis users is statistically significant with a group size of 30103.
Task 2.2 One-year follow-up of patients and controls [P4, P7]
A subsample of 20+20+20 will undergo a second CB1 receptor PET scan. An index of regional CB1 receptor
density, distribution volume is the PET study primary outcome. Clinical outcomes as in WP1 (Task 1.3).
Task 2.3 Circulating endocannabinoids in at-risk state and first-episode psychosis [P1, P4, P7]
Within the same study groups as in Tasks 2.1 and 2.2, endocannabinoids will be analysed from serum using
targeted quantitative UPLC-MS/MS methodology. In the same samples, global metabolomics platforms
(GCGC-TOFMS for polar metabolites and UPLC-MS for molecular lipids ). Raw data will be processed using
the MZmine 2 software for UPLC-MS analysis and Guineu software. Calibration will be performed based on
internal standard compound injected prior to extraction.
Clinical outcomes as in WP1 (Task 1.3). The data will be integrated with neuroimage and other clinical data
using the methodologies from WPs 3 and 5.
Person-Months per Participant
Participant number
10
11
1 VTT
10.00
4 UTU
20.00
7 KCL
12.40
WT3:
10
11
Total
42.40
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D2.1
20.40 R
RE
36
D2.2
Circulating concentrations of
endocannabinoids in 35 first-episode
patient with psychosis, 35 individuals
with an at risk mental state and 35
controls.
10.00 R
RE
36
D2.3
12.00 R
RE
48
Total
42.40
Description of deliverables
D2.1) For a subgroup of study subjects: CB1 receptor PET scans (as well as sMRI and DTI) in 35 first-episode
patient with psychosis, 35 individuals with an at risk mental state and 35 controls.: [month 36]
D2.2) Circulating concentrations of endocannabinoids in 35 first-episode patient with psychosis, 35 individuals
with an at risk mental state and 35 controls.: [month 36]
D2.3) One-year follow-up neuroimage and clinical data (including detailed data on cannabis use).: [month 48]
Schedule of relevant Milestones
Lead
beneficiary
number
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS2
12
MS4
18
Comments
WT3:
602478
Project Acronym
METSY
WP3
53
Type of activity
RTD
Start month
End month
48
54
55
1
Objectives
Main objective: To characterise genetic and lipid molecular networks as measured in biofluids in early psychosis
and identify how these networks associate with patient outcomes.
Specific objectives
O3.1 To identify candidate serum metabolite markers associated with patient outcomes in psychosis, including
metabolic co-morbidities after treatment with antipsychotics.
O3.2 To construct dependency networks based on available metabolomics, neuroimage and other data in the
context of (risk of) psychosis and antipsychotic medication use.
Description of work and role of partners
WP leader: Tuulia Hytylinen (P1).
Brief summary: This WP will pursue detailed metabolic characterization, metabolomics, genetics, studies of
immune/oxidative stress markers in the cohorts included in WP1. Data is analysed in collaboration with WP5.
Task 3.1 Predictive circulating metabolite markers in psychosis [P1, P2, P3, P5]
Using the serum samples from existing cohorts available to WP 1 (Table 1.2a), global metabolomics will be
performed (GCGC-TOFMS for polar metabolites and UPLC-MS for molecular lipids) as in WP 2. Assuming
800 metabolic variables are measured with each platform in N=160 subjects in each group, this allow for
the detection of effects sizes greater than 0.54 (=0.05, power = 0.8); applying the conservative Bonferroni
correction for multiple-comparison correction.
Two types of biomarker signatures will be sought: (1) comprising data from a single platform (e.g. single or
multiple metabolites), or (2) a combination from multiple data sources (multi-modal biomarkers). Individual
molecular signatures or multi-modal biomarkers will be studied by P1 for associations with outcomes of
interest (as outlined in WP 1). Univariate and multivariate statistical methods will be used to identify individual
biomarker candidates and to build composite biomarker models for disease prediction. Non-parametric and
parametric tests, such as Kruskal-Wallis, ANOVA and Kendalls tau, for differences between disease groups
and associations between the markers and environmental factors will be applied and accompanied by proper
post hoc analysis such as Tukeys test. Multiple hypothesis testing errors will be controlled by estimating false
discovery rates by permutation tests and by p-value distribution based q-value estimates. Composite biomarker
models will be built by various machine learning techniques, such as penalized linear least-angle regression
(LARS) and elasticnet regressions, random forests and recursive feature elimination support vector machines
(SVM). 1000 or more cross-validation runs will be performed in model building phase. In each run, 2/3 and 1/3 of
samples will be selected at random to the training and test sets, respectively. In the first phase, markers leading
to lowest CV-errors will be selected. In the second phase, a selected model, such as logistic regression for
discriminating and predicting disease status, will be applied. At this stage, optimal marker combination among
the candidate markers will be searched for by applying stepwise selection algorithm using Akaikes information
criterion. Receiver operating characteristic (ROC) curves with area under the curve (AUC) statistics, prediction
accuracy, odds-ratios and relative risks will be reported based on performance in the independently tested data
(1/3 of samples) for each cross-validation run. Examples of this approach performed by P1 include diagnostic
model for schizophrenia and predictive marker of Alzheimers disease .
The biomarker panels will be evaluated for prioritisation and validation in collaboration with WP 5 and WP 6.
Task 3.2 Dependency networks in psychosis [P1]
The causal modelling task will be based on an integrated analysis of molecular, genetic, neurocognitive
assessment, image and other phenotypic variables from WPs 1-3. In order to derive the variables from image
WT3:
10
11
1 VTT
28.00
2 BIOMAX
4.00
3 SERMAS
8.00
5 THL
6.00
Total
46.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D3.1
32.00 R
RE
24
D3.2
14.00 R
RE
36
Total
46.00
Description of deliverables
D3.1) Serum candidate molecular markers are identified to predict patient outcomes in psychosis as well as
metabolic co-morbidities after treatment with antipsychotics.: [month 24]
D3.2) Dependency networks are constructed based on available metabolomics, neuroimage and other data in
the context of (risk of) psychosis and antipsychotic medication use.: [month 36]
WT3:
Milestone name
MS3
Lead
beneficiary
number
Delivery
date from
60
Annex I
1
12
Comments
WT3:
602478
Project Acronym
METSY
WP4
53
Type of activity
RTD
Start month
End month
48
54
55
6
Objectives
Main objective: To develop and demonstrate methodology for combined PET and MRI imaging.
Specific objectives.
O4.1 To define optimised PET/MR imaging protocols for psychiatric disorders.
O4.2 To develop a software prototype to enable combined 3D/4D viewing of dynamic PET and MRI.
O4.3 To develop software tools for standardized PET/MR image processing at different clinical sites.
Description of work and role of partners
WP leader: Timo Paulus (P6).
This WP will develop methods and software tools for combined PET and MR image acquisition, processing and
analysis. Early protocols will be utilized first in healthy volunteers and then the pilot patients. Optimised protocols
for the PET/MR hybrid camera (Philips Ingenuity TF) will be developed and evaluated. Software prototypes will
be developed on the Imalytics Research Workstation platform and made available to the clinical partners for
PET/MR viewing and to standardize PET/MR image processing and analysis. Where available, existing software
tools will be optimised for the specific tasks of WP1 and WP2 and integrated into the prototypes. Finally, the
Imalytics Research workstation and the prototypes will be installed at the clinical sites, involved users will be
trained, and usability of the tools will be evaluated.
Task 4.1 Definition of optimised PET/MR imaging protocols for psychiatric disorders [P4, P6, P7]
Elaborative imaging protocols are required to capture several imaging biomarkers from each subject
incorporating one or possibly two different PET tracers acquired in a quantitative fashion and several functional
and structural MR sequences. These protocols should facilitate good image quality and quantification of the
various biomarkers in a reproducible manner. At the same time, care should be given in minimising patent
discomfort (leading to excessive motion within scans and even scan cancellations).
With these requirements in mind the PET/MR imaging protocols will be optimised to address streamlined and
fast patient set-up and imaging acquisition, considering workflow (patient preparation and set-up to minimise
any confounding effects), coil selection as well as PET and MRI acquisition parameters (for dual-tracer dynamic
PET, functional and structural MRI). Furthermore, PET reconstruction parameters will be assessed and
fine-tuned, if needed. The starting point will be combined CB1 receptor scan with [18F]FMPEP and presynaptic
dopamine synthesis scan with [18F]DOPA. We also have experience using [11C]-CB1 tracers, such as
[11C]MePPEP (Howes OD et al. Schizophrenia Research Vol. 136 Supplement 1, Page S68) which may have
advantages in same session scanning protocols due to shorter radioactivity decay half-life and less radioactivity
exposure. This will be explored. Additional multimodal structure and functional network data will be obtained in
the same session with DTI and R-fMRI. Resting-state BOLD (Blood Oxygen Level Dependent-signal) data (6 min
protocol) will be collected with the 3T Philips Ingenuity camera using an EPI (Echo Planar Imaging) sequence
(Repetition Time 2000 ms, Echo Time 20 ms, 140 axial slices and flip angle of 75 degrees.
Task 4.2 Combined 3D/4D viewing of dynamic PET and MRI [P4, P6, P7]
The multi-modal and multi-vendor image data generated in WP1 and WP2 needs to be imported, viewed and
analysed on one common software platform across the project consortium in order to ensure standardization
and reproducibility. Import and export converters from proprietary image data formats to DICOM will be
implemented. DICOM will also be used for connectivity and data exchange between the clinical sites. To support
standardization, the following will be implemented in the software platform:
Harmonized viewing protocols across clinical sites,
Automatic segmentation tools to facilitate operator-independent Volume-of-Interest definition,
WT3:
10
11
4 UTU
6.00
6 PHILIPS
38.00
7 KCL
8.00
Total
52.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D4.1
10.00 R
RE
12
D4.2
18.00 R
RE
24
D4.3
24.00 R
RE
36
Total
52.00
Description of deliverables
D4.1) Optimised PET/MR imaging protocols for psychiatric disorders.: [month 12]
D4.2) Software prototype to enable combined 3D/4D viewing of dynamic PET and MRI.: [month 24]
WT3:
Milestone name
MS4
Lead
beneficiary
number
Delivery
date from
60
Annex I
6
18
Comments
WT3:
602478
Project Acronym
METSY
WP5
53
Type of activity
RTD
Statistical and bioinformatics tools to integrate brain image information with clinical
and molecula
End month
48
54
55
2
Objectives
Main objective: To develop statistical and bioinformatics tools to integrate brain image information with clinical
and molecular profile data.
Specific objectives
O5.1 To further develop software implementing the Disease state index and Disease state fingerprint for
psychosis studies.
O5.2 To develop network inference and machine learning methods for integrative analysis of imaging and
metabolic data.
O5.3 To develop semantic model as a tool for the identification of combined neuroimage metabolic markers.
Description of work and role of partners
WP leader: Dieter Maier (P2).
Brief summary: This WP will pursue statistical developments to integrate image data with other phenotypic data,
including from omics analyses, aiming to extract the signals of potential diagnostic value. Semantic modelling
will be used to annotate these data with biological and literature-based annotations.
Task 5.1 Disease state index in psychosis [P1, P6]
To address O5.1, the disease state index (DSI) and disease state fingerprint (DSF) concepts, developed
originally for the clinical diagnostics of Alzheimer's disease and follow-up of disease progression, will be tailored
and applied to characterise psychotic disorders. In other words, optimal ways to combine heterogeneous data
measured from patients to identify characteristic patterns and possible relationships between variables, in
psychotic disorders will be studied using DSI and DSF profiling techniques. In addition to generating more
scientific understanding of these diseases by profiling, the DSI and DSF concepts provide a novel clinical
approach for prediction, diagnosis and monitoring the disease progression in psychotic diseases (O6). The
performance of this approach will be evaluated and validated using the data cohorts available in METSY.
Standard statistical measures (accuracy, sensitivity, specificity, AUC) will be used in validation. The approaches
developed will be benchmarked against state-of-the-art reference classification techniques, such as support
vector machines and random forests (Task 3.1).
In order to derived the image variables for the DSI applications, different image processing approaches will be
evaluated. P1 has established methodology for fast and robust image segmentation .
Task 5.2 Network inference and machine learning based integrative analysis of imaging and metabolic data [P1,
P2]
This task will be based on an integrated analysis of multiple high-throughput platforms as well as other complex
datasets such as image data or neurocognitive assessment data. Gaussian graphical modelling will be applied
by P1 to derive the direct interactions between the factors in selection, similarly as applied previously. Particular
focus will be on evaluating, implementing and further developing various data reduction and scaling methods
prior to network analysis, and on statistical assessments of association-strengths. Different approaches for
compressing/reducing image information for subsequent network analysis and multi-modal biomarker discovery
will be investigated. For examples, in P1s earlier studies, independent component analysis was applied to
derive specific variables from structural MRI data. Based on the derived structure of the graph, the directions
of the edges that bear causal meaning will be determined by estimating intervention effects using purely
observational data. The outcomes will provide a panel of variables directly or causally associated with the
WT3:
10
11
1 VTT
12.00
2 BIOMAX
48.00
6 PHILIPS
6.00
Total
66.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D5.1
6.00 R
RE
24
D5.2
26.00 R
PU
36
D5.3
34.00 R
RE
48
Total
66.00
Description of deliverables
WT3:
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS5
12
MS6
24
Comments
WT3:
602478
Project Acronym
METSY
WP6
53
Type of activity
RTD
Start month
18
End month
48
54
55
1
Objectives
Main objective: To identify, prioritize and evaluate multi-modal circulating and neuroimage markers with
diagnostic potential for prediction and monitoring of psychotic disorders.
Specific objectives
O6.1 To prioritize the biomarker candidates for further validation.
O6.2 To validate the metabolic biomarkers.
O6.3 To prioritize the multi-modal neuroimage and circulating biomarkers.
Description of work and role of partners
WP leader: Matej Orei (P1).
Brief summary: This WP will validate the multi-modal circulating and neuroimage markers which are sensitive
to metabolic disturbances in the brain of at-risk or psychotic patients using an independent prospective sample
series from 250 first-episode patients and their healthy controls, which were not included as part of biomarker
discovery in WPs 1-3.
Task 6.1 Prioritisation of biomarker candidates [P1, METSY Steering Committee, Foreground Evaluation
Committee]
The studies in WPs 1-3, with support of modelling in WP5, will identify multiple biomarker panels e.g. sensitive
to different patient outcomes (clinical or functional) in psychosis. Some of these markers may be considered
of clinical utility in healthcare setting, either as stand-alone or in combination with other biomarkers or data.
Starting already in the early stage of the project (Month 18), METSY Steering Committee and the Foreground
Evaluation Committee (see WP 7, Task 7.4) will monitor and prioritise the WP 1-3 outcomes as potential
biomarkers using the following four main general criteria for prioritisation:
(1) Expected impact listed in the work programme: Priority will be given to markers applicable in personalised
medicine setting;
(2) Intellectual property and exploitation potential: Priority will be given to markers with greatest exploitation
potential and strongest IP protection;
(3) Technological feasibility and impact: Given the technologies and expertise available to METSY participants,
priority will be given to biomarker assays which can be brought closest to intended end-user diagnostic
application or product;
(4) Feasibility of validation: Samples are available which may be used to validate the biomarkers against the
outcomes of interest.
Task 6.2 Validation of selected serum metabolic biomarkers [P1]
In WP 3 global metabolomics platforms will be applied by P1 for the analyses of molecular lipids and small
polar metabolites. The platforms are in part quantitative, but majority of metabolites are characterised
semi-quantitatively (i.e. relative concentrations of metabolites are determined across the samples). In the
validation phase the focus will be on implementing analytical methods affording absolute quantification, since
such approach would facilitate further developments of diagnostic toolkits applicable in healthcare setting. P1
has analytical platforms and capacities which afford development of MS-based targeted assays for a broad
range of metabolites, from lipids to small polar metabolites.
Depending on the outcomes of interest, the biomarker will be validated in collaboration with WP 1, using the
samples and image data acquired during the METSY project (n~250 subjects).
WT3:
10
11
1 VTT
12.00
2 BIOMAX
12.00
3 SERMAS
12.00
4 UTU
6.00
5 THL
6.00
6 PHILIPS
4.00
7 KCL
12.00
Total
64.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
D6.1
Estimated
indicative
personmonths
1
Total
Nature
64.00 R
62
Dissemination
63
level
PU
Delivery date
64
48
64.00
Description of deliverables
D6.1) Validation results for selected biomarker panel in the context of patient outcomes in psychosis.: [month 48]
WT3:
Milestone name
MS7
Lead
beneficiary
number
Delivery
date from
60
Annex I
1
24
Comments
WT3:
602478
Project Acronym
METSY
WP7
53
Type of activity
OTHER
Start month
End month
48
54
55
2
Objectives
O7.1 To attain a high level of public awareness of METSY activities and discoveries and of the relevance to
systems medicine.
O7.2 To maximize exploitation of METSY discoveries in the healthcare and personalised medicine settings.
O7.3 To protect METSY intellectual property.
Description of work and role of partners
The work plan in WP9 will be developed in two domains. The first includes tasks related to the scientific and
public awareness of METSY and co-morbidities associated with obesity in general, and the second addresses
tasks related to exploitation of METSY findings. Tasks in WP8 will be supported by the Project Office at VTT and
in particular by the five Patient Organizations engaged in METSY.
Task 7.1 Web page
One important mean to integrate all dissemination activities will be the web page of METSY (www.METSY.eu
or similar), where knowledge will be made available to the scientific community and the public. A private domain
(intranet) will be established in parallel to make internal knowledge easily accessible for all partners. The
private domain will include training material, internal interim reports, pre-published scientific articles, internal
news and reporting templates. The web page will be regularly updated and designed to meet the needs of
the consortium. Wiki-pages will also be available for the consortium. The private domain will be protected by
username and password. The public domain of the web page will be linked to relevant research sites in Europe
and internationally, and to participant home pages. VTT will provide its internal IT infrastructure for implementing
the project web page.
Task 7.2 Maximising public information and protecting METSY knowledge
METSY will first establish clear information/dissemination policies and actions and specify these in a report
to be used as reference for all partners. The Coordinator together with the Project Manager, Foreground
Evaluation Committee (FEC) Chair and the representatives of the patient organizations will be responsible for
the dissemination of METSY achievements to the general public and in particular patients, and for adherence
to METSY dissemination policies. The following measures will be taken with the objective to increase the public
awareness of METSY research activities and opportunities to develop potential future applications:
1. Press releases in national newspapers, initiated by the information offices at the participating organizations.
Such information releases will be approved by the Steering Committee prior to release in order to maintain
conformity in communication;
2. Newsletters a database with contact details from European societies, patients advocacies, will be
established.
Task 7.3 Preparation of joint publications and position statements
Special consideration will be made to joint publications. In addition to the original scientific publications arising
from METSY S/T activities, reviews on METSY related studies and findings prepared by investigators from more
than one partner institute will be sought. Position statements will be encouraged from more than one partner,
and from the expert committees.
Task 7.4 Establishment and operation of a Foreground Evaluation Committee (FEC) to oversee and guide
matters related to IPR and exploitation
METSY will establish the FEC, which will supervise knowledge generated by the project and advice on
dissemination and exploitation, including the management of IPR aspects, preparation of the exploitation plans,
intra-project distribution of manuscripts, supervision of publications and submitted records of invention and
WT3:
10
11
1 VTT
3.00
2 BIOMAX
6.00
Total
9.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D7.1
0.10 P
PU
D7.2
0.10 O
RE
D7.3
1.00 R
PU
18
D7.4
2.80 R
PU
18
D7.5
5.00 P
PU
36
Total
9.00
Description of deliverables
D7.1) Establishment of METSY web page.: [month 1]
D7.2) Establishment of METSY Foreground Evaluation Committee.: [month 1]
D7.3) First major collaborative publication of METSY findings.: [month 18]
D7.4) First FEC proposal for METSY technology exploitation.: [month 18]
D7.5) First opinion paper outlining METSY bioinformatics platform.: [month 36]
WT3:
Milestone name
Lead
beneficiary
number
Delivery
date from
60
Annex I
Comments
WT3:
602478
Project Acronym
METSY
WP8
53
Type of activity
MGT
Management activities
Start month
End month
48
54
55
1
Objectives
O8.1 Provide overall scientific management and coordination of the work programme, including the timely
implementation of the work plan, networking and achievement of scientific goals to ensure the overall smooth
operation of the project.
O8.2 Provide the overall coordination of all financial, legal, administrative and contractual requirements within
the contract, including audit certificates and the maintenance of the consortium agreement.
O8.3 Oversee information and knowledge management, including dissemination, Intellectual Property Rights
and exploitation.
O8.4 Oversee risk assessment and contingency plans.
O8.5 Oversee gender, ethical and wider societal issues.
O8.6 Provide communication with the European Commission.
Description of work and role of partners
METSY will set-up a management structure that will efficiently address the specific objectives via a clear
distribution of tasks and authorities. A detailed description of management is provided in section 2.1.
Key roles in management are:
Coordinator: Matej Orei (VTT, P1).
Work package leaders: Carmen Moreno (SERMAS, P3), Jarmo Hietala (UTU, P4), Tuulia Hytylinen (VTT, P1),
Timo Paulus (Philips, P6), Dieter Maier (Biomax, P2), Matej Orei (VTT, P1).
Team leaders: Participant representatives.
Steering committee comprised of Coordinator, WP leaders as well as team leaders (if not already included as
WP leaders): Jaana Suvisaari (THL, P5), Oliver Howes (KCL, P7).
Expert and advisory committees:
1. Ethics, Confidentiality and Informed Consent Expert Committee: Carmen Moreno, Chair (SERMAS, P3),
Jaana Suvisaari (THL, P5), Oliver Howes (KCL, P7), and Philip Cowen (University of Oxford, UK) as external
member.
2. Gender issues: Jaana Suvisaari (THL, P5), Tuulia Hytylinen (VTT, P1), Timo Paulus (Philips, P6).
3. Foreground Exploitation Committee: Dieter Maier, Chair (Biomax, P2), Matej Orei (VTT, P1). Other
members to be nominated and confirm at the first Steering Committee meeting (project Kick-off).
Task 8.1 Kick-off meeting, steering committee meetings, annual consortium meetings, mid-term review meeting
The consortium will meet on an annual basis to inform about the proceeding of METSY, starting with the Kick-off
meeting which will take place in the first month.
Task 8.2 Establishing METSY Standard Operating Procedures (SOPs) for informed consent, privacy, ethical and
equality issues relative to clinical studies
The Ethics Expert Committee will prepare guidelines in the form of standard operating procedures relative to
the collection, storage, use and banking of clinical material relevant to METSY. The SOPs will be reviewed
3-monthly.
Task 8.3 Preparation and submission of the financial and scientific reports to the European Commission
WT3:
10
11
1 VTT
5.00
Total
5.00
List of deliverables
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
D8.1
0.50 O
RE
D8.2
0.10 O
RE
D8.3
0.30 O
RE
D8.4
0.50 O
RE
12
D8.5
0.30 O
RE
12
D8.6
0.30 O
RE
12
D8.7
0.30 O
RE
12
D8.8
0.50 O
RE
24
D8.9
Mid-term review.
0.30 O
RE
24
D8.10
0.30 O
RE
24
D8.11
0.30 O
RE
30
D8.12
0.50 O
RE
36
D8.13
0.30 O
RE
42
D8.14
0.50 O
RE
48
Total
5.00
Description of deliverables
D8.1) Kick-off consortium meeting.: [month 1]
D8.2) Signing of consortium agreement.: [month 1]
D8.3) 6-month management report.: [month 6]
D8.4) Annual consortium meeting.: [month 12]
D8.5) 6-month management report.: [month 12]
D8.6) SOPs for data sharing.: [month 12]
D8.7) Ethical approvals, protocols and registrations: This deliverable will document all ethical approvals,
protocols and registrations needed for conducting the clinical studies included in the METSY project. [month 12]
D8.8) Annual consortium meeting.: [month 24]
D8.9) Mid-term review.: [month 24]
D8.10) 6-month management report.: [month 24]
D8.11) 6-month management report.: [month 30]
WT3:
Milestone name
Lead
beneficiary
number
Delivery
date from
60
Annex I
Comments
WT4:
List of Milestones
Project Number
602478
Project Acronym
METSY
WP number
53
Delivery date
60
from Annex I
Comments
MS1
Implementation of
between centres
clinical and
neuroimaging data
harmonisation
procedures.
WP1
MS2
WP2
12
MS3
Plasma global
metabolomics data
is available from
100 first episode
psychosis patients,
100 siblings
WP3
12
MS4
First prototype of
software tool for
advanced PET/MR
image processing
and image analysis.
WP1, WP2,
WP4
18
MS5
Specification of
psychotic disorders
specific criteria for
CDSS inclusion.
WP5
12
MS6
Availability of
integrated semantic
network.
WP5
24
MS7
Panel of multi-modal
and molecular
biomarkers is
available from
WPs 1-3 and 5 for
evaluation, priori
WP6
24
WT5:
602478
Project Acronym
METSY
Comments, if any
WT6:
602478
Project Acronym
METSY
WP 1
WP 2
WP 3
WP 4
WP 5
WP 6
WP 7
WP 8
1 - VTT
0.00
10.00
28.00
0.00
12.00
12.00
3.00
5.00
70.00
2 - BIOMAX
6.00
0.00
4.00
0.00
48.00
12.00
6.00
0.00
76.00
3 - SERMAS
36.00
0.00
8.00
0.00
0.00
12.00
0.00
0.00
56.00
4 - UTU
6.00
20.00
0.00
6.00
0.00
6.00
0.00
0.00
38.00
5 - THL
32.00
0.00
6.00
0.00
0.00
6.00
0.00
0.00
44.00
6 - PHILIPS
3.00
0.00
0.00
38.00
6.00
4.00
0.00
0.00
51.00
7 - KCL
6.00
12.40
0.00
8.00
0.00
12.00
0.00
0.00
38.40
89.00
42.40
46.00
52.00
66.00
64.00
9.00
5.00
373.40
Total
WT7:
602478
Project Acronym
METSY
Part. 1
VTT
Part. 2
BIOMAX
Part. 3
SERMAS
Part. 4
UTU
Part. 5
THL
Part. 6
PHILIPS
Part. 7
KCL
Total
1. RTD/Innovation activities
WP 1
0.00
6.00
36.00
6.00
32.00
3.00
6.00
89.00
WP 2
10.00
0.00
0.00
20.00
0.00
0.00
12.40
42.40
WP 3
28.00
4.00
8.00
0.00
6.00
0.00
0.00
46.00
WP 4
0.00
0.00
0.00
6.00
0.00
38.00
8.00
52.00
WP 5
12.00
48.00
0.00
0.00
0.00
6.00
0.00
66.00
WP 6
12.00
12.00
12.00
6.00
6.00
4.00
12.00
64.00
Total Research
62.00
70.00
56.00
38.00
44.00
51.00
38.40
359.40
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
WP 8
5.00
0.00
0.00
0.00
0.00
0.00
0.00
5.00
Total Management
5.00
0.00
0.00
0.00
0.00
0.00
0.00
5.00
WP 7
3.00
6.00
0.00
0.00
0.00
0.00
0.00
9.00
Total other
3.00
6.00
0.00
0.00
0.00
0.00
0.00
9.00
70.00
76.00
56.00
38.00
44.00
51.00
38.40
373.40
2. Demonstration activities
Total Demo
3. Consortium Management activities
4. Other activities
Total
WT8:
602478
Project Acronym
METSY
Beneficiary
short name
Effort (PM)
Personnel
costs ()
Subcontracting
()
Other Direct
costs ()
Indirect costs
OR lump sum,
flat-rate or
scale-of-unit ()
Total costs
Requested EU
contribution ()
VTT
70.00
480,762.00
8,000.00
218,000.00
562,813.00
1,269,575.00
1,005,028.00
BIOMAX
76.00
471,200.00
1,600.00
13,000.00
387,360.00
873,160.00
673,360.00
SERMAS
56.00
221,667.00
191,500.00
17,250.00
143,350.20
573,767.20
430,950.00
UTU
38.00
212,914.00
2,000.00
239,000.00
271,148.40
725,062.40
544,296.00
THL
44.00
223,564.00
45,500.00
149,850.00
147,651.00
566,565.00
425,548.00
PHILIPS
51.00
461,244.00
5,000.00
25,000.00
697,660.00
1,188,904.00
596,952.00
KCL
38.40
221,250.00
326,000.00
36,850.00
154,860.00
738,960.00
557,735.00
373.40
2,292,601.00
579,600.00
698,950.00
2,364,842.60
5,935,993.60
4,233,869.00
Total
1. Project number
The project number has been assigned by the Commission as the unique identifier for your project. It cannot be changed.
The project number should appear on each page of the grant agreement preparation documents (part A and part B) to
prevent errors during its handling.
2. Project acronym
Use the project acronym as given in the submitted proposal. It cannot be changed unless agreed so during the negotiations.
The same acronym should appear on each page of the grant agreement preparation documents (part A and part B) to
prevent errors during its handling.
53. Work Package number
Work package number: WP1, WP2, WP3, ..., WPn
54. Type of activity
For all FP7 projects each work package must relate to one (and only one) of the following possible types of activity (only if
applicable for the chosen funding scheme must correspond to the GPF Form Ax.v):
RTD/INNO = Research and technological development including scientific coordination - applicable for Collaborative Projects
and Networks of Excellence
DEM = Demonstration - applicable for collaborative projects and Research for the Benefit of Specific Groups
MGT = Management of the consortium - applicable for all funding schemes
OTHER = Other specific activities, applicable for all funding schemes
COORD = Coordination activities applicable only for CAs
SUPP = Support activities applicable only for SAs
55. Lead beneficiary number
Number of the beneficiary leading the work in this work package.
56. Person-months per work package
The total number of person-months allocated to each work package.
57. Start month
Relative start date for the work in the specific work packages, month 1 marking the start date of the project, and all other start
dates being relative to this start date.
58. End month
Relative end date, month 1 marking the start date of the project, and all end dates being relative to this start date.
59. Milestone number
Milestone number:MS1, MS2, , MSn
60. Delivery date for Milestone
Month in which the milestone will be achieved. Month 1 marking the start date of the project, and all delivery dates being
relative to this start date.
61. Deliverable number
Deliverable numbers in order of delivery dates: D1 Dn
62. Nature
Please indicate the nature of the deliverable using one of the following codes
R = Report, P = Prototype, D = Demonstrator, O = Other
63. Dissemination level
Please indicate the dissemination level using one of the following codes:
PU = Public
PP = Restricted to other programme participants (including the Commission Services)
RE = Restricted to a group specified by the consortium (including the Commission Services)
CO = Confidential, only for members of the consortium (including the Commission Services)
Restreint UE = Classified with the classification level "Restreint UE" according to Commission Decision 2001/844 and
amendments
Confidentiel UE = Classified with the mention of the classification level "Confidentiel UE" according to Commission Decision
2001/844 and amendments
Secret UE = Classified with the mention of the classification level "Secret UE" according to Commission Decision 2001/844
and amendments
64. Delivery date for Deliverable
Month in which the deliverables will be available. Month 1 marking the start date of the project, and all delivery dates being
relative to this start date
65. Review number
Review number: RV1, RV2, ..., RVn
66. Tentative timing of reviews
Month after which the review will take place. Month 1 marking the start date of the project, and all delivery dates being relative
to this start date.
67. Person-months per Deliverable
The total number of person-month allocated to each deliverable.
METSY
FP7-HEALTH-2013-INNOVATION-1
Proposal title:
Integrated neuroimaging and metabolic platform for characterisation of early psychosis and
prediction of patient outcomes
Proposal acronym:
METSY
Type of funding scheme:
Collaborative Project (small or medium-scale focused research project)
Work programme topics addressed:
HEALTH.2013.2.2.1-2
Development of effective imaging tools for diagnosis, monitoring and management of mental
disorders
Project duration:
48 months
Name of the coordinating person:
Prof. Matej Orei
VTT Technical Research Centre of Finland
Tietotie 2
Espoo, FI-02044 VTT, Finland
Phone: +358-20-722-4491
Email: matej.oresic@vtt.fi
URL: http://sysbio.vtt.fi/
-i-
METSY
FP7-HEALTH-2013-INNOVATION-1
List of participants
Participan Organization legal name
t no.
1 (Co-ord) VTT Technical Research
Centre of Finland
2
Biomax Informatics AG
3
Servicio Madrileo de
Salud
4
University of Turku
5
National Institute for
Health and Welfare
6
Philips
7
Kings College London
Country
Organization type
Finland
Research institute
Name of principal
investigator
Matej Orei
Germany
Spain
SME
University Hospital
Dieter Maier
Carmen Moreno
Finland
Finland
University
Research Institute
Jarmo Hietala
Jaana Suvisaari
Germany
UK
Industrial
University
Timo Paulus
Oliver Howes
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Abstract
The theme of this collaborative project is development and application of neuroimaging and
bioinformatics tools to study lipid metabolism as a common pathogenic link between psychotic
disorders and its metabolic co-morbidities. The overall objective is to identify, prioritize and
evaluate multi-modal blood and neuroimaging markers with diagnostic potential for prediction and
monitoring of psychotic disorders and associated metabolic co-morbidities. We aim to (1) optimise a
multidisciplinary approach for combining positron emission tomography (PET) and magnetic
resonance imaging (MRI) with metabolomics approaches, (2) develop a PET-method for exploring
endocannabinoid pathways in early psychosis in longitudinal study setting, and (3) develop
combined PET/MR biomarker methodology for psychiatric disorders by studying neurotransmitter
interactions with multiple PET scan and MRI sequences. The balance of two or more
neurotransmitter systems may function as a novel biomarker in these disorders. The expected
impacts are (1) etiopathogenic understanding, (2) new validated multi-modal markers for early
disease detection and monitoring, (3) new tools for the identification of subjects who may benefit
from specific treatment (4) discovery of new avenues for disease prevention and therapy, and (5)
new tools and processes for applying brain imaging in personalised medicine. The consortium brings
together clinicians, researchers and industry partners in the domains of psychiatry, neuroimaging,
metabolic research, systems biology and bioinformatics.
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List of abbreviations
AUC
BMI
BPRS-UCLA
CBM
CGI
CNS
CVD
DMN
DSM
DTI
FEP
GAF
GCGC-TOFMS
GWA
HOMA-IR
IDF
IR
K-SADS
LARS
MATRICS
MetS
MRI
MRS
MS
NAFLD
NCEP-ATP
ONAP
OR
PANSS
PC
PET
PUFA
P4 medicine
ROC
SCID-I
SVM
T2D
UPLC-MS
YMRS
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Table of Contents
List of participants .................................................................................................................................... ii
Abstract ................................................................................................................................................... iii
List of abbreviations................................................................................................................................. iv
1. Scientific and/or technical quality, relevant to the topics addressed by the call .....................................1
1.1. Concept and objectives .................................................................................................................1
1.1.1. Specific objectives .................................................................................................... 2
1.1.2. Relevance of METSY to Work Programme and specific call objectives ..................... 2
1.2. Progress beyond the state-of-the-art..............................................................................................3
1.2.1. Current knowledge, tools and new findings from METSY .......................................... 3
1.2.2. METSY considerations with regards to this knowledge ........................................... 12
1.3. S/T methodology and associated work plan .................................................................................18
1.3.1. Overall strategy of the work plan ............................................................................. 18
1.3.2. Project timeline (Gantt chart) .................................................................................. 19
1.3.3. Risk/Contingency analysis ...................................................................................... 20
2. Implementation ...................................................................................................................................22
2.1. Management structure and procedures .......................................................................................22
2.1.1. Decision making structure of METSY ...................................................................... 23
2.2. Individual participants ..................................................................................................................26
2.3. Consortium as whole ...................................................................................................................33
2.4. Resource to be committed ...........................................................................................................35
3. Impact ................................................................................................................................................38
3.1. Expected impacts listed in the work programme ..........................................................................39
3.2. Dissemination and/or exploitation of project results, and management of IP ................................40
3.2.1. Dissemination of METSY results ............................................................................. 40
3.2.2. Exploitation of METSY results and management of Intellectual Property ................ 41
4. Ethical issues .....................................................................................................................................45
4.1. General........................................................................................................................................45
4.2. Identification of relevant EU legislation and international texts .....................................................46
4.3. Human studies (Participants 3, 4, 5, 7) ........................................................................................47
4.4. Ethics issues table .......................................................................................................................49
5. Consideration of gender aspects ........................................................................................................51
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1. Scientific and/or technical quality, relevant to the topics addressed by the call
1.1. Concept and objectives
The theme of this collaborative project is development and application of neuroimaging, molecular
diagnostic and bioinformatics tools to study lipid metabolism in the context of patient outcomes in
psychotic disorders, with specific focus on metabolic co-morbidities.
The concept is that: (1) Primary obesity and psychotic disorders are similar with respect to the
associated changes in energy balance and co-morbidities, including metabolic syndrome (MetS). (2)
The specific underlying mechanisms linking the expansion of adipose tissue to these co-morbidities
are unknown. (3) Such similarities do not necessarily demonstrate causal links, but instead suggest
that specific causes of and metabolic disturbances associated with obesity play a pathogenic role in
the development of psychotic disorders, potentially even before obesity develops. (4) Both brain and
peripheral metabolic organs use lipids as components of their integrated homeostatic system to
control energy balance as well as to regulate peripheral insulin sensitivity. (5) Specific
neurotransmitter systems such as endocannabinoids regulate systemic lipid metabolism. (6) Given
the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which
combines brain imaging with detailed metabolic characterisation is essential to identify lipid
related contributing factors to psychotic disorders. (7) Knowledge of common and specific
mechanisms may help in the etiopathogenic understanding, early disease detection as well as
identification of subjects who may benefit from specific treatments for psychotic disorders or who
may be especially vulnerable to metabolic side effects as well as in discovery of unexpected novel
therapeutic avenues.
The overall objective is to identify, prioritize and evaluate multi-modal blood and neuroimaging
markers with diagnostic potential for prediction and monitoring of psychotic disorders and
associated metabolic co-morbidities. By combining human cohort studies, methodology
developments and translational research (Figure 1), we aim to (1) optimise a multidisciplinary
approach for combining positron emission tomography (PET) and magnetic resonance imaging
(MRI) with metabolomics approaches, (2) develop a PET-method for exploring endocannabinoid
pathways in early psychosis in longitudinal study setting, and (3) develop combined PET/MR
biomarker sets for psychiatric disorders by studying endocannabinoid-monoamine interactions with
multiple PET scans and brain morphology/connections with sMRI and fMRI.
Samples, data,
biomarker panel
Patient
outcomes
Translational research
Data
Data
Methodology developments
Tools
Tools
Figure 1. Outline of the project, in brief.
The expected impacts are (1) etiopathogenic understanding, (2) new validated multi-modal markers
for early disease detection and monitoring, (3) new tools for the identification of subjects who may
benefit from specific treatment (4) discovery of new avenues for disease prevention and therapy, and
(5) new tools and processes for applying brain imaging in personalised medicine.
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Relevance to The goal is to allow the diagnosis of mental disorders at the pre-symptomatic stage
or early during development, more accurate patient stratification and better measurement of disease
progression.
METSY focuses on identification and validation of clinically relevant biomarkers. Multiple
prospective clinical cohort studies including patients with first-episode psychosis will allow to
associate early biomarkers with disease outcomes including metabolic co-morbidities as well as
brain structural and functional changes (Table 1.1.1). Additionally, patient studies in at-risk
mental states will be conducted.
Table 1.1a. METSY clinical trial information.
Project
Number
Project
Acronym Project Title
602478-2 METSY
CT core of
project?
Integrated
neuroimaging
and metabolic
platform for
characterisation
of early
psychosis and
CT is
prediction of
included in
patient outcomes project
Number of
patients in
CT
600
Single/multiple
trial site(s)
Phases
multinational
Type of
Children Elderly
intervention Disease area involved? involved?
observational/cohort
study
diagnostic
Rare
disease?
large observational
study of patients
with first-episode
psychosis and
prodromal
symptoms of
not included not included psychosis
M. Suvisaari et al., Arch. Gen. Psychiatry 56, 733 (1999). [references in bold are contributions from METSY
participants]
2 J. D. Carver, V. J. Benford, B. Han, A. B. Cantor, Brain Res Bull 56, 79 (2001).
3J. Perl et al., Arch. Gen. Psychiatry 64, 19 (2007).
4 A. Gustavsson et al., Eur Neuropsychopharmacol 21, 718 (2011).
5 C. Arango et al., Eur. Neuropsychopharmacol. 21, 867 (2011).
6 H. Jin et al., Schizophr Res. 71, 195 (2004); J. W. Newcomer, CNS Drugs 19 Suppl 1, 1 (2005); C. U. Correll et al., Eur.
Arch. Psychiatry Clin. Neurosci. 261, 417 (2011).
7 M. De Hert et al., Eur. Psychiatry 26, 144 (2011).
8 D. Fraguas et al., J Clin Psychiatry 69, 1166 (2008).
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condition22. These findings thus link altered dopamine synthesis capacity and dopamine
dysregulation to the development of psychosis. Whilst it has been proposed that this dopamine
dysfunction is a final common path to psychosis23, preclinical models indicate that other
neurotransmitter systems are likely to have a critical role in dysregulating dopaminergic function24.
Preclinical studies show that the endocannabinoid system plays an important role in regulating
dopaminergic function25. Specifically, the underlying mechanisms include presynaptic release of
amino acid transmitters onto midbrain dopamine neurons and onto both cortical and striatal
neurons that express dopamine D1-like or D2-like receptors functionally affiliated with the CB1
receptor. However the relationship between the endocannabinoid system and dopaminergic function
remains to be investigated in humans.
The endocannabinoid system in psychotic disorders
The endocannabinoids (ECs) are derivatives of long-chain polyunsaturated fatty acids; the best
known ECs are N-arachidonylethanolamide (AEA or anandamide) and 2-arachidonyl glycerol (2AG). They mediate their effects via specific cannabinoid receptors. CB1R is expressed both in the
central nervous system (CNS) and periphery, including liver, gastrointestinal tract, pancreas and
adipose tissue,26 while CB2R is preferentially expressed in immune cells and tissues27.
Endocannabinoids are not stored in vesicles like classical neurotransmitters, but are produced on
demand from cell membrane phospholipids and degraded in a complex way e.g. via monoacylglecerol
lipase that regulates multiple lipid signalling pathways including e.g. prostaglandins. The CB1R is
one of the most abundant G-protein coupled receptors in the brain with a widespread distribution.
ECs affect appetite and food intake, energy balance, and both lipid and glucose homeostasis28. ECs
affect energy metabolism in peripheral tissues; for example, they have insulin-like effect in fat
cells29. In the CNS, they control food intake both through the homeostatic pathways in the
hypothalamus and the hedonic pathways in the mesolimbic system. Selective cannabinoid receptor
type 1 antagonists are effective weight-loss pharmacotherapy leading to favourable changes in both
lipid and glucose values, but they also cause psychiatric side effects such as anxiety and
depression30. Endocannabinoids have a variety of other roles in the brain, for example in the
neuromodulation of different neurotransmitter, e.g. monoaminergic systems, in the myelination of
developing brain and in repair of axonal myelin sheath, and their role in neurodegenerative
diseases is under extensive study31. Increasing evidence from human and animal studies suggests
that disturbances in the ECs may have an important role in schizophrenia and in cognitive deficits
associated with it32. Leweke et al. have observed that cerebrospinal anandamide levels in patients
with prodromal psychotic symptoms are elevated, and lower levels of anandamine are associated
with higher risk of transition into psychosis earlier, suggesting that an upregulation of the
endocannabinoid system in the prodromal stage is protective33. The same group recently reported
that cannabidiol treatment increases serum anandamide levels and improves symptoms of
schizophrenia34. Recently, omega-3 fatty acid supplementation was reported to reduce remarkably
psychosis conversion in high-risk individuals35 raising further interest in the fatty acid signalling
pathways in etiological psychosis research.
In vivo methodology for exploring CB1 receptors in the human brain, the primary target of major
22
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ECs, has recently been developed (Figure 2) So far, there is only one preliminary in vivo study on
CB1R in schizophrenia and no studies in early psychosis or other psychotic disorders despite the
well-known fact that many patients use or have used cannabinoids in the prodromal phase. Wong et
al. have reported an elevated but state-dependent brain CB1R binding in patients with
schizophrenia36. This result is supported by a recent post-mortem study suggesting a 20 % increase
of CB1 receptors in dorsolateral prefrontal cortex37. These findings need to be further verified and
the connection of putative CB1 receptor alterations with lipidomic changes is highly relevant for
understanding this signalling pathway and its role in early psychosis.
Imaging neurotransmitter networks and combined PET/MR imaging
A clinical PET-study typically investigates only one neurotransmitter system at a time. However,
dysregulation of several different neurotransmitter systems is practically always implicated in the
aetiology of neurological and psychiatric disorders. Still, there are only few studies that have
directly examined more than one neurotransmitter system at a time in relation to psychotic
disorders or in fact for any neuropsychiatric disorder. In vivo baseline expression of most receptor
systems appears to be very stable and reproducible in test-retest studies.. We have utilized a novel
approach exploring neurotransmitter interactions with consecutive PET scans and voxel-by-voxel
intratransmitter correlations (hub and seed analyses) for the internal structure of neurotransmitter
systems and voxel-level intercorrelations for neurotransmitter system interactions. An example of
the latter is shown in Figure 338.
Figure 2. (A) Axial, sagittal, and coronal views of the spatial distribution of a CB1 receptor inverse agonist
ligand [18F]FMPEP-d2 in the human brain, representing the distribution of CB1 receptors (left column) and
corresponding structural magnetic resonance images (middle column). Right column shows the PET image
superimposed on the magnetic resonance image. (B) Decay-corrected brain time-activity curves from a single
subject scanned for 300 min. Putamen (), prefrontal cortex (), cerebellum (), pons (), and white matter (x)
were fitted with an unconstrained 2-tissue compartment model (). Putamen was consistently the region of
highest brain uptake. White matter was consistently the region of lowest brain uptake, followed by pons.
Hirvonen et al, unpublished.
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According to the systems biology view, most of the genetic component of complex disease
susceptibility is not to be found in individual genes, but in their interactions with other genes as
well as with the environment42. In this context the measurement of traits that are modulated but
not encoded by the DNA sequence, commonly referred to as intermediate phenotypes43, is of
particular interest. Changes in the concentration of specific groups of metabolites are sensitive and
specific to pathogenically relevant factors such as genetic variation44, diet45, development46, age47,
immune system status48 or gut microbiota49.
Metabolomics has emerged as a powerful tool for the characterisation of complex phenotypes as
well as for the development of biomarkers for specific physiological responses50. Metabolome is
sensitive to genetic as well as environmental factors, which makes metabolomics a powerful
phenotyping tool needed for predictive, preventive, personalized and participatory (P4) medicine51.
Lipids are a diverse group of essential metabolites that exert many key biological functions, such
as structural components of cell membranes, energy storage sources, and intermediates in
signalling pathways. Lipids are under tight homeostatic control52 and exhibit spatial and dynamic
complexity at multiple levels53. It is thus not surprising that altered lipid metabolism has a global
reach as a pathogenic mechanism and is involved in diabetes and lipotoxicity-induced insulin
resistance54, Alzheimers disease55, schizophrenia56, autism57, cancer58, and atherosclerosis59. Until
recently, sensitive platforms have been lacking for global and quantitative studies of lipids from the
cellular to organism levels. Lipidomics emerged as a sub-discipline of metabolomics which is
dedicated to the global study of lipidomes, including pathways and networks of cellular lipids in
biological systems52.
For the reasons above, metabolomics will be the main molecular profiling technology platform in
METSY to complement the neuroimaging.
Metabolome in psychotic disorders
M. Orei and J. Suvisaari (P5) recently applied metabolomics to produce metabolic profiles
associated with schizophrenia, other nonaffective psychosis (ONAP) or affective psychosis60. The
analysis indicated that schizophrenia is associated with elevated serum levels of specific
triglycerides, hyperinsulinemia, and also upregulation of the serum amino acid proline. Using a
network approach, the metabolic profiles were then combined with other clinical and lifestyle
data (Figure 5A; next page) to create a diagnostic model which discriminated schizophrenia from
other psychoses (Figure 5B). This study demonstrated how network analysis and metabolomics
can be powerful tools for dissecting complex disease-related metabolic pathways and for
identifying candidate diagnostic and prognostic markers in psychiatric research.
Other recent studies on metabolite markers in schizophrenia and in first-episode psychosis have
J. Tang, C. Y. Tan, M. Oresic, A. Vidal-Puig, Genome Med. 1, e35 (2009).
A. Meyer-Lindenberg, D. R. Weinberger, Nat. Neurosci. 7, 818 (2006).
44 T. Illig et al., Nat. Genet. 42, 137 (2010).
45 E. M. Lenz et al., J. Pharm. Biomed. Anal. 36, 841 (2004); E. Holmes et al., Nature 453, 396 (2008).
46 J. Nikkil et al., Mol. Syst. Biol. 4, e197 (2008).
47 R. Maeba et al., J. Atheroscler. Thromb. 14, 12 (2007).
48 M. Oresic et al., J. Exp. Med. 205, 2975 (2008); M. Pflueger et al., Diabetes 60, 2740 (2011).
49 F.-P. J. Martin et al., Mol. Syst. Biol. 3, 112 (2007); V. R. Velagapudi et al., J. Lipid Res. 51, 1101 (2010).
50 M. Oresic, A. Vidal-Puig, V. Hanninen, Expert Rev Mol Diagn 6, 575 (2006).
51 J. Bousquet et al., Genome Med 3, 43 (2011).
52 M. Oresic, V. A. Hnninen, A. Vidal-Puig, Trends Biotechnol. 26, 647 (2008).
53 M. Jnis, R. Laaksonen, M. Oresic, Exp. Opin. Drug Metab. Toxicol. 4, 665 (2008).
54 R. Unger, Trends Endocrinol Metab 7, 276 (1997); G. Medina-Gomez et al., PLoS Genet. 3, e64 (2007).
55 X. Han, D. M. Holtzman, D. W. McKeel, J. Neurochem. 77, 1168 (2001); M. Orei et al., Transl. Psychiatr. 1, e57 (2011).
56 R. Kaddurah-Daouk et al., Mol. Psychiatry 12, 934 (2007); M. Orei et al., Genome Med. 3, e19 (2011).
57 J. Tamiji and D. A. Crawford, Neurosignals 18, 98 (2010)
58 J. A. Menendez, R. Lupu, Nat. Rev. Cancer 7, 763 (2007); M. Hilvo et al., Cancer Res 71, 3236 (2011).
59 A. J. Lusis, Nature 407, 233 (2000).
60 M. Orei et al., Genome Med. 3, e19 (2011).
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and skeletal muscle insulin resistance are determined by their allostatic vulnerability. According to
a recent study, the non-alcoholic fatty liver disease (NAFLD) may affect 50% of all US adults by
203069. NAFLD, which is characterised by deposits of fat in the liver, mainly in the form of
triglycerides, is a major risk factor leading to chronic liver disease, liver failure, and MetS70.
Although liver fat has not yet been studies systematically in
the context of psychosis or antipsychotic treatment, it is
notable that schizophrenia is associated with an increase of
short-chain and saturated triglycerides in serum60,65 (Figure
5). These lipids tend to be produced de novo in the liver and
are associated with increased liver fat and insulin
resistance72, as well as risk of type 2 diabetes73. It is therefore
plausible that the serum molecular lipids associated with
liver fat74 may also be early predictors of development of
metabolic co-morbidities associated with psychosis and
specific antipsychotic treatments. This hypothesis will be
investigated in METSY.
From the clinical perspective there is currently no non- Figure 6. NAFLD diagnostic model
invasive test available for determining a patients liver fat or performance (ROC curves of lipid
accurate evaluation of insulin resistance which is applicable based model comprising three
lipids and a reference
in healthcare setting. Liver fat is usually determined by molecular
model71).
histology or estimated by MRS. The former is highly invasive
as it requires the liver biopsy, so it is only applied in the case
of established liver conditions. The latter may be too expensive for healthcare screening purposes.
Recently, in a large clinical study of obese patients with NALFD, M. Orei and colleagues have as
part of FP6 project HEPADIP identified and validated a serum metabolite signature which can be
used in the estimation of liver fat and diagnosis of NAFLD (Figure 6)75.
Challenge of knowledge management and data integration
To generate actionable knowledge i.e. extracting
predictive pattern across multiple types of information
requires the integration and correlation of existing
knowledge and data from diverse sources and
formats. Currently disjunct containers for individual
scales of structured data (alone 1 400 public databases on
molecular biology related information76) exist next to
unstructured knowledge in the literature, including highcontent imaging, physiological, biochemical and clinical
data. D. Maier and colleagues have developed software
and methods77 to bridge multiple sources and scales of
knowledge into semantic networks and have recently
extended these to imaging data and computational
models as part of the FP7 AirPROM and SynergyCOPD projects (Figure 7) leveraging grid and cloud
computing technologies where appropriate. Well defined
74
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79K.
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patient data, a statistical Disease State Index (DSI) method underlying the DSF has been
developed. The method has been successfully applied to early prediction of Alzheimers disease (EU
FP7 project PredictAD) and has been demonstrated on a variety of different databases with healthdata. It has been shown to provide robust and clinically understandable disease state estimates that
correspond very well with diagnoses made by human experts. It attains a classification performance
similar to that of state-of-the-art reference classifiers. In the case of Alzheimers Disease, it has
been shown to improve experts classification accuracy and confidence about decision making as
compared to traditional, typically paper-based, decision making when large amounts of
heterogeneous data are to be considered81.
The approach is implemented as a reusable software library employing a statistical disease state
modelling method, which is able to robustly analyse the heterogeneous patient data with minimal
pre-processing. It uses context-agnostic data access, analysis, and visualization methods to allow it
to be rapidly applied in several contexts. When presented with a new problem or data, there is no
tuning of parameters, handling of missing values, or development of new user interfaces needed.
1.2.2. METSY considerations with regards to this knowledge
METSY hypotheses
We formulated three specific non-exclusive hypotheses that will guide the METSY research and
platform developments:
H1. Psychotic disorders exacerbate MetS. The development of clinical/subclinical psychotic
symptoms may be a primary event causing changes in energy balance by affecting the
neurotransmitter systems regulating food intake and/or energy expenditure. Once patients with
psychotic disorders are treated with antipsychotics these drugs can also contribute to the
development of the MetS and insulin resistance to a larger or lesser extent depending on the
drug used. Drug-induced metabolic stress adds pathological severity to these severe mental
disorders.
METSY considerations for the platform developments: Predictive and monitoring tools
are needed which would facilitate early detection of patients at risk of developing metabolic comorbidities, e.g., following the specific antipsychotic treatment. Neuroimaging needs to be
complemented by measurements of blood-based metabolic markers associated with
development of MetS and related complications.
H2. MetS exacerbates psychotic disorders. Nutrient overload normally associated to MetS may
cause metabolic lipotoxic and/or hormonal stress in the brain. These toxic events may prime,
exacerbate or accelerate psychotic disorders particularly in genetically vulnerable individuals.
METSY considerations for the platform developments: Tools are needed which would
facilitate monitoring of metabolic dysfunction in psychosis and in at-risk state. Neuroimagingbased markers need to be developed which are sensitive to early brain metabolic changes in
psychosis.
H3. Common underlying mechanisms. The pathological remodelling involving alteration of the
biosynthesis of specific set of reactive lipids important for the intercellular signalling and
membrane function, such as endocannabinoids, may not only affect neuronal development and
function, but also affect the metabolic organs such as adipose tissue, liver or muscle. Similar
perturbations in different organs do not necessarily become pathophysiologically relevant
simultaneously in the same time window.
METSY considerations for the platform developments: As in H1 and H2.
A systems approach to study MetS and psychosis
METSY recognizes that in order to address the hypotheses and reach its objectives:
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1. Research has to lean on relevant clinical data and biobanks in order to identify and
validate novel biomarkers as well as validate the existing ones.
2.
A systems biology approach needs to be adopted to develop and refine the models of relevant
pathophysiological processes, as well as to functionally characterise the candidate markers and
targets obtained from human studies. Computational modelling and its iterative integration with
the experimental platforms is a key for the success of the METSY research programme.
Accordingly, the METSY scientific strategy is translational: several clinical cohort studies in the
domain of psychosis, which include prospective studies in at-risk subjects, are included.
Neuroimaging will be complemented by neuropsychological assessment and molecular profiling in
order to identify the multi-modal biomarkers and disease networks associated with metabolic
changes and patient outcomes in the course of psychosis. Advanced modelling tools of systems
biology and computational statistics will be applied and further developed to help analyse and
interpret the acquired data. The biomarkers and networks will be evaluated, prioritized and
independently validated.
In order to reach the objectives, METSY has mobilised competencies and resources covering clinical
research and state-of-the-art technologies. As shown in Table 1.2a, the clinical resources will be
utilized to generate the key data (Objectives 1-3) as well as to validate and evaluate the key
findings and models for their clinical utility and implementation in healthcare setting (Objective 6).
Table 1.2a. A brief summary of selected available clinical resources (biobanks and ongoing studies).
Existing cohort/biobank description
PI
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P4 35 at-risk patients (age 18-40 years) with oneyear follow-up and controls. Assessment:
Structured Interview for Prodromal Symptoms
Limitation: Relatively low sample size; this limitation
(SIPS), matched controls. Neuroimaging,
will be addressed by combining the data with the data
genetics, metabolic characterisation incl.
from other similar cohorts.
metabolomics, dietary habits, neuropsychology,
immune and oxidative stress markers. [O1, O2,
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O3, O6]
P5 35 at-risk patients (age 18-40 years) with oneyear follow-up and controls. Assessment:
Structured Interview for Prodromal Symptoms
Limitation: Relatively low sample size; this limitation
(SIPS), matched controls. Neuroimaging,
will be addressed by combining the data with the data
genetics, metabolic characterisation including
from other similar cohorts.
metabolomics, dietary habits, anthropometric
measures, neuropsychology. [O1, O2, O3, O6]
40 At risk patients (age 18-40 years) and controls.
Assessment: Structured Interview for Prodromal
Symptoms (SIPS), genetics, metabolic
characterisation including metabolomics. [O1, O2]
P7 20 At risk patients (age 18-40 years) with oneyear follow-up and controls. Assessment:
Structured Interview for Prodromal Symptoms
(SIPS), matched controls. Neuroimaging,
genetics, metabolic characterisation including
metabolomics, dietary habits, anthropometric
measures, neuropsychology. [O1, O2, O3, O4, O6]
The valuable clinical resources will be accompanied by a variety of experimental and computational
strategies (Table 1.2b) which will be combined and utilized by applying the systems biology
approach.
Table 1.2b. Key components of the METSY systems biology platform (selected).
Scientific platform description
Objectives
Analytical strategies
Neuroimaging: structural MRI (sMRI) including diffusion tensor imaging (DTI) by P3, P4,
P5, P6, and P7. PET by P4, P6 and P7. Hybrid PET/MR by P4 and P6.
MRI systems: SERMAS will use General Electric 3T Signa scanner (General Electric,
Milwaukee, USA). THL uses MAGNETOM Skyra 3T (Siemens Healthcare, Erlangen,
Germany). KCL uses 3T GE Signa system (General Electric, Milwaukee, USA)
PET systems: UTU uses 3T Philips Ingenuity TF PET/MR hybrid camera (Philips
Healthcare, Cleveland, USA) for PET, fMRI and sMRI studies. KCL will use Siemens
Biograph 6 HiRez (Siemens, Erlangen, DE).
Global (UPLC-MS lipidomics83, GCGC-TOFMS metabolomics84) and targeted
metabolomics (endocannabinoids, eicosanoids, steroids, bile acids 85) (P1).
O2, O3, O6
The established lipidomics platform covers molecular lipids from major lipid classes
including phosphatidylcholines, phosphatidylethanolamines, triglycerides, ceramides,
sphongomyelins, and lysophospholipids. Typically about 800 molecular lipids are detected
from serum with this platform. The GCGC-TOFMS platform is a highly sensitive and
comprehensive platform which covers polar metabolites. The metabolite classes covered
include amino acids, fatty acids, TCA cycle metabolites, alcohols, amines, selected sterols
and sugars. Typically about 1000 metabolite peaks are detected with this platform.
Both global platforms have been applied in many human cohort studies (see
http://sysbio.vtt.fi/pubs.html). Together the global and targeted platforms allow for
hypothesis-driven as well as discovery-driven approach.
Serum biochemical assays to estimate liver fat86 (P1).
H. Nygren, T. Seppanen-Laakso, S. Castillo, T. Hyotylainen, M. Oresic, Methods Mol Biol 708, 247 (2011).
S. Castillo, I. Mattila, J. Miettinen, M. Oresic, T. Hyotylainen, Anal Chem 83, 3058 (2011).
85 S. I. Sayin, et al., Cell Metab. 17, 225-235 (2013)
86 The serum marker of liver fat was developed and validated by P1 in the EU FP6 project HEPADIP (patent application).
83
84
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O5, O6
O3, O5, O6
Disease State Fingerprint (DSF) and Disease State Index (DSI) for decision-support.
O5, O6
- 16 -
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PET imaging method- a universally agreed protocol to be applied across the sites. Training and
evaluation sessions will be held for all researchers prior to and periodically during the study to
maintain a standard approach across sites; (2) PET data procedure- a standardised file format
(DICOM) will be used and data transferred anonymously to one site for analysis iii) PET validity
checks. Standardisation will be checked by scanning the same PET phantom at each centre prior to
the study starting and at six month intervals during the study, and possibly further evaluated by
scanning a sub-group of controls (n=4) once at each site; iv) internal controls- matched controls will
be scanned at each centre to provide site-specific internal controls so that site specific effects can be
further evaluated.
[18F]FMPEP-d2 radiochemistry set up already exists in UTU and will be implemented also in UK
with blood input function determination for modelling and accurate Vt quantification. The already
existing PET scan protocol89 will be used with BMI adjustment, close scanning session control;
dietary factors, smoking, benzodiazepine use and detailed drug screens. 18F-DOPA PET scan is a
well-established method for measuring striatal DA synthesis capacity at these centres21. In brief, after
urine drug screen to confirm no substance use, subjects will receive 150MBq of 18F-DOPA IV and an
emission scan over 90 minutes. The primary regions of interest (the striatum) will be defined blind to
group status using the HAMNET maximum probability atlas, which will be spatially normalised to the
PET dynamic images, and striatal Ki values (representing dopamine synthesis capacity) will be
determined using a Patlak graphical method with a cerebellar reference region. Our test retest data has
shown that this method has high reliability90.
Intergroup, intragroup and correlation analyses with clinical parameters will be done primarily at
voxel level using Vt parametric maps and SPM/PMOD softwares (PMOD Technologies, Zurich,
Switzerland).
Metabolomics platform
Samples
Analytical methods
Metabolic profiling
Additionally, several targeted methods for specific groups of metabolites are available based on
UPLC-MS/MS and GC-MS platforms. In METSY, UPLC combined with triple quadruple mass
epctrometry (QqQMS) will be used for the quantitative determination of endocannabinoids. The
QqQ system utilizes collision-induced dissociation while monitoring unique precursor to product ion
transitions, affording superior sensitivity, precision, and accuracy, especially for simultaneous
analysis of multiple endocannabinoids, including derivatives of ethanolamide, ethanolamine as well
as glyceride derivatives.
J. Hirvonen et al., Mol Psychiatry 17, 642 (2012).
A. Egerton, A. Demjaha, P. McGuire, M. A. Mehta, O. D. Howes, Neuroimage 50, 524 (2010).
91 http://sysbio.vtt.fi/pubs.html
92 T. Pluskal, S. Castillo, A. Villar-Briones, M. Oresic, BMC Bioinformatics 11, 395 (2010).
89
90
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Endocannabinoid pathways in
early psychosis neuroimaging
studies
WP2
Patient
outcomes
Translational research
Evaluation and validation
of biomarkers of patient
outcomes in psychosis
WP6
Data
Data
Tools
Methodology developments
Methodologies for combined
PET and MR imaging
WP4
Tools
93
- 18 -
WP No
WP1
WP2
WP
WP4
WP5
WP6
WP7
- 19 -
WP8
Task description
2
M1.1
D8.3
Year 1
10
D8.5
D8.6,
D8.7
D8.4
M5.
1
D4.1
M3.1
M2.1
12
14
16
D7.4
D7.3
M4.1
D1.1
18
Year 2
20
22
D8.10
D8.8
D8.9
M6.1
M5.2
D5.1
D4.2
D3.1
24
26
28
D8.11
30
Year 3
32
34
D8.12
D7.5
D5.2
D4.3
D3.2
D2.2
D2.1
D1.3
D1.2
36
38
40
D8.13
42
Year 4
44
D6.1
D2.3
48
D8.14
46
METSY
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WPs 1 and 2, and the contingency has been dealt with in WP 1 above.
WP 4 (also relevant to WP 1, WP 2)
Risk. (1) The envisioned combined PET/MR protocol cannot be implemented due to technical
reasons or because it is too complex in practical use. (2) Standardized image viewing and analysis
does not work due to different scanners being used at different sites.
Contingency. (1) The protocol can be split up over two or more imaging sessions using simpler
protocols, respectively. (2) Robust derived parameters need to be established that are less impacted
by differences in scanner specifications (e.g. relative uptake changes rather than absolute uptake
values for PET).
WP 5 (also relevant to WP 4)
Risk. The biggest risk for the development of integrative analytical methods and related software
is normally a delay in availability of appropriate experimental data, which in this project is
mitigated by the participation of already existing studies with data and samples in WPs 1-3. The
next biggest risk is that the existing and developed methods are insufficient for the targeted level of
integrated analysis, providing no significant markers and clinical decision support suggestions for
validation in WP6.
Contingency. If the available methods indeed do not allow reaching the full level of integrated
analysis, keeping in mind that a multitude of state-of-the-art methods will be applied in parallel, we
will instead apply a multi-step process. First well established single data type methods such as
differential voxel analysis or metabolic network analysis will be applied and the results be used
directly in the clinical decision support disease state index (Task 5.1) the semantic mapping
knowledge base (Task 5.3) and the biomarker validation (WP6). Second machine learning and
correlation analysis will be applied on the mapped initial analysis results to gain insights on
modules and mechanisms connecting brain functional/structural attributes with gene and lipid
metabolism networks providing a significance ranking of individual analysis results for validation
in WP6.
WP 6
Risk. Success of this WP dedicated to biomarker validation largely depends on the findings from
other WPs, which are used as input for the work in WP 6. Two extreme outcomes from WPs 1-3
have been identified as risks:
A. no suitable biomarker or target candidates have been identified in WPs 1-3;
B. very large number of biomarker or target candidates has been identified for most outcomes of
interest in WPs 1-3, and not all biomarkers or targets can be validated and developed further in
WP 6 given the resources and time available.
Contingency. Milestone M6.1 was set to assess the status of biomarker discovery across the WPs 13, prior to the start of Tasks 6.2 and 6.3.
Risk A has been dealt with in Risk/Contingency analyses of other WPs above. In general, given the
recognized role of lipid metabolism in co-morbidities associated with obesity including psychosis, it
is highly unlikely that no metabolism related biomarkers of potential clinical significance will be
identified from neuroimaging or metabolic profiling in any of the WPs. The METSY participants
involved have extensive experience in applications of their technology platforms and modelling
methods, respectively, therefore the technical risk which could affect the outcome of biomarker
discovery can be considered minimal. The participants have the means and experience to deal with
any technical challenges that may occur during the project.
Given the multiple possible endpoints of interest and anticipated strong performance of molecular
lipids in particular as potential markers, the scenario B is more likely. For this reason, Task 6.1 has
been set up to prioritise the biomarker candidates.
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2. Implementation
2.1. Management structure and procedures
The coordinator Matej Orei and VTT have vast experience in coordinating, managing and
participating in projects funded by EC. Effective management and coordination of METSY will
ensure that all goals of the project are met, especially in light of the complexity and the high degree
of integration required.
The project organization consists of the following elements (Figure 11): (1) Steering Committee,
which is the highest management body of METSY. The Steering Committee comprises the work
package leaders and representatives of each participant (team leaders); (2) Work package
management, which will take care of conducting the work in respective work packages (consisting of
WP-leader and participants involved). In addition, two different teams will assist the Steering
Committee: administration team (coordinator, financial officer, administrative and legal officers)
and Foreground Evaluation Committee (FEC) (coordinator, exploitation manager, legal officers,
research and industry representatives).
METSY will set-up a Steering Committee (SC) and FEC that will efficiently address the specific
objectives via a clear distribution of tasks and authorities. METSY will be managed by applying the
following criteria:
1. The overall scientific management and coordination of the work programme, including the timely
implementation of the work plan, networking and achievement of scientific goals to ensure the
overall smooth operation of the project; (SC)
2. The overall coordination of all financial, legal, administrative and contractual requirements
within the contract, including certificates on the financial statements and the maintenance of the
consortium agreement; (SC)
3. Overseeing information and knowledge management, including dissemination, Intellectual
Property Rights and exploitation; (FEC)
4. Overseeing risk assessment and contingency plans; (SC + Coordinator)
5. Overseeing gender, ethical and wider societal issues; (Coordinator)
6. Relationship and communication with the European Commission. (Coordinator)
Work Packages
European
Commission
Contractual
relationship
Advice
Interaction
Scientific Director
(P1)
WP 1
WP 2
WP 3
Coordinator
Project Office
FEC
WP 4
WP 5
WP 7
WP 8
Management activities
Steering Committee
(Coordinator, WP and Team leaders)
WP 6
External Advisory Board
Expert Committee
Ethics
Gender issues
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Teleconferences will be organised among members of the consortium, for example via Skype or
similar technology.
Web page. METSY will use an internal domain on the METSY web page for making internal
information accessible to all beneficiaries. This will include access to the publications,
presentations, internal documents, reporting templates, as well as the datasets (e.g. as relevant for
the assessment of milestones). All web access will be protected with individual access codes changed
on a 6-monthly basis.
Overview of meetings during the course of the project:
Meeting
Time (months)
Beneficiaries
Subject
Kick-off meeting
Consortium
Information on structure
of METSY
Annual consortium
meeting
Consortium, FEC
Information on progress
of METSY
Meetings of the
steering committee
Coordinator, WP
leaders, SME and
patient organization
representatives
Assembly of interim
reports and
dissemination
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http://www.symmys.fi/
http://sybio.vtt.fi/
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Biomax Informatics AG
(Biomax; team leader Dr. Dieter Maier) P2
Biomax Informatics AG is a Munich based SME that, since 1997,
provides services and computational solutions for better decision making and knowledge
management in the life sciences, with a special focus on semantic knowledge representation, data
integration and knowledge aggregation. Knowledge generation is based on proprietary tools for textand data-mining (e.g. generating the NCI cancer gene index in collaboration with the NCI or data
mining based patient stratification and biomarker profile development)
Team leader: Dr. Dieter Maier currently serves as Head of Project Management at Biomax. A
molecular biologist with eleven years of experience in bioinformatics and software project
management, his areas of expertise in bioinformatics include knowledge management, pathway
modelling, statistical data analysis and the prediction of gene structure and function. Software
projects he managed encompass systems biology infrastructure, automatic function prediction and
IP management.
Key people in the team: Dr. Wenzel Kalus is the lead Software Developer at Biomax with
thirteen years of experience in bioinformatics, molecular dynamics and software development. His
expertise is in system architecture and data integration. He managed several software development
projects in the field of sequence analysis, gene expression and data integration frameworks. Dr.
Karsten Wenger is a Computational Linguist who for the last 12 years has specialised on the area
of medical information systems. He managed several life sciences text mining projects for example
the NCI cancer gene index.
Expertise and resources: The team of experts at Biomax provides resources and experience in
knowledge generation and management including literature-mining, semantic data integration,
database management, IT infrastructure design and software customisation and development.
Biomax will provide access to its IT infrastructure including compute cluster and database servers.
Making available existing, in-house developed software applications to the project for knowledge
management (BioXM), data integration (BioRS) and literature mining (BioLT) contributes over 100
man-years of software development efforts.
Participation in EU programmes: Biomax is currently involved in three EU projects, the FP7ICT AirPROM and Synergy-COPD and the FP7-HEALTH MeDALL projects which interconnect
current knowledge with clinical and experimental data, in silico analysis and simulation.
Recent publications relevant to the project
1. Maier D, Kalus W, ..., Losko S. Knowledge management for systems biology a general and
visually driven framework applied to translational medicine. BMC Syst Biol 2011, 5:38.
2. Bousquet J, ... Maier D, ..., Zuberbier T. MeDALL (Mechanisms of the Development of
ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011, 6, 596604
3. Sameith K, ..., Maier D, ..., Falciani F. Functional Modules integrating essential cellular
functions are predictive of the response of leukaemia cells to DNA damage. Bioinformatics 24,
2602-2607 (2008)
4. Losko S, Wenger K, Kalus W, ..., Heumann K. Knowledge Networks of Biological and Medical
Data: An Exhaustive and Flexible Solution to Model Life Science Domains. Lecture Notes in
Computer Science 4075, 232-239 (2006).
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University of Turku
(UTU; team leader Prof. Jarmo Hietala) P4
The University of Turku is a research-led university with seven
faculties (21 000 students) and internationally acknowledged expertise from humanities to medicine
and natural sciences. Psychiatry is one of the biggest clinical departments in our Medical School
and has activities in the fields of adult, adolescent and also forensic Psychiatry in the South-West
Finland. The population base is almost 1 million (the Hospital Districts of Southwest Finland and
Satakunta, Turku City Psychiatric Clinic and also the Vaasa Hospital District).
Team leader: Prof. Jarmo Hietala, MD, PhD, Head of Department of Psychiatry, University of
Turku. He became associate professor of Pharmacology in 1991, served as professor of
Neurotransmission at the Turku PET centre and was appointed professor of Psychiatry (UTU) in
2004. Prof. Hietala has a well-established track record in clinical psychosis/schizophrenia research.
His focus has been in particular on the biological aspects of schizophrenic and affective psychosis
using clinical, genetic and imaging methodologies with relevant original findings in the field
(Hietala et al Lancet. 1995 Oct 28;346(8983):1130-1, Pohjalainen et al Mol Psychiatry. 1998
May;3(3):256-60)
Key people in the team: The Psychosis research team at our department is a multidisciplinary one
covering fields of psychiatry, (neuro)psychology, radiology and isotope medicine with extensive
networking. The larger project is co-lead by Prof Hietala and Prof. emeritus Raimo Salokangas.
Key clinical people are clinical Lecturer Markus Heinimaa, associate professor of neuropsychology
Tuula Ilonen and research nurse Pivi Jalo. Docent Jussi Hirvonen, MD and Lauri Tuominen
MD are key persons in carrying out the PET studies. The collaborators at the Turku PET Centre
are of crucial importance for functional and structural imaging projects. There are currently 19
researchers in the team (6 at post-doc level) and Ph.D students.
Expertise and resources: The core expertise and know-how lies in clinical psychosis research with
a large collaboration networks in Europe and also in North America. The research greatly benefits
from the well-established population/register research traditions in Finland (e.g. the twin register).
We are now also collaborating with the CRYF-cohort study (Cardiovascular risk factors in Young
Finns) started in 1980 in Finland in order to study the time course of metabolic changes in
individuals with a later psychosis diagnosis. Another area of strength is the possibility to combine
state-of art imaging with clinical research. Functional (PET, fMRI) and structural imaging started
in 1988. We have now a newly installed PET/MR hybrid camera at the Turku PET centre which
provides us with new possibilities for multi-modal imaging.
Participation in EU programmes: The group has participated in several EU-funded programs
starting from EU BioMed2 programs (CPFIDOTS, BMH4-CT96-0220). We recently completed the
EPOS project (European Prediction of Psychosis Study, QLG4-CT-2001-01081). We participate in
many European research projects such as the ECNP Imaging Network initiative (see publications).
Recent publications relevant to the project
1. Delvecchio G, ..., Hietala J, Lawrie SM, , Meisenzahl E, Frangou S. Common and Distinct
Neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: A
voxel-based meta-analysis of functional magnetic resonance imaging studies. European
Neuropsychopharmacology. 2011 Aug 4. [Epub ahead of print].
2. Ruhrmann S, , Salokangas RK, Heinimaa M,, Klosterktter J, EPOS group. Prediction
of psychosis in adolescents and young adults at high risk: results from the prospective European
prediction of psychosis study. Arch Gen Psychiatry. 2010;67(3):241-51.
3. Huttunen J, , Heinimaa M, , Ilonen T, , McGlashan T, Salokangas RK, Hietala J.
Striatal Dopamine Synthesis in First-degree Relatives of Patients with Schizophrenia. Biol
Psychiatry. 2008;63(1):114-7.
4. Hirvonen J et al. Reversible and regionally selective downregulation of brain cannabinoid CB1
receptors in chronic daily cannabis smokers. Mol Psychiatry . 2012 June ; 17(6): 6429
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Metabolomics (P1)
Decision-support
systems (P1)
Human genetics
(P3, P5)
Principal outcomes
Neuroimaging platform
for metabolic studies in
psychosis (P3, P4, P6,
P7)
Validated metabolic
biomarker assays (P1)
Semantic
Network biology
The proposed studies will be guided
modelling
(P2)
(P1)
by a continuous interplay between
computational
modelling,
Image processing
Diagnostic models
applications and developments of
(P1, P6)
(P1)
multiple technology platforms and
human cohort studies. Owing to the
complexity of the problems tackled, Figure 12. METSY competencies.
our research goals could never be
accomplished by individual scientists working alone. As a consortium, investigators have the
combined clinical, experimental, and modelling experience, as well as the equipment and logistics,
required to pursue globally leading research and platform development in systems medicine as
related to psychiatric research.
METSY
FP7-HEALTH-2013-INNOVATION-1
systems biology. The omics base of METSY is leaning on metabolomics/lipidomics as the key
molecular profiling technology relevant to the objectives of the project (Matej Orei and Tuulia
Hytylinen, VTT, P1).
In order to facilitate the uses of multi-modal markers acquired with the above technologies in
healthcare setting, software applications are needed for decision support. Jyrki Ltjnen (VTT,
P1) has developed such a system based on the Disease State Index (DSI) method. The approach has
so far been applied in the domains of Alzheimers disease (PredictAD EU FP7 ICT-VPH project) and
traumatic brain injury (TBIcare EU FP7 ICT-VPH project).
Computational systems biology
METSY has considered that modelling of biological systems at multiple levels in the context of
human health requires applications of multiple modelling strategies. METSY brings together
complimentary expertise in neuroimage data processing and related statistical methodology and
software development (Timo Paulus, Philips, P6; Jyrki Ltjnen, VTT, P1), integrative
bioinformatics and semantic modelling (Dieter Maier, Biomax, P2), network biology and diagnostic
models (Matej Orei and Marko Sysi-Aho, VTT, P1).
Collective management experience of participants
The management team is based on a structure of responsible partners. Effective management and
coordination of METSY will ensure that all goals of the project are met, especially in the light of
complexity and high degree of integration required.
The coordinator, Matej Orei (VTT) is Research Professor in Systems Biology and Bioinformatics
at VTT Technical Research Centre of Finland. He coordinates VTTs activities related to systems
biology and bioinformatics. Previously he was leading the computational biology efforts at BG
Medicine, Inc. (Waltham, MA, USA), one of the pioneers of medical systems biology as applied to
biomarker discovery and pharmaceutical R&D. Dr. Orei has experience with coordinating larger
consortia. For example, he coordinates the EU FP7 project ETHERPATHS (Characterization and
modelling of dietary effects mediated by gut microbiota on lipid metabolism; FP7-KBBE-222639;
1/2009-12/2012,) and directs the new Academy of Finland Centre of Excellence in Molecular
Systems Immunology and Physiology Research SyMMyS (2012-2017, www.symmys.fi).
The coordinating institution, VTT, has vast experience in coordinating, managing and participating
in projects funded by EC. Effective management and coordination of METSY will ensure that all
goals of the project are met, especially in light of the complexity and the high degree of integration
required.
Several other project participants have been collectively involved in multiple European
collaborative projects as coordinators or work package leaders.
Role of SMEs and industrial partners
One SME and one industrial partner have been engaged as participants. They are fully integrated
into the METSY consortium as partners.
Biomax Informatics AG (Biomax, P2) will play an important role in data integration,
bioinformatics analysis and mining of data acquired in WPs 1-3 and 6. As part of WP 5 activities,
Biomax will apply its BioXMTM Knowledge Management Framework to integrate data acquired in
METSY or made available to the project by METSY participants with the existing knowledge.
Philips (Philips, P6) will focus on methodological developments and applications of the PET/MR
imaging system. The system will also be applied by all clinical partners in the project (P3, P4, P7).
Third parties
The Fundacin para la Investigacin Biomdica del Hospital Gregorio Maran is the third party
linked to Hospital Gregorio Maran. Collaboration between P3 SERMAS (Hospital) and Fundacin
is carried through a prior collaboration agreement, by means of which the latter handles the
financial and administrative aspects of the Hospital involvement in research projects, including all
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issues relating to the employment and payment of additional personnel, purchase of equipment and
consumables, etc. The Foundation is situated in the premises of the Hospital.
Sub-contracting
Subcontracting will be performed following the rules under FP7.
Sub-contracting will be performed by all partners who need audit certificates.
Three participants (SERMAS, THL, KCL) will sub-contract image analyses.
SERMAS (P3) will use a General Electric 3T signa scanner as a subcontract to improve scan
acqusition (3T is an improvement over 1.5T) and make inter-site comparability feasible. The centres
in Finland use 3T scanners, therefore it is advantageous to use a 3T scanner in Madrid to reduce
potential noise due to inter-scanner variability.
THL (P5) will use subcontracting for laboratory services (phlebotomies) that are taken at the
hospitals where the patients are treated and in laboratories that are close to the outpatient services,
for a neuroradiologist who writes clinical reports of the images that are given to the participants,
and for the services of an X-Ray nurse.
KCL (P7) will subcontract the PET/MR imaging so the CB1 imaging is comparable to that in
Finland.
Other countries
There are no participants from non-EU countries.
METSY
FP7-HEALTH-2013-INNOVATION-1
(3.1%) to management activities, and 179,280 Euro (4.2%) to dissemination activities. Industrial
participants have been allocated 1,270,312 Euro (30%) of the total EC requested budget.
Table 2.4b. METSY budget per participant.
Partner
no
Partner
name
1
2
3
4
5
VTT
Biomax
SERMAS
UTU
THL
1,058,185
799,200
571,267
723,062
564,065
-
-
-
-
-
-
-
-
-
-
115,030
1,600
2,500
2,000
2,500
96,360
72,360
-
-
-
1,269,575
873,160
573,767
725,062
566,565
6
7
Philips D
KCL
1,183,903
724,900
-
-
-
-
5,000
3,500
-
10,560
1,188,903
738,960
5,624,582
3,922,461
-
-
-
-
132,130
132,130
179,280
179,280
5,935,992
4,233,871
92.6 %
0.0 %
0.0 %
3.1 %
4.2 %
100.0 %
Total costs
Requested EU funding
Share of EU funding %
Training
Management
Other
activities
Total
Share of
total cost
budget %
21%
15%
10%
12%
10%
20%
EC contrib
1,005,029
673,360
430,950
544,297
425,549
12%
596,952
557,735
100%
4,233,871
Share of
EC
contrib
%
24%
16%
10%
13%
10%
14%
13%
100%
METSY
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3. Impact
The adverse influence of weight gain and associated metabolic co-morbidities in the lives of people
with psychotic disorders is substantial. Body image affects self-esteem and desire for thinness is
common for women in all Western cultures96. Consequently, weight gain is among the most
distressing side effects for people with psychotic disorders, and one of the major causes for
medication non-compliance97,98. People with schizophrenia have over 20 years shorter life
expectancy than the general population99, and metabolic comorbidities, especially type 2 diabetes,
are among the major determinants of excess mortality100. Metabolic comorbidities increase the
health care costs of people with schizophrenia101, but more alarming is that patients with
schizophrenia do not get adequate treatment for comorbid physical diseases102. Therefore, more
detailed understanding of the development of metabolic comorbidities, as well as methods that
would allow early identification of those at greatest risk would greatly benefit patients with
psychotic disorders.
Methods that allow identification those patients with prodromal symptoms who are at greatest risk
of developing psychotic disorder would enable targeting intensive early interventions. It has been
shown that most of the psychosocial impairment develops during the prodromal stage of the illness
and does not usually improve when the treatment is started after the onset of psychotic
symptoms103. Therefore, the earlier the treatment is started, the larger impact it has, and intensive
treatment during the prodromal stage has been shown to improve outcome substantially104.
Although it has been known for decades
that psychotic disorders are associated
with structural and functional brain
changes, this information is currently not
used in clinical decision making except for
excluding general medical conditions.
Tools that would allow better utilization
of brain imaging as a diagnostic and
prognostic tool would improve the care of
people with psychotic disorder.
The expected impacts of METSY are (1)
etiopathogenic understanding, (2) new
validated multi-modal markers for early
disease detection and monitoring, (3) new
tools for the identification of subjects who
may benefit from specific treatment (4)
discovery of new avenues for disease
prevention and therapy, and (5) new tools
and processes for applying brain imaging
in personalised medicine.
Healthcare professionals
Patient
care
Improved
decision
making
EU R&D
Increased
knowledge
Increased
competitiveness
EU
industry
Treatment
Better therapeutic
options
METSY
Reduced
cost
Improved
quality of life
Patient
Society
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For healthcare professionals the impacts are in improvements in the healthcare system.
Additionally, the project is expected to generate new scientific knowledge about the pathophysiology
behind different biomarkers in psychosis and its metabolic co-morbidities.
For the citizens, the impacts lie in better tools to predict the health-related outcomes in psychosis,
leading to better treatment options and ultimately to improved quality of life.
For the European industry and decision makers METSYs results give input for development
and exploitation of products based on innovative methods developed in the project, thereby
increasing global competitiveness.
(tissue specificity,
In metabolomics studies, the discovery
disease specificity, )
and validation steps are usually
performed by using global platforms,
covering a broad range of analytes. Once
Healthcare providers
Pharma R&D
Diagnostic providers
the biomarker analytes are known, a
Insurance companies
(or other related)
Pharma (early clinical)
robust and rugged method needs to be
Pharma (Phase 3 trials)
Food industry (claims)
developed and validated which may be
applicable in clinical setting. VTT (P1) Figure 14. Typical biomarker development pipeline. Shown
has the capacities for such assay at the bottom of the figure are also specific stages where
developments for metabolite based specific industry sectors become relevant.
biomarkers. Due to time and resource
constraints it is unlikely that any of the biomarkers will be brought to the very end of the assay
development stage, e.g. as a diagnostic kit ready for use in healthcare setting. However, they will be
developed far enough that commercial exploitation and pilot studies in healthcare setting can be
considered. The commercial exploitation of such biomarkers and related assays will be considered
case-by-case according to METSY management procedures, and may involve further in house
developments, launching spin-outs, licensing, or industrial partnerships.
For broad acceptance of the biomarker in healthcare setting, biomarker needs to be further
confirmed in independent replication studies and its utility needs to be demonstrated in
multiple studies, with some leading to publications in notable medical journals. Although these
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additional studies are not considered within METSY; once the assays and multi-modal panels are
developed in WP 6, METSY will consider offering them for applications in other on-going or future
studies or projects. The conditions of involvement will be considered on case-by-case basis according
to METSY management procedures.
In addition to participating SME and industrial partner, also other METSY partners have a strong
track record in commercial exploitation of scientific findings, including in launching multiple spinout companies, licensing deals, or industry partnerships across a broad range of business areas.
2. Contribution to It will also encourage SME participation and foster innovation in Europe in
line with the Europe2020 agenda.
METSY includes one SME in the domain of bioinformatics. In line with Europe 2020 Smart Growth
priorities, and strongly facilitated by the integration with a large European industry partner,
METSY will for example have a strong impact on creating new products/services that generate
growth and jobs and help address social challenges with the help of innovative combination of
neuroimaging and metabolic research via the use of state-of-the-art methods of bioinformatics and
statistics.
3. Contribution to In addition, it will support the goals of the European Pact for Mental Health.
Affective and non-affective psychoses are relatively prevalent mental illnesses. It has been
estimated that the lifetime prevalence of all psychotic disorders is about 3.5 %105. Psychotic bipolar
disorder and psychotic depression are common affective psychoses whereas schizophrenia is the
most common as well as the most severe one among the non-affective psychoses in terms of
functional outcome106. Schizophrenia is clinically characterised with a typical onset in adolescence
or early adulthood with disturbances of perception, thinking, behaviour and emotional life.
Schizophrenia and other psychotic disorders are also a major public health problem because of their
burden and prevalence. Brain disorders cost Europe almost 800 billion a year107. Among all brain
disorders psychotic disorders come second, only after mood disorders, in terms of cost to Europe. In
a recent report it has been estimated that in Europe there are over 5 million people with psychotic
disorders and that the cost to Europe is 93.6 billion a year108.
METSY will provide better predictive diagnostic tools to detect and monitor psychosis, which is
directly relevant to two priority areas of the European Pact on Mental Health and Well-being: (II)
Mental health in youth and education, and (III) Mental health in workplace settings.
To attain a high level of public awareness of METSY activities and discoveries and of the
relevance to systems medicine;
To maximize exploitation of METSY discoveries in healthcare and personalised medicine
settings;
To protect METSY intellectual property.
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The project manager will have the responsibility to oversee all dissemination activities, which also
will be defined in the Consortium Agreement.
Means to disseminate new knowledge within the scientific community are:
1.
2.
3.
4.
5.
6.
7.
Means to disseminate to patients as well as healthcare professionals and decision makers are:
1.
2.
Press releases in national newspapers, initiated by the information offices at the participating
organizations;
Open door events in the participating organizations;
Science and Society events;
Presentation of METSY, its objective, aims and potentials on a public domain web page.
METSY web page. One important means to integrate all dissemination activities will be the
web page of METSY, where knowledge will be made available to the scientific community and
the public. A private domain will be established to make internal knowledge easily accessible
for all partners. The private domain will include internal interim reports, pre-views of scientific
publications, and internal news. The web page will be regularly updated and designed to meet
the needs of the consortium.
2.
Preparation of joint papers and position statements. The Steering Committee will actively
pursue opportunities for METSY to publish joint papers and position statements in the name of
METSY. The METSY joint papers will attract more attention to other means of dissemination
such as the METSY web page, and will therefore have a multiplication value.
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FP7-HEALTH-2013-INNOVATION-1
is available as a commercial product in life science research and clinical application environments.
Generation of a psychotic disease and metabolic co-morbidities knowledgebase and integration with
newly developed clinical decision support systems (WP 5) will broaden the clinical applicability of
the system to psychotic disease (currently it is focused on pulmonary care).
The experience and research results gained during the project, regarding structuring, mapping and
mining results of brain imaging technologies in the context of diagnostics will allow Biomax to
further extend its established commercial footprint in the field of clinical knowledge management in
research and application. While there is strong competition from large non-European companies
(e.g. Microsoft Almaga Life Sciences) regarding general clinical data management infrastructure
the added value provided by targeted content and knowledge representation, developed in projects
such as MetSY, will allow Biomax to provide added value and expand its position in the life science
knowledge management and bioinformatics market with a total volume in 2010 of about $ 3.5
billion and a focus on content in purchase decisions (Frost&Sullivan Market report 2010, RNCOS
Market Outlook 2010, Global Industry Analysts report 2011).
Philips
The Imalytics Research Workstation is developed by Philips Research and is available as a
commercial product. It serves as a platform for new applications to be used in preclinical and
clinical research environments. Project results of WP 4 are intended to become new modules on the
Imalytics platform, and thereby have the potential for direct commercialisation.
Insights and first prototypes generated in this project will also be transferred to various business
units within Philips Healthcare at a later stage. Developed modules may also be made available on
the clinical workstation IntelliSpace Portal (requiring regulatory approval, which is out of scope for
this project).
Furthermore, the demonstration of the clinical benefits of hybrid PET/MR neuroimaging that will
be pursued in this project will substantiate the need for this innovative hybrid imaging technology
for early prediction and monitoring of psychotic disorders, thus fostering sales to academic hospitals
and specialized neuroimaging centres.
Overview of Intellectual Property (IP) opportunity
The effective management and exploitation of Intellectual Property (IP) is a critical component of
METSY. It is essential that the outcomes of the research are adequately protected in such a way
that they are attractive for commercial exploitation. Consideration must be given to the categories
of IP that are likely products of the Work Packages. For example:
1.
Diagnostic biomarkers applicable in healthcare setting. Activities in WPs 1-3 and 6 will
lead to novel biomarkers for the specific clinical outcomes of relevance to healthcare and
personalized medicine. The IP may include specific analytical assays for the biomarkers or more
broadly the multi-modal biomarker signatures together with the method to predict the relevant
outcomes using these analyte(s) as well as potentially other information.
2.
Management of IP
As recommended in the FP7 guidelines and according to standard practice, IP will be considered in
the following categories:
1.
2.
Foreground may be owned by the single party that generated the Foreground or jointly owned by
several parties that have contributed to the Foreground. The ownership and rights of use of
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Foreground generated through the performance of this collaborative project will be defined in the
consortium agreement, which will combine standard practice with several innovative features to
enhance the effectiveness through which Foreground can be exploited and/or commercialized. A
summary of the key considerations is provided here:
1. Identification. Academic research scientists will often not recognize valuable Foreground that
could form the basis of a patent. This is not surprising since such training is not routinely provided
or available to researchers. The current program will address this by two actions:
1. It will provide training in knowledge protection and transfer, and IP. This action will take
advantage of the existing technology transfer organizations within METSY. The partner
organizations have well developed and professional technology transfer offices. In addition,
the program includes two SMEs, for which the effective management of IP is an essential
part of their activities. METSY will offer a workshop taught by experts from the technology
transfer organizations and with representatives from SMEs to provide the industry
perspective. The workshop will focus on how to identify a Foreground opportunity that
should be protected and on the best strategy for its protection.
2. Technology scouts. This is, relative to academic practice, a highly innovative feature of the
current proposal that has been inspired by current industry practice. Industry employs
technology scouts who are trained in the identification of valuable IP and technology
partnering opportunities and who attend meetings and conferences or visit biotechnology or
academic clusters in order to identify what may be of interest to their company. METSY will
collect volunteers within the programme (preferably at the Postdoctoral level) who have an
interest in the exploitation of Foreground and commercialization of research results. These
will be briefed, mentored and trained by the technology transfer specialists to act as
technology scouts within METSY. Their task will be to identify opportunities arising from
the research that should be protected and/or exploited. This activity will also serve to provide
a first training to the postdoctoral fellows in industry-relevant actions and may be
particularly attractive to those researchers considering a career in industry.
2. Protection. The breadth of claims and positioning of the claims are essential elements in
establishing the value of a patent. Consequently, it is important to consider the full possible breath
of claims that could be made regarding a particular asset of Foreground. This will be achieved
within the current proposal by implementation of a Foreground Evaluation Committee (FEC),
which will include a blend of expertise that can add value to patents by identifying enlarged scope
or wider positioning of claims. The FEC will be composed of clinical researchers, academic
researchers, representatives of the technology transfer offices and a patent attorney. The FEC will
review each opportunity presented by the technology scouts (or directly by research scientists
whenever they should take such initiative) with a view to maximising its value and to recommend
an effective patent filing strategy or other form of protection strategy. The FEC will also assist in
determining the assignment of ownership of jointly-owned Foreground.
3. Rights of Use. All Foreground generated within METSY will be made available to the
consortium for non-commercial research, training and educational purposes. Whenever possible this
philosophy will also be applied on a Europe-wide scope to any Foreground that has potential for
creation of value in the European research base such that the Foreground will be made available
non-exclusively for non-commercial research, training and education to the research community.
Pending confirmation of this and other stipulation by the negotiated consortium agreement, it is
anticipated that any party generating individually Foreground that is the subject of a patented
invention has the right to use and licence such invention at their sole discretion. Rights of use of
patented inventions developed with contributions of more than one partner within METSY will be
determined by agreement between the concerned partners on an exploitation and licensing plan.
This plan may stipulate that one contributing partner licenses exclusively their share of the joint
invention to another contributing partner for commercialization. Alternatively, each party sharing
the ownership of Foreground may be entitled to issue non-exclusive licenses at their sole discretion
but without the right to sublicense. Please note that patented Background that is required for the
performance of METSY will be provided by each party as a royalty-free non-exclusive license
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4. Ethical issues
The METSY consortium recognizes the need to carry out all the work in this project to the highest
ethical standards. The work will be carried out within full compliance with the relevant
requirements of the latest version of the Declaration of Helsinki.
The Coordinator has prepared a comprehensive documentation of all terminated, on-going and
novel clinical studies including information on sampling and data collection, number of subjects,
informed consent, sample storage and data protection. This documentation further includes all
ethical permissions and accompanying documents. It will be used by the ethics steering group and
the external expert for regular periodic monitoring and for preparation of an ethics section that will
be part of the reports to EC.
4.1. General
We confirm that the proposed research within METSY does not involve:
1.
2.
Research activity intended to modify the genetic heritage of human beings which could make
such changes heritable,
3.
Research activities intended to create human embryos solely for the purpose of research or for
the purpose of stem cell procurement, including by means of somatic cell nuclear transfer,
4.
All participating laboratories will fulfil local and national safety requirements. Utilisation of
chemicals in this project will be subject to Institutional and National safety regulations to ensure
the safety of employees and to prevent damage to the environment both in the European community
and elsewhere. People handling biohazardous material will do so only after they have received
proper training. Disposal of hazardous materials will be performed according to EC-regulations. The
compliance with these rules is supervised by institutional safety officers. Problems will be reported
to the relevant director. All storage of samples and data will follow EU guidelines. All data collected
in METSY will be subject to the core data protection principles and requirements of the Data
Protection Act 1998 and the Council of Europe Committee of Ministers Recommendation No. R (97)
5 on the protection of medical data. These include the removal of all personal identifiers from
samples and data. Both national and EU guidelines will be considered.
Ethics committee. A special expert committee will be established to oversee all ethical issues in
METSY. This committee will be responsible for establishing METSY policies with respect to ethics
in human and animal studies and biological material, and for monitoring that policies are adhered
to. The composition of the committee will be as follows: three members from the METSY
consortium (Carmen Moreno, Chair (SERMAS, P3), Jaana Suvisaari (THL, P5), Oliver Howes
(KCL, P7)) and one external member, Prof. Philip Cowen (University of Oxford, UK).
The ethical issues in METSY project will essentially deal with human data and biological samples
used for research (informed consent and data protection);
In addition to the questions regarding informed consent and data protection, the project will take
into account the following issues:
1. Approval of the study: Samples will be collected and processed strictly after the approval of
relevant local/national ethics committees, based on national laws, EU legislation and
international declarations and conventions;
2. Sources of samples: All human tissues will be obtained from medical sources.
General aspects: All members, the physicians and researchers have given their full commitment
to to protect the life, health, privacy, and dignity of the human subject in medical
research (WMA Declaration of Helsinki 2000, Basic Principles of all Medical Research, 10), and
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this principle will be present all along the existence and within all the activities started by our
network.
To ensure the rights and safety of all patients and to ensure the integrity of research date
all studies will perform according the criteria of Good Clinical Practice (GCP).
This project will include data from adolescents and adults with psychotic disorders as well as
matched controls. We intend to include at least 30 adolescents with psychosis and their matched
controls in the study. The inclusion of minors is justified based on the frequency of psychotic
disorders, with a typical onset in adolescence or early adulthood, and due to the fact that metabolic
issues related to psychosis may be even more relevant when psychosis starts at early ages. METSY
will provide better predictive diagnostic tools to detect and monitor psychosis, which is directly
relevant to one of the priority areas of the European Pact on Mental Health and Well-being: (II)
Mental health in youth and education. In addition, the study proposal involves only minor harmful
effects to the participants (mild discomfort related to drawing a venous blood sample, need to stay
still during MRI imaging), and the scientific benefits of discovering new biomarkers related to
psychotic disorders and improving the utilization of brain MRI information are unequivocal. PET
imaging data will only be obtained from adult participants.
8. The Human Tissue Act 2004; The Medicines for Human Use (Clinical Trials) Regulations 2004:
SI 2004/1031; The Data Protection Act 1998; and Medicines (Administration of Radioactive
Substances) Regulations 1978, all regulating medical research relevant aspects in the UK.
International Conventions and Declarations
1. Universal declaration on the human genome and human rights (UNESCO);
2. Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects
(http://www.wma.net/e/policy/b3.htm);
3. UN Convention on the Rights of the Child
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4. Convention of the Council of Europe for the Protection of Human Rights and Dignity of the
Human Being with regard to the Application of Biology and Medicine: Convention on Human
Rights and Biomedicine signed in Oviedo on 4th April 1997, and the additional protocols:
on the Prohibition of Cloning Human Beings, signed in Paris on 12th January 1998;
Opinion of the European Group on Ethics in Science and New Technologies to The European
Commission, Number 11, 21st July 1998 (human tissue banking);
Opinion of the European Group on Ethics in Science and New Technologies to The European
Commission, Number 8, 25th September 1996 (patenting inventions involving elements of
human origin);
Opinion of the European Group on Ethics in Science and New Technologies to The European
Commission, Number 7, 21st May 1996 (genetic modification of animals).
Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on
setting standards of quality and safety for the donation, procurement, testing, processing,
preservation, storage, and distribution of human tissue and cells.
The ethical expert committee will provide a section on ethics in each project annual report.
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All experiments and analysis of clinical data will take place in EU countries. The laws and
regulation for each country will be taken into consideration.
Informed Consent
Sample collection or use of clinical data will be done only from patients who have given their
informed consent.
The informed consents used in METSY will take into account the following:
1. Both oral as well as written information will always be given to potential participants, after
which the participants give written informed consent. There will be age-appropriate information
sheets and consent forms so adolescent and adult participants could both receive all study
information taking their developmental level into consideration. Of special interest for studies
including psychiatric patients is that if the treating physician, e.g., psychiatrist, considers the
patient too ill to give informed consent, the patient will not be approached until the situation
has stabilized.
2. The Spanish FEP study (P12) recruits also adolescents with first-episode psychosis. The consent
procedure includes obtaining written informed consent from both patients and their parents or
legal guardians after a careful explanation of the study, including both oral and written
information. Language and terms will be appropriate to the participants. There will be specific
consent forms for minors that will provide all study information in an age-appropriate fashion.
When minors are involved, they will be asked for their consent after having opportunity to solve
all questions regarding their participation with a clinician with expertise in children and
adolescents. Involved minors will be re-asked for their consent as soon as they reach legal
majority, in compliance with the Article 29 working group WP 147 00483/08/EN Document 5.
The Minors Attorney has been informed about the inclusion of minors in the study.
3. Consent forms will make explicit that participants have the right to know that participation is
voluntary; to ask questions and receive understandable answers before making a decision; to
know the degree of risk and burden involved in participation; to know if there are any benefits
involved in participation; to know the procedures that will be implemented in the case of
incidental findings (see above); to receive assurances that participating centres have appropriate
insurance cover in place; to withdraw themselves and their biosamples from the project at any
time; and to know procedures of data collection and protection during and above the project.
4. All research files used for data analysis will have deidentified, coded id-numbers. The data will
not contain any sensitive information such as names, addresses or social security numbers. All
analyses will be done with deidentified data that will not allow identification of individuals. All
data will be stored on a secure computer located behind a firewall or a central server with very
restricted access, depending on the institution, complying in any case with national and EU
legislation on data storage. Data will be encrypted and password protected if transferred
between secure servers.
5. Shipping of samples will be done according to the regulations of participating countries and
institutions.
Confirmation on Ethical Committee Decisions
Ethical issues will be evaluated on a continuous basis by the METSY Ethical Committee, with the
occasion of meetings of the project consortium. Each group leader, representing a project partner
will be responsible for ethical issues involved by own translational research part or collection of
biological samples and clinical data. All project partners should report the ethical issues involved in
different sections of the study to one defined representative of the consortium, who will be in charge
with harmonizing and observing the ethical issues relevant for the overall project. This person will
also contact the EC representatives and will report all changes done to the ethical issues of the
research project.
Data protection, storage and handling
All samples and associated clinical data will be collected and stored at the individual institutions.
These data will be processed for research-related specified purposes and on the basis of the consent
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or other legitimate basis laid down by law. The study data will be de-identified. All patients will
receive a study code, which will be central, unique and abstract. Researchers in the study will be
responsible to use this code to refer to participants through the development of the project. No
personal data, including names or other identifying data, will be released in any communication
related to the study or its results nor will they be accessible by internet or by any other means. Only
the principal investigator from the working group has full access to respective patient identification.
For biological samples we intend to use barcodes, which will be generated at the time of sample
collection. These barcodes will enable the easy tracking of samples.
Linked coded data will be generated which will contain no personal information about the patient.
Besides, secure procedures for electronic data handling will be developed, by keeping a record of
researchers allowed to access data and implementing an authentication procedure. In addition, to
be transported, data will be previously encrypted. The patient identifier will be kept securely
separate by the keyholder of each study group. The coded data will be a part of extensive data
mining and will therefore be stored permanently. It is unlikely that the data will be disposed of. The
research teams, as above, will have access to the coded data. Procedures that will be implemented
for data collection, storage, access, sharing policies, protection, retention and destruction will
comply with national and EU legislation, including Article 29 workgroup paper nWP131 on the
processing of personal data relating to health in electronic health records.
Any clinically significant finding from neuroradiological examinations or from routinely basic lab
screens will be communicated to the participant and legal representatives with advice concerning
any recommended further course of action. Participants will be informed that they will not receive
any feedback regarding results from genetic testing or other biochemical measurements, as these
studies serve only the scientific questions, not existing currently clear reference values, and because
significance of these measurements is currently not clear at the individual level.
PAGE
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Informed Consent
Does the proposal involve patients or persons not able to give consent?
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Privacy
Research on Animals
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Dual Use
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