Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium (ENIGMA) –
Obsessive Compulsive Disorder (OCD) Working Group
Secondary Proposal Form for Meta-Analyses
Please complete all fields and return this form by e-mail to:
Odile A. van den Heuvel
Email: oa.vandenheuvel@vumc.nl
1. Policy
Members of the ENIGMA Consortium include investigators from different centers around the world who are actively
engaged in neuroimaging research and who have contributed results from primary analyses of imaging, genetic data,
and/or algorithm development for the purpose of meta-analysis, replication, and/or algorithm testing in a collaborative
manner.
Although the data contributed to the ENIGMA consortium consist of group-level summaries and post-estimation
statistics rather than raw genotype and phenotype data, there is theoretically a minute risk of determining whether a
given individual participated in a study. While the re-identification of samples requires access to the raw genotype data
of the target individual and constitutes scientific misconduct, most groups have opted to appoint a gate-keeper
approach rather than allowing full public access to the results of their analyses or meta-analyses. Within the
ENIGMA-OCD working group any consortium member wishing to access the results of specific analyses or
meta-analytic results will be asked to complete a short proposal describing why they wish to access the results files
from each group, and submit that for review.
All consortium members are encouraged to submit such proposals, to follow up on ideas which the group as a whole
cannot pursue, which involve novel analyses, or subsets of the available sites. The ENIGMA-OCD working group will
screen OCD-relevant proposals for scientific interest, and will help enlist members who might be interested in
collaborating. Proposals will be discussed on ENIGMA-OCD working group calls and emails to encourage the broadest
participation.
The proposal will then be posted on an ENIGMA forum page and an email will be sent to all consortium members
alerting them to the posting. ENIGMA members will have 14 days from the time of the posting to opt-out of the analysis,
ask for clarification, voice concerns or objections and/or give feedback to the proposal. No site data will be shared
without the consent of the PI of that site, who may opt to impose specific conditions or limitations on the use of the data;
also ENIGMA PIs and members are not required to take part in any proposed project, they can opt out.
If the author of the proposal agrees to the authorship and publication policies of the consortium the access request will
be granted to the results files for those groups who have not opted-out of the analysis and a member of the
Enigma-OCD working group or one of the Enigma-OCD working group PIs will be assigned as a project liaison. The
liaison will be responsible for providing the data and answering any queries relating to the project, and providing the
contributing site PIs with updates. The results files from each group will be housed at the VU university medical center,
Amsterdam, The Netherlands. If there is no possibility of determining if a particular individual participated in a study
(e.g. limited imaging or genetic markers are requested), results from these markers may be sent by the liaison to other
sites if available. If genome-wide results are requested from individual groups, the person submitting the proposal may
be granted an account on Laboratory of Neuro Imaging (LONI) servers or may visit LONI, if desired, to make it easier to
complete the analysis.
We request that the ‘ENIGMA-OCD Working Group’, and the liaison person will be listed as co-authors. The
ENIGMA-OCD Working Group on the byline, will reference the PIs of each study, in addition to contributors at their site.
In this way the authors contributing data to the consortium will be appropriately acknowledged on any publication.
1
2. Requestor Information
Date of Submission:
Name:
Jun Soo Kwon
Institution/Affiliation:
Email:
24th April, 2015
Department of Psychiatry & Behavioral Science, Seoul National University Hospital College
of Medicine.
kwonjs@snu.ac.kr
Have you signed and return the ENIGMA Memorandum of Understanding? If
yes
no, read, check and sign the Memorandum of Understanding and send to oa.vandenheuvel@vumc.nl
2. Results request proposal
Proposal Title: Meta analysis of cortical structural covariance network in OCD
Co-author names and e-mail addresses (initial list):
Je-Yeon Yun
jeyeon.yun@gmail.com
Kang Ik Kevin Cho
kangik@snu.ac.kr
Myong-wuk Chon
mwchon@gmail.com
Sung Nyun Kim
zoouncle@gmail.com
Odile A. van den Heuvel
OA.vandenHeuvel@vumc.nl
Premika Boedhoe
p.boedhoe@vumc.nl
Neda Jahanshad
neda.jahanshad@gmail.com
Dan Stein
dan.stein@uct.ac.za
Paul Thompson
pthomp@usc.edu
+ ENIGMA-OCD consortium members contributing with T1WI scans
Order co-authors to be determined
Proposed Timeline for Completion of Study:
META-ANALYSIS
Months
0-2: (using freesurfer processed T1WI data) QC check and data collection
3-4: graph theory analysis for structural covariance matrix (retrieved from each site) at SNUH
 Resultant global and local network characteristic stats of structural covariance matrix sent back to
each site (from SNUH) for final regression analyses using demographic/clinical variables
5-6: collection of final statistical analysis results from each site  final meta-analysis at SNUH
7-8: manuscript preparation
Please confirm that you have reviewed the ENIGMA website for potential areas of overlap. If you see a project
that may overlap, please list along with any plans for addressing this:
Note: this website is not yet ready for the ENIGMA-OCD working group. Overlap needs to be discussed during the
ENIGMA-OCD teleconferences, and in the meantime, we will prepare the listing of proposals on the website.
Please list any conflicts of interest:
No conflicts of interest to declare.
2
Please describe the proposed analyses. Include hypothesis, specific results requested, a brief analysis plan
and methods, and references.
STUDY BACKGROUND
Previous neuroimaging studies on OCD have reported morphological or functional derangement of multiple
brain regions, such as the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), insula, inferior parietal
lobule (IPL), precuneus, superior temporal cortex and lingual cortex, which collectively constitute the
pathophysiological brain circuit of OCD called the ‘cortico-striato-thalamo-cortical’ loop.1-4 However, those
approaches which decode alteration of cortical morphology per region-of-interest or per cluster of statistical
significance cannot address the primal distortion of coordinated cortical connectomics among distributed brain
regions in OCD.5 The coordinated variation in brain morphological features, such as cortical thickness, among
brain structures anatomically or functionally interconnected to one another is referred to as the structural
covariance.6 Specifically, the high phenotypic covariance of brain morphology among several brain areas could
be interpreted as evidence supporting the existence of coordinated neurodevelopmental, maturational and
evolutionary processes in the mammalian brain.7 In this study, we propose a meta-analytic multicenter mapping
of individualized cortical structural covariance network alteration in OCD, from the OCD-ENIGMA multisite
sample. Overcoming the shortcomings of inter-individual cortical structural covariance (which can be difficult to
interpret at the individual level), the newer frame of individualized structural covariance (CMF) combined with
graph theory analysis will be able to decode the disease-related brain changes in each subject with psychiatric
disorders including OCD into more primal patterns of hub-related brain connectivity.
META-ANALYSIS PROCEDURE
In order to provide an updated and also comprehensive quantitative summary of the evidence for potential
differences in cortical structural covariance network between OCD versus healthy controls (HC), we plan to
perform data aggregation by meta-analytic pooling, in which not raw data themselves but statistically calculated
matrices of individualized cortical structural covariance network are shared between sites. We will take
advantage of prior cortical parcellation work of ENIGMA-OCD per site using Freesurfer software suite version
5.3.0 (http://surfer.nmr.mgh.harvard.edu) with existent data gathering/analysis protocols within the ENIGMA
consortium (e.g. http://enigma.ini.usc.edu/ongoing/gwasma-of-cortical-measures/) for preparation, quality
control and extraction of mean cortical thickness values for a total of 148 regions-of-interests (ROIs) based on
the 2009 Destrieux atlas8 be used in the final calculation of cortical structural covariance matrix per subject in
each study sites. Firstly, the cortical thickness values are z-scored using the mean and standard deviation
values of cortical thickness per each individual. Then, the relative intra-individual cortical morphological
similarities between various ROIs will be computed.9 The resulting 148x148 matrix (containing a total of 10,878
CMFs per individual) produced per subject in each site will be sent to the CCNC of South Korea (lead by prof.
Jun Soo Kwon) for final meta-analysis of global and local parameters from the additional graph theoretical
analyses10 at CCNC using the retrieved cortical structural covariance matrix. Possibly, additional
meta-regression analyses using age, sex, age of onset, duration of illness, medication status and/or symptom
severity scores as regressors will be conducted.
REFERENCES: 1. Fallucca E et al. (2011). Arch Gen Psychiatry 68(5): 527-533. 2. Fan Q et al. (2013). Psychol
Med 43(5): 1081-1091. 3. Nakamae T et al. (2012). PNBP 37(1): 90-95. 4. Pauls DL et al. (2014). Nat Rev
Neurosci
15(6):
410-424.
5.
Wheeler
AL
et
al.
(2015)
JAMA
Psychiatry
doi:
10.1001/jamapsychiatry.2014.3020. 6. He Y et al. (2008). J Neurosci 28(18): 4756-4766. 7.
Alexander-Bloch A et al. (2013). J Neurosci 33(7): 2889-2899. 8. Destrieux C et al. (2010). NeuroImage 53(1):
1-15. 9. Wee CY et al. (2013). Hum Brain Mapp 34(12): 3411-3425. 10. van den Heuvel MP et al. (2013). JAMA
psychiatry 70(8): 783-792.
3
Resources: Please describe what resources you can commit to the project - junior researcher time,
troubleshooting, computational server time, helping writing and testing scripts, etc.
META-ANALYSIS
The project will be carried out by a multidisciplinary team including a junior research neuroscientist and
licensed psychiatrist (Dr. Je-Yeon Yun, expert in MRI processing and medical bioinformatics), two junior
research neuroscientist, (Kang Ik Kevin Cho and Myong-wuk Chon, expert in MRI database management,
images quality check and MRI processing) and two senior research neuroscientists (prof. Jun Soo Kwon
and prof. Sung Nyun Kim, Dr. Sung Nyun Kim, faculties of the department of Psychiatry and Behavioral
Science in SNU). All personnel involved have a strong expertise in scripts writing and testing.
4