Kerr et al. BMC Medical Genetics 2010, 11:166
http://www.biomedcentral.com/1471-2350/11/166
RESEARCH ARTICLE
Open Access
Generation Scotland: Donor DNA Databank; A
control DNA resource
Shona M Kerr1*, David CM Liewald1, Archie Campbell1, Kerrie Taylor2, Sarah H Wild2, David Newby2,
Marc Turner3, David J Porteous1
Abstract
Background: Many medical disorders of public health importance are complex diseases caused by multiple
genetic, environmental and lifestyle factors. Recent technological advances have made it possible to analyse the
genetic variants that predispose to complex diseases. Reliable detection of these variants requires genome-wide
association studies in sufficiently large numbers of cases and controls. This approach is often hampered by
difficulties in collecting appropriate control samples. The Generation Scotland: Donor DNA Databank (GS:3D) aims
to help solve this problem by providing a resource of control DNA and plasma samples accessible for research.
Methods: GS:3D participants were recruited from volunteer blood donors attending Scottish National Blood
Transfusion Service (SNBTS) clinics across Scotland. All participants gave full written consent for GS:3D to take spare
blood from their normal donation. Participants also supplied demographic data by completing a short
questionnaire.
Results: Over five thousand complete sets of samples, data and consent forms were collected. DNA and plasma
were extracted and stored. The data and samples were unlinked from their original SNBTS identifier number. The
plasma, DNA and demographic data are available for research. New data obtained from analysis of the resource
will be fed back to GS:3D and will be made available to other researchers as appropriate.
Conclusions: Recruitment of blood donors is an efficient and cost-effective way of collecting thousands of control
samples. Because the collection is large, subsets of controls can be selected, based on age range, gender, and
ethnic or geographic origin. The GS:3D resource should reduce time and expense for investigators who would
otherwise have had to recruit their own controls.
Background
This paper describes the collection and initial characterisation of a resource of control DNA and plasma samples accessible for research, the Generation Scotland
Donor DNA Databank (GS:3D). Common conditions
such as cancer, cardiovascular disease, diabetes and
mental illness create a heavy burden of morbidity and
mortality in developed countries and are consequently
of major public health importance [1,2]. These diseases
have a significant heritable component but are difficult
to analyse by traditional genetic techniques because they
typically result from the combined effect of multiple
* Correspondence: shona.kerr@ed.ac.uk
1
Medical Genetics Section, Centre for Molecular Medicine, University of
Edinburgh, Institute of Genetics and Molecular Medicine, Western General
Hospital, Crewe Road, Edinburgh, UK
Full list of author information is available at the end of the article
genetic, lifestyle and environmental factors rather than
from the effect of a single gene [2-4]. The completion of
the Human Genome Project and the availability of costeffective, high-throughput methods for systematically
characterising genome-wide sequence variation have
made it possible to dissect the genetic variants that predispose to complex diseases [2,3]. This is accomplished
through genome-wide association studies in which
genetic variants (such as single nucleotide polymorphisms or copy number variants) are typed across the
whole genome in large numbers of cases and controls. If
a statistically significant increase in the frequency of a
variant is observed in cases compared to controls, the
region of the genome in linkage disequilibrium with the
variant is implicated in disease risk [2,3]. Genome-wide
association studies have already yielded promising
results for a number of common diseases [5,6], with
© 2010 Kerr et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Kerr et al. BMC Medical Genetics 2010, 11:166
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wide-ranging implications for the future of healthcare
including better understanding of disease mechanisms,
more accurate diagnosis, and personalised therapy [2,7].
Nevertheless, reliable detection of disease-associated
genetic variants requires very large sample and data sets
and considerable associated infrastructure [5,7]. Generation Scotland is a multi-institution, cross-disciplinary collaboration which aims to create an ethically sound,
family- and population-based resource for identifying the
genetic basis of common complex diseases [8,9]. One of
Generation Scotland’s resources, the Generation Scotland: Donor DNA Databank (GS:3D), is a collection of
5,000 control DNA and plasma samples taken with full
consent from blood donors across Scotland. This will
help solve the problem of gathering the large numbers of
controls that are essential for the success of case-control
studies. GS:3D has also helped to develop an information
technology infrastructure to support large-scale genetics
research studies, including the implementation of systems to ensure efficient management of data and samples. GS:3D samples, together with non-identifiable
demographic information, will be made available to
researchers under appropriate standards of governance.
The objectives of GS:3D were
1. To recruit and minimally phenotype a cohort of
healthy control participants from across Scotland, facilitating studies aimed at identification of genetic variants
relevant to common complex diseases.
2. To extend a technology platform of informatics in
genetics research, including the creation of user-friendly
databases of study data.
Methods
Recruitment of participants
The steps used to implement the GS:3D protocol are
illustrated schematically in Figure 1. Participants were
recruited through the donor services directorate of the
Scottish National Blood Transfusion Service (SNBTS).
Each donor undergoes a careful assessment to determine their eligibility to donate blood, requiring answers
to a series of standard questions relating to their general
health, lifestyle, past medical history and medication.
They were eligible to participate in GS:3D if they were
not first time donors, were aged between 17 and 70
years, and fulfilled the other clinical criteria for eligibility
of blood donors. Most relevant among these clinical criteria for genetic research of common complex conditions are exclusion if an individual:
(1) has a history of angina, ulcerative colitis or Crohn’s
disease.
(2) is taking anticoagulant medication.
(3) is taking beta blockers to treat cardiovascular
disease.
Page 2 of 9
(4) has had cardiac surgery, a malignancy, a stroke or
transient ischaemic attack.
(5) has ischaemic heart disease, dementia, inflammatory bowel disease, multiple sclerosis, narcolepsy or
active rheumatoid arthritis.
(6) has diabetes insipidus or diabetes mellitus which
requires medication.
(7) requires maintenance treatment for mental health
problems.
Potential donors are also excluded if their haemoglobin levels are below a threshold (125 g/L females,
135 g/L males). Donors must weigh at least 7st 12lb
(50 kg). Blood donors are therefore people in good general health, especially regarding cardiovascular health.
Participants were recruited through the local management of SNBTS Donor Centres in Aberdeen, Dundee,
Edinburgh, Glasgow and Inverness (represented by large
circles in Figure 2). A wide geographic range was
sampled by targeting recruitment to mobile clinics, as
well as the Donor Centres. The study recruited participants at a total of 144 different sites, the locations of
which are illustrated schematically in Figure 2. Where
possible, an additional donor care assistant was provided
for each clinic in which recruitment took place, funded
through the award for the project. Statistics were not
gathered as to the percentage of donors who agreed to
participate in the research, but this proved to be ample
for the requirements of the study, with recruitment
completed within a period of seven months.
Collection and processing of consent forms and
demographic data
Following introduction to the study by means of a publicity poster and leaflet, supplied upon attendance at a
blood donation session, individuals who agreed to consider taking part were given a copy of the Participant
Information Leaflet (PIL), a consent form, and a questionnaire [10]. The consent form was discussed and
completed prior to any sample or phenotypic details
being taken. Participants were informed that they were
free to withdraw from the study during the following 28
days. Participants then returned the completed questionnaire (at which time there was an opportunity to clarify
any matters arising with an SNBTS nurse), and gave
permission for a blood sample to be used for research,
all according to Standard Operating Procedures. Data
were entered by each participant on a paper optical
mark read (OMR) questionnaire, illustrated in Figure 3.
The collection of data aimed to maximise the research
benefit of each individual’s participation while minimising inconvenience to the donor and disruption to the
work of the National Health Service.
The questionnaires and attached consent forms from
each session (up to 30 participants) were posted to the
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Figure 1 GS:3D Schematic. Schematic outline of the GS:3D study methodology.
central research office in Edinburgh. On arrival,
unique research ID labels corresponding to the appropriate paired filter and blood samples (see below) were
added to the questionnaire and consent forms.
Questionnaire data were entered on to a secure database by OMR scanning with a DRS Photoscribe PS900
IM2 scanner, which included a scan of the research
ID barcode.
Kerr et al. BMC Medical Genetics 2010, 11:166
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Figure 2 GS:3D Locations. Map of Scotland showing locations in which participants were recruited to GS:3D. SNBTS Donor Centres in
Inverness, Aberdeen, Dundee, Edinburgh and Glasgow are indicated by large circles and clinics under the management of each centre are
indicated by smaller circles with connecting lines.
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Figure 3 GS:3D Questionnaire. The Optical Mark Read Questionnaire.
Processing of leucodepletion filters and blood samples
As part of the routine processing procedure of volunteer
blood donations in the U.K., blood is filtered to remove
cells, and the used filters are an excellent source of
DNA [11]. Leucodepletion filters identified as coming
from study participants and containing cells for DNA
extraction were sent from the SNBTS process and testing laboratories to the research laboratory (WTCRF
Genetics Core, University of Edinburgh) in batches and
stored for up to seven days prior to extraction. Whole
Kerr et al. BMC Medical Genetics 2010, 11:166
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blood samples taken from the prefiltration pouch were
also received by the research laboratory in 9 ml EDTA
(Becton Dickinson) tubes and stored at room temperature for up to five days from the date of collection until
plasma was purified and stored. Although some plasma
analytes are unstable over this period of time, many epidemiologically useful measurements can reliably be
made [12]. Filters and EDTA tubes were physically
paired up by matching SNBTS barcodes. A unique
GS:3D research sample ID was then assigned to each
SNBTS barcode. Paired samples were logged by scanning barcodes into the GS:3D database, a bespoke study
management program. The GS:3D sample ID was subsequently entered into a Starlims Laboratory Information
Management System (LIMS), which assigned the
required number of LIMS barcode labels and storage
space for the resulting processed sample aliquots of
DNA and plasma. Use of a LIMS in an SOP-driven core
laboratory operating to a GLP standard helps to minimise the risk of sample mix-up.
Extraction and storage of DNA
The initial steps of the protocol for extracting DNA from
the leucodepletion filters followed the method described
by Cook et al, 2003 [11]. All filters underwent a “drawthrough” step to wash out and collect leucocytes. This
involved cutting the inlet and outlet tubes at either side
of the filter and dispensing 20 ml of phosphate buffered
saline (PBS) (GIBCO) pH7.4 through the filter in the
counter-direction to that indicated by the arrow on the
side of the filter. PBS was dispensed using a 30 ml Terumo syringe (TERUSS-30E5Z1) and 20 ml of drawthrough was collected in a labelled 50 ml falcon tube
with screw lid (Greiner Bio-one Ltd) and stored at -40°C
until ready for extraction. As a quality control procedure,
100 μl of blood cells from the 20 ml sample were spotted
onto an FTA nucleic acid capture card (Whatman) which
was archived at room temperature in a secure store. This
is designed to allow investigation of any sample mix-up
during the process of DNA extraction.
Each 20 ml sample was split into two samples of 10
ml each for DNA extraction using a Nucleon Kit (Tepnel Life Science) with the BACC3 protocol. At the DNA
precipitation stage, both the upper phases from the two
corresponding DNA extractions (originating from the
same filter) were layered into a 15 ml EZ Flip tube. The
precipitated DNA was hooked out and placed directly
into a labelled 2.0 ml microtube (Scientific Specialities
Inc) containing 1.5 ml TE buffer pH 7.5 (10 mM TrisCl pH 7.5, 1 mM EDTA pH 8.0). Microtubes were
rotated for 2 weeks at room temperature until DNA was
fully re-suspended. 8 out of every batch of 92 samples
were electrophoresed on a 1% agarose gel to test for
integrity of the DNA, and all were satisfactory. DNA
Page 6 of 9
concentrations (ng/μl) and levels of protein and RNA
contamination were determined for all samples using
the NanoDrop method (Thermo Scientific). 500 μl of
each DNA master stock were transferred to a deep well
plate then normalised to 50 ng/μl to make working
stock plates. The remaining 1000 μl were archived in a
microtube at -40°C.
Purification and storage of plasma
Whole blood in EDTA tubes was centrifuged for 15 minutes at 2000 g to separate plasma. Two aliquots of 1 ml
of plasma were dispensed into 2 × 1.4 ml tubes (Fluid X
Robo-rack-96) and labelled with a printed LIMS label
and barcode. Pierceable lids (TPE Capclusters) were
fitted to the tubes which were stored at -80°C in 96
position racks.
Results
Recruitment
A total of 5,934 participants were recruited to the study
by SNBTS donor services staff. However, leucodepletion
filters were not received from some participants, and
these individuals were excluded as they were of no value
to the study. Filters were not received by the research
laboratory for a variety of reasons. These include the
participant being enrolled in the study but then failing
to provide a full donation of blood; the identifying marker on the filter not being noticed by the SNBTS laboratory and therefore not being diverted into the onward
transport protocol after processing; or the blood failing
one of the many sensitive safety tests routinely performed on it by the SNBTS.
A total of 5,230 filters which passed all tests were
received by the University of Edinburgh WTCRF
research lab. However, the corresponding consent and
questionnaire forms were not received for every filter.
This occurred for a variety of reasons including a single
batch of 22 forms being lost in transit. All consents
received were checked by the research team, and some
were found to be invalid (unsigned or undated, etc),
which meant that the participant had to be removed
from the study. A small number of samples were
destroyed due to problems during processing in the
research lab. Together, this resulted in a total of exactly
5,000 participants with a complete set of data, valid consent and filter processed to cells ready for DNA extraction. Two of these participants withdrew from the study,
after leaving the clinic and having time to reflect.
Questionnaire data
The questionnaire (Figure 3) collected data on age
group, sex, cultural origin, and place of birth of the participant, parents and grandparents. The forms were
filled in well by participants. For example, Question 2,
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“What is your sex?” gave responses from the 4,998 study
participants of 2,209 female, 2,775 male, 1 multiple
marks and 13 missing marks. The age range and sex of
the participants is illustrated schematically in Figure 4.
Over 88% of participants recorded their ethnicity as
“White - Scottish”, and 98% were in one of the four
“White” categories (Table 1). This ethnicity pattern was
similar to that reported in the Census of Population for
Scotland, 2001, General Register Office for Scotland, (c)
Crown copyright 2003. There is an under-representation
of participants with “Asian” categories of ethnicity
(0.12% in GS:3D and 1.41% in the Census) as is found
for blood donors in general. 71% of participants had
either three or four grandparents born in Scotland.
Table 1 Recorded ethnicity of GS:3D participants
Statistical power
Black - Caribbean
0.00
0.00
0.00
0.04
The primary objective of this study was to establish a
collection of samples and an accompanying database of
demographic data as a resource for future analysis.
Association studies, particularly genome-wide association studies using high density microarrays, are currently a widely used design for investigating the genetics
underlying complex diseases [5,6]. This approach looks
for a statistical association between genetic variants
(SNP or copy number variants) and a defined phenotype
[2]. An association study is usually conducted in a population-based sample of unrelated affected and unaffected
individuals (a case-control study). The selection of
appropriate and sufficient control samples is therefore
crucial for success [5,7]. Ideally, control samples should
reflect the ethnic and geographic (as a proxy for genetic)
composition of case samples, and blood donors have
been shown to be an appropriate control group for
many complex conditions [5,6]. The statistical power of
Black - African
0.00
0.00
0.00
0.10
Black - Other
0.00
0.00
0.00
0.02
Other
0.05
0.07
0.06
0.19
Number of GS:3D Participants
500
450
400
Male
Female
350
300
250
200
150
100
50
0
17-25
26-30
31-35
36-40
41-45
46-50
51-55
56-60
61-65
66+
Age Range (years)
Figure 4 Age Range and Sex of GS:3D participants. Chart
showing age range and sex of GS:3D participants. Males are
represented by pale bars and females by dark bars.
Ethnicity
%
Female
%
Male
All GS:3D
(%)
2001
Census
White - Scottish
87.66
88.95
88.38
88.09
White - Other
British
10.07
8.95
9.45
7.38
White - Irish
1.04
0.90
0.96
0.98
White - Other
0.77
0.69
0.72
1.54
Mixed
0.36
0.25
0.30
0.25
Asian - Indian
0.00
0.11
0.06
0.30
Asian - Pakistani
0.00
0.00
0.00
0.63
Asian - Bangladeshi 0.00
0.00
0.00
0.04
Asian - Chinese
0.05
0.07
0.06
0.32
Asian - Other
0.00
0.00
0.00
0.12
case-control studies can be increased by increasing the
numbers of controls.
Data and sample extraction and access
The GS:3D DNA samples all passed the routine quality
control tests of intactness and purity described in Methods. While a few samples had low yield (less than
30 μg), the vast majority yielded over 1 mg of purified
DNA. This is a significant amount of material, as each
Taqman SNP genotype assay consumes up to 20 ng of
DNA, and each Illumina whole genome scan (of up to
1 million markers) consumes around 200 ng of DNA.
The GS:3D resource therefore should have an extremely
long lifespan. If necessary, at some future point sample
stocks could be replenished through the technique of
whole genome amplification [13].
Genotype data from analysis of the DNA samples is at
an early stage, but initial results show the first few hundred samples to be of good quality with a high call rate
in Taqman SNP genotyping assays (L. Murphy, WTCRF,
pers. comm.). Master and working stocks of DNA and
aliquots of plasma are available to researchers in the U.
K. for hypothesis-driven analyses with appropriate ethical approval. An access process has been defined with
reference to Wellcome Trust and Medical Research
Council guidance [14]. Access to the samples and data
is reviewed by the Generation Scotland Resource Management and Development Committee, and only deidentified data can be made available. Researchers will
be obliged to return derived data after an agreed time
period, and acknowledge the resource in publications
arising.
Kerr et al. BMC Medical Genetics 2010, 11:166
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IT infrastructure
The development of an IT infrastructure that can support genetics research is an important part of Generation Scotland. Innovative aspects of the IT infrastructure
in GS:3D are primarily in the use of optical mark read
(OMR) technology to collect questionnaire data and the
development and implementation of web-based study
management tools. A web-based interface provides password-protected access to summary statistics on the
questionnaire data. Participants are identified by a
unique research ID number, the production and usage
of which is tightly monitored. Systems were developed
to ensure efficient and confidential handling and management of all data and samples. The GS:3D database
was used to record all exceptions (e.g. consent form not
fully filled in, no tube received for plasma), resulting in
a complete audit trail of all samples and data that were
part of the study. These study management systems are
outlined in Macleod et al, 2009 [9]. In due course a
cumulative genotype database will be available to
researchers through a web portal with appropriate permissions and security. Genotype data across the whole
set of DNA samples, ideally genome wide at high density, should be available in the future.
Ethical issues
All components of GS:3D, including the protocol and
written materials provided to participants, have received
ethical approval from the NHS Research Ethics Committee for Scotland A (REC reference number: 06/
MRE00/105). In addition, local approval has been
obtained from NHS Lothian, Glasgow and North of
Scotland Research Ethics Committees, from NHS
Research and Development Offices, and from an SNBTS
management committee. GS:3D has been granted
Research Tissue Bank status by the Tayside Committee
on Medical Research Ethics B (REC Reference Number:
10/S1402/21).
The study aimed to minimise several risks to
participants:
1. The physical and administrative separation of the
clinical (SNBTS) and research (University of Edinburgh)
teams was designed to minimise the risk to the privacy
of participants, while maximising rate of recruitment.
2. No personal or identifier information was given to
the research team by the SNBTS and there is no mention of participation in the study on the donor service
record. After a period of 28 days during which participants were able to withdraw, all links to the SNBTS
identifier were broken.
3. It is impossible to know what precise purposes the
resource will be used for in the future; therefore fully
informed consent for the use of data and DNA and plasma
samples cannot be obtained. Instead, “blanket” consent
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was sought, with ethics approval through the research tissue bank access process required for each new use.
4. It was emphasised that participation was entirely
voluntary. Withdrawal was allowed up to 28 days after
the donation session, upon which all data and samples
relating to the withdrawing participant were destroyed.
After the 28 day period, withdrawal was not possible
because the samples and data were de-identified.
Discussion
GS:3D will be of particular utility to studies of Caucasian populations, but should also have wider applications, for example in testing new genotyping
methodologies. The resource is complementary to
other population-based genetic epidemiology studies,
such as the Generation Scotland: Scottish Family
Health Study [8] and the UK Biobank [15], which were
established primarily to characterise genes and genetic
risk in the population. The model of recruitment
described here differs from that of most genetic cohort
studies by using the infrastructure and expertise of the
Blood Transfusion Service. Other study designs usually
involve research clinics, which have the advantage of
allowing more study-specific data to be collected, but
the disadvantage of significantly increased recruitment
costs. Such models of recruitment require funding at
the level of programme grants, rather than the project
grant which was sufficient to implement GS:3D.
Although detailed phenotyping of traits relevant to
complex diseases is not available in GS:3D, inclusion
of participants who would meet the criteria for a case
is likely to be rare, due to the stringent blood donor
exclusion criteria described in the Methods section.
Furthermore, low levels of such misclassification
should only have a small adverse effect on power [7].
The Wellcome Trust Case-Control Consortium initially used a control:case ratio of 1.5:1, combining 1958
Birth Cohort and UK Blood Transfusion Service controls, but also expanded this to up to 7.5:1 by including cases for other diseases as controls. This expansion
increased evidence for association at most of the loci
that received the strongest support from the primary
analysis [5].
Conclusions
The GS:3D study protocol has allowed the efficient generation of a new large scale resource of DNA and
plasma samples. This collection is suitable for use in
genetic studies of human disease and the sample size is
large enough to give substantial numbers of controls
selected on the basis of age range, gender, ethnic or
geographic origin. The use of blood donors is a costeffective way to collect a large number of control DNA
samples. The availability of the GS:3D resource should
Kerr et al. BMC Medical Genetics 2010, 11:166
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reduce costs to investigators who would otherwise have
had to recruit their own controls.
Acknowledgements
We are extremely grateful to all the participants, and the SNBTS donor
services, transport and Process and Testing laboratory teams. The
contribution of Carol Garnett, SNBTS National Standards Manager, was
particularly valuable. We thank SNBTS Local Investigators Dr Rhona Watkins,
Glasgow, Dr Sam Rawlinson, Dundee and Dr Peter Forsyth, Inverness.
Samples were booked in and processed by the expert staff at the Genetics
Core of the Wellcome Trust Clinical Research Facility, Edinburgh. The whole
Generation Scotland team, which includes academic researchers, IT staff,
laboratory technicians, clerical workers, statisticians and research managers,
was vital to the success of the study. We gratefully acknowledge the
statistical genetics expertise provided by Dr Andy Macleod and constructive
advice on drafting the manuscript from Dr Isabel Hanson. Generation
Scotland (GS) is a collaborative initiative between the Universities of
Aberdeen, Dundee, Edinburgh and Glasgow and the National Health Service
(NHS) Scotland. The Chief Scientist Office of the Scottish Government and
the Scottish Funding Council provide core support for Generation Scotland.
GS:3D was funded by a project grant from the Scottish Executive Health
Department, Chief Scientist Office, grant number CZB/4/285.
Author details
1
Medical Genetics Section, Centre for Molecular Medicine, University of
Edinburgh, Institute of Genetics and Molecular Medicine, Western General
Hospital, Crewe Road, Edinburgh, UK. 2Wellcome Trust Clinical Research
Facility, University of Edinburgh, Western General Hospital, Crewe Road,
Edinburgh, UK. 3Scottish National Blood Transfusion Service, Royal Infirmary,
Edinburgh, UK.
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[http://www.generationscotland.org/access_policy.htm].
Elliott P, Peakman TC, UK Biobank: The UK Biobank sample handling and
storage protocol for the collection, processing and archiving of human
blood and urine. Int J Epidemiol 2008, 37:234-44.
Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2350/11/166/prepub
doi:10.1186/1471-2350-11-166
Cite this article as: Kerr et al.: Generation Scotland: Donor DNA
Databank; A control DNA resource. BMC Medical Genetics 2010 11:166.
Authors’ contributions
All authors contributed to the writing of the manuscript, in an iterative
manner. SK was the study co-ordinator and project manager. DCML and AC
designed and implemented the IT systems used to manage the study data
and samples. KT performed the laboratory work to extract and characterise
DNA and plasma from blood. SW and DN provided clinical and
epidemiological advice and expertise. MT was Chief Investigator and led the
clinical aspects of the study. DP was Principal Investigator, conceived the
study and led the scientific aspects. The main text was written by the study
co-ordinator SK, with comments and amendments made by all authors, who
have each read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 26 May 2010 Accepted: 23 November 2010
Published: 23 November 2010
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