Transcript Clinical Trial Service Unit & Epidemiological Studies Unit

UK Biobank: an open-access resource
for international health research
Rory Collins
UK Biobank Principal Investigator/Chief Executive
BHF Professor of Medicine & Epidemiology
Clinical Trial Service Unit
& Epidemiological Studies Unit
University of Oxford
Requirements for the appropriately reliable
assessment of risk factors for disease
Study many more “cases” of the disease of interest
(in individual studies or meta-analyses), in a wider
range of circumstances, than is currently customary
Pay greater attention to important statistical details
in analyses (e.g. potential biases due to regression
dilution, confounders, and selective emphasis)
Otherwise, risk factor associations with disease
may be seriously under- and over-estimated
UK Biobank Prospective Cohort
• 500,000 UK men and women aged 40-69 years
• Extensive baseline questions and measurements,
with stored blood and urine samples that will allow
many types of different assay in the future
• Repeat assessments over time in subsets of the
participants to allow for sources of variation
• General consent for follow-up through all health
records and for all types of health research
• Sufficiently large numbers of people developing
different conditions to assess causes reliably
No preferential or exclusive access to the resource
(available for academic and commercial research)
Advantages of PROSPECTIVE
epidemiological studies
• Risk factors can be measured before the disease
develops (helping to avoid “reverse causality”)
• Associations can be assessed with a range of
diseases (provided sufficient numbers occur)
• Appropriate controls can be selected from within
the same population as the disease cases
• Confounding by other factors may be less extreme
(but need corrections for regression dilution)
Need for prospective studies to be LARGE:
CHD versus SBP for 5K vs 50K vs 500K people
in the Prospective Studies Collaboration (PSC)
5000 people
50,000 people
256
256
128
128
500,000 people
Age at risk:
80-89
Age at risk:
80-89
256
128
70-79
64
60-69
32
50-59
70-79
Age at risk:
80-89
64
64
60-69
32
32
70-79
50-59
60-69
16
16
8
50-59
40-49
4
16
8
40-49
8
4
4
2
2
2
1
1
1
120
140
160
180
Usual SBP (mmHg)
120
140
160
180
Usual SBP (mmHg)
40-49
120
140
160
180
Usual SBP (mmHg)
Recruitment of 500,000 participants achieved
between April 2007 and July 2010
Numbers of participants by age, sex and deprivation
Age
Sex
Deprivation
Total
40-49
119,000
50-59
168,000
60-69
213,000
Male
228,000
Female
270,000
More
92,000
Average
166,000
Less
241,000
500,000
Strategy for inclusion of questions/measures
in the baseline assessment of participants
• Public health importance of relevant condition
as a cause of mortality and/or morbidity
• Likely importance of the factors assessed as
determinants of subsequent health outcomes
• Reliability and validity of assessment methods
• Lower threshold for inclusion on touchscreen,
and limited time for measurements (~30 mins)
• Availability of alternate sources of information
about the factor (e.g. previous medical records;
biological samples; internet diet/activity diaries)
Topics covered by touchscreen (left)
and subsequent nurse interview (right)
Topic
Median time
(minutes)
Socio-demographics
1.7
Ethnicity
0.1
Work-employment
1.4
Physical activity
4.4
Smoking (non-smokers)
0.5
(past/current smokers)
1.5
Diet
4.5
Alcohol
1.1
Sleep
1.2
Sun exposure
1.3
Environmental exposures
1.0
Early life factors
0.8
Family history of common diseases
1.6
Reproductive history & screening (women)
2.4
(men)
0.8
Sexual history
0.4
General health
2.1
Past medical history & medications
1.6
Noise exposure
1.0
Psychological status
4.5
Cognitive function tests
10.0
Hearing speech-in-noise test
8.0
Total time
52.5
Topic
Median time
(minutes)
Medical history/medication
Occupation
Other
3.1
0.4
0.6
Total time
4.1
Touchscreen and interview questions
(plus extra enhancement questions)
available at www.ukbiobank.ac.uk
Numbers of prevalent disease cases
reported at baseline assessment visit
Condition
Number
Diabetes
24,000
Myocardial infarction
12,000
Stroke
7,000
COPD
5,000
Breast cancer
11,000
Prostate cancer
4,000
Rheumatoid arthritis
6,000
Production line approach to assessment visit
(improved throughput; efficient staffing)
Retinal detachment: photography and OCT
Incorporation of baseline enhancements:
number of participants with extra measures
Enhancement
• category
Enhancements
Number of
participants
1
 Extra touchscreen questions
 Auditory acuity
 Vascular reactivity
170,000
2a
 Visual acuity, refractive index,
intra-ocular pressure
 Blood for RNA
 Saliva sample
120,000
2b
 Retinal photograph, optical
coherence tomography (OCT)
 Fitness assessment with limb
lead ECG recording
80,000
Invitation to wear a wrist-worn accelerometer
to be sent to all 500,000 participants from Q2 2012
Immediate coding and direct data entry
of interviews and physical measures
• Immediate coding of text
data (e.g. drugs, disease
history, occupation)
• Direct capture of all raw
data and any meta-data
• Quality checks and rules
for acceptable data
IT aids central targeting of monitoring and training
Strategy for sample collection and handling
• Blood and urine collected because of wide range of
possible assays and wide physiological coverage
• Careful choice of anticoagulants and preservatives to
allow widest possible range of potential future uses
• Detailed pilot studies show that the sample processing
procedures allow wide range of assays (Int J Epi 2008)
• Minimal processing in local assessment centres, with
overnight transport to coordinating centre laboratory
for automated blood fractionation and processing
• Storage facilities (automated -80ºC and back-up liquid
nitrogen) provide physical security and reliable tracking
of individual samples
Collection and use of biological samples
Sample collection tube
Fractions collected
Potential assays
Na+
• Plasma
• Buffy coat
• Red cells
• Plasma proteome and metabonome
• Assays of genomic DNA
• Membrane lipids and heavy metals
Lithium Heparin (PST)
• Plasma
• Plasma proteome and metabonome
(without haemolysis)
Silica clot accelerator (SST)
• Serum
• Serum proteome and metabonome
(without haemolysis)
Acid citrate dextrose
• Whole blood
• Assays of DNA extracted from EBV
immortalised cell lines
• (B-cell transcriptome)
EDTA (4 ml)
• Whole blood
• Standard haematological parameters
Urine
• Urine
• Urine proteome and metabonome
• Gut microbiome
Tempus RNA stabilisation
• Whole blood with lysis reagent
• Blood transcriptome
• Representative transcriptomes of other tissues
• Mixed saliva sample
• Salivary proteome and metabonome
• Salivary microbiome
• (Mucosal proteome and metabonome)
EDTA
Saliva
Average processing time for all samples: 24.6h (SD 2.1)