Dow Metsy (602478) 2013-06-18

Ref.
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
Annex I - "Description of Work"

Project acronym: METSY
Project full title: " Neuroimaging platform for characterisation of metabolic co-morbidities in
psychotic disorders "
Grant agreement no: 602478
Version date: 2013-06-18
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
One form per project

General information
Project title
Neuroimaging platform for characterisation of metabolic co-morbidities in psychotic

disorders
Starting date
01/09/2013
Duration in months
48
Call (part) identifier
FP7-HEALTH-2013-INNOVATION-1
Activity code(s) most

7
relevant to your topic
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.
602478 METSY - Part A - Page 3 of 5
A2:
List of Beneficiaries
Project Number
602478
Project Acronym
METSY
List of Beneficiaries
Name
Short name
Country
Project entry
10
month
Project exit
month
TEKNOLOGIAN TUTKIMUSKESKUS VTT
VTT
Finland
48
BIOMAX INFORMATICS AG
BIOMAX
Germany
48
SERVICIO MADRILENO DE SALUD
SERMAS
Spain
48
TURUN YLIOPISTO
UTU
Finland
48
TERVEYDEN JA HYVINVOINNIN LAITOS
THL
Finland
48
PHILIPS TECHNOLOGIE GMBH
PHILIPS
Germany
48
KING'S COLLEGE LONDON
KCL
United Kingdom
48
No
A3:
Budget Breakdown
Project Number
602478
Project Acronym
METSY
One Form per Project
Participant
number in
11
this project
Estimated eligible costs (whole duration of the project)

Participant
short name
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.
* The following funding schemes are distinguished

Collaborative Project (if a distinction is made in the call please state which type of Collaborative project is referred to: (i) Small
of medium-scale focused research project, (ii) Large-scale integrating project, (iii) Project targeted to special groups such as
SMEs and other smaller actors), Network of Excellence, Coordination Action, Support Action.
1. Project number
The project number has been assigned by the Commission as the unique identifier for your project, and it cannot be changed.
The project number should appear on each page of the grant agreement preparation documents to prevent errors during
its handling.
2. Project acronym
Use the project acronym as indicated in the submitted proposal. It cannot be changed, unless agreed during the negotiations.
The same acronym should appear on each page of the grant agreement preparation documents to prevent errors during
its handling.
3. Project title
Use the title (preferably no longer than 200 characters) as indicated in the submitted proposal. Minor corrections are possible if
agreed during the preparation of the grant agreement.
4. Starting date
Unless a specific (fixed) starting date is duly justified and agreed upon during the preparation of the Grant Agreement, the
project will start on the first day of the month following the entry info force of the Grant Agreement (NB : entry into force =
signature by the Commission). Please note that if a fixed starting date is used, you will be required to provide a detailed
justification on a separate note.
5. Duration
Insert the duration of the project in full months.
6. Call (part) identifier
The Call (part) identifier is the reference number given in the call or part of the call you were addressing, as indicated in the
publication of the call in the Official Journal of the European Union. You have to use the identifier given by the Commission in
the letter inviting to prepare the grant agreement.
7. Activity code
Select the activity code from the drop-down menu.
8. Free keywords
Use the free keywords from your original proposal; changes and additions are possible.
9. Abstract
10. The month at which the participant joined the consortium, month 1 marking the start date of the project, and all
other start dates being relative to this start date.
11. The number allocated by the Consortium to the participant for this project.
12. Include the funding % for RTD/Innovation either 50% or 75%
13. Indirect cost model
A: Actual Costs
S: Actual Costs Simplified Method
T: Transitional Flat rate
F :Flat Rate
Workplan
Tables
Project number
602478
Project title
METSYNeuroimaging platform for characterisation of metabolic

co-morbidities in psychotic disorders
Call (part) identifier
Funding scheme
Collaborative project
WT1
List of work packages

Project Number
602478
Project Acronym
METSY
LIST OF WORK PACKAGES (WP)

WP
Number
Type of
54
activity
WP Title
53
Lead
beneficiary
55
number
Person56
months
Start
month
End
month
57
58
WP 1
Brain structural changes and metabolism

neuroimaging studies
RTD
89.00
48
WP 2
Endocannabinoid pathways in early

psychosis neuroimaging studies
RTD
42.40
48
WP 3
Lipid molecular networks, insulin resistance

and metabolic markers in psychosis
RTD
46.00
48
WP 4
Methodologies for combined PET and MR

imaging
RTD
52.00
48
WP 5
Statistical and bioinformatics tools to

integrate brain image information with
clinical and molecula
RTD
66.00
48
WP 6
Evaluation and validation of biomarkers of

patient outcomes in psychosis
RTD
64.00
18
48
WP 7
Awareness and dissemination
OTHER
9.00
48
WP 8
Management activities
MGT
5.00
48
Total
602478 METSY - Workplan table - Page 1 of 34
373.40
WT2:
List of Deliverables
Project Number
602478
Project Acronym
METSY
List of Deliverables - to be submitted for review to EC

Deliverable
Number
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:
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
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:
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
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:
Deliverable
Number
Deliverable Title
61
Estimated
WP
Lead
benefiindicative
number
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
SOPs for data

sharing.
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:
Deliverable
Number
61
Deliverable Title
Estimated
WP
Lead
benefiindicative
number
months
Total
Nature
373.40
62
Dissemination level
63
Delivery date
64
WT3:
Work package description

Project Number
602478
Project Acronym
METSY
One form per Work Package

Work package number
WP1
53
Work package title
Type of activity
RTD
Brain structural changes and metabolism neuroimaging studies
Start month
End month
48
Lead beneficiary number
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:

findings from WPs 2 and 3). Subjects included have been carefully characterized for psychopathological,
neuropsychological and demographic variables. Patients included in this task will share inclusion criteria. Three
different subsamples (P3, P4 and P5) will be analyzed independently. Primary clinical outcomes linked to this
task will be change in BMI z-score (corrected for age and gender) and change in psychiatric domains, including
change in GAF and BPRS scores.
Task 1.3 Neuroimaging in first-episode psychosis [P3, P4, P5]
Baseline and one-year neuroimaging (MRI, DTI) assessments will be performed in parallel with clinical and
neuropsychological assessments (MATRICS components) in a new sample of FEP and controls. This new
sample will be also studied in WP6 to validate prior biomarker discovery (WP 1-3).
The main outcomes will be divided into psychiatric (psychosis conversion, change in BPRS and GAF, SOFAS)
and metabolic (change in BMI z-score, abdominal fat, and homeostasis model assessment insulin resistance
(HOMA-IR) index, and liver fat (as estimated by a serum signature86; see also page 10).
Task 1.4 Neuroimaging in at-risk state [P4, P5, P7]
Baseline and one-year neuroimaging assessments will be performed in parallel with clinical and
neuropsychological assessments (MATRICS components) in a new sample of psychosis risk individuals and
controls.
The outcomes are same as in Task 1.3.
Person-Months per Participant
Participant number
Participant short name
10
Person-months per participant
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
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
Total
89.00
Description of deliverables
D1.1) Panel of neuroimage biomarker candidates associated with patient outcomes in psychosis.: [month 18]
WT3:

D1.2) Baseline and one-year follow-up evaluation of 250 first episode schizophrenia patients from METSY
cohorts and their controls.: [month 36]
D1.3) Baseline and one-year follow-up evaluation of 100 at-risk patients and their controls.: [month 36]
Schedule of relevant Milestones
Lead
beneficiary
number
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS1
Implementation of between centres clinical

and neuroimaging data harmonisation
procedures.
Report posted on internal

project web site.
MS4
First prototype of software tool for advanced

PET/MR image processing and image
analysis.
18

project web site
Comments
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP2
53
Work package title
Type of activity
54
RTD
Endocannabinoid pathways in early psychosis neuroimaging studies
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.
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.
Participant number
10
11
1 VTT
10.00
4 UTU
20.00
7 KCL
12.40
WT3:

Participant number
10
11
Total
42.40
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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 state and 35
controls.
10.00 R
RE
36
D2.3
One-year follow-up neuroimage and

clinical data (including detailed data
on cannabis use).
12.00 R
RE
48
Total
42.40
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]
Lead
beneficiary
number
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS2
CB1 receptor PET scans available from

5 first-episode patient with psychosis, 5
individuals with an
12

project web site.
MS4

analysis.
18

project web site
Comments
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP3
53
Work package title
Type of activity
RTD
Lipid molecular networks, insulin resistance and metabolic markers in psychosis
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.
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:

analyses, image data will be first decomposed using independent component analysis. The neuropsychiatric
assessment data will be rescaled to allow parametric modelling, as described in our earlier study. Gaussian
graphical modelling will be applied by P1 to derive the direct interactions between the factors in selection.. The
outcomes will provide a panel of variables directly or causally associated with the outcomes of interest listed
above. This information will be used to gain an insight into which biomarker variables from Task 3.1 are directly
associated with the outcomes of interest, as e.g. applied in P1s earlier studies in schizophrenia107, , and this
way help in the prioritisation of the biomarkers (input for WP 6) or in narrowing down in biomarker search.
Participant number
10
11
1 VTT
28.00
2 BIOMAX
4.00
3 SERMAS
8.00
5 THL
6.00
Total
46.00
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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
Total
46.00
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
59
number
Milestone name
MS3
Plasma global metabolomics data is available

from 100 first episode psychosis patients,
100 siblings
Lead
beneficiary
number
Delivery
date from
60
Annex I
1
12
Comments

project web site.
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP4
53
Work package title
Type of activity
RTD
Methodologies for combined PET and MR imaging
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.
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:

Representation of VOI statistics in quantitative units.
These tools will be evaluated and calibrated using phantom studies. In addition, advanced viewing tools will be
developed to support:
Visualization of parametric maps
Fusion visualization of functional and structural imaging
Fusion visualization of two 4D datasets, ensuring viewing of matching time-points,
Visualization of vector and tensor maps.
Task 4.3 Advanced PET/MR image processing and analysis [P4, P6, P7]
Advanced PET and MR image analysis methods will be developed/applied in WPs 1 and 2 at different clinical
sites (P3, P4, P7). The resulting (potential) image biomarkers will further be evaluated in WP6 and integrated
with other biomarkers in WP5.
Easy-to-use software tools will be developed to ensure standardized PET and MR image processing at the
different clinical sites. While task 4.2 will enable multi-vendor data import and viewing, here, advanced image
processing will be addressed. This includes development of new software modules as well as integration of tools
that are currently used at individual partner sites. In particular, the following functionality will be implemented:
Pharmacokinetic modeling, neuroreceptor mapping, and analysis,
Gray/white matter segmentation (structural T1-weighted MRI),
Structural and functional connectivity imaging (DTI; voxel-wise analysis, Fractional Anisotropy mapping,
tractography),
Interface to existing tools, e.g. SPM,
Correlation and analysis tools for sequential scans.
Participant number
10
11
4 UTU
6.00
6 PHILIPS
38.00
7 KCL
8.00
Total
52.00
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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 processing and image
analysis.
24.00 R
RE
36
Total
52.00
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:

D4.3) Software tools for advanced PET/MR image processing and image analysis.: [month 36]
Milestone
59
number
Milestone name
MS4

analysis.
Lead
beneficiary
number
Delivery
date from
60
Annex I
6
18
Comments

project web site
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP5
53
Type of activity
RTD
Statistical and bioinformatics tools to integrate brain image information with clinical
and molecula
Work package title

Start month
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.
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:

outcomes of interest listed above, which will be considered in biomarker discovery for specific outcomes of
interest.
Task 5.3 Integrative bioinformatics in psychosis [P1, P2, P6]
To address O5.3, P2 will relate and connect the structural (WP 1) and functional (WP 2) imaging related and
clinical data with the metabolic information created in WP3 and prior knowledge. We will semantically represent
molecular networks, anatomic structures and functional circuits on the level of concepts such as object, relation,
subnetwork etc. The semantic model will provide the framework to study the molecular, clinical and imaging data
in a disease context-dependent manner by participant P1. Technically we will employ the BioXM Knowledge
Management Environment developed by Biomax which features natural language based wizards to generate
semantic mappings, complex queries and reports. It provides Directive 95/46/EC and ISO27000 conforming
secure storage for clinical and experimental data, images and analysis results with encryption, access control
and auditing. The concepts (e.g., endocannabinoid network, hypothalamus, specific proteins, metabolites etc)
will be represented as nodes and their relationships (e.g., regulates, is involved in, ) as edges. Literature
mining techniques as well as clinical expertise provided by partners P3, P4 and P5 and from integration with
existing sources of structured knowledge (e.g. Reactome molecular pathways, FMA human anatomy) will be
used to generate and populate the network. The literature mining will be based on dictionary co-occurrence as
well as full syntactic parsing approaches. Initial expert derived (partners P3-5) term lists will be automatically
expanded and manually validated from the relevant literature corpus ensuring only terms of relevance are
used. Where available we will use and if necessary map existing controlled vocabularies such as the DSM,
ICD-9 or ICD-10 while covering gaps e.g. for the description of imaging and image analysis workflow metadata
(structured, systematic information about the actual data generation process). Clinical data will be harmonised
during integration in collaboration with WP1. Where necessary pointers to data on storage clouds will be used.
Networks, classifications and other analysis results generated during the project will iteratively be mapped to
the prior knowledge and data enabling interpretation of e.g. an inferred metabolic network in the context of the
compound gene and gene disease associations available from public sources.
Participant number
10
11
1 VTT
12.00
2 BIOMAX
48.00
6 PHILIPS
6.00
Total
66.00
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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
Total
66.00
WT3:

D5.1) Prototype software implementation of Disease state index and Disease state fingerprint for psychosis.:
[month 24]
D5.2) Network inference and machine learning based integrative analysis of imaging and metabolic data.:
[month 36]
D5.3) Semantic model as a tool for the identification of combined neuroimage metabolic markers.: [month 48]
Lead
beneficiary
number
Delivery
date from
60
Annex I
Milestone
59
number
Milestone name
MS5
Specification of psychotic disorders specific

criteria for CDSS inclusion.
12

project web site.
MS6
Availability of integrated semantic network.
24

project web site.
Comments
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP6
53
Work package title
Type of activity
RTD
Evaluation and validation of biomarkers of patient outcomes in psychosis
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.
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:

The sample size was estimated based on power calculations for diagnostic tests (sample size for a diagnostic
case control study regarding test with binary outcome , requiring approximately 90% specificity and sensitivity
with 10% CI (Power = 0.9, =0.05).
Task 6.3 Validation of multi-modal markers [P1, P2, P3, P4, P5, P6, P7]
Using the predictions from WP 3 and WP 5, the analytical approach from Task 6.2 will be combined with derived
variables from acquired image data and other clinical data from the same subjects (WPs 1 and 2) which were
included in multi-modal biomarker candidates. 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).
The disease state index approach developed in Task 5.1 will also be validated. This will be realised by first
taking into account specific needs in psychotic disorders (to be crystallised in the early phases of METSY)
and then by advancing the clinical decision support software (CDSS) tool developed for Alzheimer's disease
(implementing the DSI and DSF concepts) to meet these needs. Specifically we will apply a structured
consensus generation process (such as DELPHI, Cochrane or nominal group technique) to integrate literature
review results with expert opinion.
Tasks 6.2 and 6.3 will be performed in parallel on the same patient series.
Participant number
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
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
D6.1
Validation results for selected

biomarker panel in the context of
patient outcomes in psychosis.
Estimated
indicative
personmonths
1
Total
Nature
64.00 R
62
Dissemination
63
level
PU
Delivery date
64
48
64.00
D6.1) Validation results for selected biomarker panel in the context of patient outcomes in psychosis.: [month 48]
WT3:

Milestone
59
number
Milestone name
MS7
Panel of multi-modal and molecular

biomarkers is available from WPs 1-3 and 5
for evaluation, priori
Lead
beneficiary
number
Delivery
date from
60
Annex I
1
24
Comments
Minutes of the steering

committee meeting.
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP7
53
Work package title
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.
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:

patent applications made by the project. The FEC will be chaired by Dieter Maier (Biomax, P2), and will be
composed of researchers representing core METSY competencies, representatives of the technology transfer
offices and a patent attorney. The composition of FEC will be determined at the first METSY General Assembly
meeting (at the project Kick-off).
The tasks of the FEC will be complemented by local technology transfer experts who will be in charge to
identify protectable know-how and patentable research findings before they are disclosed in abstracts or
peer-reviewed publication. The FEC will also identify and train technology scouts who will come from within the
METSY scientific teams and whose task will be to identify opportunities arising from the research that should be
protected and/or exploited.
The management of knowledge and of intellectual property within this IP will be performed according to the
following steps:
1. Identification of patentable research findings.
2. Assignment of inventorship and institutional ownership.
3. Recommendation whether or not to file for IPR.
4. Assist any partner within METSY to define the best patent preparation and filing strategy.
Rules governing IPR protection and sharing in METSY will be laid down and agreed in the consortium
agreement (see WP8, deliverable 8.2).
Participant number
10
11
1 VTT
3.00
2 BIOMAX
6.00
Total
9.00
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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
D7.5
First opinion paper outlining METSY

bioinformatics platform.
5.00 P
PU
36
Total
9.00
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
59
number
Milestone name
Lead
beneficiary
number
Delivery
date from
60
Annex I
Comments
WT3:

Project Number
602478
Project Acronym
METSY

Work package number
WP8
53
Work package title
Type of activity
MGT
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.
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:

Participant number
10
11
1 VTT
5.00
Total
5.00
Deliverable
Number
Lead
beneficiary
number
Deliverable Title
61
Estimated
indicative
personmonths
Nature
62
Dissemination
63
level
Delivery date
64
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
0.30 O
RE
12
D8.6
SOPs for data sharing.
0.30 O
RE
12
D8.7
Ethical approvals, protocols and

registrations
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
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]
D8.6) 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]
D8.9) Mid-term review.: [month 24]
WT3:

Milestone
59
number
Milestone name
Lead
beneficiary
number
Delivery
date from
60
Annex I
Comments
WT4:
List of Milestones
Project Number
602478
Project Acronym
METSY
List and Schedule of Milestones

Milestone
59 Milestone name
number
WP number
53
Delivery date
60
from Annex I
Comments
MS1
Implementation of
between centres
clinical and
neuroimaging data
harmonisation
procedures.
WP1

project web site.
MS2
CB1 receptor PET

scans available
from 5 first-episode
patient with
psychosis, 5
individuals with an
WP2
12

project web site.
MS3
Plasma global
metabolomics data
is available from
100 first episode
psychosis patients,
100 siblings
WP3
12

project web site.
MS4
First prototype of
software tool for
advanced PET/MR
image processing
and image analysis.
WP1, WP2,
WP4
18

project web site
MS5
Specification of
psychotic disorders
specific criteria for
CDSS inclusion.
WP5
12

project web site.
MS6
Availability of
integrated semantic
network.
WP5
24

project web site.
MS7
Panel of multi-modal
and molecular
biomarkers is
available from
WPs 1-3 and 5 for
evaluation, priori
WP6
24
Minutes of the steering

committee meeting.
WT5:
Tentative schedule of Project Reviews

Project Number
602478
Project Acronym
METSY
Tentative schedule of Project Reviews

Review
Tentative Planned venue
65
timing
of review
number
Comments, if any
WT6:
Project Effort by Beneficiary and Work Package

Project Number
602478
Project Acronym
METSY
Indicative efforts (man-months) per Beneficiary per Work Package

Beneficiary number and
short-name
WP 1
WP 2
WP 3
WP 4
WP 5
WP 6
WP 7
WP 8
Total per Beneficiary
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:
Project Effort by Activity type per Beneficiary

Project Number
602478
Project Acronym
METSY
Indicative efforts per Activity Type per Beneficiary

Activity type
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:
Project Effort and costs

Project Number
602478
Project Acronym
METSY
Project efforts and costs

Estimated eligible costs (whole duration of the project)
Beneficiary
number
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
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
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
- ii -
METSY
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.
- iii -
METSY
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
Area under the ROC curve

Body mass index
Brief psychiatric rating scale UCLA version
Constraint-based modelling
Clinical Global Impression
Central nervous system
Cardiovascular disease
Default mode network
Diagnostic and Statistical Manual of Mental Disorders
Diffusion tensor imaging
First episode psychosis
Global assessment of functioning
Tow-dimensional gas chromatography coupled to time-of-flight MS
Genome-wide association
Homeostasis model assessment insulin resistance
International Diabetes Federation
Insulin resistance
Kiddie Schedule for Affective Disorders and Schizophrenia
Least-angle regression
Measurement and Treatment Research to Improve Cognition in Schizophrenia
Metabolic syndrome
Magnetic resonance imaging
Magnetic resonance spectroscopy
Mass spectrometry
Non-alcoholic fatty liver disease
The National Cholesterol Education Program Adult Treatment Panel
Other non-affective psychosis
Odds ratio
Positive and negative syndrome scale
Phosphatidylcholine
Positron emission tomography
Polyunsaturated fatty acid
Predictive, preventive, personalized and participatory medicine
Receiver operating statistics
Structured Clinical Interview for DSM-IV Axis I Disorders
Support vector machnine
Type 2 diabetes mellitus
Ultra performance liquid chromatography coupled to MS
Young mania rating scale
- iv -
METSY
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
-v-
METSY
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.
Human cohort studies
Brain structural changes and metabolism neuroimaging studies

Endocannabinoid pathways in early psychosis neuroimaging studies
Lipid molecular networks, insulin resistance and metabolic markers in psychosis
Samples, data,
biomarker panel
Patient
outcomes
Translational research
Data
Data
Methodology developments
Evaluation and validation

of biomarkers of patient
outcomes in psychosis
Tools
Methodologies for combined PET and MR imaging

Statistical and bioinformatics tools to integrate brain image
information with clinical and molecular profile data
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.
-1-
METSY
1.1.1. Specific objectives

The main objective of METSY will be met by combinations of clinical research, state-of-the-art
technologies and systems biology, divided into six specific objectives:
O1. To apply neuroimaging strategies to characterise structural and metabolic changes in the brain
during the first stages of psychosis.
Detailed multimodal neuroimaging (MRI, PET) and neuropsychiatric characterisation will be
performed in longitudinal studies involving patients at-risk or with first episode of psychosis.
O2. To apply imaging strategies to characterise the endocannabinoid pathways in the brain and
relate them to lipid molecular networks.
Detailed neuroimaging and metabolic studies of endocannabinoid pathways will be performed,
including synthesis and degradation systems.
O3. To characterise genetic and lipid molecular networks as measured in biofluids in early
psychosis and identify how these networks associate with patient outcomes.
Detailed metabolic characterisation, as well as metabolomics studies, will be performed in
longitudinal studies involving patients at-risk or with first episode of psychosis.
O4. To develop and demonstrate methodology for combined PET and MRI imaging.
Methods and tools for combined PET and MR image acquisition and analysis will be developed.
Early protocols with multiple PET scans along with MRI sequences will be utilised first in
healthy volunteers, then in pilot patients. The protocols will be optimised for the PET/MR
hybrid camera (Philips Ingenuity TF).
O5. To develop bioinformatics tools to integrate brain image information with clinical and molecular
profile data.
Computational methods will be developed which integrate image data with other phenotypic
data, including from omics analyses, in order to extract multi-modal signals of potential
diagnostic value.
O6. To identify, prioritize and evaluate multi-modal circulating and neuroimaging markers with
diagnostic potential for prediction and monitoring of psychotic disorders and associated
metabolic co-morbidities.
The multi-modal circulating and neuroimaging markers identified in METSY will be validated
in an independent prospective study.
1.1.2. Relevance of METSY to Work Programme and specific call objectives
The objectives of METSY directly address the overall theme of the FP7 Cooperation Work
Programme: FP7 Cooperation Work Programme: Health-2013, and the specific call
HEALTH.2013.2.2.1-2.
Relevance to This topic invites researchers, industry and SMEs to develop new or optimise
existing imaging technologies, and validate their application to mental disorders by integrating
imaging data with complementary knowledge resulting from e.g. genomics, biomarkers,
bioinformatics and clinical data.]
METSY brings together researchers, clinicians and industry partners from across the domains of
imaging technologies, metabolic research, psychiatry, systems biology and bioinformatics. METSY
targets early detection and monitoring of psychotic disorders, with specific focus on metabolic
abnormalities. Multiple imaging techniques will be developed and applied for this purpose, with
emphasis on PET and MRI imaging as well as a combination of both. In parallel, comprehensive
metabolic phenotyping will be applied including metabolomics in biofluids, and advanced statistical
and bioinformatics approaches will be developed and applied to integrate the image data with other
phenotypic data. Together, the tools developed will be applicable in personalised medicine setting by
helping to predict and identify patients responses to specific therapies.
-2-
METSY
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
mental health included
Rare
disease?
"Title" of the trial +

comments,
explanations
large observational
study of patients
with first-episode
psychosis and
prodromal
symptoms of
not included not included psychosis
1.2. Progress beyond the state-of-the-art

1.2.1. Current knowledge, tools and new findings from METSY
Psychotic disorders exacerbate obesity and MetS
Psychotic disorders are mental disorders characterised by impaired reality testing or reality
distortion. Psychotic symptoms can appear in many psychiatric disorders such as schizophrenia or
psychotic episodes of affective disorders (bipolar and unipolar depression). Psychotic symptoms are
typically observed as delusions, hallucinations, disorganized speech, and bizarre or catatonic
behaviour. The incidence of psychotic disorders peaks in young adulthood1, a period of development
when significant changes in fatty acid composition occur in the cerebral cortex due to axonal
myelination2, and their lifetime prevalence is about 3.5 %, the most common being schizophrenia
with approximately 1 % lifetime prevalence, as found by J. Suvisaari (P5) in a general populationbased study3. The cost of psychotic disorders in Europe was estimated at 93.3 billion euros in 20104.
Unhealthy lifestyle and pharmacological side effects have been suggested as major causes of excess
morbidity and mortality in patients with psychotic disorders. Within these patients, those with
negative or deficit symptoms are more prone to be overweight and have greater rates of MetS.
These patients with deficit schizophrenia (e.g., negative symptoms) have less healthy and more
sedentary lifestyles, which may in turn induce increased cardiovascular morbidity5. On the other
hand, the use of antipsychotics drugs, especially second generation ones, has been consistently
associated with weight gain, insulin resistance and the development of MetS6, which seems to be
more marked in younger people7. After only six months of treatment with some second-generation
antipsychotics, the percentage of previously drug nave first episode adolescent patients at risk of
developing MetS rises from 17% to 40%8. This evidence suggests that these psychotropic drugs
target CNS neurons that also regulate mechanisms controlling energy balance and associated
metabolic alterations.
1J.
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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METSY
Determinants of MetS as risk factors of psychosis

Data from schizophrenia patients from the pre-antipsychotic era already showed that the
prevalence of diabetes mellitus or glucose intolerance was higher in patients than in controls9.
Abnormal glucose tolerance, hyperinsulinemia and accumulation of visceral fat are already detected
during the first-episode, in drug-nave patients, prior to antipsychotic treatment and
independently of obesity10. Furthermore, unaffected first-degree relatives of people with
schizophrenia also have high rates of diabetes mellitus (19-30%, as compared to 1.2-6.3% in the
general population)11. Of relevance, recent genetic studies have detected genes that increase the
risk of both schizophrenia and T2D12. Taken together, these observations suggest that metabolic
disturbances associated with obesity may contribute to the etiopathogenesis of psychotic disease.
Along those lines C. Arango (P3) analysed data from the worldwide cross-national World Health
Organization (WHO) World Health Survey (WHS) and found increased probability of having
diabetes as the number of psychotic symptoms increased13. T2D, in turn, is among the major
determinants of excess mortality in people with psychotic disorder14.
Imaging of specific neurotransmitter pathways in psychotic disorders
Extensive body of literature over the last 40 years has documented subtle but widespread structural
and functional changes in the brains of patients with non-affective and affective psychotic disorders.
These changes are usually most prominent in the fronto-temporal regions but it is now evident that
these changes have a more widespread pattern including also more posterior brain regions.
Psychoses and most notably schizophrenia are widely characterized as disorders of brain
disconnectivity. The term connectome coined by Sporns and colleagues emphasizes the importance
of appreciating network-level connectivity in order to understand brain function and dysfunction15.
The connectomics imaging -literature suggests two overlapping dysconnection types in psychosis
i.e. more general, context-independent functional connectivity deficits and context-dependent
alterations with transient hypo- and hyperactivity patterns16. At the same time, it is increasingly
clear that these studies need to be complemented with information what happens in these networks
at the molecular level in vivo. The advances of multimodal brain imaging techniques have made
these kinds of studies possible.
Multiple neurotransmitter systems have been implicated in the dysconnectivity patterns of
psychotic disorders, such as monoamines (dopamine, serotonin, noradrenaline) and amino acid
transmitters (glutamate and GABA). Dopamine is the most studied one so far. It is well established
that elevated dopamine synthesis capacity as measured with PET and [18F]DOPA is associated
with schizophrenia, including early psychosis17. Recent meta-analyses of all the studies to date
found that this was a consistent finding with a large effect size elevation in patients with psychosis
(cohens d effect size>0.8)18. Elevated dopamine synthesis capacity has also been found in people at
risk of psychosis19, and now replicated in an independent cohort20. The elevated dopamine synthesis
capacity was greatest in those with the most severe symptoms and linked to the later progression to
schizophrenia21. Furthermore there was a longitudinal increase with the worsening clinical
D. H. Henneman, M. D. Altschule, R. M. Goncz, AMA Arch Intern Med 94, 402 (1954).
B. Kirkpatrick, B. J. Miller, C. Garcia-Rizo, E. Fernandez-Egea, M. Bernardo, Schizophr Bull, (2010).
11S. Mukherjee, D. B. Schnur, R. Reddy, Lancet 1, 495 (1989).
12 T. Hansen et al., Biol Psychiatry 70, 59 (2011).
13 R. Nuevo et al., J Clin Psychiatry 72, 1592 (2011).
14 J. Suvisaari et al., Psychosom Med 75, 60 (2013).
15 O. Sporns, G. Tononi, R. Kotter, PLoS Comput Biol 1, e42 (2005).
16 A. Fornito, A. Zalesky, C. Pantelis, E. T. Bullmore, Neuroimage 62, 2296 (2012).
17 J. Hietala et al., Schizophr Res 35, 41 (1999); J. Hietala et al., Lancet 346, 1130 (1995); J. Reith et al., Proc Natl
Acad Sci U S A 91, 11651 (1994).
18 O. D. Howes et al., Arch Gen Psychiatry 69, 776 (2012); P. Fusar-Poli, A. Meyer-Lindenberg, Schizophr Bull 39, 33
(2013).
19 O. D. Howes et al., Arch Gen Psychiatry 66, 13 (2009).
20 A. Egerton et al., Biol Psychiatry, (2013).
21 O. D. Howes et al., Am J Psychiatry 168, 1311 (2011).
9
10
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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
O. Howes et al., Mol Psychiatry 16, 885 (2011).

O. D. Howes, S. Kapur, Schizophr Bull 35, 549 (2009).
24 J. E. Lisman et al., Trends Neurosci 31, 234 (2008).
25 M. L. Fitzgerald, E. Shobin, V. M. Pickel, Prog Neuropsychopharmacol Biol Psychiatry 38, 21 (2012).
26 N. L. Cluny, R. A. Reimer, K. A. Sharkey, Brain Behav Immun 26, 691 (2012).
27 V. Di Marzo, A. Ligresti, L. Cristino, Int J Obes (Lond) 33 Suppl 2, S18 (2009).
28 H. N. Ginsberg, S. C. Woods, Obesity (Silver Spring) 17, 1821 (2009).
29 C. Pagano, M. Rossato, R. Vettor, J Neuroendocrinol 20 Suppl 1, 124 (2008).
30 R. Christensen, P. K. Kristensen, E. M. Bartels, H. Bliddal, A. Astrup, Lancet 370, 1706 (2007).
31 E. L. Scotter, M. E. Abood, M. Glass, Br J Pharmacol 160, 480 (2010).
32 E. M. Marco et al., Front Behav Neurosci 5, 63 (2011).
33 D. Koethe et al., Br J Psychiatry 194, 371 (2009).
34 F. M. Leweke et al., Transl Psychiatry 2, e94 (2012).
35 G. P. Amminger et al., Arch Gen Psychiatry 67, 146 (2010).
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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.
Intercorrelations between the [11C]MADAM, a serotonin transporter tracer and [11C]carfentanil, a

u-opioid receptor tracer were also regionally distinct, and significant neurotransmitter interaction
was found in anteromedial thalamus, amygdala, dorsalanterior cingulate cortex and in dorsolateral
prefrontal cortex i.e. in regions relevant for several neuropsychiatric disorders, also psychotic
D. F. Wong et al., Neuroimage 52, 1505 (2010).
K. J. Jenko et al., Schizophr Res 141, 185 (2012).
38 L. Tuominen, J. Hietala et al, Hum Brain Mapp (revised version submitted).
36
37
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disorders. Quantification of functional neurotransmitter balance may be a useful approach in

etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based
rationale for targeted modulation of neurotransmitter networks.
PET and MRI are established neuroimaging
tools.
However,
the
complementary
information (e.g., neurotransmitter binding,
white matter integrity) provided by the
different modalities is currently not fully
exploited. METSY will take advantage of a
hybrid PET/MR system which allows for
acquisition
of
such
complementary
Figure 3. A novel approach exploring neurotransmitter
information consecutively in the same study
interactions with consecutive PET scans and voxel-bysession without repositioning of the subject
voxel inter-transmitter correlation analyses. Note a very
(Figure 4). MRI-based data on brain
strong interaction in the anterior cingulate that
morphology and white matter tracts (DTI)
integrates emotional and cognitive information.
will be useful for more precise quantification
and in particular for exploring the connectivity patterns of different neurotransmitter systems as
measured with PET such as the links between (1) dopamine and cannabinoid system themselves as
well as (2) dopamine-endocannabinoid balance and network connectivity, such as the default mode
network (DMN) in the brain. DMN is activated when the brain is at wakeful rest and not focusing
on the outer world but rather engaged with internal tasks (e.g. daydreaming, spontaneous thoughts,
memories). DMN is usually regarded as a predominantly context-independent phenomenon. Despite
the fact that resting state functional magnetic resonance imaging (R-fMRI) has become a powerful
tool to explore the dysconnectivity of brain networks in psychotic disorders, very little is known
about the role of specific neurotransmitters involved in emergence and maintaining DMN activity.
PET/MR hybrid technology readily enables such studies in the same scanning session.
A large number of neuroimaging software tools
are available to the research community. Some of
those tools have very specific functionality for
certain research tasks (e.g. the Camino package
http://cmic.cs.ucl.ac.uk/camino/
for diffusion
imaging), some have a broader scope (e.g.
Freesurfer http://surfer.nmr.mgh.harvard.edu/ or
SPM
http://www.fil.ion.ucl.ac.uk/spm/spm/).
However, in order to achieve the desired
functionality for a given research task, several of
those tools have to be used in combination. This
in turn results in multiple common problems
encountered in practical use: data exchange and
compatibility between different applications,
integration into clinical and research workflows, Figure 4. Hybrid imaging strategy.
and usability. METSY will develop an integrated
software for combined PET and MRI data visualization and analysis.
Metabolome in health and disease
Despite the undeniable strong genetic component of many complex diseases, with heritability
estimated at 40% or higher in MetS39 or in the order of 65% or higher in schizophrenia40, it is
becoming increasingly evident that current approaches studying genetic associations with disease
traits can explain only a fraction of the known disease heritability41.
A. J. Lusis, A. D. Attie, K. Reue, Nat. Genet. 9, 819 (2008).
P. Lichtenstein et al., Lancet 373, 234 (2009).
41 B. Maher, Nature 456, 18 (2008).
39
40
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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).
42
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METSY
also highlighted the significance of

A
B
glucoregulatory processes61 and lipid
62
abnormalities
in
psychotic
disorders and in schizophrenia in
particular. Interestingly, some of the
disturbances
in
glucoregulatory
processes in first-episode psychosis
seem to improve after the initiation
of antipsychotic medication63. Lipid
abnormalities in the brain in
C
schizophrenia include alterations in
free fatty acids and PC in gray and
white matter, and an increase in
ceramides in white matter64. M.
Orei et al. studied plasma
lipidomic profiles in twin pairs
discordant for schizophrenia and
found that patients were more
insulin resistant and had higher Figure 5. Systems approach to study psychosis. (A)
triglycerides than their co-twins65. Dependency network in schizophrenia and other psychotic
Furthermore, integrative analysis disorders, in the context of other environmental, metabolic and
of MR image and lipidomics data drug use data60. (B) Diagnostic model of schizophrenia, separating
revealed significant associations of schizophrenia from other psychoses, based on proline and
decreased gray matter density and triglyceride TG(18:1/18:0/18:1) concentrations60. (C) Significant
elevated triglycerides in plasma correlations between serum triglyceride levels, as obtained from
(Figure 5C). Recently, Yang et al. lipidomics, and cortical gray matter density, based on65integrative
analysis of MR images and plasma lipidomics in twins .
found multiple fatty acids and
ketone bodies to be elevated in the
serum and urine of patients with schizophrenia66. The changes were similar in first-episode and
more chronic patients. Kaddurah-Daouk examined the effects of antipsychotic medication on serum
lipidome, and found significant changes in lipid metabolism already after 2-3 weeks of medication
use67. In line with these findings, gene expression studies have detected that antipsychotics strongly
activate genes involved in lipid homeostasis68.
In search of risk biomarkers for developing co-morbidities associated with obesity
In traditional epidemiological setting, molecular biomarkers are associated with specific clinical
end-points. Such markers may perform statistically well in a large population settings, but may
hold little value when applied to individuals. This has important implications when considering
early risk biomarkers of co-morbidities associated with obesity. Biomarkers should be sensitive
to the organ-specific genetic vulnerability and to specific pathophysiological mechanisms
leading to obesity-related complications.
In addition to adipose tissue, liver and skeletal muscles are other key organs early associated with
insulin resistance and diabetes. Whereas fat deposition in the liver and muscle may be secondary to
adipose tissue failure, it is likely that the pathogenic evolution and severity of the hepatic disease
E. Holmes et al., PLoS Med. 3, e327 (2006); P. C. Guest et al., Mol. Psychiatry 15, 118 (2010); M. Herberth et al., Mol
Psychiatry 16, 848 (2011).
62 E. Schwarz et al., J. Proteome Res. 7, 4266 (2008); J. Yang et al., Mol Psychiatry, 10.1038/mp.2011.131 (2011); R.
Kaddurah-Daouk et al., Psychiatry Res 198, 347 (2012).
63 E. Holmes et al., PLoS Med. 3, e327 (2006).
64 E. Schwarz et al., J. Proteome Res. 7, 4266 (2008).
65 M. Oresic et al., Genome Med 4, 1 (2012).
66 J. Yang et al., Mol Psychiatry, 10.1038/mp.2011.131 (2011).
67 R. Kaddurah-Daouk et al., Mol. Psychiatry 12, 934 (2007).
68 J. Ferno et al., Pharmacogenomics J 5, 298 (2005); M. H. Polymeropoulos et al., Schizophr Res 108, 134 (2009).
61
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METSY
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
Figure 7. Semantic mapping based

network of non-linear, dynamic, multiscale, multi-force effectors
Z. M. Younossi et al., Clin Gastroenterol Hepatol 9, 524 (2011).

A. Kotronen, H. Yki-Jarvinen, Arterioscler Thromb Vasc Biol 28, 27 (2008).
71 A. Kotronen et al., Gastroenterology 137, 865 (2009).
72 A. Kotronen et al., Diabetologia 52, 684 (2009); A. Kotronen et al., Diabetes 58, 203 (2009).
73 E. P. Rhee et al., J Clin Invest 121, 1402 (2011).
69
70
74
J. Westerbacka et al., Gastroenterology 139, 1961 (2010).
M. Orei et al. (submitted manuscript and patent application).

M. Y. Galperin, X. M. Fernandez-Suarez, Nucleic Acids Res 40, D1 (2012).
77 S. Losko, K. Heumann, Methods Mol Biol 563, 241 (2009); D. Maier et al., BMC Syst Biol 5, 38 (2011).
75
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METSY
vocabularies and standards exist to represent

molecular and biochemical processes78, but at other
measurements the corresponding representations and
concepts are still incomplete79. Correspondingly, the
technical infrastructure needs to provide an adaptive
architecture and the ability to develop and add concepts
as needed. Another challenge is the representation of
gained knowledge e.g. how to do changes of a specific
receptor detected by PET imaging influence our prior
knowledge about the overall phenomenon. The current
state of the art for brain-imaging in psychosis is focused
on correlation of voxel pattern to outcomes largely
neglecting existing mechanistic and structural
understanding during the analysis process. We will go
beyond this stage by structuring current knowledge
from the scientific literature and implicit expert
knowledge of the project partners into concepts and
mapping these to the experimental and clinical data to
provide systematic, structured information suitable for
algorithmic analysis.
The BioXM Knowledge
Management Environment (Biomax, P2) is a
generic, project-centred, distributed software platform
with full ontology support that provides an object
oriented inventory of information and knowledge with
natural language based creation of mapping rules and
XML based definition of access rules to distributed
resources. Both features will be used by Biomax to
create the rules for a disease specific knowledge
ontology network from semantically mapping clinical,
experimental and image analysis results to prior e.g.
anatomic structures, molecular objects or co-morbidities
networks.
Implementation of the neuroimaging platform in
healthcare setting a decision support system
Figure 8. Example of Disease State

Fingerprint (DSF) and Disease State Index
(DSI) as applied to AD. In the DSF, an easyto-interpret overview is given of which
variables are relevant for the disease
diagnosis (size of the boxes) and the degree of
similarity to an earlier diagnosed disease
population (colour and number value). The
bottom panel shows additional information
about the statistics of specific biomarker.
VTT has developed a novel Clinical Decision Support

and Data Vizualisation framework that takes as input
heterogeneous patient information, rapidly analyses it,
and provides a comprehensive view of its relationship
to the patients disease state80. This is done by
statistically modelling a disease from large quantities
of many-modal multi-scale data of previously diagnosed cases and highlighting relevant
relationships in the patients data to the disease under study. Concretely, the method computes an
evidence-based estimate of the patients disease state by comparing his or her observed
heterogeneous data comprehensively to those of the previously diagnosed cases. The disease state in
this context denotes a patients degree of similarity to a previously diagnosed disease population. A
summary of patient data and results of the computation are displayed in a succinct Disease State
Fingerprint (DSF) visualization (Figure 8). The visualization clearly discloses how different
components of the patient data contribute to the disease state, facilitating rapid interpretation of
the information. To model and quantify the disease state from such complex and heterogeneous
M. Ashburner et al., Nat. Genet. 25, 25 (2000).
S. Burrowes, A. J. Swan, N. J. Warren, M. H. Tawhai, Philos Transact A Math Phys Eng Sci 366, 3247 (2008).
80 J. Mattila et al., J Alzheimers Dis 27, 163 (2011); J. Mattila, J. Koikkalainen, A. Virkki, M. van Gils, J.
Lotjonen, IEEE Trans Biomed Eng 59, 234 (2012).
78
79K.
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METSY
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:
81
A. H. Simonsen et al., Dement Geriatr Cogn Disord 34, 344 (2012).
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METSY
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
Cohorts to be collected during METSY

[Relevance to specific METSY Objectives]
General population cohort

A longitudinal population-based survey of 8000 Finns, P5 Baseline metabolomic and lipidomic analysis
including detailed assessment of psychotic disorders
already completed60. An 11-year follow-up has
just been completed, which allows investigation
(n=250) and psychotic-like symptoms (n=800)3.
of midlife progression of observed changes in
Strength of this cohort: This is a very well phenotyped
people with psychotic disorder and their
general population-based sample, with prospective
association with cardiovascular and metabolic
data.
diseases. [O3]
Limitations: the sample is relatively old and the mean
duration of illness among subjects with psychotic
disorders has been long. No neuroimaging data is
available.
First-episode cohorts
The SERMAS has been actively recruiting subjects
P3 Neuroimaging, genetics, metabolic
with first-episode psychosis and age- and gendercharacterisation including metabolomics, dietary
matched controls for the past years82. Ongoing studies
habits, anthropometric measures,
have been designed as prospective cohorts, and followneuropsychology. [O1, O2, O3, O6]
up time for some subjects has already reached 5 years.
160 first-episode patients (age 14-45 years) with
Subjects included have an age range between 7 and 35
one-year follow-up, matched controls.
years of age and have psychotic symptoms within a
psychotic diagnosis for less than 12-24 months. They
are excluded if they were mentally retarded, had
history of head trauma with loss of consciousness or
neurological disease. For controls, inclusion criteria
are absence of DSM-IV psychopathology and the same
exclusion criteria apply.
Our dataset includes 330 patients and 232 controls
with follow ups. The protocol includes K-SADS-PL or
82
J. Castro-Fornieles et al., Schizophr Res 91, 226 (2007).
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METSY
SCID, clinical assessments, neuropsychological

testing, anthropometric measures, MRI, DTI, fMRI,
and collection of DNA. Serum samples for metabolic
determinations and oxidative stress markers have
been collected for 120 subjects.
Strength of this cohort: This is a large and actively
recruiting first-episode psychosis sample, with an age
range from adolescents to adults.
Limitation: Not PET image data is available.
Strength of this cohort: Well characterised first
episode cohort with follow-up. PET image data
available.
P4 50 first episode psychosis patients (age 18-40

years) with one-year follow-up, matched controls.
Neuroimaging, genetics, metabolic
characterisation including metabolomics, dietary
Limitation: Relatively low sample size; this limitation
will be addressed by combining the data with the data
neuropsychology. [O1, O2, O3, O4, O6]
from other similar cohorts.
Ongoing first-episode psychosis study in Finland with P5 60 first-episode psychosis patients (age 18-40
three assessment points (baseline, 2 months, 12
years) with one-year follow-up, matched controls.
years). Age range 18-40 years, both affective and
Neuroimaging, genetics, metabolic
nonaffective psychoses included. Exclusion criteria:
characterisation including metabolomics, dietary
psychotic disorder due to substance use or a general
medical condition Matched population-based controls
neuropsychology. [O1, O2, O3, O6]
from the Population Register Centre, exclusion
criteria: a history of psychotic disorder, conditions
that would prevent MRI, history of head trauma or
neurological condition. 45 patients and controls
available now with follow-ups, The protocol includes
BPRS-Extended, SCID-I, neuropsychological testing,
3T MRI, DTI, fMRI, and collection of DNA, RNA,
serum, plasma and fecal samples. Information on
dietary habits, exercise and substance use,
measurements (BMI, waist circumference, blood
pressure, extrapyramidal symptoms). Insulin
resistance measures (HOMA, QUICKI).
episode cohort with follow-up.
Limitation: PET image data not available. Relatively
low sample size; this limitation will be addressed by
combining the data with the data from other similar
cohorts.
episode cohort with follow-up. PET image data
available.
P7 15 first episode patients (age 18-40 years) with

one year 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]
At-risk cohorts
Strength of this cohort: Well characterised at risk
cohort with follow-up. PET image data available.
P4 35 at-risk patients (age 18-40 years) with oneyear follow-up and controls. Assessment:
genetics, metabolic characterisation incl.
metabolomics, dietary habits, neuropsychology,
immune and oxidative stress markers. [O1, O2,
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METSY
O3, O6]

P5 35 at-risk patients (age 18-40 years) with oneyear follow-up and controls. Assessment:
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:
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.
O1, O2, O4, O6
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).
O1, O2, O3, O5,

O6
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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METSY
Computational and bioinformatics methods

Management and semantic annotation (e.g., text mining) of heterogeneous data (clinical,
non-clinical) generated within METSY as well as other relevant publicly available data 87.
O5, O6
Dependency networks and diagnostic models: Identification of networks comprising

molecular (incl. neurotransmitter), neuroimage and other phenotypic data, which are
associated with disease progression and patient outcomes.
O3, O5, O6
Disease State Fingerprint (DSF) and Disease State Index (DSI) for decision-support.
O5, O6
Neuroimaging methods -- MRI

Clinical and neuroimaging assessments will be performed at baseline and after one year, in
subjects at-risk of psychosis, FEP (first psychotic positive symptom within a psychotic disorder;
DSM-IV criteria) less than two years ago, subjects between 13 and 45 years of age, no neurological
diseases, autism spectrum disorders (ASD) or mental retardation (MR)) and controls (only excluded
in case of psychosis, antipsychotic medication, or first-degree relative with psychosis besides
exclusion criteria for FEP). Neuroimaging assessments will be performed with 3 different 3T MR
scanners. Using a dedicated automated image processing pipeline we will extract morphological
information (T1) as well as tractography (DTI). For 3T scanners, imaging parameters for T1weighted images are about TR 2.5 s, TE 3.3 ms, flip angle 7 , voxel size 1x1x1 mm, whole brain
coverage with sagittal slides without gap, and for DTI, TR 9.5 s, TE 81 ms, whole brain coverage
with voxel size 3x3x3 mm, 64 directions. We preprocess and analyze T1-weighted images by using
SPM8-VBM8 for voxelwise gray and white matter volumes (http://dbm.neuro.uni-jena.de/vbm/) and
Freesurfer (http://surfer.nmr.mgh.harvard.edu/) for cortical thickness. White and gray matter are
segmented, images are normalized to a common template. Resulting parametric maps reflect the
voxel-wise gray and white matter volume. In addition, cortex thickness measures are assessed
separately. For the white matter tracks analysis, we use FSL-Tract-Based Spatial Statistics
(http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS)): white matter tracks are determined on the basis of
diffusion anisotropy, average map of white matter tracks is formed, and individual maps are
normalized to the average map, which enables track-wise comparison of diffusion parameters.
Image processing will take place at each site that acquires neuroimaging data. Images will also be
transported to a secure server for a combined, multi-site, image processing (VBM and DTI
analyses). This multi-processing will take advantage of the large number generated by combining
the acquired sets of images at the various sites. Subjects included will be studied thoroughly from a
clinical perspective, by using clinical measures informing on different psychopathological domains
(such as BPRS, YMRS, PANSS, HAM-D), and a standardized neuropsychological battery
(MATRICS components). Physical measures, including height, weight and waist circumference,
blood pressure and blood draws for different metabolic parameters will also be obtained. All these
measures will be obtained at each visit.
We took as a reference the results of a naturalistic follow-up study that includes 248 patients on
antipsychotics, most of them FEP, reporting significant differences in BMI z-score in patients
(59.2%) and in controls (15.38%) (Arango et al, in preparation), and prior studies using a total
sample size of 70 (34 patients) showing that brain morphological abnormalities can be detected in
first-episode psychosis patients after a one-year follow-up88. Due to the multiplicity of metabolic and
imaging outcomes explored and considering an attrition rate of 30%, inclusion of 250 subjects with
FEP, 100 subjects at-risk of psychosis, and half of controls for each cohort would be amply sufficient
for assessing reliable brain biomarkers.
Neuroimaging methods PET
The PET Centres will use their previously evaluated and published methods to standardise PET
imaging in multi-centre PET studies (Whone et al 2004). In brief there are four elements to this: (1)
87
88
D. Maier et al., BMC Syst Biol 5, 38 (2011).

W. Cahn et al., Arch Gen Psychiatry 59, 1002 (2002).
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METSY
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
(biofluids, cells, tissue)

(UPLC-QTOFMS, UPLC-QQQMS,
VTT (P1) has a state-of-the-art facility for
UPLC-LTQ-Orbitrap, GCxGCTOFMS, GC-MS, NMR)
Global
metabolomics (Figure 9), which has been
Polar
metabolites
applied
in
many
biomedical
studies91.
Global
Lipids
Lipidomics profiles will be obtained from serum
Targeted
Targeted
Lipids
Eicosanoids
using Waters Q-Tof Premier mass spectrometer
combined with an Acquity Ultra Performance
LCTM (UPLC)83. Metabolic profiles of polar
compounds will be obtained by comprehensive
two-dimensional gas chromatography combined
with time-of-flight mass spectrometry (GCGCBioinformatics
Statistical analysis
Data processing
TOFMS)84, one of the most powerful analytical
tools for the separation of organic compounds in
Biomarkers, biological insight
complex samples. Raw data will be processed
using the MZmine 2 software92 for UPLC-MS Figure 9. Metabolomics workflow at VTT.
analysis and Guineu software84. Calibration will
be performed based on internal standard compound injected prior to extraction.
(S1P, PIPs)
Sample preparation, quality control
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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METSY
1.3. S/T methodology and associated work plan

1.3.1. Overall strategy of the work plan
Research comprises three activity areas, articulated into six S/T workpackages (WPs): (1) human
cohort studies (WPs 1-3), (2) methodology developments (WPs 4 and 5), and (3) translational
research (WP 6) (Figure 10; next page). METSY also includes two WPs dedicated to dissemination
and management. The S/T WPs follow the progression of the work plan and reflect the six
specific objectives.
WP 1 will pursue detailed neuroimaging and neuropsychology characterisation in longitudinal
studies involving patients at-risk or with first episode of psychosis (as listed in Table 1.2a). WP 2
will pursue detailed 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 proposal93. WP 3 will pursue detailed metabolic
characterization, metabolomics as well as studies of immune/oxidative stress markers in the cohorts
included in WP 1. Data will be analysed in collaboration with WP 5.
WP 4 will develop methods for combined PET and MR image acquisition and analysis. Consecutive
baseline scans, i.e., CB1R and the presynaptic dopamine synthesis tracer [18F]DOPA will be
performed and the binding outcome interactions (correlation and hub analyses) will be a starting
point for methodology testing. Early protocols will be utilized first in healthy volunteers and then
later in early pilot patients. Optimised protocols for the PET/MR hybrid camera (Philips Ingenuity
TF) will be developed and evaluated. Dedicated software packages, specifically adapted to match
the requirements of WP1 and WP2 for combined PET and MRI data visualization and analysis will
be developed on the Imalytics Research Workstation (Philips Research, Aachen, DE). WP 5 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. Disease State
Index will be evaluated as a decision-support system in psychosis.
WP 6 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.
Human cohort studies

Brain structural changes and
metabolism neuroimaging
studies
WP1
Samples, data,
biomarker panel
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
Figure 10. METSY S/T workflow and project structure.
93
Lipid molecular networks, insulin

resistance and metabolic markers
in psychosis
WP3
J. Hirvonen et al., Mol Psychiatry 17, 642 (2012).
- 18 -
Statistical and bioinformatics

tools to integrate brain image
information with clinical and
molecular profile data WP5
WP No
WP1
WP2
WP
WP4
WP5
WP6
WP7
- 19 -
WP8
Task 3.1 Predictive circulating metabolite markers in psychosis

Task 3.2 Dependency networks in psychosis
Task 4.1 Definition of optimized PET/MR imaging protocols for
psychiatric disorders
Task 4.2 Combined 3D/4D viewing of dynamic PET and MRI
Task 4.3 Advanced PET/MR image processing and analysis
Task 5.1 Disease state index in psychosis
Task 5.2 Network inference and machine learning based
integrative analysis of imaging and metabolic data
Task 5.3 Integrative bioinformatics in psychosis
Task 6.1 Prioritisation of biomarker candidates
Task 6.2 Validation of selected serum metabolic biomarkers
Task 6.3 Validation of multi-modal markers
Task 9.1 Webpage
D7.1
Task 9.2 Maximising public information and protecting METSY
knowledge
Task 9.3 Preparation of joint publications and position
statements
Task 9.4 Establishment and operation of FEC to oversee and
D7.2
guide matters related to IPR and exploitation
Task 11.1 Kick-off meeting, steering committee meetings, D8.1
annual consortium meetings, mid-term review meeting
D8.2
Task 11.2 Establishing METSY SOPs for informed consent,
privacy, ethical and equality issues relative to clinical studies
Task 11.3 Preparation and submission of the financial and
scientific reports to the European Commission
Task 1.1 Harmonization of the data acquisition and processing

protocols
Task 1.2 Analysis of neuroimage data in early psychosis
Task 1.3 Neuroimaging in first-episode psychosis
Task 1.4 Neuroimaging in at-risk state
Task 2.1 Quantification of brain CB1 receptors in at-risk state
and first-episode psychosis
Task 2.2 One-year follow-up of patients and controls
Task 2.3 Circulating endocannabinoids in at-risk state and firstepisode psychosis
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
1.3.2. Project timeline (Gantt chart)
METSY
1.3.3. Risk/Contingency analysis

As part of proactive program management, the METSY consortium intends to implement regular
reviews of the program and technical risk. Risk management is a continuous process that requires
an organized review to ensure that new risks are identified as the project progresses. The METSY
collaborators will review program and technical risk as part of regular review meetings. The risk
review will be organized according to a documented procedure which will use the following steps: (1)
risk analysis and evaluation, (2) risk control, (3) residual risk evaluation, and (4) risk management
review and sign-off. As part of the review of the programmatic and technical risks associated with
this study, the METSY collaborators have subjected the proposed study to a preliminary risk
analysis and mitigation process.
Overall, the participants are leading experts in their domains and thus technical risks which could
affect the outcomes of utilisation of specific technology platforms can be considered minimal.
The following risks have been identified in relation to the programmatic aspects of the project,
divided according to the work packages:
WP 1 (also relevant to WP 2)
Risk. One of the risks in cohort studies is the attrition rate as patients do not attend follow-up
visits, this is more so in studies with patients that may lack insight into the disease as it is the case
with patients with psychosis. Another problem is that 4 different cohort studies are going to be
combined and the variability of the different assessments may introduce reliability problems and
difficulties in combining the data. This applies particularly to previously collected study samples,
whereas in the cohorts collected as a part of the METSY the assessment methods are harmonized as
much as possible.
Contingency. The three clinical groups responsible for the cohort studies with first episode
patients have a long lasting experience in this type of studies. Most of the patients (n=300) in the
largest study have already been recruited and have at least one follow-up visit. The three centers
have specific clinical programs for first episode psychotic patients where the patients receive and
integrative treatment. Having the research centre where the primary care is provided reduces the
number of patients lost to follow-up. The centres of Turku and Helsinki have harmonized their
assessments prior to the inclusion of patients. Most diagnostic (SCID), clinical (BPRS, PANSS, CGI,
YMRS), neuropsychological assessments (MATRICS components), functioning scales (GAF) are the
same in the three cohorts. Neuroimaging studies will not be combined but as numbers are large
enough in each one of the 3 cohorts the independent samples will be used as replications.
WP2 (also relevant for WP1, WP4)
Risk. Potential risks from this study include those associated with: i) medical examinations
including laboratory testing that may reveal previously undiagnosed medical disorders, ii) radiation
exposure from the PET and transmission scans, iii) PET scanning, iv) placement of arterial and
venous lines, v) blood sampling, and vi) MRI.
Contingency. The PET groups have a 20+ year experience in doing PET studies even with fairly
complex protocols including arterial lines. There is a possibility that the imaging protocol is too
demanding for patients, especially so in the lengthy protocols in WP4. However, so far two
consecutive PET scans during same day have been done for controls and also patients with
schizophrenia. Support and appropriate breaks have increased the acceptability of the scan
protocol. Same factors are relevant for the sMRI and fMRI protocols. The harmonization of PET
procedures between centres is challenging but prospects for merging the data are good with already
existing between-center collaboration.
Risk. WP 3 (and similarly WP 6) relies on the availability of serum samples from WPs 1 and 2.
Contingency. The samples for analyses in WP 3 have already been collected, or are in the process
of being collected. For analyses in WP 6, new samples will be collected as part of project activities in
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METSY
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).
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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METSY
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
Brain structural changes and metabolism

neuroimaging studies
WP 2
Endocannabinoid pathways in early

psychosis neuroimaging studies
Lipid molecular networks, insulin
resistance and metabolic markers in
psychosis
Methodologies for combined PET and MR
imaging
WP 3
Coordinator
Project Office
FEC
WP 4
WP 5
WP 7
Statistical and bioinformatics tools to

integrate brain image information with
clinical and molecular profile data
Evaluation and validation of biomarkers of
patient outcomes in psychosis
WP 8
Steering Committee
(Coordinator, WP and Team leaders)
WP 6
External Advisory Board
Expert Committee
Ethics
Gender issues
Figure 11. METSY management chart.
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METSY
2.1.1. Decision making structure of METSY

Tailored to the size of the consortium and the degree of integration required, METSY will
implement a decision making structure which enables the consortium to take all decisions in a
timely and appropriate manner. The structure is composed of the Coordinator (Matej Orei, P1,
VTT), the Steering Committee (Work Package leaders, Team leaders), and expert advisory panels.
Management will be integrated and assisted by a project office.
The Coordinator VTT Prof. Matej Orei (P1) - will be responsible for the overall legal,
contractual, ethical, financial and administrative management of the project. He is also the
Scientific Director, and thus in charge of the scientific management and coordination of METSY.
The Coordinator will:
1. Sign the contract with the European Commission;
2. Be responsible for the relation to the European Commission and will act as the single contact
point between the European commission and the METSY consortium;
3. Will receive the payments from the EU and administer and distribute the funds according to the
regulations, which will be specified in the contract and the consortium agreement;
4. Will, in a timely manner, collect and prepare the annual activity, management and financial
report, including the certificates on the financial statements, for submission to the European
Commission;
5. Will chair the Steering Committee.
The Coordinator will be supported in his tasks by a Project Office, which will be established at
VTT. The Project Office will be in charge of all day-to-day management, and provide administrative
help and advice on financial issues to all beneficiaries. The project office is responsible for the
following tasks:
1. Support of the Coordinator in all legal, contractual, ethical, financial and administrative
management tasks;
2. Assistance to the decision bodies of the consortium, including the organizations, preparation and
follow-up of the meetings of the Steering Committee;
3. Setting up and maintaining platforms for internal and external dissemination, i.e. a web page
with a public and an internal domain;
4. Administrative responsibilities associated with receipt of a contract awarded from the
Commission including collecting financial and yearly reports and any other information
requested or required by the Commission, and the coordination of internal reporting activities,
i.e. intermediate internal scientific and financial reporting (see below). The project manager will
request and review regular intermediate financial reports of the beneficiaries to ensure the
appropriate usage of the allocated funds.
5. Providing information and guidelines to beneficiaries to ensure they are in compliance with EU
funding rules and policies, including specific advice in regard on financial, contractual and
administrative issues on a need-to-know basis;
6. Overseeing and integrating all aspects of intellectual property protection, licensing and the
commercial exploitation of research and dissemination activities.
The project office will be overseen by Riitta Honkanen, a member of VTTs EU Team which is
set up to administer the VTTs EU projects, and staffed with a full-time METSY project manager
Dr. Tuulia Hytylinen, and a part-time assistant (provided by VTT). VTT will further support
the project office in fulfilling its tasks with all existing expertise and infrastructures.
The Steering Committee is in charge of the overall scientific coordination of METSY. The Steering
Committee will have monthly telephone conferences and meet every six months to
1. Review the scientific progress within the work packages, and to monitor the completion of tasks
as has been set out in the detailed implementation plan;
2. Identify synergies in the execution of the research work packages so that extra value can be
identified and realized, and to keep METSY beneficiaries informed and abreast of research
developments occurring elsewhere in the consortium such that new synergies and collaboration
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METSY
within the scope of existing Work Packages can be introduced;

3. Continued development of the detailed implementation plan;
4. Review of the use of financial resources;
5. Review of new knowledge for dissemination and exploitation, taking the advice from the FEC
into account;
6. Review the risk and contingency plans;
7. Ensure that the centralised facilities are working well and that they are accessible and available
to all participating beneficiaries;
8. Inform the Commission of requests (e.g. re-budgeting) coming from the beneficiaries via the
Coordinator.
As one important task, the Steering Committee is also in charge of risk management, and will
propose changes in assignment of tasks, or subtasks, and budget allocation, if appropriate. Details
on the decisions to be made will be set out in the Consortium Agreement.
The Work Package Leaders are responsible for overseeing the scientific progress in the respective
work package, to monitor the achievement of milestones and deliverables as set out in the
implementation plan, and to report on the progress of the work package on occasion of the Steering
Committee meeting.
To fulfil this task, the Work Package Leaders are the point of contact for the Team Leaders, who
report regularly on the progress of their work via informal means (e.g., phone or email) and to
submit a written report every 6 months prior to the meeting of the Steering Committee. Such
regular reporting will facilitate the periodic reports to the Commission. Each Team Leader will
report on severe delays or problems in meeting milestones as soon as such problems become
obvious. The Work Package Leader will summarise the proceedings of the work package for review
by the Steering Committee.
The Steering Committee is the principal decision-making body of METSY. The Steering
Committee will have a meeting at the project start (kick-off meeting) where the decision making
bodies and the management procedures are confirmed and communicated to all participants.
Details on the decision hierarchy and authorities will be defined in the Consortium Agreement.
Thereafter on an annual basis the Steering Committee will receive and approve the accounts for the
past (financial) year, and approve the budget and Annual Implementation Plan for the following
year.
Management of knowledge (internal)
Knowledge and information about the proceedings are the basis for integration and networking of
all on-going activities. Consequently, there will be a strict regime for the internal dissemination of
knowledge, including:
Kick-off meeting and annual consortium meetings. The consortium will meet on an annual
basis to share and discuss the progress of METSY, starting with the Kick-off meeting which will
take place in the first month of the project in Espoo, Finland. Regular annual consortium meetings
will include the participation of the members of the FEC. The Coordinator, in conjunction with the
Commission services will organize annual consortium meetings (Kick-off in Espoo, then in Madrid,
Munich, London, Helsinki), in which the progress of the project will be evaluated. The annual
consortium meetings will be attended by members of the external advisory board. The Commission
services may be assisted by one or more other external experts. All external experts shall be subject
to confidentiality agreements.
Meetings of the Steering Committee. The steering committee will meet at the Kick-off meeting,
at month 6, 12, 18, 24, 30, 36 and 42 to review the progress of METSY. On this occasion, the interim
reports of the team leaders to the WP leaders will be assembled and made available to the
consortium.
Newsletter. The project office will be the point of contact for distributing knowledge of general
interest for the whole consortium via an electronic newsletter.
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METSY
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
12, 24, 36, 48
Consortium, FEC
Information on progress
of METSY
Meetings of the
steering committee
6, 12, 18, 24, 30,

36, 42
Coordinator, WP
leaders, SME and
patient organization
representatives
Assembly of interim
reports and
dissemination
Ethics, Confidentiality and Informed Consent issues

Because of the collection, storage and use of clinical material, METSY has established a committee
that will address ethical, confidentiality and informed consent issues. The Ethics, Confidentiality
and Informed Consent Expert Committee is headed by Dr. Carmen Moreno (SERMAS, P3),
who has extensive experience in these issues. The committee will be completed by Dr. Jaana
Suvisaari (THL, P5), who has a long time experience on ethical issues as related to mental health,
and Prof. Oliver Howes (UCL, P7). Additionally, an external member of the committee Prof. Philip
Cowen (University of Oxford, UK) will be appointed. The committee is responsible for (1) ensuring
that ethical committee approval is obtained for all studies on humans and animals; (2) overseeing
informed consent forms for collection and storage of clinical material; (3) ensuring privacy and
confidentiality of subject material are maintained and within national and EU regulations.
Gender issues
METSY will establish an advisory panel on gender issues. The panel will be headed by Jaana
Suvisaari (THL, P5), and completed by Tuulia Hytylinen (VTT, P1) and Timo Paulus
(Philips, P6). The panel will pursue four tasks: (1) the promotion of gender equality policies, (2)
overseeing gender equality issues relevant for the consortium, (3) raising awareness within the
consortium to the relevance of these issues, and (4) actively promoting a gender equality policy at
each of the participating institutions.
External Advisory Board
The METSY project will establish an independent External Advisory Board of distinguished
scientists and representatives of key stakeholders. The composition of the External Advisory Board
will be discussed at the project Kick-off meeting and will be completed during the first 6 months of
the project. The members of the External Advisory Board will be appointed by the METSY
consortium and should be approved by the Commission Services. The Scientific Advisory Board will
be called upon by the project consortium annually at the consortium annual meetings.
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METSY
2.2. Individual participants

VTT Technical Research Centre of Finland
(VTT; team leader Prof. Matej Orei) P1
VTT Technical Research Centre of Finland is with approx. 2400 employees the biggest
multitechnological applied research organisation in Northern Europe. VTT provides high-end
technology solutions and innovation services. VTT is a part of the Finnish innovation system under
the domain of the Ministry of Employment and the Economy.
Team leader: Prof. Matej Orei, PhD, graduated from Cornell University (Ithaca, NY, USA) in
biophysics. He was exposed to metabolomics and systems biology early at Boston-based BG
Medicine Inc., which is among the first companies dedicated to systems biology in medicine. He
founded a lipidomics company Zora Biosciences Oy and serves on the board of the Metabolomics
Society. Prof. Orei investigates how are the genetic and environmental factors imprinted in the
metabolome, and the mechanisms by which alterations of the metabolome lead to
(patho)physiological changes at the systems level. Prof. Orei leads the Academy of Finland Centre
of Excellence in Molecular Systems Immunology and Physiology Research94 (2012-2017).
Key people in the team: The Quantitative Biology and Bioinformatics (QBIX) group95 led by Prof.
Orei consists currently of 22 scientists, among whom are 15 with PhD degree, combining expertise
in computational modelling, bioinformatics, and analytical methods for metabolomics. The
metabolite analytics are managed by Dr. Tuulia Hytylinen, an experienced chemist with PhD
degree and excellent track record in analytical chemistry. Bioinformatics and modelling are
managed by Dr. Marko Sysi-Aho, who has a background in computational science. This is
complemented by work on multi-variate, multi-scale modelling for decision support as managed by
Adjunct Professor Dr. Jyrki Ltjnen who has an outstanding track record in medical image
processing and EU-VPH (Virtual Physiological Human) projects.
Expertise and resources: The core expertise of the research team covers the areas of
computational biology, bioinformatics, metabolomics, medical systems biology and decision support.
The team has state-of-the-art facilities in these domains. The analytical infrastructures for
metabolomics include seven mass spectrometers coupled to various chromatographic systems.
Participation in EU programmes: Currently involved in ten EU projects in HEALTH, ICT, and
KBBE domains.
Recent publications relevant to the project
1. Orei M. Obesity and psychotic disorders: uncovering common mechanisms through
metabolomics. Dis Model Mech. 2012;5(5):614-20.
2. Orei M, , Sysi-Aho M, Hytylinen T, Perl J, Suvisaari J. Metabolome in
schizophrenia and other psychotic disorders: a general population-based study. Genome Med.
2011;3(3):19.
3. Orei M, , Hytylinen T, ,Suvisaari J,, Cannon TD. Phospholipids and insulin
resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia.. Genome
Med. 2012;4:1.
4. Mattila J, Soininen H, Koikkalainen J, Rueckert D, Wolz R, Waldemar G, Ltjnen J; for the
Alzheimers Disease Neuroimaging Initiative. Optimizing the diagnosis of early Alzheimer's
disease in mild cognitive impairment subjects. J Alzheimers Dis. 2012;32(4):969-79.
5. Orei M, Hytylinen T, , Sysi-Aho M, , Ltjnen, J., Soininen H. Metabolome in
progression to Alzheimers disease. Transl Psychiatr. 2011;1:e57.
6. Pietilinen KH, , Hytylinen T, , Vattulainen I, Vidal-Puig A, Orei M. Association of
lipidome remodeling in the adipocyte membrane with acquired obesity in humans. PLoS Biol.
2011;9(6):e1000623.
94
95
http://www.symmys.fi/
http://sybio.vtt.fi/
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METSY
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.
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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METSY
Hospital General Universitario Gregorio Maraon

(SERMAS; team leader Dr. Carmen Moreno) P3
Gregorio Maran General Hospital (HGUGM) part of the SERMAS is the largest University
Hospital in Spain. It is the co-ordinating centre for the Spanish Psychiatric Research Network
(CIBERSAM), a consortium funded by the Spanish Ministry of Science and Innovation.
Team leader: Carmen Moreno, MD, PhD is a psychiatrist at the Universidad Complutense in
Madrid. She did her training both in Spain and the Columbia University/New York State
Psychiatric Institute in NY, USA. She has been involved in the first episode program developed in
the Child and Adolescent Department of Psychiatry at HGUGM for the last 6 years. She is also a
participant in the First Episode Psychosis and Psychiatry Network funded by the Spanish Ministry
of Health and the Spanish Psychiatric Research Network, and member of the Child and Adolescent
Neuropsychiatry Network funded by the European College of Neuropsychopharmacology (ECNP).
Her current developments are focused on the study of the aetiology and treatment of metabolic
alterations in early-onset psychiatric disorders. Dr. Moreno is currently PI on a longitudinal study
assessing the relationship between progression of neuroimage changes and oxidative stress in earlyonset bipolar disorders. She is also PI in two independent RCT comparing PUFAS with placebo for
developmental disorders.
Key people in the team: CelsoArango, MD, PhD is Associate Professor of Psychiatry at the
University of Maryland in Baltimore and the Universidad Complutense in Madrid, and head of the
Child and Adolescent Department of Psychiatry at HGUGM. He is the Scientific Director of the
Spanish Mental Health Research Network with more than 400 researchers and co-ordinator of the
Child and Adolescent Neuropsychiatry Network funded by the European College of
Neuropsychopharmacology. Mara Parellada MD, PhD is a psychiatrist at HGUGM. Joost
Janssen, MSC, PhDis a neuroimaging expert involved in projects involving first-episode patients.
Laura Pina MD is a psychiatrist who coordinates research in the Child and Adolescent
Department of Psychiatry. Goretti Morn MD is a psychiatrist involved in research with subjects
with psychotic disorders. Covadonga Martinez MD, is a psychiatrist performing her main
research activity in the fields of first-episode and early-onset psychosis.
Expertise and resources: The Hospital has a long tradition in research on first episode psychoses
and is actively participating in another related FP funded research projects: EU-GEI or OPTIMISE.
We attend around 40-50 new first psychotic cases per year. We have experts in neuropsychology,
neuroimaging (functional and structural MRI, DTI, MRS, etc).
Participation in EU programmes: The group has participated in several EU-funded programs.
At the present time members of the group are leading WP in the following 6 EU funded projects:
FP7 EU-GEI, FP7 OPTIMISE, FP7 STOP, FP7 PERS, FP7 ROAMER and ERANET-NEURON.
1. Arango C, ,Moreno C, , Janssen J, Parellada M. Progressive brain changes in children
and adolescents with first-episode psychosis. Arch Gen Psychiatry. 2012;69(1):16-26.
2. Moreno C, ..., Parellada M, ,Arango C. Metabolic effects of second-generation antipsychotics
in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses. Bipolar Disord.
2010;12(2):172-84.3.
3. Fraguas D,....,Janssen J, Arango C.Decreased glutathione levels predict loss of brain volume
in children and adolescents with first-episode psychosis in a two-year longitudinal
study.Schizophr Res. 2012 May;137(1-3):58-65.
4. Nuevo R, ,ArangoC.Increased risk of diabetes mellitus among persons with psychotic
symptoms: results from the WHO World Health Survey. J Clin Psychiatry. 2011;72(12):1592-9.
5. Arango C, ,Rejas J. Psychopathology, coronary heart disease and metabolic syndrome
inschizophrenia spectrum patients with deficit versus non-deficit schizophrenia: findings from
the CLAMORS study.EurNeuropsychopharmacol. 2011;21(12):867-75.
6. Mic JA, ,Parellada M, .Arango C, Reduced antioxidant defense in early onset first-episode
psychosis: a case-control study. BMC Psychiatry. 2011 11:20-6.
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METSY
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).
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
- 29 -
METSY
National Institute for Health and Welfare (THL; team

leader Associate Professor Jaana Suvisaari) P5
THL is a large governmental institute with approximately 1200 employees for research related to
chronic diseases. THL has the highest ranking of Finnish research institutions in SCImagos
Ranking of Research Institutions. THL has excellent facilities and expertise in conducting
population-based and clinical studies of mental disorders.
Team leader: Jaana Suvisaari has investigated the etiology and epidemiology of psychotic
disorders for 16 years. Her Psychoses in Finland-study is a general population-based study of
psychotic disorders in Finland, in which she and her group have shown that people with
schizophrenia have 5-fold risk of type 2 diabetes compared to the general population, increased
prevalence of abdominal obesity, hypertriglyceridemia, hyperinsulinemia, low HDL, poor skeletal
status, and inflammation. Such changes are also common in other nonaffective psychotic disorders
but not in affective psychoses. In the Finnish Schizophrenia Family study, she and her group have
shown that high birth weight and maternal diabetes are risk factors of schizophrenia, and have
participated in international collaboration that found shared genetic risk factors in schizophrenia
and type 2 diabetes and risk alleles of schizophrenia in the major histocompatibility locus, linking
schizophrenia to autoimmune diseases. Her other studies include a longitudinal study of the adult
mental health of children of mothers with schizophrenia as well as several epidemiological studies
investigating risk factors, treatment, comorbidity and outcome of adult mental disorders.
Key people in the team: Suvisaari has in this project 3 PhD students and in her other projects 10
Ph.D. students, most of whom investigate environmental and developmental risk factors and geneenvironment interactions of psychotic disorders, clinical high-risk subjects and links between
schizophrenia and physical illnesses. In particular, she has investigated metabolic
comorbidities and factors contributing to their development, including lifestyle, medication

and inflammation, and their influence on the outcome of psychotic disorders. The key senior
investigators in this project are Tuukka Raij, M.D., Ph.D., and Tuula Kiesepp, M.D., Ph.D.,
who are responsible for brain structural and functional imaging studies. Dr. Raij has investigated
different aspects of brain function using functional MRI, magnetoencephalography and
electroencephalography. Dr. Kiesepp has previously investigated genetic risk factors and
structural brain changes in major mood disorders.
Expertise and resources: The research group has expertise in the following areas: clinical
assessment of psychotic disorders, brain structural and functional MRI, metabolic and
inflammatory changes related to psychotic disorders, genetic studies, biostatistics, analysis of
lipidomic and metabolomic data (collaboration with P1).
Participation in EU programmes: SGENE (LSHM-CT-2006-037761).
1. Suvisaari J,, Hrknen T. Mortality and its determinants in people with psychotic disorder.
Psychosom Med. 2013;75:60-7.
2. Orei M, , Sysi-Aho M, Hytylinen T, Perl J, Suvisaari J. Metabolome in
schizophrenia and other psychotic disorders: a general population-based study. Genome Med.
2011;3(3):19.
3. Suvisaari J, ..., Jula A. Inflammation in psychotic disorders: a population-based study.
Psychiatry Res. 2011;189:305-11.
4. Saarni SE, ..., Suvisaari J, Lnnqvist J. Body composition in psychotic disorders a general
population survey. Psychol Med. 2009;39:801-10.
5. Stefansson H, ..., Suvisaari J, ..., Arango C, ..., Collier DA. Common variants conferring risk of
schizophrenia. Nature. 2009;460:744-747.
6. Suvisaari J, ..., Reunanen A. Metabolic syndrome among persons with schizophrenia and other
psychotic disorders in a general population survey. J Clin Psychiatry. 2007; 68:1045-55.
7. Perl J, Suvisaari J, ..., Kiesepp T, , Lnnqvist J. Lifetime prevalence of psychotic and
bipolar I disorders in a general population. Arch Gen Psychiatry. 2007; 64:19-28.
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METSY
Philips (Philips; team leader Dr. Timo Paulus) P6

Royal Philips Electronics is a world-wide company with a turnover of
22.3 billion and 120.000 employees improving peoples lives through meaningful innovations. The
organization focuses on three sectors: Healthcare, Consumer Lifestyle and Lighting. The healthcare
sector is among the top three players in imaging systems, and market leader in cardiac care, acute
care, home healthcare as well as in other areas.
The Global Philips Research Organization plays an important role in innovation and produces more
than half of the many patents that Philips files. R&D activities of Philips Research have led to the
publishing of thousands of technical and scientific papers. In terms of publications, Philips ranks
4th among Europes most important and actively publishing research institutions. In Europe 3 labs
employ about 1250 people.
Philips Research in Germany is based in Hamburg and Aachen and counts about 100 employees,
focused in the healthcare area. The Molecular Imaging Systems department is composed of 20,
mainly post-doctoral, scientists and performs research in the areas of clinical applications (oncology,
neurology, and cardiology) as well as hybrid imaging systems (especially PET/MR). One project in
the group develops a translational research workstation called IMALYTICS.
Team leader: Timo Paulus received his PhD in theoretical high-energy physics in 2002 at the
University of Heidelberg, Germany. In 2003, he joined Philips Research in Aachen, Germany, where
he was involved in various projects on image processing with a focus on pharmacokinetic modeling
of dynamic PET data. Since 2009, he manages the TRANSLATE venture within Philips Research,
which develops the IMALYTICS Research Workstation. Dr. Paulus has initiated and coordinated
the Philips contribution to several large scale public funding projects.
Key people in the team: Antonis Kalemis is a PhD in Medical Physics with experience in
PET/MR imaging, clinical research using hybrid medical imaging and project management. He
works as Clinical Science Manager for PET/MR in Philips Healthcare. Frank Thiele is a physicist
with many years of experience in algorithm development for PET and MRI brain image analysis. He
filed several patent applications in this field.
Expertise and resources: Hybrid image acquisition and reconstruction, multi-modal imaging and
image processing, quantitative imaging, PET and MR brain image analysis, software development,
quality management, project management
Participation in EU programmes:
1. Kalemis A, ..., Heinzer S (2012) Sequential whole-body PET/MR scanner: concept, clinical
use, and optimisation after two years in the clinic. The manufacturer's perspective. MAGMA
doi: 10.1007/s10334-012-0330-y.
2. Buchert R, Thiele F, ..., Clausen M. Ecstasy-induced reduction of the availability of the
brain serotonin transporter as revealed by [11C](+)McN5652-PET and the multi-linear
reference tissue model: loss of transporters or artifact of tracer kinetic modelling? Journal of
Psychopharmacology 2007;21:628-34
3. Thiele F, Buchert R. Evaluation of non-uniform weighting in nonlinear regression for
pharmacokinetic neuroreceptor modeling. Nucl Med Commun 2008; 29:179-188
4. Buchert R, Thiele F. About the interpretation of the parameters of the simplified reference
tissue model for SPECT / PET brain receptor studies. Nuklearmedizin 2008; 47:167-174.
5. Arlt S, ..., Thiele F, ..., Buchert R. Association between FDG uptake, CSF biomarkers and
cognitive performance in patients with probable Alzheimers disease. Eur J Nucl Med Mol
Imaging 2009; 36;1090-1100.
6. Thiele F, ..., Boy C. The quantification of dynamic FET PET imaging and correlation with
the clinical outcome in patients with glioblastoma. Phys Med Biol 2009;54;5525-5539.
7. Wiemker R, Paulus T, , Klutmann S. Combined motion blur and partial volume correction
for computer aided diagnosis of pulmonary nodules in PET/CT. International Journal of
Computer Assisted Radiology and Surgery Volume 3, Numbers 1-2, 105-113.
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METSY
Kings College London

(KCL; team leader Prof. Oliver Howes) P7
Kings College London is the largest healthcare learning centre in Europe
and
ranked
amongst
the
top
universities
in
the
World
(http://www.timeshighereducation.co.uk/world-university-rankings/2012-13).
The Institute of Psychiatry, Kings College London, is the largest and most cited psychiatric
research centre in Europe globally, only the NIMH, USA is more cited; source Thompson ISI
rankings). The Institute of Psychiatry has particular strengths in imaging, and genetic research in
psychiatry. The Maudsley Hospital (where Oliver Howes is a consultant psychiatrist) is attached to
the Institute of Psychiatry and is the largest psychiatric service in the UK - treating over 7000
patients/year with schizophrenia alone.
Team leader: Oliver Howes is a Clinician Scientist and trained psychiatrist (MD and PhD). He
heads the Psychiatric Imaging Group. His research interests focus on the metabolic syndrome and
clinical imaging research in psychotic and related disorders. He has been awarded the European
Association Prize for Biological Psychiatry, Honorary Membership of the European Association of
Neuropsychopharmacology, & Royal Society of Medicine Psychiatry Prize amongst other awards for
his research work.
Key people in the team: The psychiatric imaging group comprises 3 postdocs, 5 graduate students,
4 MDs plus support staff and students. 2 postdocs (Dr. Mouchilianitis and Dr. Selvaraj) have
extensive experience in clinical studies & Profs Turkheimer & Gunn provide methodology expertise.
Expertise and resources: Access to state-of-the-art PET/MR, clinical research facilities, and
facilities for metabolomic research. The imaging facilities include dedicated neuroimaging
methodology groups, including World leading PET and MR methodologists (Profs Turkheimer,
Williams and Gunn).
Participation in EU programmes: Currently involved in one EU project.
1. Howes, OD., et al. The link between cannabis and schizophrenia: dopaminergic or cannabinoid
systems- in vivo evidence. Schizophrenia Research 136 (2012): 68.
2. Demjaha A,... Howes OD. Dopamine Synthesis Capacity in Patients With Treatment-Resistant
Schizophrenia. Am J Psychiatry. 2012 Oct 3. doi: 10.1176/appi.ajp.2012.12010144.
3. Selvaraj S... Howes O. Measuring endogenous changes in serotonergic neurotransmission in
humans: a [(11)C]CUMI-101 PET challenge study. Mol Psychiatry. 2012 Jun 5. doi:
10.1038/mp.2012.78.
4. Stokes PR, ... Howes OD. Nature or Nurture? Determining the Heritability of Human Striatal
Dopamine Function: an [18F]-DOPA PET Study. Neuropsychopharmacology. 2012 Oct 24. doi:
10.1038/npp.2012.207.
5. Howes OD, et al. A prospective study of impairment in glucose control caused by clozapine
without changes in insulin resistance. Am J Psychiatry. 2004 Feb;161(2):361-3.
6. Howes OD, et al. The relationship between prolactin levels and glucose homeostasis in
antipsychotic-treated schizophrenic patients. J Clin Psychopharmacol. 2006 Dec;26(6):629-31.
7. Howes OD, et al. The effect of clozapine on factors controlling glucose homeostasis. J Clin
Psychiatry. 2004 Oct;65(10):1352-5.
- 32 -
METSY
2.3. Consortium as whole

METSY brings together researchers,
clinicians and industry partners
from across the domains of imaging
technologies, metabolic research,
psychiatry, systems biology and
bioinformatics. Each has its own
national,
European,
and
international reputation in one or
more of these fields, and the
majority are international opinion
leaders.
Within
METSY,
all
participants have a defined scientific
role relevant to his or her expertise
(Figure 12), and many have
managerial
and
dissemination
expertise
at
international
consortium level.
Technologies and resources

Brain imaging (P3,
P4, P6, P7)
Metabolomics (P1)
Decision-support
systems (P1)
Human genetics
(P3, P5)
Principal outcomes
Human cohorts and

biobanks
Psychosis
(P3, P4, P5, P7)
Computational systems biology
Neuroimaging platform
for metabolic studies in
psychosis (P3, P4, P6,
P7)
Software tools for

psychiatric research
(P1, P2, P6)
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.
Human cohorts and biobanks

METSY understands that the clinical level is the ultimate reference in medical setting. METSY
clinical competencies cover the domains of metabolic and psychiatric research. The cohort studies
and biobanks included provide valuable and sometimes unique sample materials and information
needed to address or generate new hypotheses.
METSY includes prospective at-risk and first-episode cohorts from four teams and three countries,
led by Carmen Moreno (SERMAS, P3), Jarmo Hietala (UTU, P4), Jaana Suvisaari (THL, P5)
and Oliver Howles (KCL, P7). In addition to larger sample size, which is needed for biomarker
discovery and validation, the value of combining multiple cohorts is also in providing data from
populations with different genetic backgrounds. Additionally, The expertise of the three
participating teams is also complimentary. Dr. Moreno has a long track record of research in firstepisode psychosis, Dr. Suvisaari investigates etiology and epidemiology of psychosis (particularly
metabolic co-morbidities), Drs. Hietala and Howles are leading experts in medical imaging and
biological psychiatry.
Technologies and resources
Given the primary objective of the call, METSY brought together four teams specializing in
neuroimaging applications and methodology. Carmen Moreno, Jarmo Hietala and Oliver
Howles have a long track record in applications of neuroimaging methods in psychiatry, including
MRS, MRI and PET-based approaches. Philips (P6) is a leading provider of molecular imaging
systems including the hybrid PET/MR system.
METSY also understands that omics revolution has been one of the key enabling factors for
- 33 -
METSY
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
- 34 -
METSY
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.
2.4. Resource to be committed

Resources committed to METSY
METSY is planned as a 4Table 2.4a. METSY budget overall
year project. A general
RTD
MGT
Other
Total
budget of 4,233,869 Euro
Person months
358.4
5
10
372.4
has been requested as the
Personnel costs
2,187,591 42,088 62,922 2,292,601
EC
contribution,
and
Travel Costs
126,250
8,000
3,000 137,250
assigned to the METSY
Consumables
324,000
-
- 324,000
partners to cover the
Other costs ("the rest")
181,100 10,000 46,600 237,700
expenses
for
RTD,
Direct costs excl. subcontr.
2,818,941 60,088 112,522 2,991,551
demonstration, other and
Subcontracting
554,500 25,100
- 579,600
management
activities,
Indirect costs (= overheads)
2,251,142 46,942 66,758 2,364,842
taking into account the
Total
costs
5,624,582 132,130 179,280 5,913,269
budgetary requirements of
Requested
EC
contribution
3,922,461 132,130 179,280 4,233,871
each individual academic
institution, SMEs and the
personnel expenses at each partner institute required to implement specific deliverables (Table
2.4a shows overall budget, Table 2.4b shows budget per participant). On top of the requested EC
contribution, there are 1,679,398 Euro total costs (not covered by the EC contribution). Importantly,
each partner will commit a substantial additional resource by way of person-months from scientists
already employed by partner institutes, services and facilities provided by partner institutes, and
consumable budgets provided by the partner institutes.
Personnel mobilized. The effort to be spent on METSY over 48 months of execution has been
calculated to amount to an equivalent of 7.8 full time positions. Many additional personnel
contributions are at experienced levels since WP leaders and expert committee members will
provide substantial time to management activities in addition to their RTD efforts. It is estimated
that over 15 persons will be directly engaged in METSY at full or part-time levels.
Use of EC requested resources
Of the 4,233,871 Euro requested, 3,922,461 Euro (92.6%) are dedicated to RTD activities, 132,130
- 35 -
METSY
(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
RTD activities Demonstrat

ion
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%
RTD related activities

Each partner has been allocated a budget to fund the personnel expenses of team members, who
will be recruited for fulfilling the tasks of their respective objectives in the project. The recruited
team staff includes early (PhD students) and experienced (postdoctoral) researchers and technical
assistants. All budget calculations with respect to personnel correspond to remuneration in
accordance with the normal practices of the participant. The consumable budget (included in the
Other direct costs category), total 324,000 Euro, has been calculated on an individual base
depending on the costs of each particular technology and the work executed by each partner.
Overall, consumables range between 0 and 204,000 Euros per partner during the project. Major
consumable costs are related to PET imaging (UTU) and reagents for metabolomics analysis (VTT).
All costs in the Other direct costs category comply with the provisions of FP7 financial guidelines.
A travel budget of no more than 10,000 Euro per year has been allocated to partners for activities
related to secondments and exchange of technology and expertise, and dissemination through
scientific meetings.
Management budget
The management budget requested from the EC in the amount of 107,030 Euro is assigned
centrally to VTT to cover personnel costs for a programme manager and a financial officer that is
requested to carry out the activities described in WP 8 and as described in Section 2.1. The role of
the Project Manager and financial officer are essential for fiscal and legal requirements of the
project, dissemination of material within and outside the METSY consortium, maintaining an up to
date METSY webpage, and all coordination activities necessary for collaborative tasks and expert
committee tasks within METSY. In addition to the above mentioned management costs, costs for
audits of 25,100 Euro are estimated to be required during the 48 months are requested.
Other costs budget
Dissemination. The Project Manager as well as Biomax will have an active role in WP7 dedicated
to awareness and dissemination, IPR and Technology transfer. A budget of 179,280 Euro to cover
personnel costs and publication costs in WP7 is requested from the EC.
Sub-contracting
All participants need audit certificates. A total of 25,100 Euro is reserved for this purpose.
Three participants will subcontract the image analyses, with a combined budget of 554,500 Euro.
The breakdown of the sub-contracting budget is shown below:
SERMAS (P3) RTD sub-contracting budget of 189,000 Euro.
MRI acquisition at an estimated cost of 480 Euro per subject

- 36 -
METSY
THL (P5) RTD sub-contracting budget of 43,000 Euro.
Drawing of blood samples: 7,000 Euro

Neuroradiologists statement from MRI images for participants: 18,000 Euro
Services from radiology nurse (assisting the MRI imaging sessions): 18,000 Euro
KCL (P7) RTD sub-contracting budget of 322,500 Euro
PET scans at an estimated cost of 6,450 Euro / PET scan
- 37 -
METSY
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
Figure 13. The impacts METSY has on different areas and

lead users.
Three lead user groups can be identified

that benefit from METSYs impact:
healthcare professionals, the citizens, and European industry and decision makers. The overall
impact in different areas and lead users can be depicted as in Figure 13.
V. Swami et al., Pers Soc Psychol Bull 36, 309 (2010).
P. J. Weiden, J. A. Mackell, D. D. McDonnell, Schizophr Res 66, 51 (2004).
98 K. Usher, T. Park, K. Foster, J Psychiatr Ment Health Nurs, (2012).
99 J. Tiihonen et al., Lancet 374, 620 (2009).
100 J. Suvisaari et al., Psychosom Med 75, 60 (2013).
101 L. A. Chwastiak et al., Gen Hosp Psychiatry 31, 1 (2009).
102 D. E. H. M et al., World Psychiatry 10, 52 (2011).
103 H. Hafner, K. Maurer, World Psychiatry 5, 130 (2006).
104 A. Bechdolf et al., Br J Psychiatry 200, 22 (2012).
96
97
- 38 -
METSY
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.
3.1. Expected impacts listed in the work programme

1. Contribution to This topic is expected to develop new or optimise existing imaging technology
for the benefit of patients with psychiatric disorders.
METSY is optimising the use of existing MRI and PET technologies for the study of psychotic
disorders, with specific focus on their metabolic co-morbidities. Additionally, the project will further
develop the tools (procedures, software) for combined MRI and PET neuroimaging, as well as
develop statistical and bioinformatics tools to integrate this information with other phenotypic data
including metabolic characterisation as obtained from metabolomics of biofluids.
Specifically, METSY will develop and validate multiple innovative multi-modal biomarkers
based on neuroimaging and metabolic profiling to the stage where they can be considered for
developments towards the implementation in healthcare setting
A typical clinical biomarker development pipeline is shown in Figure 14. Needless to say, further
the biomarker is developed, more value it
carries. Discovery studies will be carried
Replication
out in WPs 1-3, while the validation
Replication
studies
Demonstration
Replication
studies
studies
studies
studies will be carried out in WP 6.
Notably, all these activities are highly
integrated
and
include
a
strong
Validation
Assay development &
Discovery
study
component of computational systems
Approval
study
(independent
validation
biology (WP 5) and neuroimaging
cohort)
technology development (WP 4).
Functional validation
(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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METSY
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.
3.2. Dissemination and/or exploitation of project results, and management of IP

3.2.1. Dissemination of METSY results
Dissemination of new knowledge within the scientific community is an intrinsic interest of research,
and aims at strengthening and reinforcing the European research activities by multiplication and
initiation of networking and collaborations beyond the consortium. Dissemination of results and
new knowledge obtained in METSY is of high priority, emphasized by the dedication of a work
package to dissemination issues. The WP 7 objectives are:
1.
2.
3.
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.
J. Perl et al., Arch. Gen. Psychiatry 64, 19 (2007).

J. Perala et al., Schizophr Res 106, 337 (2008).
107 K. Smith, Nature 478, 15 (2011).
108 A. Gustavsson et al., Eur Neuropsychopharmacol 21, 718 (2011); H. U. Wittchen et al., Eur Neuropsychopharmacol 21,
655 (2011).
105
106
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METSY
Effectiveness in achieving the objectives will be measured by seven specified deliverables.

Objectives 1 and 2 (O9.1 and O9.2) deal with dissemination of knowledge to the public and scientific
domain.
Dissemination of knowledge will take place at different levels:
1.
2.
3.
4.
Within the METSY consortium (internal meetings and reports);

To the scientific community (publication in international peer reviewed journals, presentations
at national and international conferences);
To patients as well as healthcare professionals and decision makers via patient organizations;
To the broad public.
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.
Publications in high-impact, peer-reviewed international journals;

Presentations at international conferences;
METSY Workshops;
Filing of patent applications;
Multiplication by recruitment and training of scientists at the PhD and postdoctoral level;
Open workshops;
Presentation of METSY, its objective, aims and potentials on a public domain web page.
Means to disseminate to patients as well as healthcare professionals and decision makers are:
1.
2.
Organization of special workshops for patients and/or healthcare professionals related to

specific METSY S/T activities and outcomes,
Active participation in international conferences, such as organization of METSY sessions at
these meetings. As an already existing example of such activities, M. Orei (P1) is organizing a
symposium at 14th International Congres on Schizophrenia Research (April 2013;
Orlando/FL/USA) on the topic of molecular biomarkers in schizophrenia.
Means to disseminate to the public are:

1.
2.
3.
4.
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 has specific initiatives to strengthen its dissemination potential:

1.
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.
3.2.2. Exploitation of METSY results and management of Intellectual Property

Exploitation of METSY results industry participants
Biomax
The BioXMTM Knowledge Management Environment is developed by Biomax Informatics AG and
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METSY
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.
Technology solutions for neuroimaging. The technology/software developments in WPs 2, 4,

and 5 have a potential to lead to new or improved existing products by the industrial
participants, as well as to novel product ideas, e.g., software tools for diagnostics and patient
monitoring in psychiatric disorders (WPs 4, 5).
Management of IP
As recommended in the FP7 guidelines and according to standard practice, IP will be considered in
the following categories:
1.
2.
Background (pre-existing IP);

Foreground (knowledge generated from the Collaborative Project whether or not it may be
patentable).
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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METSY
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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METSY
limited to use required for implementation of the project.

4. Exploitation. Foreground and patents arising from the research will first be offered to
companies and institutions of the Member States of the European Union. However, the
pharmaceutical and diagnostic industries are so globalised that this may be limited in effectiveness.
The European Commission will be consulted with regard to the exploitation of Foreground should
non-member states provide the major licensing opportunities. Equally, should no licensee or
appropriate avenue for exploitation be identified, the EC will be consulted on whether other options
are recommended to be pursued.
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METSY
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.
Research activity aiming at human cloning for reproductive purposes,
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.
Research involving the use of human embryos or embryonic stem cells.
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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METSY
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.
4.2. Identification of relevant EU legislation and international texts

In all the activities performed, METSY will observe the law of the country and will take into
account the relevant guidelines and opinions, as follows:
EU legislation and guidelines relevant to research
1. The Charter of Fundamental Rights of the EU (2000/C 364/01);
2. Directive 95/46/EC of the European Parliament and of the Council of Europe dated 24th October
1995 on the protection of individuals with regard to the processing of personal data and on the
free movement of such data;
3. Council Directive dated 24th November 1986 on the Approximation of Laws, regulations and
administrative provisions of the Member States regarding the protection of animals used for
experimental and other scientific purposes (86/609/EEC);
4. Directive 2004/23/EC of the European Parliament and of the Council of Europe dated 31st
March 2004 on setting standards of quality and safety for the donation, procurement, testing,
processing, preservation, storage and distribution of human tissues and cells.
5. EU Database Directive 96/9/EC on legal protection of databases
6. Medical Research Act (488/1999; 313/2004; 794/2010), regulating the protection of individuals
participating in medical research in Finland.

7.
Ministry Order SAS/3470/2009, regulating participation of subjects, including minors, in

observational medical research studies, as well as aspects related to quality and safety on the
development of those studies in Spain
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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METSY
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;
concerning Biomedical Research, signed in Strasbourg on 25th January 2005.
Opinions of the European Groups on Ethics

1. The opinions of the European Group of Advisers on the Ethical Implications of Biotechnology;
2. The opinions of the European Group on Ethics in Science and New technologies:
Opinion of the European Group on Ethics in Science and New Technologies to The European
Commission, Number 11, 21st July 1998 (human tissue banking);
Commission, Number 8, 25th September 1996 (patenting inventions involving elements of
human origin);
Commission, Number 7, 21st May 1996 (genetic modification of animals).
The committee will apply the following legislative documents:
European Group of Advisors on the Ethical Implication of Biotechnology (1991-1997);
The Charter of Fundamental Rights of the EU Directive 2001/20/EC of the European

Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations
and administrative provisions of the Member States relating to the implementation of good
clinical practice in the conduct of clinical trials on medicinal products for human use; and its
update by the Commission Directive 2005/28/EC;
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.
4.3. Human studies (Participants 3, 4, 5, 7)

The Consortium consists of very experienced and scientifically high-qualified
participants, coming from well-established comprehensive research centres in human
physiology, endocrinology and psychiatry guaranteeing the best possible quality and
responsibility of the translational research (according to Declaration of Helsinki 2000, 15).
Present Status of Project-relevant Ethical Committee Decisions
Finland: All projects including human subjects are approved by the ethical committees.
Spain: All projects including human subjects are approved by the ethical committees.
UK: All project involving human volunteers (patients and healthy volunteers) are approved by the
independent NHS research ethics committees, fully indemnified, including for non-negligent harm
and audited by an independent R&D office. All PET imaging projects, the UK Government
Regulatory Committee for the administration of radioactive studies.
Where necessary, all partners will apply to the local ethic committees (Institutional Review
Board) specifically for the experiments planned within METSY consortium, as soon as an official
positive answer, regarding granting of the project, will be received from European Committee.
Institutional Review Board approval for secondary research use of already collected data will be
sought when needed. In order to receive the allowance, all national regulations will be respected,
therefore no major objections are expected.
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METSY
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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METSY
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.
4.4. Ethics issues table

YES
PAGE
13-15
13-15
Informed Consent
Does the proposal involve children?
Does the proposal involve patients or persons not able to give consent?
Does the proposal involve adult healthy volunteers?
Does the proposal involve Human Genetic Material?
Does the proposal involve Human biological samples?
13-15
Does the proposal involve Human data collection?
13-15
13-15
Research on Human embryo/foetus
Does the proposal involve Human Embryos?
Does the proposal involve Human Foetal Tissue / Cells?
Does the proposal involve Human Embryonic Stem Cells?
Privacy
Does the proposal involve processing of genetic information or personal

data (eg. health, sexual lifestyle, ethnicity, political opinion, religious or
philosophical conviction)
Does the proposal involve tracking the location or observation of

people?
Research on Animals
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METSY
Does the proposal involve research on animals?
Are those animals transgenic small laboratory animals?
Are those animals transgenic farm animals?
Are those animals cloning farm animals?
Are those animals non-human primates?
Research Involving Developing Countries
Use of local resources (genetic, animal, plant etc)
Benefit to local community (capacity building ie access to healthcare,

education etc)
Dual Use
Research having potential military / terrorist application
I CONFIRM THAT NONE OF THE ABOVE ISSUES APPLY TO MY PROPOSAL
- 50 -
METSY
5. Consideration of gender aspects

Among the seven partner teams of METSY, women are directly involved at all levels of the project,
including the scientific partnership as scientific team leaders. The partners are committed to
maintain this relatively high level and further improve the participation of women in the course of
the project.
Women participating in METSY will be given equal resources and involvement in decision-making.
Regarding the leadership positions METSY shows a commitment to support women scientists in
their ability to occupy management posts. At the consortium level, Carmen Moreno (P3, WP 1
leader), Tuulia Hytylinen (P1, WP 3 leader) and Jaana Suvisaari (P5) are members of the
Steering Committee. Dr. Moreno leads the Ethics, Confidentiality and Informed Consent Expert
Committee, of which Dr. Suvisaari is also a member.
The METSY consortium will actively support the research activities and career prospects of women
scientists and will actively encourage the participation of women in research with a number of key
initiatives:
1. Employment practice in all participating centres will be in accordance with European Equal
Opportunities Legislation. In order to secure an appropriate gender balance, local, national
and European networks of Women in Science will be used to advertise any vacant positions.
Adopting and developing family-friendly policies at the participating institutions will be
closely monitored.
2. It is proposed that any meeting would not extend beyond the normal working week. This
would allow parents to spend time with their family and would not encroach upon members
personal time.
3. Women as scientific team leaders are expected to provide role models for more junior female
researchers helping to counteract the progressive loss of women from the academic career
structure at the post-doctoral level. Female team/WP leaders will have a high profile at all
consortium meetings, as session chairs and/or platform speakers. They will also serve as
mentors to junior women scientists.
4. Participation of women in METSY activities will be promoted by monitoring a balanced
representation of female researchers in the workshops organized by the Consortium and by
guaranteeing a good gender balance in the program of scientific meetings.
Committees on gender issues and ethical issues have already been established to oversee all the
METSY activities related to gender balance. The committee on gender issues will monitor the
practices and evolution of gender equity and provide annual reports with conclusions and
recommendations to the METSY Steering Committee for actions to be carried out in the next years
of the project. The reports will be made available on the internal domain of the METSY web page.
- 51 -

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Ref.

Annex I - "Description of Work"

One form per project

Neuroimaging platform for characterisation of metabolic co-morbidities in psychotic

Call (part) identifier

Activity code(s) most

602478 METSY - Part A - Page 3 of 5

TEKNOLOGIAN TUTKIMUSKESKUS VTT

SERVICIO MADRILENO DE SALUD

TERVEYDEN JA HYVINVOINNIN LAITOS

PHILIPS TECHNOLOGIE GMBH

KING'S COLLEGE LONDON

602478 METSY - Part A - Page 4 of 5

One Form per Project

Estimated eligible costs (whole duration of the project)

602478 METSY - Part A - Page 5 of 5

* The following funding schemes are distinguished

METSYNeuroimaging platform for characterisation of metabolic

List of work packages

LIST OF WORK PACKAGES (WP)

Brain structural changes and metabolism

Endocannabinoid pathways in early

Lipid molecular networks, insulin resistance

Methodologies for combined PET and MR

Statistical and bioinformatics tools to

Evaluation and validation of biomarkers of

Awareness and dissemination

602478 METSY - Workplan table - Page 1 of 34

List of Deliverables - to be submitted for review to EC

602478 METSY - Workplan table - Page 2 of 34

602478 METSY - Workplan table - Page 3 of 34

602478 METSY - Workplan table - Page 4 of 34

SOPs for data

602478 METSY - Workplan table - Page 5 of 34

602478 METSY - Workplan table - Page 6 of 34

Work package description

One form per Work Package

Work package title

Brain structural changes and metabolism neuroimaging studies

Lead beneficiary number

602478 METSY - Workplan table - Page 7 of 34

Work package description

Participant short name

Person-months per participant

Panel of neuroimage biomarker

Baseline and one-year follow-up

Baseline and one-year follow-up

602478 METSY - Workplan table - Page 8 of 34

Work package description

Implementation of between centres clinical

Report posted on internal

First prototype of software tool for advanced

Report posted on internal

602478 METSY - Workplan table - Page 9 of 34

Work package description

One form per Work Package

Work package title

Endocannabinoid pathways in early psychosis neuroimaging studies

Lead beneficiary number

Participant short name

Person-months per participant

602478 METSY - Workplan table - Page 10 of 34

Work package description