Clinical Trials // · CLINICAL TRIALS DESIGN Clinical Trials 2013; 10: 568–586 The Epilepsy...

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DOI: 10.1177/1740774513484392

2013 10: 568 originally published online 1 July 2013Clin TrialsThe EPGP Collaborative

The Epilepsy Phenome/Genome Project

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CLINICALTRIALS

DESIGN Clinical Trials 2013; 10: 568–586

The Epilepsy Phenome/Genome Project

The EPGP Collaborative

Background Epilepsy is a common neurological disorder that affects approximately

50 million people worldwide. Both risk of epilepsy and response to treatment partly

depend on genetic factors, and gene identification is a promising approach to target

new prediction, treatment, and prevention strategies. However, despite significant

progress in the identification of genes causing epilepsy in families with a Mendelian

inheritance pattern, there is relatively little known about the genetic factors responsi-

ble for common forms of epilepsy and so-called epileptic encephalopathies.

Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institu-

tional, retrospective phenotype–genotype study designed to gather and analyze

detailed phenotypic information and DNA samples on 5250 participants, including

probands with specific forms of epilepsy and, in a subset, parents of probands who

do not have epilepsy.

Results EPGP is being executed in four phases: study initiation, pilot, study

expansion/establishment, and close-out. This article discusses a number of key

challenges and solutions encountered during the first three phases of the project,

including those related to (1) study initiation and management, (2) recruitment

and phenotyping, and (3) data validation. The study has now enrolled 4223

participants.

Conclusions EPGP has demonstrated the value of organizing a large network into

cores with specific roles, managed by a strong Administrative Core that utilizes fre-

quent communication and a collaborative model with tools such as study timelines

and performance-payment models. The study also highlights the critical importance

of an effective informatics system, highly structured recruitment methods, and

expert data review. Clinical Trials 2013; 10: 568–586. http://ctj.sagepub.com

Introduction

This article describes lessons learned thus far from theEpilepsy Phenome/Genome Project (EPGP), a large,multi-institutional international study that is creatingthe world’s most comprehensive database of pheno-typic characteristics of participants with epilepsypaired to biobanked DNA samples (Table 1). Spon-sored by the National Institute of Neurological Disor-ders and Stroke (NINDS), the study was launched inMay 2007 and aims to enroll 1500 pairs of first-degreerelatives (termed ‘family pairs’) who both have eitheridiopathic generalized epilepsy (IGE) or localization-related epilepsy (LRE), and 750 probands with

epilepsy related to infantile spasms (IS), Lennox–Gas-taut syndrome (LGS), or specific malformations ofcortical development. In the second group (termed‘triads’), both biological parents without epilepsyare enrolled. Enrollment, which can occur directlyat EPGP clinical centers or via phone and mailfrom remote distance, involves structured interviews,collection of relevant medical records, magnetic reso-nance imaging (MRI) studies and electroencephalo-gram (EEG) findings, and sending blood samples forDNA preparation at the NINDS Repository at CoriellInstitute of Medical Research.

Author for correspondence: Catharine Freyer Karn, The Epilepsy Phenome/Genome Project, Department of Neurology,University of California, Box 0114, San Francisco, CA 94143, USA.Email: [email protected]

� The Author(s), 2013Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1740774513484392



Table

1.EPGPCollaborative

authorsandco

ntributions.

Author

Institution

StudyPIClin

ical

site

PI

Clin

ical

site

Co-PI

Referral

Center

PI

Administrative

Core

Phenotyping

Core

Inform

atics

Core

Neurophysiology

Core

Imaging

Core

Pharm

aco

genomics

Core

Genomics

and

Data

Analysis

Core

Data

Review

Core

Publications

Committee

Writingof

man

uscript

Abou-Khalil,

Bassel,MD

Vanderbilt

University

Med

icalC

enter

XX

Alld

redge,

Brian

,PharmD

University

ofCalifornia,

San

Fran

cisco

X

Bau

tista,

Jocelyn,MD

ClevelandClin

icX

Berko

vic,

Sam,

MD

TheUniversity

of

Melbourne

X

Bluvstein,

Judith,MD

New

York

University

Sch

oolofMed

icine

XX

Boro,Alex,MD

AlbertEinstein

College

ofMed

icine

X

Cascino,

Gregory,MD

MayoClin

icCollegeof

Med

icineRoch

ester,

Minnesota

XX

Consalvo,

Damian,MD,

PhD

HospitalGeneralde

AgudosJose

Maria

RamosMejıa

X

Cristofaro,

Sabrina,RN,

BSN,

Phenotyping

Director

New

York

University

XX

Crumrine,

Patricia,

MD

Child

ren’sHospitalof

PittsburghofUniversity

ofPittsburghMed

ical

Center

X

Devinsky,

Orrin,MD

New

York

University

Sch

oolofMed

icine

XX

XX

X

Dlugos,

Dennis,MD,

MCSE

TheChild

ren’sHospital

ofPhiladelphia

XX

XX

Epstein,

Michael,PhD

Emory

University

Sch

oolofMed

icine

X

(continued)

The EPGP Collaborative 569

http://ctj.sagepub.com Clinical Trials 2013; 10: 568–586



Table

1.(C

ontinued)

Author

Institution

StudyPIClin

ical

site

PI

Clin

ical

site

Co-PI

Referral

Center

PI

Administrative

Core

Phenotyping

Core

Inform

atics

Core

Neurophysiology

Core

Imaging

Core

Pharm

aco

genomics

Core

Genomics

and

Data

Analysis

Core

Data

Review

Core

Publications

Committee

Writingof

man

uscript

Fahlstrom,

Robyn,MPH,

Data

Monitor

University

ofCalifornia,

San

Fran

cisco

XX

X

Fiol,Miguel,

MD

University

of

Minnesota

Medical

Center

X

Fountain,

Nathan,MD

University

ofVirginia

HealthSystem

X

Fox,Kristen,

RN,MS,

Recruitment

Director

University

ofCalifornia,

San

Fran

cisco

XX

French

,

Jacq

uelin

e,MD

New

York

University

Sch

oolofMed

icine

X

FreyerKarn,

Catharine,

Project

Director

University

ofCalifornia,

San

Fran

cisco

XX

X

Friedman,

Daniel,MD

New

York

University

Sch

oolofMed

icine

X

Geller,Eric,

MD

St.BarnabasHealth

CareSystem

X

Glauser,Tracy,

MD

CincinnatiChild

ren’s

HospitalMedical

Center

XX

Glynn,Sim

on,

MD

University

ofMichigan

X

Haas,Kevin,

MD

Vanderbilt

University

Med

icalC

enter

X

Hau

t,Sheryl,

MD,MS

AlbertEinstein

College

ofMed

icine

X

Hayward,Jean,

MD

KaiserPerm

anente:

Oa klandMed

ical

Center

X

Helmers,

Sandra,MD

Emory

University

Sch

oolofMed

icine

X

(continued)

570 Epilepsy Phenome/Genome Project

Clinical Trials 2013; 10: 568–586 http://ctj.sagepub.com



Table

1.(C

ontinued)

Author

Institution

StudyPIClin

ical

site

PI

Clin

ical

site

Co-PI

Referral

Center

PI

Administrative

Core

Phenotyping

Core

Inform

atics

Core

Neurophysiology

Core

Imaging

Core

Pharm

aco

genomics

Core

Genomics

and

Data

Analysis

Core

Data

Review

Core

Publications

Committee

Writingof

man

uscript

Joshi,Such

eta,

MD

University

ofMichigan

X

Kanner,

Andres,MD

Rush

University

Med

icalC

enter

X

Kirsch,Heidi,

MD,MS

University

ofCalifornia,

San

Fran

cisco

XX

Knowlton,

Robert,MD

University

ofAlabama

atBirmingham

Sch

ool

ofMed

icine

XX

Kossoff,Eric,

MD

TheJohnsHopkins

University

Sch

oolof

Med

icine

X

Kuperm

an,

Rach

el,MD

Child

ren’sHospital&

Research

Center

Oakland

X

Kuzn

iecky,

Ruben,MD

New

York

University

Sch

oolofMed

icine

XX

XX

XX

Lowenstein,

Daniel,MD

University

ofCalifornia,

San

Fran

cisco

XX

XX

XX

McG

uire,

Shannon,MD

LouisianaState

University

Health

SciencesCenter

X

Motika,Paul,

MD

Rush

University

Med

icalC

enter

X

Nesbitt,

Gerard,MBA,

Directorof

Inform

atics

University

ofCalifornia,

San

Fran

cisco

XX

X

Novo

tny,

Edward,MD

Seattle

Child

ren’s

Hospital

X

Ottman,Ruth,

PhD

ColumbiaUniversity

XX

XX

Pao

licch

i,

Juliann,MD

Vanderbilt

University

Med

icalC

enter

XX

X

(continued)





Table

1.(C

ontinued)

Author

Institution

StudyPIClin

ical

site

PI

Clin

ical

site

Co-PI

Referral

Center

PI

Administrative

Core

Phenotyping

Core

Inform

atics

Core

Neurophysiology

Core

Imaging

Core

Pharm

aco

genomics

Core

Genomics

and

Data

Analysis

Core

Data

Review

Core

Publications

Committee

Writingof

man

uscript

Parent,Jack,

MD

University

ofMichigan

X

Park,

Kristen,

MD

Child

ren’sHospital

Colorado

X

Poduri,

Annapurna,

MD

Child

ren’sHospital

Boston

XX

X

Risch

,Neil,

PhD

University

ofCalifornia,

San

Fran

cisco

X

Sadleir,

Lynette,

MBChB,

FRACP,MD

WellingtonSch

oolof

Med

icineandHealth

Sciences,Universityof

Otago

X

Sch

effer,

Ingrid,MBBS,

PhD

TheUniversity

of

Melbourne

X

Shellh

aas,

Renee,MD

University

ofMichigan

X

Sherr,Elliott,

MD,PhD

University

ofCalifornia,

San

Fran

cisco

XX

Shih,JerryJ.,

MD

MayoClin

icCollegeof

Med

icineJacksonville,

Florida

XX

X

Shinnar,

Shlomo,MD,

PhD

AlbertEinstein

College

ofMed

icine

X

Singh,Rani,

MD

University

ofMichigan

X

Sirven,Joseph,

MD

MayoClin

icCollegeof

Med

icineSco

ttsdale,

Arizo

na

X

Smith,

Michael,MD

Rush

University

Med

icalC

enter

X

Sullivan,Joe,

MD

University

ofCalifornia,

San

Fran

cisco

X

(continued)





Table

1.(C

ontinued)

Author

Institution

StudyPIClin

ical

site

PI

Clin

ical

site

Co-PI

Referral

Center

PI

Administrative

Core

Phenotyping

Core

Inform

atics

Core

Neurophysiology

Core

Imaging

Core

Pharm

aco

genomics

Core

Genomics

and

Data

Analysis

Core

Data

Review

Core

Publications

Committee

Writingof

man

uscript

Thio,LiuLin,

MD,PhD

WashingtonUniversity

inSt.Lo

uis

XX

Venkat,Anu,

MD

TheChild

ren’sHospital

ofPhiladelphia

X

Vining,Eileen

,

MD

TheJohnsHopkins

University

Sch

oolof

Med

icine

XX

VonAllm

en,

Gretchen,MD

University

ofTexas

HealthScience

Center

atHouston

X

Weisenberg,

Judith,MD

WashingtonUniversity

inSt.Lo

uis

XX

Widdess-W

alsh,

Peter,MB,

FRCPI

St.BarnabasHealth

CareSystem

XX

Winaw

er,

Melodie,MD,

MS

ColumbiaUniversity

XX

EPGP:Epilepsy

Phenome/G

enomeProject;PI:principalinvestigator.





Background and study design

Epilepsy affects approximately 50 million peopleworldwide and has a lifetime risk of about 3% [1–3].More than 1,750,000 people develop epilepsy everyyear [4]. The World Health Organization estimatedthat epilepsy accounts for 1% of the global burden ofdisease, as measured by disability-adjusted life years(DALYs: number of years lost due to disability or pre-mature death). Among people with epilepsy who haveaccess to treatment (a minority worldwide), 30%–40%have seizures that are refractory to medication [5].People with refractory epilepsy have poorer employ-ment status, significantly limited activities, impairedquality of life, and increased mortality rates comparedto the general population. Even people with well-con-trolled seizures or those whose seizures completelyremit have relatively poor educational and social out-comes years after their seizures have resolved [6].

In the search for new strategies to reduce the bur-den of epilepsy, the discovery of specific genes thatinfluence risk offers a novel opportunity to clarifypathogenic mechanisms, to identify susceptibleindividuals prior to seizure onset, and to treat andprevent seizures in people at risk. Converging datasupport a pathogenic role of genetics in epilepsy:epidemiologic studies show a two- to four-foldincreased risk in the first-degree relatives of peoplewith epilepsy of unknown cause (either IGE or non-acquired LRE) [7–10]; twin studies show higher con-cordance in monozygotic than dizygotic pairs, withheritability estimates of 70%–80% [11–14]; andmore than 20 genes with a major effect on suscept-ibility have been identified [15–17]. However, theknown genes affect risk in a very small proportionof individuals – primarily those with extensivefamily histories consistent with Mendelian inheri-tance. Most epilepsies occur without a significantfamily history, and identifying and characterizingthe genetic mechanisms in these ‘complex epilep-sies’ are major challenges in the coming years [18].

The genetic architecture of complex epilepsiescould involve common variants with small effectson risk, consistent with the ‘common disease, com-mon variant hypothesis’ [19,20] or multiple rare var-iants with larger risk-raising effects [21]. Althoughthe distribution of these types of variants in the epi-lepsies is uncertain, evidence from epilepsy [22,23]and other disorders [24,25] suggests that commonvariants contribute little to epilepsy heritability. Incontrast, accumulating evidence for association ofcomplex epilepsies with rare microdeletions suggeststhat rare variants are important [26–30]. In addition,de novo genetic events can cause some ‘catastrophicepilepsies’, such as IS and LGS [31–33], and certainmalformations of cortical development that includeintractable epilepsy as a principal feature [34–40].

The EPGP was designed to address the hypothesisthat genetic variation contributes to risk of develop-ing epilepsy and pharmacological intractability andthat the variation may (1) include common poly-morphisms, rare variants, or private mutations; (2)range in scale from single nucleotide alterations tolarge genomic rearrangements; (3) be inherited orarise de novo; and (4) occur in the germ line orsomatically. EPGP is a multi-institutional, collabora-tive network of 27 academic epilepsy centersthroughout the United States, Australia, New Zeal-and, and Argentina, which is carrying out detailedphenotyping and banking DNA samples from 1500pairs of first-degree relatives (3000 individuals) witheither IGE or LRE, and 750 triads (2250 individuals)with one child with either IS, LGS, or specific mal-formations of cortical development (polymicrogyriaor periventricular nodular heterotopia), plus bothbiological parents. Completion of this work will setthe stage for large-scale genome analyses of theseindividuals. The overall design of the study is asfollows.

Participants

The inclusion criteria for participants and epilepsytypes are listed in Table 2.

Participant recruitment

Participants are identified primarily through theEPGP Clinical Centers by prospective screening ofclinic patients, retrospective medical record reviews,and ongoing education of colleagues within theinstitution and from neighboring hospitals andpractices. There is also an EPGP National Recruit-ment Campaign to recruit eligible families outsideof the Clinical Centers through community advo-cacy groups, the Internet, news articles, advertising,and other forms of communications with patientsand healthcare professionals.

Phenotype data collection

Figure 1 and Table 3 provide an overview of theEPGP clinical data collection protocol. After givinginformed consent, participants undergo a series ofdetailed, semistructured web-based interviews(including Subject Demographics, Eligibility Screen-ing, and a Diagnostic Interview) administered bystudy coordinators. Additional information isextracted from the participant’s medical records tosupport the epilepsy diagnosis, categorize responseto antiepileptic drugs (AEDs), and to provide addi-tional phenotypic data. Informatics tools were devel-oped for the recording and reviewing of responses to





Table 2. Epilepsy Phenome/Genome Project (EPGP) inclusion and exclusion criteria.

All participants with epilepsy

� Current age 4 weeks and older. No restriction on upper age limit

� Two or more UNPROVOKED seizures. (Febrile seizures, acute symptomatic seizures, seizures from alcohol, metabolic seizures, or toxic

seizures are allowed, in addition to unprovoked seizures.)

� If one unprovoked seizure with epileptiform electroencephalogram (EEG) with clear diagnosis of epilepsy type, send for adjudication

� No identified antecedent cause of epilepsy (i.e., a structural or metabolic insult to the CNS (central nervous system) prior to the first

unprovoked seizure, such as stroke, brain tumor, severe head trauma, etc., or a progressive neurodegenerative disorder)

� Head circumference\2.5 standard deviations from normal at the time of enrollment

� Age at first unprovoked seizure\45 years. If age of onset is � 45 years, send for adjudication

� No recognized genetic syndrome, chromosomal abnormality, or pathogenic mutation in a previously identified epilepsy gene. If

positive genetic result, send for adjudication

� High-quality clinical and laboratory data (medical records, magnetic resonance imaging (MRI) file or EEG file or report, or reference in

the medical record of EEG and/or MRI results for the past 2 years, or from seizure onset if\2 years). If medical records are not available,

site principal investigator (PI) is to obtain details from the participant regarding eligibility, and history is sent for adjudication

Idiopathic generalized epilepsy (IGE)

� Clinical seizures consistent with IGE

� Subject has affected full sibling, a biological parent, or a biological child with nonsymptomatic epilepsy willing to enroll in EPGP

� Sibling is not an identical twin of participant (fraternal twin is allowed)

� Brain MRI optional: results of MRI normal, if done

� EEG or video EEG required: shows generalized epileptiform activity and a normal posterior dominant rhythm for age

� If normal EEG, clear and compelling clinical history required, send for adjudication

� No history of premature birth before 32 weeks gestation

� No evidence of moderate to severe developmental delay prior to the onset of seizures and medication (severe delay is characterized by

50% or more delay in any area: motor, social, language, cognition, or activities of living; or global delay). Cases with Attention Deficit

Disorder, Attention Deficit Hyperactivity Disorder and Learning Disorders are ok for inclusion.

� No history of autism or clear signs of autistic function (decreased eye contact, social interactiveness, moderate to severe language delay

in a child who subsequently develops autism). Asperger’s syndrome okay for inclusion

Localization-related epilepsy (LRE)

� Clinical seizures consistent with LRE

� Subject has affected full sibling, a biological parent, or a biological child with nonsymptomatic epilepsy willing to enroll in EPGP

� Sibling is not an identical twin of participant (fraternal twin is allowed)

� Brain MRI required: results of MRI were normal, show focal cortical dysplasia (FCD), or show mesial temporal sclerosis

� Brain MRI optional: results of EEG consistent with benign rolandic epilepsy

� If normal MRI, EEG, or video EEG required: shows interictal focal abnormality OR clinical or electrographic seizures on ictal EEG

� If normal MRI, normal interictal EEG, and no or normal ictal EEG, clear and compelling clinical history required, send for adjudication

� No history of premature birth before 32 weeks gestation

� No evidence of moderate to severe developmental delay prior to the onset of seizures and medication (severe delay is characterized by

50% or more delay in any area: motor, social, language, cognition, or activities of living; or global delay). Cases with Attention Deficit

Disorder, Attention Deficit Hyperactivity Disorder and Learning Disorders are ok for inclusion.

� There is no autism or clear signs of autistic function (decreased eye contact, social interactiveness, moderate to severe language delay

in a child who subsequently develops autism). Asperger’s syndrome okay for inclusion.

Infantile spasms (IS) or Lennox–Gastaut syndrome (LGS) – cryptogenic

� Clinical seizures and EEG consistent with IS or LGS

� No history of congenital TORCH infection, premature birth before 32 weeks gestation, neonatal hypoxic ischemic encephalopathy

with or without neonatal seizures, meningitis/encephalitis, stroke, intracranial hemorrhage, or significant head trauma

� No evidence of severe (50% or more delay in any area: motor, social, language, cognition, or activities of living; or global delay)

developmental impairment prior to the onset of spasms

� Both biological parents available and willing to enroll in EPGP

� EEG required: results consistent with IS (hypsarrhythmia or hypsarrhythmia variant OR electrodecremental discharge) or LGS (slow or

disorganized background, and slow spike and wave activity less than 2.7 Hz or generalized paroxysmal fast activity (GPFA))

� Brain MRI required: normal, mild atrophy, or steroid-induced atrophy

� If present, autism or signs of autism developed after the onset of seizures

IS or LGS – FCD

� Clinical seizures consistent with IS or LGS

(continued)





AEDs. The tools include (1) a decision tree that leadsthe study coordinator through a series of decisionpoints that will ultimately result in the phenotypicclassification of individual AED trials as either unin-formative, success, or failure, (2) a web-based datacollection form to collect the subject’s AED trialsand drug response history, and (3) a web-based AEDreview process that allows the AED Core to reviewall AED data.

The source medical records are de-identified,scanned, and stored at the Clinical Center anduploaded to the EPGP Data Repository. EEG andMRI studies are also submitted by the Clinical Cen-ter and uploaded to the EPGP Data Repository,reviewed by the EEG and MRI Cores, and used toconfirm the diagnoses. Finally, at each EPGP Clini-cal Center, the site principal investigator (PI) exam-ines all collected clinical data (interviews, medicalrecord abstraction, MRI, and EEG) and completesthe web-based Final Diagnosis Form, where detailsregarding seizure semiology and epilepsy classifica-tion are documented.

Blood, cell line and DNA logistics

For each enrolled participant, two tubes of blood aresubmitted to the NINDS Human Genetics Reposi-tory at the Coriell Institute for Medical Research,where DNA is extracted and cell lines are generatedto serve as a perpetual resource to the research

community. EPGP uses an advanced web-based sys-tem, designed by the Informatics Core, for trackingspecimen shipments from the clinical site to theCoriell Institute for Medical Research and for record-ing when a specimen has been accessioned at theCoriell Institute for Medical Research.

Data surveillance and quality control

Systematic quality reviews are conducted to identifyand correct errors in phenotypic data. The followingactivities are conducted on an ongoing basis: (1)qualitative and quantitative data monitoring activ-ities by the EPGP statistician, (2) automated errorchecks programmed by the Informatics Core, (3) in-person data review meetings to examine forms andmedical records for a subset of participants, and (4)expert reviews by EPGP scientific cores, includingEEG, MRI, Pharmacogenomic, Phenotyping, andData Review Cores.

Informatics infrastructure

EPGP developed a suite of custom web-based infor-matics solutions for participant tracking, electronicdata collection, and data review. Details of the plat-form design, along with an interim assessment of itseffectiveness by end users, are provided in Ref. [41].The core application is called Participant ActivityTracker, which allows new patients to be registered

Table 2. (Continued)


� EEG required: results are consistent with IS (hypsarrhythmia or hypsarrhythmia variant OR electrodecremental discharge) or LGS (slow

or disorganized background, and slow spike and wave activity less than 2.7 Hz or GPFA)

� Brain MRI required: shows FCD


Polymicrogyria (PMG) or bilateral periventricular nodular heterotopia (PVNH)

� Clinical seizures consistent with IGE, LRE, IS, LGS (mixed permitted)


� No family history of X-linked PVNH, if known

� Filamin A sequence analysis for PVNH is negative

� Normal karyotype: no confirmed genetic syndrome or metabolic disease (chromosome work up strongly suggested)

(1) If chromosomal analysis has been done and results show normal chromosomes, person can be enrolled

(2) If chromosomal analysis has been done and results show an abnormality, enrollment depends on the abnormality: send for

adjudication

(3) If not yet done, chromosomal analysis is encouraged but not required prior to enrollment

� EEG not required for inclusion

� Brain MRI required: shows PMG (of any type) or bilateral PVNH (but NOT neural tube defects or schizencephaly or

band heterotopia)


Parent controls

� No history of epilepsy (toxic/metabolic seizures and/or febrile seizures okay to include)





and data collection forms to be completed. Theforms and activities completed for a study partici-pant vary depending upon the participant’s study

arm and participant type. Therefore, it was neces-sary to define these rules in the database, so that theexecution and completion status of these activities

Identify Potential Participant: IGE/LRE Pair or Triad

Confirm Eligibility: - Eligibility Screening Checklist - Consent - Review of Medical Record, EEG, MRI

Final Diagnosis Form - Review Medical Record & Abstractions - Review Interviews - Review EEG/MRI

EEG Core Review

MRI Core Review

Data Review Core Review

Phenotyping Core Review

Final Consensus of Diagnosis

Blood Draw and Shipment to Coriell

Interviews - EPGP Eligibility (Risk

Factors) Interview - Diagnostic Interview - Demographic Screen

Abstraction - Detailed Medical

Record Abstraction - AED Data Sheet

Digital File Upload and Review - EEG - MRI - Medical Record

Participant Eligible?

Yes

STOP

Yes

Participant Eligible?No

STOP

Yes

No

Participant Eligible? NoSTOP

Completed Enrollment, Site Reimbursement

Figure 1. EPGP enrollment, phenotyping, and data review process.IGE: idiopathic generalized epilepsy; LRE: localization-related epilepsy; EEG: electroencephalogram; MRI: magnetic resonance imaging; EPGP: Epilepsy Phe-

nome/Genome Project; AED: antiepileptic drug.





could be tracked in real time and reportedaccurately.

Collecting the data electronically using web-basedforms enabled EPGP to streamline the data collec-tion process and reduce data errors. It has decreasedthe time taken to collect data and increased the dataaccuracy. Methods used to realize these benefitsinclude specifying allowable values and data rangesin each form field, automatically hiding questionsthat do not apply to the study participant, andbranching to only the relevant sections in the formbased on specified conditions. Input fields that donot satisfy the data validation criteria prompt theend user to rectify the data error, preventing the enduser from proceeding to the next page in the formuntil all data errors are corrected. Another advantageof using web-based forms is that the research dataare available immediately, enabling monitoring,reporting, and review in real time.

EPGP also collects source files belonging to studyparticipants. These include medical records, EEGs,and MRIs. On receipt of these files, any residual pro-tected health information (PHI) that could poten-tially identify a patient is removed from the sourcefiles, and the files are converted to an accessible for-mat. Medical records are converted to portable docu-ment format (PDF), EEGs are converted to PersystInsight format, and MRIs are converted to digitalimaging and communications in medicine (DICOM)format. All source files are stored on a secure, pass-word-protected File Transfer Protocol (FTP) fileserver.

A number of electronic workflows were designedand implemented to facilitate peer reviews per-formed by the EEG, MRI, and Data Review Cores.Web-based tools were developed for this purposeand enable the EEGs and MRIs to be characterizedaccurately using structured data collection forms

and deemed acceptable or not for the study. Oncethe entire study participant’s data are collected andtheir source EEG, MRI, and medical records are avail-able (where applicable), the Data Review Core isalerted automatically, at which point the study par-ticipant’s complete data and final epilepsy classifica-tion are reviewed and confirmed, or corrected ifnecessary.

The entire informatics platform was designed anddeveloped in approximately an 8-month timeframe.There was a lack of any suitable off-the-shelf solu-tion in the marketplace when we commenced thestudy, and a custom-developed solution was theonly option available at that time. We continued todevelop new enhancements and changes to theplatform over the duration of the EPGP study, and ithas served its purpose well. EPGP’s data warehousecontains over 3.5 million completed data points,1775 MRIs, and 2,245 EEGs. More than 33,000 web-based activities have been completed thus far.

Results

EPGP is organized into four phases of execution:study initiation, pilot, study expansion/establish-ment, and close-out. Each of these phases is pre-sented here for the purpose of emphasizing thechallenges and lessons learned.

Study initiation and management

Study initiation, which occurred during the first 6months, involved hiring of staff, approval of Institu-tional Review Board (IRB) applications, developmentof phenotyping tools and training materials, andprogramming of informatics systems. Key decisionswere made during this period that contributed to

Table 3. Activities included in data collection protocol, by participant type.

Activity name IGE participant LRE participant IS/LGS proband PMG/PVNH proband Parent controls

Eligibility checklist Yes Yes Yes Yes Yes

Consent Yes Yes Yes Yes Yes

Screening interview Yes Yes Yes Yes Yes

Specimen collection Yes Yes Yes Yes Yes

Subject demographics Yes Yes Yes Yes Yes

Diagnostic interview Yes Yes

Medical record abstraction Yes Yes Yes Yes

Pharmacogenomics form Yes Yes

AED web form Yes Yes

Electroencephalography review Yes Yes Yes

MRI review Optional Yes Yes Yes

Final diagnosis form Yes Yes Yes Yes

IGE: idiopathic generalized epilepsy; LRE: localization-related epilepsy; IS: infantile spasms; LGS: Lennox–Gastaut syndrome; PMG: polymicrogyria; PVNH:

periventricular nodular heterotopia; AED: antiepileptic drug; MRI: magnetic resonance imaging.





the overall success of the project: the network wasorganized into cores and managed by an Adminis-trative Core, study timelines were generated and fol-lowed closely, communications were frequent andstandardized, and a pay-for-performance financialmodel was established.

Core-based organizational structure

In addition to the Clinical Centers staffed by siteinvestigators and study coordinators, the decisionwas made at the start to rely on an organizationalstructure that included cores serving specific admin-istrative and scientific functions (Figure 2); thedesign of this structure was generated empiricallybased on the complex organizational needs of theproject.

Overall leadership of EPGP is provided by anExecutive Committee comprised of the Core chairsand administrative personnel of the AdministrativeCore and the Phenotyping Core. EPGP is overseenby an Observational Study Monitoring Board(OSMB) appointed by NINDS and an Advisory Com-mittee selected by the EPGP PIs. The OSMB isresponsible for certifying to NINDS on a biannualbasis that the study is proceeding according to planand for approving any proposed modifications instudy design made by the investigators. The Advi-sory Committee meets with the EPGP leadershipannually and is used primarily as a ‘sounding board’when problems arise and external perspectives maybe of benefit in devising solutions. Coordinating theactivities of the five scientific cores, 27 Clinical

Centers, and two advisory bodies required a strongAdministrative Core, the central operations groupfor the network. The Informatics Core manages allaspects of the software and hardware related to thecollection, storage, and retrieval of phenotype data,collection and sending of blood for DNA banking,and design and maintenance of the study website.The Phenotyping Core oversees all phenotypingactivities, including careful tracking of progress ateach Clinical Center. The EEG Core oversees andreviews all electroencephalography-related data, andthe Imaging Core oversees and reviews all imaging(primarily MRI) data. The Pharmacogenomics Corereviews and validates the data related to AEDresponse and adverse effects. A Data Review Core,implemented in the fourth year of the project,assesses the accuracy of phenotyping data throughreviews of both randomly and specifically selectedstudy participants.

The Administrative Core coordinates and tracksall activities of the study and oversees the work ofthe other Cores and Clinical Centers, communica-tions, national and site-specific recruitment, publi-city, financials, and interactions with NINDS andoversight bodies. A full-time Project Director han-dles the overall implementation of the project,tracks deliverables from sites and cores, maintainsstudy documentation and reports, and generatesand tracks budgetary and phenotyping costs andmetrics. A full-time Phenotyping Director trains andmonitors clinical centers and handles all day-to-dayeligibility and protocol questions. A full-timeRecruitment Director was added to the Administra-tive Core to study clinical center recruitment trends

Figure 2. The EPGP organizational structure.EPGP: Epilepsy Phenome/Genome Project; OSMB: Observational Study Monitoring Board; EEG: electroencephalogram.





and to manage a national campaign for participantrecruitment. Later in the study, a full-time Statisti-cian was hired to handle the new Data Review Coreand data queries and to generate datasets forpublication.

During the study initiation phase, the Administra-tive Core made three critical decisions: to integratethe study timeline; to put energy into frequent, stan-dardized study communications; and to focus onrobust financial tracking systems.

Study timeline

The Administrative Core tracked the Clinical Cen-ters and Cores against a robust study timeline (seeSupplemental Materials, Figure 1), which illustratedthe ways in which the efforts of the individual coresand centers affected each other and the study’s suc-cess overall. The timeline was developed by the Pro-ject Director, agreed upon by the network at thevarious progress meetings, and updated every 3–6months, depending on the level of change beingexperienced by the network. Deviations from thetimeline were identified early, and interventionscould be applied rapidly to minimize the time andresources lost to the study.

Communications

To organize the efforts of more than 100 personnelworking on the project, teleconferences were estab-lished at fixed times every week (later, every 2 weeksor every month), and these proved invaluable. TheAdministrative and Informatics Cores met internallyat least once per week, and the study PIs met withthe Administrative Core and Informatics Directorweekly. At study start, the leaders of each scientificcore met weekly with the Administrative Core,Informatics Core, and the Executive Committee toclosely track progress and discuss challenges, andthese meetings were scaled back to a monthly sche-dule as the study matured through the study expan-sion or establishment phase. Additionally, the stafffrom all Clinical Centers met at a set time each weekfor the EPGP ‘All Sites Call’ with the AdministrativeCore and Executive Committee. These meetingsenabled the study administrators to check in onstudy deliverables, such as first recruitment and pro-gress of IRB approvals, but more importantly, theycreated a forum for the investigators and coordina-tors of the Clinical Centers to describe both chal-lenges and innovations. For example, numerousideas were exchanged for maintaining awareness byfaculty and trainees at Clinical Centers about EPGPand the need to identify potential participants.

Separate teleconferences were conducted monthlyfor study coordinators, and these were frequently

utilized to review details of the study workflowwhen problems had been identified, such as bestpractices for the administration of the participantinterviews. The network scheduled at least one face-to-face meeting each year and structured theseannual meetings to meet the needs of the group atthe time, including training, expansion of the net-work, data integrity issues, or planning for thefuture. Finally, agendas were followed closely and allmeetings were followed by emails in a standardizednewsletter template (see Supplemental Materials,Figure 2), so that all members of the study couldkeep track of critical information efficiently.

Key aspects of EPGP communications weretransparency, regular reminders of the value of thecollaborative and study achievements, and team-building. Updated tables and graphs of enrollmentand phenotyping activities completion by each sitewere circulated before meetings, highlighting bothhigh-performing and poor-performing sites, andthis typically led to an exchange of informationbetween sites as to how to improve performance.Important successes, such as recognition of the top-performing sites, enrollment of the 1000th partici-pant, approvals by the OSMB, and acceptance ofabstracts at national meetings, were highlighted atteleconferences and in the newsletter. Finally, in allcommunications, the study team focused on thecontributions of the study coordinators at the Clini-cal Centers by highlighting coordinators who hadachieved high recruitment or phenotyping in amonth, by remembering birthdays, and by creatingteam-building materials, such as trivia booklets,about the coordinator team.

The study’s website (http://www.epgp.org) hasalso proved to be a critical communications tool forall aspects of the project. The public site providesinformation to potential participants regarding thegoals and design of the study, eligibility criteria, anda phone number and email address to inquirefurther about the study and express interest inenrollment. The ‘members only’ area contains allthe tools required by study personnel, including theapplications for enrollment, phenotyping, specimendelivery and follow-up, study documentation, andtraining material.

Pay-for-performance financial model

The funding agency, NINDS, required a per-activityfunding model for EPGP from the start. This provedto be a powerful study management tool, since theClinical Centers were strongly incentivized to iden-tify, enroll, and fully complete the required studyprocedures for as many participants as possible.Based on our prior experience, there is no doubt thiswas far more effective than the traditional model of





committing to a ‘percent effort’ for site investigatorsand study coordinators, which is disconnected fromsite performance. However, this model was initiallydifficult to implement because of the way in whichU01 awards (the National Institutes for Health(NIH) designation for grants that are cooperativeagreements and include substantial oversight by thefunding agency) are handled by most institutions:they are treated as cost-reimbursement contracts,and provisions do not currently exist to establishperformance contracts on a U01 award. Nonethe-less, in the first year of the project, the Project Direc-tor established tools to supplement universitysystems, so that the Administrative Core could effec-tively execute contracts, update budgets, trackspending, and monitor the correctness of ClinicalCenter invoices within budget categories of eachsubcontract.

Recruitment and phenotyping

With the structure of the project established, thestudy entered its pilot period and we quickly rea-lized that a major challenge was overcoming recruit-ment difficulties: the participants specified by theprotocol were, in all but the IS category, more diffi-cult to find than initially estimated. We also discov-ered that despite a considerable effort to finalize allof the phenotyping procedures, there were manychanges needed to make them acceptable to boththe study participants and personnel. In response tothese challenges, we revised the plan for participantrecruitment and streamlined the phenotypinginstruments, which led to a major improvement invirtually all aspects of project execution.

Participant recruitment

After 1 year of participant enrollment, more than10,000 potential families had been screened for elig-ibility and 782 individual participants had enrolled(this was 45% of our goal for that time point). Eligi-ble sibling pairs were more difficult to identify thanwas originally estimated, probably due to differencesbetween epidemiological estimates of the prevalenceof sibling pairs (which were used to predict enroll-ment numbers) and the observed prevalence of sib-ling pairs in academic epilepsy centers. In addition,obtaining the signed consent document from bothfamily members proved to be a challenge. Often,one of the family members was not seen at an EPGPClinical Center, and so completing the informedconsent process by phone and mail was cumber-some for participants. It is possible that these familymembers were less inclined to participate becausethey did not feel a close affiliation with the PI. Toclose the enrollment gap, the Administrative Core

hired a full-time Recruitment Director at the end ofthe first year. The Recruitment Director improvedrecruitment at the EPGP Clinical Centers by workingwith sites to tailor recruitment plans for their needs,establishing EPGP Referral Centers that identifiedparticipants to be directly enrolled at nearby EPGPClinical Centers, recognizing monthly achievementswith coordinator awards and acknowledgments,providing standardized recruitment materials thatwere visually appealing and easily understandable(such as participant brochures, posters, and pocketeligibility cards for clinicians), establishing a recruit-ment probation plan for sites with monthly enroll-ment expectations and interventions if goals werenot met, and sharing best practices at all groupmeetings. The best practices included tips for con-senting participants via phone and mail, how toconvey complicated information about genetics andresults during the consent process, and how to estab-lish a mechanism at each site to ensure that all clinicpatients were screened for the study. Prior to thisintervention, many sites relied on the family historyin the medical chart for screening. However, thisinformation was often not complete or updated, andsites incorporated basic EPGP eligibility questionsinto every patient visit to ensure that all eligiblefamilies were identified.

The Recruitment Director also launched a nationalrecruitment campaign to identify potential studyparticipants from outside of the EPGP Clinical Cen-ters. These participants were screened for eligibilityby central study staff and then referred to ClinicalCenters for enrollment. The national campaignincluded sending out ‘Dear Colleague’ letters andstudy update newsletters, collaborating with patientadvocacy groups and other epilepsy research studies,cost-effective advertising directed at a targeted audi-ence, establishing an online presence via websitesand social networking sites, developing creative stra-tegies to motivate attendees at national professionalconferences to refer patients, creation of the EPGPCommunity Referral Network (CRN) (consisting ofhundreds of neurologists and healthcare profes-sionals who referred families), and generating addi-tional recruitment materials (such as pens, coffeemugs, post-it pads, and magnets with eligibility cri-teria) to increase visibility of project in clinicsaround the country. The CRN, the most effective ofthese strategies, identified almost 100 eligiblefamilies who subsequently enrolled in EPGP.

Phenotyping workload

In the second year of the grant, we recognized thatthe recruitment and phenotyping workload of theClinical Centers exceeded human resources for theprojected timelines. The research team studied





the phenotyping metrics across the sites, modeledthe workload through the end of the study, and incollaboration with the OSMB, worked to streamlinethe EPGP dataset without sacrificing phenotypingdepth. For example, the Diagnostic Interview under-went several revisions that reduced its averagelength from 2 h to 45 min, mainly by reducingredundancy and consolidating question sets. Theoriginal version of this form had been modifiedfrom an instrument used in a single-site geneticstudy, in which the interview length averaged 60min. However, both the phenotyping staff and themethod of administration differed in our study fromthose in the original study from which the instru-ment was derived. In the original study, the formwas administered on paper by closely supervisedstaff dedicated to working exclusively on that study.Budgetary considerations, as well as the projectedrate of enrollment at each site, precluded use ofdedicated phenotyping staff in our study. Instead,we used clinical staff engaged in multiple tasks inaddition to their work on the study, who had toadminister a new instrument using an unfamiliarelectronic platform. In addition, our large team ofexpert diagnosticians had expanded the previouslyused form before we initiated data collection, andthis new form was not sufficiently pilot-tested toensure its length was manageable. In retrospect, alonger pilot phase would have been advisable.

Additional changes included elimination of the 2-to 3-h pharmacogenomics abstraction for severe epi-lepsies (triads), since nearly all these participantswere pharmacoresistant. A cap was set for the num-ber of times a study coordinator should attempt toget medical records from referring institutions, andan Adjudications Core, managed by the Phenotyp-ing Director, was established to review such cases.The adjudications process was later expanded toreview a wide range of eligibility questions, in orderto retain as many eligible participants as possibleand limit the dropout rate. Each case was carefullyscrutinized by the Phenotyping Director and theAdjudications Core. Finally, in the third year, weallocated an American Recovery and ReinvestmentAct (ARRA)-funded administrator to each of the 13actively enrolling Clinical Centers to close out thephenotyping backlog that developed in the secondyear.

Expanding the network

By the end of the second year of the grant, the studywas fully established. All Clinical Centers had over-come their recruitment and phenotyping obstacles,or had been dropped. However, we were projectingwe would end the study with approximately 50% ofour cohort if enrollment continued at the same rate.

The study team therefore considered three options:further reduce phenotyping from the protocol (toallow sites to focus even more on recruitment),increase the size of the network, or both. TheAdministrative Core used real-time study data togenerate models that projected the impact of eachchange financially, to recruitment and phenotyping.These analyses suggested that the best strategy wasto immediately expand the network. The Recruit-ment Director oversaw the addition of 14 new Clini-cal Centers, using a selection process designed toyield the most promising sites. The PhenotypingDirector scheduled and conducted extensive on-sitetraining with each new center’s PI and study staff, toensure that all sites were well-equipped to completethe numerous study procedures. Not surprisingly,the effort to successfully bring new sites on-boardand have them fully functional benefitted from theexperience gained during the initial phase of thestudy.

Addition of parent–child pairs with IGE/LRE

To further improve recruitment, and after consulta-tion and review by our OSMB, the decision wasmade to expand the potentially eligible IGE/LREcohort to include parent–child pairs in addition tothe sibling pairs. The scientific drawback of includ-ing parent–child pairs (which could be included ingenetic association studies but not genetic linkagestudies) was felt to be worth the considerable advan-tage of enrolling as many familial cases as possible.

This expansion and change in inclusion criterialed to a marked upswing in enrollment, such thatwe now project we will reach at least 80% of our tar-get recruitment by the end of the sixth year.

Data validation

In year 3 of the grant, when the initial 13 centerswere fully operational and phenotype data wereflowing in steadily, the research team began the pro-cess of review of interview, EEG, MRI, AED response,and final diagnosis data. Two in-person data reviewmeetings were convened at which PhenotypingCore members reviewed samples of records from theClinical Centers. From these meetings emerged therecognition that despite the in-depth interviews,medical record documentation, and laboratory data,there were still aspects of phenotyping that wereopen to interpretation, especially in the area of sei-zure semiology and classification. This led to extraphenotyping instructions and training for study per-sonnel and more data checks being programmedinto the informatics system. In addition, the datareview meetings prompted the EPGP AdministrativeCore to create a Data Review Core, managed by the





EPGP Statistician. The Data Review Core devised aprotocol in which participant data are reviewedindependently by two reviewers, potential discre-pancies are reported back to the site, additionalinput is forwarded back to the reviewers, and a finaladjudication is made based on all the available infor-mation. A custom module was designed by theInformatics Core that allows for this entire workflowto take place on a web-based platform (Figure 3).

As a start, the Data Review Core reviewed the firstthree cases from each Clinical Center, with the planto review an additional case from each center forany that had an error and eventually at least 6% ofthe EPGP dataset in detail (i.e., approximately 225 ofthe total number of expected probands). However, itquickly became apparent that in keeping with theresults of the initial face-to-face data reviews, therewere discrepancies in the dataset, although the vastmajority were very minor in terms of the main scien-tific goals of the project. For example, in a review of351 participants with LRE, errors have been foundfor 210 participants (60%). Importantly, most of theerrors are related to seizure semiology (which isoften open to interpretation by patients, familymembers, and epileptologists), and there have beenonly three cases with a major error such as an incor-rect epilepsy diagnosis that affected eligibility. None-theless, this experience has emphasized the criticalimportance of added data validation in the study ofa disorder such as epilepsy, and our plans are now tocarry out this additional data review on all partici-pants with LRE and a random subset of the remain-ing participants.

Conclusions

EPGP is a large-scale, multicenter, collaborativeeffort that is well on the way to completing thegoals of creating the following: (1) a detailed pheno-type database on a large number of very carefully

selected individuals with specific forms of epilepsy,along with first-degree relative controls and (2) a per-manent repository of DNA and cell lines linked to thephenotype data. As of June 2013, 5,535 participantshave been consented, with 4,223 currently enrolled.In addition to the individuals identified directlythrough the Clinical Centers, more than 2000families have contacted the national recruitmentoffice for information and eligibility screening as aresult of the National Recruitment Campaign; 328 ofthese families (16%) have been enrolled in EPGP.

In working toward these goals, we developedinnovative approaches for carrying out a pheno-type–genotype project of this scale, including solu-tions for some of the unexpected challenges thatinevitably arise in large studies. These include newmethods for standardized data collection and phe-notyping (including clinical, electrophysiologic,and neuroimaging characteristics, and the creationof a schema for assessing AED response), novel web-based informatics tools for data collection and sto-rage in a common repository, automated systems forshipment and receipt of blood samples, a nationalrecruitment campaign to identify potential partici-pants, and effective communication systems formanaging the activities of the entire organization.We also benefitted from a variety of mechanisms foroversight and continuous quality improvement,which enabled us to rapidly identify and efficientlyaddress problems such as lower than projectedenrollment, an excessive phenotyping workload,and the need for further verification of phenotypedata.

AcknowledgmentsWe would like to acknowledge the contributions toepilepsy research made by the staff, patients, andfamily members who are participating in EPGP, aswell as the recruitment efforts of the EPGP Commu-nity Referral Network (CRN). The CRN consists of

Figure 3. Workflow for the review of participant data by the EPGP Data Review Core.EPGP: Epilepsy Phenome/Genome Project.





healthcare professionals not paid by the EPGP grant,who refer eligible families to EPGP. A list of indivi-dual contributors can be found at http://www.epgp.org.

Administrative Core Members:- Kathleen McGovern, Recruitment Assistant- Nora Stillman, Recruitment Assistant

Informatics Core Members:- Kevin McKenna, Database Manager- Vickie Mays, Data Coordinator- Michael Williams, Informatics- Alan Carpenter, Programmer Analyst- Kevin Miller, Programmer Analyst

Study Coordinators:- Prashant Agarwal, Study Coordinator, The Chil-dren’s Hospital of Philadelphia

- Jennifer Ayala, Study Coordinator, Albert Ein-stein College of Medicine

- Cate Bakey, Study Coordinator, The Children’sHospital of Philadelphia

- Thomas Borkowski, PhD, Study Coordinator,Albert Einstein College of Medicine

- Riann Boyd, CCRP, Study Coordinator, MayoClinic College of Medicine Jacksonville, Florida

- Alicia Camuto, CCRP, Study Coordinator, TheChildren’s Hospital Denver

- Cendy Carrasco, Study Coordinator, Universityof California, San Francisco

- Jennifer Cassarly, Study Coordinator, CincinnatiChildren’s Hospital Medical Center

- Yong Collins, RN, Study Coordinator, The Chil-dren’s Hospital of Philadelphia

- Kevin Collon, Study Coordinator, University ofMichigan

- Sean Collon, Study Coordinator, University ofMichigan

- Heather Eckman, Study Coordinator, New YorkUniversity School of Medicine

- Susan Fogarty, RN, Study Coordinator,University of Texas Health Science Center atHouston

- Dolores Gonzalez Moron, MD, Study Coordina-tor, Hospital General de Agudos Jose MariaRamos Mejıa

- La June Grayson, Study Coordinator, Washing-ton University in St. Louis

- Samantha Hagopian, RN, Study Coordinator,The Children’s Hospital of Philadelphia

- Emily Hayden, Study Coordinator, University ofMichigan

- Kristin Heggeli, Study Coordinator, Mayo ClinicCollege of Medicine Jacksonville, Florida

- Rachel Hennessy, Study Coordinator, New YorkUniversity School of Medicine

- Jody Hessling, RN, Study Coordinator; Cincin-nati Children’s Hospital Medical Center

- Emily Hirschfield, Study Coordinator, Cincin-nati Children’s Hospital Medical Center

- Jennifer Howell, BA, BS, Study Coordinator, Uni-versity of Alabama at Birmingham School ofMedicine

- Sherry Klingerman, Study Coordinator, MayoClinic College of Medicine Rochester,Minnesota

- Maritza Lopez, RN, Study Coordinator, Univer-sity of California, San Francisco

- Heather Marinelli, Study Coordinator, TheJohns Hopkins University School of Medicine

- Brandy Maschhaupt, Study Coordinator, MayoClinic College of Medicine Scottsdale, Arizona

- Jennie Minnick, Study Coordinator, The Chil-dren’s Hospital of Philadelphia

- Jade Misajon, RN, Study Coordinator, St. Barna-bas Health Care System

- Jennifer Monahan, RN, Study Coordinator,Children’s Hospital of Pittsburgh of Universityof Pittsburgh Medical Center

- Karen Oliver, Study Coordinator, The Universityof Melbourne

- Isha Parulkar, Study Coordinator, Children’sHospital Boston

- Laura Przepiorka, RN, Study Coordinator, RushUniversity Medical Center

- Paula Pyzik, BA, CRT, Study Coordinator, TheJohns Hopkins University School of Medicine

- Brigid Regan, Study Coordinator, The Universityof Melbourne

- Catherine Shain, Study Coordinator, Children’sHospital Boston

- Lexie Slingerland, Study Coordinator, The Uni-versity of Melbourne

- Caitlin Stanton, MPH, Study Coordinator, Seat-tle Children’s Hospital

- Kelly Taylor, MS, CGC, Study Coordinator, Van-derbilt University Medical Center

- Stacy Thompson, RN, BSN, CCRC, Study Coor-dinator, University of Virginia Health System

- Jennifer Turczyk, Study Coordinator, ClevelandClinic

- Alexander Vara, Study Coordinator, Universityof Texas Health Science Center at Houston

- Cindy Wesolowski, RN, NP, Study Coordinator,Cincinnati Children’s Hospital Medical Center

- Andrew Yourich, Study Coordinator, Universityof Alabama at Birmingham School of Medicine

Conflict of interestNone declared.

FundingThis work is supported by National Institute of Neu-rological Diseases and Stroke (NINDS) grant U01





NS053998, as well as planning grants from theFinding a Cure for Epilepsy and Seizures (FACES)Foundation and the Richard Thalheimer Philanthro-pic Fund.

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Clinical Trials // · CLINICAL TRIALS DESIGN Clinical Trials 2013; 10: 568–586 The Epilepsy...

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