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The Marshfield Clinic Personalized Medicine Research Project: 2008 scientific update and lessons learned in the first 6 years
Catherine A McCarty1†, Peggy Peissig2, Michael D Caldwell3 & Russell A Wilke4,5,6†Author for correspondence1Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 N Oak Avenue (ML1), Marshfield, WI 54449, USATel.: +1 715 389 3120;Fax: +1 715 389 4950;E-mail: [email protected] Informatics Research Center, Marshfield Clinic Research Foundation, 1000 N Oak Avenue (ML1), Marshfield, WI 54449, USA3Department of Surgery, Marshfield Clinic, 1000 N Oak Avenue (ML1), Marshfield, WI 54449, USA4Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee,WI, USA5Department of Pharmacology and Toxicology, Medical College of Wisconsin, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee,WI, USA6Human and Molecular Genetics Center, Medical College of Wisconsin, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee,WI, USA
part of
Keywords: biobank, genetic epidemiology, methods, pharmacogenetics
10.2217/17410541.5.5.529 © 2
The Marshfield Clinic Personalized Medicine Research Project is the largest population-based biobank in the USA, with the ability to recontact subjects to obtain additional information to facilitate gene–environment studies. Nearly 20,000 adults have enrolled in the Personalized Medicine Research Project since 2001, after providing active written consent to access their Marshfield Clinic medical records to define phenotype and providing blood samples from which DNA, plasma and serum samples were stored. Numerous studies are underway in the area of pharmacogenetics and genetic epidemiology. In addition to the scientific discoveries being made, much has been learned regarding biobanking and the management of large amounts of data being generated. The purpose of this paper is to share the advice provided by the external Scientific Advisory Board and the scientific lessons learned along the way to build this research infrastructure and facilitate its use.
The Marshfield Clinic Personalized MedicineResearch Project (PMRP) was launched, alongwith other international biobanking efforts, in2002 [1]. This was followed by a Grand Chal-lenge issued in 2003 by Francis Collins and hiscolleagues from the National Human GenomeResearch Institute (MD, USA) to ‘developrobust strategies for identifying the genetic con-tributions to disease and drug response’ [2]. Inthis visionary paper, Collins et al. mentionedthe PMRP and two other large biobanks as lon-gitudinal population-based cohort studies thatcould help to address this Grand Challenge.
The ultimate goal of the PMRP is totranslate genetic data into specific knowledgeabout disease that is clinically relevant and willenhance patient care, with the short-term goalof establishing a database to allow research ingenetic epidemiology, pharmacogenetics andpopulation genetics. The PMRP is a biobankwith DNA, plasma and serum samples andaccess to the Marshfield Clinic medical recordsof nearly 20,000 actively consented adults aged18 years and older. Details about the studymethodology have been published previously [3].The purpose of the current review is to providea scientific update on the PMRP after 6 years ofenrollment, to provide information regardingprojects currently using the PMRP database,and to survey some of the lessons learnedduring the establishment of this biobank forstudies involving genetic epidemiologyand pharmacogenetics.
Scientific Advisory BoardA tremendous amount of effort was invested inthe preparation of the PMRP biobank, longbefore its activation in 2002. The details of ourefforts have been presented previously withinPersonalized Medicine, within the specific con-text of discussing infrastructure development(Scientific Advisory Board [SAB], CommunityAdvisory Group, and the Ethics and SecurityAdvisory Board) [3]. The SAB met twice priorto the launch of the PMRP in September2002, and once again 15 months after enroll-ment had commenced. Tables 1–3 summarizethe recommendations made by the SAB attheir three meetings and the actions taken.Funding to support the SAB ran out before thecohort was large enough to undertake studiesusing the biobank.
Oversight committeePartly in response to the advice of the SAB that acommittee be formed to review and approveapplications to use the biobank, Tissue AccessGuidelines and an Oversight Committee werewritten and formed. The Tissue Access Guide-lines are available on the PMRP website [101]. Inbrief, in addition to Marshfield Clinic Institu-tional Review Board approval, scientific meritand approval by the Oversight Committee isrequired for the release of samples from thebiobank. Where external scientific merit has notbeen approved through a traditional peer-reviewmechanism, such as the NIH for funding, the
008 Future Medicine Ltd ISSN 1741-0541 Personalized Medicine (2008) 5(5), 529–541 529
SPECIAL REPORT – McCarty, Peissig, Caldwell & Wilke
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Table 1. Recommenactions taken.
Recommendation
Collect the DNA as plan
Include a control popula
Limit yourself to a smallperhaps two to three
Create a process for peothat include the core idedata, how many subjectphenotyping will be und
Consider the warfarin pproof-of-concept study very quickly and demonsufficient resources to th
Identify external collabo
Consider allowing de-idoff site for genotyping
PMRP: Personalized Medic
Research Committee at the Marshfield Clinicwill review research proposals. The compositionof the Oversight Committee is as follows:
• Director of Medical Research, Chair ofOversight Committee
• Principal Investigator of the PMRP• Department Chair of Medical Genetics• Director of the Center for Human Genetics• Director of the Marshfield Clinic Laboratories,
or his/her designee• Director of Informatics and Decision Support• One or two members from the University of
Wisconsin, Madison (WI, USA), ideally onewith expertise in statistical genetics
The Director of Medical Research has discre-tion to add additional ad hoc, permanent or ex-officio members as necessary. The OversightCommittee meets monthly to review applica-tions to use the biobank and to prioritize infra-structure projects, such as the many informationsystems projects to facilitate access and qualityassurance for the three specimen types. They donot assess scientific merit; rather, they considerissues such as the amount of sample remainingand the quantity of sample requested for a study.
Requests to the Oversight Committee toaccess PMRP samples are submitted and trackedonline. Laboratory staff do not release samplesuntil all approvals have been documented,
including a Material Transfer Agreement if nec-essary. The legal department at the MarshfieldClinic developed a template for Material Trans-fer Agreements involving PMRP samples tospeed up the approval process.
So far, no requests to access the plasma orserum samples have been reviewed by the Over-sight Committee. We anticipate that the deci-sions surrounding the release of those specimensmay be more challenging, given the smallerquantity and the lack of an equivalent technol-ogy to whole-genome amplification to allowpreservation of the original sample.
Sample trackingA significant challenge for the PMRP was theability to manage the collection and tracking ofbiological samples. The PMRP uses MarshfieldClinic’s practice management and laboratoryinformation systems (LIS) for subject recruit-ment and DNA, plasma and serum sample col-lection. The initial decision to use these systemswas based on cost and the length of time itwould take to implement another informationsystem to support the recruiting and sample col-lection efforts. The LIS was not designed to linkmultiple samples together for an individual or totrack the location of an individual’s geneticmaterial within the freezer or elsewhere, afterseveral generations of plating. In addition,
dations from the first Scientific Advisory Board meeting, held in November 2001, and
Actions taken
ned Recruitment commenced in September 2001
tion Cohort is population-based, allowing for case–control or case–cohort designs
number of focused studies, Initially, the warfarin pharmacogenetics study was the only study being undertaken
ple to develop project proposals as about hypothesis, preliminary s, study power, and how the ertaken, in 3–5 pages
The Research Foundation already has a process to review studies for scientific merit. We are looking to streamline the process for PMRP studies where institutional funding is not requested
harmacogenetics study as a where you could have results strate the success if you assign e project
The warfarin pharmacogenetics study became the main study undertaken. To speed the process, recruitment was performed outside the biobank because the biobank was conducting general population recruitment
rators – academic versus industry The decision was made to concentrate on academic partnerships initially, in part because of a negative (although not universal) reaction from the Community Advisory Group to discussion regarding potential collaboration with industry
entified DNA samples to be sent The written informed consent document allows for sharing of samples and data. Sharing of both data and samples has already occurred
ine Research Project.
Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
future science groupfuture science group
Table 2. Recommenactions taken.
Recommendation
Publish a paper in a peecharacteristics of the popower of the populationdid not slow the time to
Expand on the collection
Proceed with clinical stustudy within 6 months
Consider alliances with collections of SNPs/hapl
Continue diligence in sefor genotyping
Consider how in-house
quality information for each sample was storedin another unrelated database and needed to bemerged into a single system for efficient speci-men management. Owing to these limitations,the PMRP evaluated options to either modifythe existing LIS for biospecimen management orpurchase a commercial system. At an early stage,focus was directed at evaluating commercial bio-specimen tracking systems because the internalsoftware development resources were limited.Four commercial systems were evaluated, with afinal selection of the Nautilus® biospecimentracking system (Thermo Fischer, PA, USA).The Nautilus product offered a complete speci-men tracking system with many out-of-the-boxcustomizable features and integration tools thatwould allow PMRP software developers to cus-tomize user interfaces and interface to Marsh-field Clinic information systems. The laboratorytechnicians found the Nautilus user interfaceeasy to follow and felt that the solution met thefunctionality requested. The PMRP laboratoryand informatics teams are currently redesigningmany workflow processes and integrating Nauti-lus to promote efficient specimen handling forPMRP and other research activities.
Informatics has been a critical part of thePMRP since its infancy. One of the basic goalsof this project was to use both genetic sequencedata and existing clinical data to accelerate thestudy of diseases. To this end, PMRP capitalizes
on the use of Marshfield’s in-house developedCattail’s Software Suite to provide most of theclinical data for this effort. Data from the Cat-tails Suite are deposited into a centralized datarepository, where they are used for the ongoingclinical care of patients. Data from the central-ized data repository are transferred nightly toMarshfield Clinic’s data warehouse, where thedata are cleansed and integrated into the exist-ing data warehouse structure. Prior to addingdata sources to the data warehouse, the datasource is modeled and then integrated into theenterprise data model. This enables the datawarehouse development team to standardizenames, data types and variable definitions. Thedata are also grouped into logical subject areasthat are understandable to the users of the data.Internally developed applications and commer-cial bioinformatics tools provide access to thedata for a variety of clinical and business users.Figure 1 denotes the strategy used to develop thedata warehouse. Within the data warehouse,patient data from as early as 1960 are availableelectronically and linked together by a uniquepatient identifier. The data carry a time stampso historical profiles of clinical activity can bedeveloped for each PMRP participant. Datafrom the data warehouse are used for PMRPstudies and enable scientists to accurately iden-tify and categorize patient’s phenotypes forresearch studies.
dations from the second Scientific Advisory Board meeting, held in April 2002, and
Actions taken
r-reviewed journal defining the pulation and demonstrating the , incorporating genetic data if it publication
Two papers were published, one in 2005 [3] and one in 2007 [18], describing the biobank and available data
of family cohorts Information about relatedness is collected on the enrollment questionnaire. The decision was made not to recruit families specifically but to build a population-based biobank for association studies
dies; complete the warfarin The initial paper from this study was published in 2004 [27]; it was delayed, in part, by recruitment difficulties in the clinic. The prospective clinical study commenced immediately after the retrospective study was completed, with results published in 2005 [29]
other entities to obtain otypes and software for analysis
Collaborations have been initiated with scientists at the University of Wisconsin (WI, USA), with support from the Clinical and Translational Science Award, and with scientists at Vanderbilt University (TN, USA)
eking appropriate methods Genotyping technologies are continually assessed. In the context of multicenter studies, whole-genome association genotyping is being conducted at core laboratory facilities. Candidate-gene studies in-house are completed on the Sequenom® platform
SNP discovery will be undertaken This has not been undertaken due to limited staff and the decision to prioritize the development of the phenotypic infrastructure
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SPECIAL REPORT – McCarty, Peissig, Caldwell & Wilke
532
Table 3. Recommenactions taken.
Recommendation
Have a narrow focus onwith more depth
Define an overall conceppriorities. Consider hirin
Develop more external c
Decide on the relative bthe PMRP as a national activity at Marshfield. If resource, more details abe available
The SAB should meet mtwice per year
PMRP: Personalized Medic
Personalized Medicine Research Project par-ticipants are asked to supply information ontheir health habits, environment, family historyand parent–sibling–child relationships. Thesedata reside in the data warehouse and are therebyuseful for PMRP studies. The InstitutionalReview Board and PMRP Oversight Committeeprovide approval for the use of these data. Datasecurity controls have also been developed toensure use of these data for PMRP studies onlyunless appropriate approval has been granted foradditional use.
Figure 2 denotes three distinct sources of dataused by the PMRP. The data within this figureflow from left to right into the PersonalizedMedicine Research Database (PMRD). The clin-ical data flow was described previously in thedata warehouse discussion. Clinical data consist-ing of diagnoses, laboratory values, procedures,insurance claims, clinical registry, billing andmedications data, found within the data ware-house, are used to phenotype PMRP subjects.Once a study population (and associated studydata) are identified and validated, data analysisvariables are packaged and sent to an encryptionprocess prior to being merged with the geneticdata located in the PMRD.
Personalized Medicine Research Project datarepresent a second data flow (shown in green inFigure 2). The movement of these data is similar
to the clinical data flow, except that the data arecollected as part of the PMRP. These datainclude information on a subject’s environment,health habits, pedigree and family history. ThePMRP data can either be packaged with the clin-ical data or packaged separately before sending tothe encryption process.
When genetic samples are genotyped, thegenetic data are deposited directly into thePMRD. A map between the genetic data sampleidentification number and the patient’sencrypted identification number is kept so thatall types of data can be combined for analysis.The PMRD has dramatically expanded in sizesince inception, and genotype data storage esti-mates are expected to exceed 10 terabytes overthe next 2 years. The current database and datastorage architecture will not support the esti-mated growth, thus the PMRP informatics teamis evaluating options for future system growth.
Study infrastructure & additional dataManolio and Collins of the National HumanGenome Research Institute discussed the com-plexity of studying the interaction of genes andenvironment in health and disease [4]. Limitedpersonal exposure information was collected onthe original PMRP enrollment questionnaire(smoking and alcohol use primarily), in part toencourage a high participation rate, leaving the
dations from the third Scientific Advisory Board meeting, held in November 2003, and
Actions taken
a smaller set of projects After initiating three internal studies initially, the decision was made to further encourage external collaborations and use of the database, thus the number and scope of projects increased
t, vision and well-defined g a Scientific Director
The overall goal of the PMRP is to translate genetic data into specific knowledge regarding disease that is clinically relevant and will enhance patient care, with a short-term goal to establish a database to allow research in genetic epidemiology, pharmacogenetics and population genetics. Funding limitations have precluded the hiring of a full-time Scientific Director, but the Oversight Committee fulfills this role
ollaborations Members of the Pharmacogenetics Research Network were invited to Marshfield in July 2006 to learn more about the PMRP. This visit resulted in the establishment of several collaborations, as mentioned in Tables 5 & 6. The Clinical and Translational Science Award is helping to facilitate increased collaboration with scientists at the University of Wisconsin (WI, USA)
alance between creating resource versus a research it is going to be a national bout data sharing need to
The decision was made to further encourage external collaborators, in part to realize the potential of the resource for genetic discovery. Guidelines for access are available on the PMRP website [101]
ore regularly, perhaps The grant that supported the SAB meetings ended, so additional meetings could not be held
ine Research Project; SAB: Scientific Advisory Board.
Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
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Figure 1. The Marsh
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possibility of recontact open through the writ-ten informed consent document. Given thatdietary intake and physical activity are relatedto so many health outcomes, the strategic deci-sion was made to retrospectively collect the dataon enrolled subjects and to add the data collec-tion prospectively with new enrollment. Marsh-field Clinic is a partner with the University ofWisconsin in their Clinical and TranslationalScience Award and Institute for Clinical andTranslational Research [102], and this collectionof dietary intake and physical activity data wasa major infrastructure project in years 1 and 2of Clinical and Translational Science Award toincrease the value of PMRP as a researchresource for gene–environment studies. TheMarshfield Clinic Institutional Review Boardreviewed and approved the protocol.
Dietary intakeConsideration of several dietary assessment toolswas undertaken. The gold standard, weighedfood records, were deemed to be impractical dueto the respondent burden and expense to quan-tify nutrient intake from the records. The 24-h
recalls were also considered to be too burden-some to subjects and staff. Food frequency ques-tionnaires (FFQs) are widely used to assessdietary intake in epidemiologic studies becausethey are more representative of usual intake andless expensive to implement than other method-ologies, including weighed food records and24-h dietary recalls, as they are usually self-administered [5,6]. The selected FFQ for thePMRP, the Diet History Questionnaire (DHQ)[103], was developed by researchers at theNational Cancer Institute and has been shown tobe superior to the commonly used Willett FFQand similar to the Block FFQ for estimatingabsolute nutrient intakes [7–13]. The DHQ com-prises 124 separate food items and asks aboutportion sizes for most foods. In addition, thereare ten questions regarding nutrient supplementintake. The DHQ is printed and scanned byOptimum Solutions (CA, USA). After scanning,the data from the questionnaires will be stored inASCII format and uploaded into the nutrientanalysis software package. Diet*Calc software,available from the NIH, will be used for thenutrient analyses of the DHQ data [104].
field Clinic data warehouse.
from Marshfield Clinic. © 2000.
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Personalized Medicine, © Future Science Group Ltd (2008)
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SPECIAL REPORT – McCarty, Peissig, Caldwell & Wilke
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534 Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
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Table 4. Comparison
Nutrient
Total energy (kcal)
Fat (%kcal)
Saturated fat (%kcal)
Protein (%kcal)
Carbohydrate (%kcal)
Calcium (mg)
Dietary fiber (g)
Iron (mg)
Vitamin A (µg)
Vegetable servings
Dairy servings
Grain servings
Quantification of physical activityAs with measurement of dietary intake for epide-miologic studies, there are a number of differentvalidated tools that have been used to measurephysical activity in previous studies. The agree-ment between physical activity questionnaire andgold standard tends to be somewhat lower thanfor dietary intake, but is reasonable for rankingrelative activity levels in groups. We have chosento use a previously developed physical activityassessment tool to allow comparison with resultsfrom other study populations. Requirements ofthe selected tool for the current study included:
• Self-administered
• Previously validated
• Validated for use in a similar study populationacross a range of ages
The selected physical activity questionnaire, theBaecke questionnaire, is self-administered, vali-dated for use in both men and women, and cur-rently being used in a large, prospective study inthe USA [14–17]. The questionnaire has been shownto have high reliability (coefficients ranging from0.74 to 0.88) and accurate assessment of bothhigh-intensity activity and light-intensity activity,such as walking. It comprises 16 questions andgenerates three indices of activity: a work index, asport index and a leisure-time index.
The initial selection of PMRP subjects fromwhich to obtain the DHQ and physical activitydata included people with a BMI of 40 or overand two age- and sex-matched subjects with aBMI under 25 per obese subject. Two mailingsand a follow-up telephone call led to a 65%response rate (n = 2103 completed question-naires) in subjects who could be contacted. Sum-
mary DHQ data are presented in Table 4.Although average total daily caloric intake was notsignificantly different between the two groups, thedata reveal significant differences in many of theother specific nutrient and food categoriesbetween obese and healthy weight subjects. Fol-low-up with the rest of the PMRP cohort toobtain these data is anticipated to be completedby the end of 2008.
The DHQ and physical activity question-naires have been added prospectively for all newsubjects being enrolled into PMRP. Subjects aregiven the questionnaires and asked to completethem and return them in stamped, self-addressedenvelopes. With no further reminders, theresponse rate for prospective collection has been74%, thus demonstrating the efficiency ofcollecting information at the time of enrollment.
Genetic association studiesThe following sections outline the studies thatare currently accessing the PMRP biobank underthe categories of pharmacogenetics and geneticepidemiology. Although the PMRP was alsodesigned to support studies of population genet-ics, to date there are no projects in this area. Inaddition to summarizing the study objectives, wehave included infrastructure lessons learnedthrough these studies. Results appear in separatepeer-reviewed publications, as well as the PMRPstudy newsletters available on the PMRPwebsite [101]. As suggested by the SAB in theirearly meetings, scientific discoveries using thePMRP have been enhanced through externalcollaborations, with a number of collaborationswith members of the Pharmacogenetics ResearchNetwork [105].
of daily dietary intake between healthy weight (BMI <25) and obese (BMI ≥40) subjects.
Median (5th percentile, 95th percentile) p-value
Healthy weight, n = 1249 Obese, n = 529
1654 (815, 3749) 1711 (764, 3827) 0.23
32.0 (19.9, 42.9) 33.7 (21.8, 44.8) <0.001
10.7 (6.0, 16.7) 11.4 (7.1, 17.0) <0.001
15.5 (10.6, 20.3) 16.7 (11.1, 21.4) <0.001
52.2 (38.2, 67.5) 49.8 (37.0, 65.0) <0.001
844.7 (295.6, 2059.4) 819.8 (283.7, 2086.1) 0.35
16.4 (6.7, 37.8) 16.1 (6.0, 38.8) 0.54
13.3 (5.9, 28.5) 13.2 (5.8, 29.1) 0.73
759.5 (272.4, 1820.7) 764.5 (287.1, 1910.7) 0.01
3.2 (1.1, 8.9) 3.5 (1.0, 10.1) 0.01
1.6 (0.3, 5.4) 1.5 (0.3, 5.3) 0.18
4.0 (1.6, 9.7) 4.1 (1.5, 10.5) 0.56
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SPECIAL REPORT – McCarty, Peissig, Caldwell & Wilke
Table
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resi
dent
s. A
noth
er le
sson
lear
ned
with
thi
s pr
ojec
t, t
he f
irst
to g
enot
ype
PMRP
sam
ples
, was
the
nee
d fo
r m
ore
qual
ity a
ssur
ance
as
the
sam
ples
are
pro
cess
ed. O
ne e
rror
in t
he s
ex
mar
kers
was
iden
tifie
d in
thi
s st
udy
of 4
50 s
ubje
cts,
and
hig
hlig
hted
th
e ne
ed to
dev
elop
a m
olec
ular
fing
erpr
int t
o id
entif
y th
e sa
mpl
es. T
he
resu
lts o
f th
is p
roje
ct w
ill b
e re
port
ed s
epar
atel
y. A
noth
er le
sson
le
arne
d in
this
pro
ject
was
the
amou
nt o
f tim
e ne
cess
ary
to c
hara
cter
ize
drug
exp
osur
e fr
om t
he m
inin
g of
ele
ctro
nic
note
s fo
r in
dica
tion
of
drug
use
. Fin
ally
, we
disc
over
ed t
hat
the
smok
ing
ques
tions
in t
he
orig
inal
PM
RP q
uest
ionn
aire
did
not
allo
w f
or t
he c
alcu
latio
n of
pac
k ye
ars
beca
use
they
did
not
incl
ude
a qu
estio
n ab
out
how
long
sub
ject
s ha
d sm
oked
. Sub
sequ
ently
, pos
tcar
ds w
ere
mai
led
to th
e ne
arly
10,
000
PMRP
sub
ject
s w
ho r
epor
ted
that
the
y ha
d ev
er s
mok
ed c
igar
ette
s to
co
llect
info
rmat
ion
abou
t du
ratio
n of
sm
okin
g.
In p
repa
ratio
n
FMS
To s
tudy
a c
andi
date
gen
e fo
r FM
S an
d qu
antif
y ge
ne–e
nviro
nmen
t in
tera
ctio
n w
ith c
igar
ette
sm
okin
g, m
otor
veh
icle
ac
cide
nts
and
othe
r tr
aum
a
Non
eIn
itial
fea
sibi
lity
estim
ates
ove
rest
imat
ed t
he n
umbe
r of
FM
S ca
ses
in
the
PMRP
coh
ort
whe
n ap
plyi
ng s
tric
t di
agno
stic
crit
eria
. The
pro
ject
tim
elin
e w
as a
ltere
d to
allo
w f
or t
arge
ted
recr
uitm
ent
of F
MS
subj
ects
fr
om z
ip c
odes
oth
er t
han
the
orig
inal
19
zip
code
s se
lect
ed f
or
PMRP
enro
llmen
t
In p
repa
ratio
n
Ost
eopo
rosi
sTo
iden
tify
cand
idat
e ge
nes
for
oste
opor
osis
and
to
quan
tify
pote
ntia
l ge
ne–e
nviro
nmen
t in
tera
ctio
ns w
ith
ciga
rett
e sm
okin
g an
d st
atin
use
PGRN
col
leag
ues
Man
y w
omen
had
not
und
ergo
ne B
MD
tes
ting
to c
onfir
m c
ontr
ol
stat
us. A
n ar
ticle
was
writ
ten
for
the
twic
e-ye
arly
PM
RP n
ewsl
ette
r de
scrib
ing
the
stud
y an
d in
form
ing
wom
en o
f sc
reen
ing
guid
elin
es
rela
ted
to B
MD
tes
ting
in w
omen
age
d 50
year
s an
d ol
der
In p
repa
ratio
n
AD
: Alz
hei
mer
’s D
isea
se; B
MD
: Bo
ne
min
eral
den
sity
; CA
D: C
oro
nar
y ar
tery
dis
ease
; FM
S: F
ibro
mya
lgia
syn
dro
me;
GW
AS:
Gen
om
e-w
ide
asso
ciat
ion
stu
die
s; H
DL:
Hig
h-d
ensi
ty li
po
pro
tein
; M
I:M
yoca
rdia
l in
farc
tio
n; P
MR
P:Pe
rso
nal
ized
Med
icin
e R
esea
rch
Pro
ject
.
536 Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
CA
DTo
ser
ve a
s a
repl
icat
ion
coho
rt f
or
GW
AS
to id
entif
y m
arke
rs a
ssoc
iate
d w
ith C
AD
Med
ical
Col
lege
of
Wis
cons
inC
hang
es in
the
rea
ding
of
caro
tid u
ltras
onog
raph
y ov
er t
ime
nece
ssita
te m
anua
l rev
iew
of
char
ts t
o cl
assi
fy c
ase–
cont
rol s
tatu
sN
one
yet,
as
the
stud
y w
as o
nly
rece
ntly
fun
ded
Cat
arac
t an
d lo
w H
DL
To d
evel
op e
lect
roni
c al
gorit
hms
for
cata
ract
and
low
HD
L, t
o co
nduc
t co
mm
unity
con
sulta
tion
activ
ities
re
late
d to
dat
a sh
arin
g, a
nd t
o co
nduc
t a
GW
AS
of c
atar
act
and
low
HD
L
Uni
vers
ity o
f W
isco
nsin
(WI,
USA
), M
edic
al
Col
lege
of
Wis
cons
in,
Vand
erbi
lt U
nive
rsity
(T
N,U
SA)
The
amou
nt o
f di
sc s
pace
to
stor
e an
d m
anag
e da
ta f
rom
GW
AS
is
subs
tant
ial.
Alth
ough
the
PMRP
con
sent
form
allo
ws
for d
ata
shar
ing,
it
need
s to
be
mor
e ex
plic
it ab
out
the
data
-sha
ring
requ
irem
ents
of
GW
AS
fund
ed b
y th
e N
IH
Com
mun
ity
cons
ulta
tion
man
uscr
ipt
unde
r re
view
Dys
lipid
emia
in
sev
erel
y ob
ese
subj
ects
To s
tudy
can
dida
te g
enes
ass
ocia
ted
with
dia
bete
s an
d dy
slip
idem
ia in
su
bjec
ts w
ith a
BM
I of
40+
and
iden
tify
pote
ntia
l gen
e–en
viro
nmen
t in
tera
ctio
ns w
ith d
iet
and
activ
ity
Med
ical
Col
lege
of
Wis
cons
inA
sta
ndar
d te
mpl
ate
for
Mat
eria
l Tra
nsfe
r A
gree
men
ts s
peed
s th
e le
gal
proc
ess
to a
llow
the
shi
pmen
t of
sam
ples
to
othe
r la
bora
torie
s fo
r ge
noty
ping
Non
e ye
t, a
s th
e pr
ojec
t ha
s on
ly r
ecen
tly
been
initi
ated
Hyp
erte
nsiv
e he
art
dise
ase
To id
entif
y ca
ndid
ate
mar
kers
in t
he
vita
min
D p
athw
ay t
hat
incr
ease
ris
k fo
rhy
pert
ensi
on a
nd h
yper
tens
ive
hear
tdi
seas
e
Uni
vers
ity o
f M
ichi
gan
(MI,
USA
)
Repl
icat
ion
of f
indi
ngs
from
ani
mal
mod
els
is a
sou
nd s
trat
egy
In p
repa
ratio
n
Myo
card
ial i
nfar
ctio
nTo
rep
licat
e tw
o SN
Ps o
n 9p
21
iden
tifie
d in
GW
AS
for
MI [
21] i
n th
e co
ntex
t of
kno
wn
clin
ical
cov
aria
tes,
in
clud
ing
age,
sex
, sm
okin
g, p
hysi
cal
activ
ity, d
iabe
tes,
BM
I, fa
mily
his
tory
of
MI,
and
hype
rten
sion
Med
ical
Col
lege
of
Wis
cons
in,
Uni
vers
ity o
f W
isco
nsin
The
first
stu
dy t
o us
e al
l 20,
000
PMRP
sam
ples
, thi
s st
udy
bene
fited
fr
om a
mas
ter
plat
ing
proj
ect
that
sig
nific
antly
red
uced
the
tim
e to
cr
eate
pla
tes
to s
hip
off
site
for
gen
otyp
ing
Non
e ye
t, a
s th
e pr
ojec
t w
as o
nly
rece
ntly
initi
ated
Tab
le 5
. Gen
etic
ep
idem
iolo
gy
stu
die
s u
sin
g t
he
Pers
on
aliz
ed M
edic
ine
Res
earc
h P
roje
ct b
iob
ank,
less
on
s le
arn
ed a
nd
res
ult
ing
pu
blic
atio
ns
(co
nt.
).
Stu
dy
Purp
ose
Exte
rnal
co
llab
ora
tio
ns
Less
on
s le
arn
edPu
blic
atio
ns
AD
: Alz
hei
mer
’s D
isea
se; B
MD
: Bo
ne
min
eral
den
sity
; CA
D: C
oro
nar
y ar
tery
dis
ease
; FM
S: F
ibro
mya
lgia
syn
dro
me;
GW
AS:
Gen
om
e-w
ide
asso
ciat
ion
stu
die
s; H
DL:
Hig
h-d
ensi
ty li
po
pro
tein
; M
I:M
yoca
rdia
l in
farc
tio
n; P
MR
P:Pe
rso
nal
ized
Med
icin
e R
esea
rch
Pro
ject
.
537future science groupfuture science group www.futuremedicine.com
SPECIAL REPORT – McCarty, Peissig, Caldwell & Wilke
Table
6. P
har
mac
og
enet
ic s
tud
ies
usi
ng
th
e PM
RP
bio
ban
k, le
sso
ns
lear
ned
an
d r
esu
ltin
g p
ub
licat
ion
s.
Stu
dy
Purp
ose
Exte
rnal
co
llab
ora
tio
ns
Less
on
s le
arn
edPu
blic
atio
ns
Topi
cal β
-blo
cker
s fo
r gl
auco
ma
To id
entif
y ca
ndid
ate
mar
kers
th
at p
redi
ct a
20%
or g
reat
er
drop
in in
trao
cula
r pr
essu
re
Med
ical
Col
lege
of
Wis
cons
in (W
I, U
SA)
Con
serv
ativ
e de
finiti
ons
for
win
dow
s of
fol
low
-up
data
cre
ate
hom
ogen
ous
data
sets
, whi
le d
ecre
asin
g sa
mpl
e si
ze[2
2–24
]
Stat
in e
ffic
acy
To id
entif
y ge
netic
mar
kers
of
LD
L re
spon
se t
o at
orva
stat
in
Phar
mac
ogen
etic
s Re
sear
ch N
etw
ork
colle
ague
s (C
hild
ren’
s H
ospi
tal
Oak
land
Res
earc
h In
stitu
te, C
A, U
SA)
Allo
w a
dditi
onal
tim
e fo
r M
TAs
that
nee
d to
be
revi
ewed
and
app
rove
d by
m
ultip
le in
stitu
tions
. Mas
ter
DN
A p
late
s dr
amat
ical
ly d
ecre
ase
the
amou
nt
of t
ime
nece
ssar
y to
iden
tify
and
plat
e D
NA
sam
ples
for
gen
otyp
ing
[25,
26]
Met
form
in
for
diab
etes
To e
valu
ate
cand
idat
e m
arke
rs f
or H
bA1c
res
pons
e to
met
form
in in
Cau
casi
ans
from
PM
RP a
nd
Afr
ican
–Am
eric
ans
from
K
aise
r G
eorg
ia (G
A, U
SA)
Phar
mac
ogen
etic
s Re
sear
ch N
etw
ork
(Uni
vers
ity o
f C
alifo
rnia
, San
Fr
anci
sco,
CA
, USA
), K
aise
r G
eorg
ia
As
the
PMRP
is 9
8% C
auca
sian
, col
labo
ratio
n w
ith o
ther
gro
ups
is e
ssen
tial
to a
llow
rep
licat
ion
of f
indi
ngs
in o
ther
rac
e/et
hnic
gro
ups
War
farin
To id
entif
y pr
edic
tors
of
stab
le w
arfa
rin d
ose
and
deve
lop
a do
sing
cal
cula
tor
to in
clud
e al
l kno
wn
mod
ifier
s of
sta
ble
dose
Phar
mac
ogen
etic
s Re
sear
ch N
etw
ork
(Uni
vers
ity o
f Flo
rida,
FL
, USA
), In
tern
atio
nal
War
farin
Con
sort
ium
As
reco
mm
ende
d by
the
SA
B, t
his
was
the
firs
t st
udy
to s
how
case
the
po
tent
ial o
f th
e M
arsh
field
bio
bank
and
to
deve
lop
man
y ex
tern
al
colla
bora
tions
, inc
ludi
ng o
ne to
iden
tify
new
com
poun
ds f
or c
linic
al t
estin
g.
Thes
e st
udie
s ha
ve le
d to
sev
eral
pee
r-re
view
ed p
ublic
atio
ns, t
he d
isco
very
of
a n
ew g
enet
ic a
ssoc
iatio
n w
ith w
arfa
rin s
tabl
e th
erap
eutic
dos
e, f
undi
ng
from
the
Age
ncy
for
Hea
lthca
re R
esea
rch
and
Qua
lity
to p
rosp
ectiv
ely
eval
uate
the
eff
icac
y of
gen
e-ba
sed
pres
crib
ing
for
war
farin
, and
the
de
velo
pmen
t of
the
IWPC
, an
inte
rnat
iona
l con
sort
ium
agg
rega
ting
6000
patie
nt’s
data
to
stud
y w
arfa
rin p
harm
acog
enet
ics.
The
dat
a fr
om t
he
IWPC
will
be
plac
ed in
the
pub
lic d
omai
n th
roug
h th
e Ph
arm
GK
B w
ebsi
te[1
09] i
n la
te20
08
[27–
31]
Tam
oxife
n in
br
east
can
cer
To id
entif
y m
aker
s fo
r re
spon
se a
nd a
dver
se
reac
tions
(dee
p-ve
in
thro
mbo
sis)
to
tam
oxife
n fo
r br
east
can
cer
Phar
mac
ogen
etic
s Re
sear
ch N
etw
ork
(Indi
ana
Uni
vers
ity,
IN, U
SA),
Med
ical
C
olle
ge o
f W
isco
nsin
A s
tand
ard
tem
plat
e M
TA s
peed
s th
e le
gal p
roce
ssU
nder
rev
iew
Stat
in m
yoto
xici
ty
and
rhab
dom
yoly
sis
To id
entif
y ge
netic
mar
kers
th
at p
redi
ct t
he m
ost
com
mon
tox
icity
for
one
of
the
mos
t co
mm
only
pr
escr
ibed
dru
gs in
the
wor
ld
Phar
mac
ogen
etic
s Re
sear
ch N
etw
ork
(Chi
ldre
n’s
Hos
pita
l O
akla
nd R
esea
rch
Inst
itute
), M
edic
al
Col
lege
of
Wis
cons
in
Stat
in m
yoto
xici
ty is
ver
y di
ffic
ult
to p
heno
type
usi
ng m
edic
al r
ecor
ds
beca
use
the
docu
men
tatio
n of
pai
n sy
mpt
oms
is n
ot s
tand
ard
[32,
33]
IWPC
: In
tern
atio
nal
War
fari
n P
har
mac
og
enet
ic C
on
sort
ium
; LD
L: L
ow
-den
sity
lip
op
rote
in; M
TA: M
ater
ial T
ran
sfer
Ag
reem
ents
; PM
RP:
Per
son
aliz
ed M
edic
ine
Res
earc
h P
roje
ct; S
AB
: Sci
enti
fic
Ad
viso
ry B
oar
d.
538 Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
future science groupfuture science group
Genetic epidemiologyIn addition to standard case–control studies ofdisease onset, the PMRP is ideally suited to thestudy of risk factors for disease progression,because over 20 years of medical history infor-mation is available for approximately 75% of thecohort [18]. Table 5 summarizes the genetic epide-miology studies using the PMRP database andthe many lessons learned.
Pharmacogenetic studies Prior to the implementation of electronic pre-scribing and a paperless environment in 2007,mention of medication use in the text was cap-tured through natural language processing and isavailable back to 1993. These resources haveallowed the initiation of many pharmacogeneticstudies, several of which are in collaborationwith colleagues in the PharmacogeneticsResearch Network [105]. As with genetic epidemi-ology, many lessons have been learned to increaseefficiency and accuracy (Table 6).
ConclusionIn summary, much has been learned since thePMRP was launched in 2002, and many discov-ery projects are underway. With each new studyundertaken, it is important to revisit proceduresto be sure that they keep pace with genetic andstatistical tools that are being developed andrefined. We have found that it is far more efficientto collect personal exposure and environmentaldata at the time that people are enrolled into thebiobank and to conduct quality assurance on thesamples as they are received. Collaboration hasgreatly enhanced the science, and multidiscipli-nary teams are essential to address the complexissues involved with studying complex diseases. Asnew biobanks are being initiated, the sharing ofmethods and standards will help to facilitatesharing of data for comparison and replication.
Future perspectiveBiobanking Banking of biological materials for research andclinical purposes will likely continue to increaseand will decrease the time between discoveryand clinical translation. Much can be learnedby sharing the success and failures of theseendeavors. The PMRP has been committed tosharing data, and lessons learned, for the widerscientific community.
The current National Human GenomeResearch Institute-funded electronic medicalrecords and genomics (eMERGE) network [106],
of which PMRP is a member, is charged withdeveloping standards to allow for the efficientsharing of data from across the network. TheeMERGE network is a national consortiumformed to develop, disseminate and applyapproaches to research that combine DNAbiorepositories with electronic medical recordsystems for large-scale, high-throughput geneticresearch. Through researching new method-ologies and disseminating the information, thisconsortium will improve the use of bioreposito-ries for genomic research. The five sites fundedincluded Marshfield Clinic, Northwestern Uni-versity (IL, USA), Vanderbilt University (TN,USA), Mayo Clinic (MN, USA) and GroupHealth Cooperative (WA, USA).
Organizations such as the Public PopulationProject in Genomics (P3G) [107] are also seekingto develop best practice for biobanking. P3G is anot-for-profit international consortium to pro-mote collaboration between researchers in thefield of population genomics. It was launched toprovide the international population genomicscommunity with the resources, tools and know-how to facilitate data management for improvedmethods of knowledge transfer and sharing. Itsmain objective is the creation of an open, publicand accessible knowledge database. The motto is‘transparency and collaboration’. All groups ben-efit from the sharing of methodologies and data.
The challenge for all of these groups is toidentify infrastructure funding and to ensuretimely translation of research results.
Translation into personalized healthcareSmall- and large-scale genetic association studiesare moving expert biological knowledge from thebench to the bedside at an unprecedented rate.The Personalized Health Care Initiative from theDepartment of Health and Human Services seeksto “improve the safety, quality and effectiveness ofhealthcare for every patient in the US by usinggenomics … to enable medicine to be tailored toeach person’s needs” [108]. The substrate of func-tional genomics is expanding geometrically, andefficient bioinformatics resources are being devel-oped feverishly in an effort to help scientists andclinicians leverage this knowledge to improvehealthcare. The potential seems unlimited.Genetic risk determinants can be merged withclinical data to predict patient risk, before theonset of disease. This should allow focused earlyintervention for patients at highest risk. Geneticmarkers can also be used for risk stratification oncea particular condition has developed. This should
539www.futuremedicine.com
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540
Executive summary
Scientific Advisory Bo
• The Scientific Advisoryhave been useful to hfunding to support thfrom the Marshfield Cbioinformatics tools n
Oversight Committee
• It is neccessary to devCommittee should hacrucial to the studies.
Sample tracking
• It is neccessary to outdataset that allows fopurchasing a system a
Study infrastructure &
• The collection of persorequired to collect thedata collected should
Genetic association st
• Many lessons have beprocedures to keep p
optimize secondary prevention and reduce theburden of comorbidity being placed upon ourhealthcare infrastructure as the population contin-ues to age. Genetic markers will also be highly use-ful in directing therapy, in the context ofpharmacologic as well as nonpharmacologic inter-vention. For drugs with a narrow therapeuticindex, this has already become a clinical reality.Many antineoplastic agents are prescribed and/ordosed based upon genotype in an effort to reducethe risk of adverse drug reactions, and evidence ismounting that this approach will be beneficial forother drugs, such as anticoagulants. As technologyadvances (e.g., genome-wide association studies),the genetic architecture underlying drug responsewill almost certainly become more fully character-ized for a multitude of therapeutic agents, makingthis prospective gene-based approach to risk reduc-tion and treatment prescription advantageous forall drugs, including those with a relatively widetherapeutic index [19,20]. Proteomics and metabo-lomics will further the usefulness of genomics dis-covery for personalized healthcare. The vastamount of information necessary for discovery anddecision support requires a robust informaticsinfrastructure. A well-designed and -executedbiobank is merely the first step in the path frombasic discoveries to personalized healthcare.
Acknowledgements
The authors acknowledge Dr Laura Coleman and BickolMukesh for their contributions to the analysis of the dietaryintake data.
Financial & competing interests disclosure The research was funded, in part, by grant number 1 D1ARH00025-01 from the Office of Rural Health Policy,Health Resources and Services Administration, from theDepartment of Commerce (WI, USA) and grant number1UL1RR025011 from the Clinical and Translational Sci-ence Award (CTSA) program of the National Center forResearch Resource National Institute of Health. The mem-bers of the PMRP Scientific Advisory Board include: DavidAltshuler, MD, PhD, Massachusetts Institute for Technology(MA, USA), Chair; David Flockhart, MD, PhD, IndianaUniversity (IN, USA); Stephen Liggett, MD, University ofMaryland (MD, USA); Gabor Marth, DSc, Boston College(MA, USA); Jurg Ott, PhD, Rockefeller University (NY,USA); Lenna Peltonen, MD, PhD, Biomedicum Helsinki(Helsinki, Finland); Wendell Weber, MD, PhD, Universityof Michigan (MI, USA). The authors have no other rele-vant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financialconflict with the subject matter or materials discussed in themanuscript apart from those disclosed.
No writing assistance was utilized in the production ofthis manuscript.
ard
Board was very useful in advising on design and strategic issues for growth and development, and it would ave their advice on issues that developed as the biobank grew, such as new technologies. Infrastructure e continued engagement of the Scientific Advisory Board has been difficult to identify. Institutional support linic on an annual basis must be prioritized, and has been used to continue recruitment and to develop the ecessary to access the biobank.
elop the process and procedures to access the biobank and make forms available online. The Oversight ve representation from content experts in the types of samples available, as well as the informatics support
line the computer hardware and software needs to manage an ever-growing genotypic and phenotypic r easy searchability. The advantages and disadvantages of developing the necessary software in-house or nd having it customized as needed must be weighed up.
additional data
nal/environmental exposure data at the time of study enrollment should be considered. Fewer resources are information at the time of enrollment, and the participation will be higher then. However, the amount of
be weighed against the potential for a lower participation rate initially because of respondent burden.
udies
en learned in the conduct of the genetic discovery studies, as outlined in Tables 5 & 6. Constant review of ace with changes in technology is essential.
Personalized Medicine (2008) 5(5) future science groupfuture science group
The Marshfield Clinic Personalized Medicine Research Project – SPECIAL REPORT
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Websites101. Marshfield Clinic Research Foundation
Personalized Medicine Research Projectwww.marshfieldclinic.org/pmrp
102. University of Wisconsin Institute for Clinical and Translational Research www.ictr.wisc.edu
103. US NIH, National Cancer Institute: Risk factor monitoring and methods: diet history questionnaire (2007) http://riskfactor.cancer.gov/DHQ
104. US NIH, National Cancer Institute: Risk factor monitoring and methods: diet history questionnaire: Diet*Calc Software (2007) http://riskfactor.cancer.gov/DHQ/dietcalc
105. US NIH, National Institute of General Medical Sciences: Pharmacogenetics research network (2008) www.nigms.nih.gov/Initiatives/PGRN
106. The eMERGE Network – Electronic Medical Records and Genomics www.gwas.org
•• Public website for the eMERGE network, a consortium of five sites funded by the National Human Genome Research Institute to develop, disseminate and apply approaches to research that combine DNA biorepositories with electronic medical record systems for large-scale, high-throughput genetic research.
107. Pharmacogenetics Research Network www.nigms.nih.gov/Initiatives/PGRN
•• Includes information about the Pharmacogenetics Research Network, which is funded by the NIH. The goal of the network is to discover how the genes that vary among individuals affect drug safety and efficacy.
108. HHS.gov: Personalised Health Care www.dhhs.gov/myhealthcare
•• Released in September 2007, this document outlines opportunities, challenges, pathways and resources to make personalized healthcare a reality through expansion of the science base, health information technology, intervention development and review, and integration into clinical practice.
109. PharmGKB: The Pharmacogenetics and Pharmacogenomics Knowledge Basewww.pharmgkb.org
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