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 metaanalytic 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.
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2. Requestor Information
Date of Submission:
Name:
Fabrizio Piras
Institution/Affiliation:
Email:
10th April, 2015
Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
f.piras@hsantalucia.it
Have you signed and return the ENIGMA Memorandum of Understanding?
yes
If no, read, check and sign the Memorandum of Understanding and send to oa.vandenheuvel@vumc.nl
2. Results request proposal
Proposal Title: Meta analyses of DTI data in OCD
Co-author names and e-mail addresses (initial list):
Chiara Chiapponi
c.chiapponi@hsantalucia.it
Tommaso Gili
t.gili@hsantalucia.it
Mariangela Iorio
m.iorio@hsantalucia.it
Federica Piras
federica.piras@hsantalucia.it
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 DTI scans
Order co-authors to be determined
Proposed Timeline for Completion of Study:
META-ANALYSIS
Months
0-2: preprocessing, QC and processing protocol definition
3-12: data collection
13-16: data analysis
17-18: manuscript/s 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.
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Please list any conflicts of interest:
No conflicts of interest to declare
Please describe the proposed analyses. Include hypothesis, specific results requested, a brief analysis plan
and methods, and references.
Neuroimaging studies have indicated several neurobiological changes underlying the psychological and
behavioral deficits of OCD. Evidence from functional and structural MRI has supported the notion that
abnormalities in key gray matter (GM) regions, such as the orbitofrontal, dorso-medial prefrontal and inferior
frontal areas, anterior cingulate cortex, insula, thalamus and striatum play an important role in its
pathophysiology1,2,3. However, the overall picture is still rather heterogeneous and recent studies employing
whole-brain analyses also indicate more distributed neuroimaging alterations in patients with OCD, implicating
other brain regions such as parietal cortex, dorsolateral prefrontal cortex and posterior temporo-parieto-occipital
associative areas4. Instead, the white matter (WM) tracts connecting the cortical and subcortical regions involved
in OCD pathophysiology are relatively unexplored5. Consistently with current frontal-striatal, fronto-parietal and
fronto-limbic models of the disorder, recent studies6 showed altered functional connectivity among GM matter
nodes of the cortico-striato-thalamo-cortical circuitry. Moreover, the existence of additional abnormalities in
specific WM tracts (e.g. internal capsule (IC), cingulate bundle (CB), and corpus callosum (CC)) and in different
brain regions (medial frontal and parietal WM), in the OCD population has been recently suggested7. These WM
abnormalities may be familial1 and responsive to serotonin reuptake inhibitor treatment (SSRI) 5 and vary
according to the severity of different symptom dimensions8 and possibly depending upon therapeutic drugs 9.
Here we propose a meta-analytic approach to further study structural brain architecture abnormalities in the
OCD-ENIGMA multisite sample.
META-ANALYSIS
In order to quantitatively summarize the evidence of potential differences in diffusion tensor imaging (DTI)
parameters between OCD and HC, we plan to perform data aggregation by meta-analytical pooling, where no
raw data are shared between sites. We will take advantage of existent data gathering/analysis protocols within
the ENIGMA consortium (e.g. http://enigma.ini.usc.edu/protocols/dti-protocols/) for multi-site processing and
extraction of DTI values. Briefly, once FA and diffusivity maps are computed, the first step will consist of quality
control in order to remove scans with abnormalities and artifacts. Then, data will be processed using the tractbased spatial statistics (TBSS) analytic method10 modified to project individual FA values on the ENIGMA-DTI
skeleton. Following the extraction of the skeletonized white matter and projection of individual FA values,
ENIGMA-tract-wise regions of interest (ROIs), derived from the Johns Hopkins University white matter
parcellation atlas11 will be transferred to extract the mean FA across the full skeleton and average FA values for
twelve major white matter tracts, breaking down the corpus callosum into 3 regions, for a total of 15 regions of
interest (ROIs)12. Subsequently, summary statistics (i.e. Cohen’s d), expressing the magnitude of the potential
difference in DTI parameters within ROIs, will be produced.
Possibly, meta-regressions will be performed using age, medication and symptom severity scores as regressor.
References: 1.Menzies, L. et al. Am. J. Psychiatry 165, 1308–1315 (2008). 2. Radua J et al, The British Journal
of Psychiatry, 195, 393–402 (2009). 3. de Wit SJ et al, Am J Psychiatry,171, 340-9 (2014). 4.Piras, F. et al.
Cortex (2013). 5.Yoo, S. Y. et al. Acta Psychiatr. Scand. 116, 211–219 (2007). 6.Stern, E. R., Fitzgerald, K. D.,
Welsh, R. C., Abelson, J. L. & Taylor, S. F. PLoS One 7, (2012). 7. Piras, F., Piras, F., Caltagirone, C. &
Spalletta, G. Neuroscience and Biobehavioral Reviews (2013). 8.Koch, K. et al. J. Psychiatr. Res. 46, 264–270
(2012). 9. Radua J et al, Neuropsychopharmacology, 39,1547-57 (2014). 10.Smith, S., Jenkinson, M. &
Johansen-Berg, H. Neuroimage 31, 1487–1505 (2006). 11.Mori, S. et al. Neuroimage 40, 570–82 (2008).
Kochunov P, Neuroimage, 95, 136-50, (2014).
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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 two senior research physicists, PhD level (Chiara
Chiapponi and Tommaso Gili, expert in DTI processing and analysis), a junior research psychologist, PhD level
(Mariangela Iorio, expert in MRI database management, images quality check and DTI processing) and two senior
research neuroscientists (Fabrizio Piras and Federica Piras, head of the neuroimaging section and of the
neuropsychology section of the Neuropsychiatry Laboratory, respectively). All personnel involved have a strong
expertise in scripts writing and testing.
+ input from ENIGMA-DTI working group
+ maybe specific input from Benedetti-group (see proposal Irene Bolletini)?
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