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Features of Biobank

• Conceptually relatively simple
• Complex to execute
• Big
• Innovative
• Famous!

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Life expectancy in England and Wales
Note Estimated figures for the year
1990 Sources OPCS and WHO
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The New Genetics
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The post-genome challenge

• We should be interested in humanitys genes
  rather than the human genome, moving from the
  individual towards the population
• Sydney Brenner

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21st Century question Which HRT users will
develop breast cancer and why?
20th Century knowledge Smoking causes lung
cancer Genome sequences
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Power associated with 5,000 events

• Main effects departures from multiplicity
• Genotype frequency 0.1, correctly classified 1
  (.95), genotype relevant 1 (0.5)
• Reliability of environmental determinant 1
  (0.5)
• Correct classification of outcome 1 (0.5)
• 90 power at p0.0001
• ORgen 1.26 (1.49)
• ORenv 1.11 (1.14) effect across
  interquartile range
• ORinter 1.33 (2.17) effect across
  interquartile range
• Source Paul Burton, Leicester University

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Age-adjusted CHD death rates per 10 000
person-years by level of serum cholesterol and
SBP for cigarette smokers screened in MRFIT Study
Neaton JD et al. Arch Intern Med 1992 152 56-64
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Quantity has a quality all of its own Henry
Ford
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The national resource of large long-term cohort
studies
has or is about to collect DNA () has
applied for funding to collect DNA
Source M. Wadsworth
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UK COHORT STUDIES (10,000 participants)
Cohort size (thousands)
Smaller UK studies Regional Heart Study 8000
1946 Birth Cohort 5000 Caerphilly Speedwell
4000 Ely study 2000.
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The UK Biobank will

• follow the health of a large group of volunteers
  for many years
• collect information on environmental and
  lifestyle factors
• link these to medical records and stored
  biological samples
• samples can be used for biochemical and genetic
  analysis

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UK population 2001
Biobank target population
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Benefits of UK Biobank

• Measure the effect of environmental, lifestyle
  and genetic risk factors in populations
• Understand heterogeneity within disease groups
• Identify important biomarker-disease associations

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Possible additional benefits national health
intelligence

• Develop and use routine information systems to
  their full potential
• Describe patterns of morbidity and mortality
  across the UK and over time
• Quantify and predict use of health care
• Provide a low cost follow up system for any
  consented group of individuals

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Other objectives

• Develop standards for ethics and governance in
  this field
• Contribute to the overall research strategy of
  the funders and UK science
• Collaborate internationally
• Operate efficiently and economically
• Recover costs by trading

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The Early Challenges

• Strategic
• External relations
• Internal relations
• Technical
• Practical

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UK Biobank - organisational relationships
Manchester University
MRC, Wellcome, DH, SE
Funding
Science sub-groups
UK Biobank Ltd
Briefing
Board of Directors
Advice
Ethics and Governance Council
CEO and staff
Advice
Science Committee
Funded contracts
Regional Collaborating Centres
Representation
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Scientific Committee

• Professor John Bell Oxford
• Dr Bernard Keavney ICL, Newcastle
• Professor Raj Bhopal Edinburgh
• Professor Mike Pringle Nottingham
• Dr Richard Durbin Sanger, Cambridge
• Professor John Todd CIMR, Cambridge
• Professor Paul Elliot Imperial
• Professor Alan Silman Manchester
• Dr Jill Pell Greater Glasgow Health Board
• Professor Valerie Beral Oxford
• Professor Paul Burton Leicester
• Professor Stephen Palmer Cardiff
• Madeline Wang EGF Committee
• Dr John Newton UK Biobank
• Professor Dame Jill Macleod Clark Southampton
• Professor Hilary Graham Lancaster
• Professor Catherine Peckham UCL

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Additional groups

• 1.Science Committee subgroups
• Recruitment
• Questionnaire and measurements
• Data management
• Sample handling and storage
• Validation of endpoints
• 2.Biobank Implementation Group
• Recruitment of ethnic minorities
• 3.Communications Group

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Manchester Co-ordinating Centre
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Recruitment Plan Co-ordinating Centre
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Manchester Innovation Incubator Building
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Phases of the Biobank Project
RCC contracts
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Recruitment

• Representative or generalisable
• Minority groups
• Settings GP / GP networks / occupational
• Sampling frames

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Questionnaires and measurement

• 90 minutes
• Use existing instruments
• Use CAPI
• Nurses only where necessary
• Diet?
• Mental health?
• Family history?
• Blood and spot urine samples

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Data management, IT

• Handling the epidemiological data
• tracking the biological samples
• linkage across datasets including DNA data
• obtaining data from disparate GP systems
• identifying outcomes
• tracking participants around the country

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Prevalence of diabetes routine data cf. Health
Survey for England

• Males Females
• England ORLS-GP England ORLS-GP
• 20-39 0.5 0.5 0.4 0.7
• 40-59 2.5 2.2 1.6 1.7
• 60 6.2 5.6 4.7 4.2

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Indicative IT architecture for Biobank
Web based ordering
Web based registration
Web based interface ordering and control
Collaboration, directory and security tools
Application layer Sample inventory control, MES,
SPC, sample tracking, Sample registration,
Automation control software, supply
chainmanagement, data analysis and manipulation
tools
Middleware integration layer
Patient registration
QA/QC
Sample inventory
Biobank data
ONS
EMR
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Key decisions for the sample handling
sub-committee
Primary sample collection
Transport to local Spoke (daily orweekly)
Primary processingat spoke
Transport to hub
Store in hub
Distribute samples
What biomolecules will be assayed? How tightly
coupled is the process? How much (if any) of the
process is outsourced?
What storage temperature(s) and format?
How is the geography of the collection
areas structured?
Should all processing be done centrally?
Will the hub do any additionalprocessing e.g.
make DNA
What is the collectionprotocol and volume
What is the processingprotocol fractions,
volumesaliquots, temperatures
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Summary of processing protocol
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Summary of processing approach
Scenario 1 - Low automation
Scenario 2 - High automation
Registration
Registration
Automated processing
Automated processing
Blood count and biochemistry
Blood count and biochemistry
Lab manager
Automated fractionation
Manual fractionation
Headcount 18-22
Headcount 5-10
Cellular processing team
Cellular processing team
Cellular processing team
Cellular processing team
Storage
Storage
-80C
N2
-80C
N2
Each processing team consists of team leader
(senior technician), three technicians and one
junior technician
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The liquid nitrogen facility in Cowley, Oxford
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Benefits of Dry-Store Approach

• Proven Format FTA Paper
• Instantaneous DNA Extraction
• Room temperature operation
• Virus/Bacteria Inactivated
• Standard multi-well plate format is easily
  automated
• Designed to isolate and preserve DNA for decades

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The Early Challenges

• Set up a new organisation ?
• Manage the internal relations ?
• Develop an ethics and governance approach ?
• Communicate with the public and stakeholders ?
• Overcome scientific scepticism /-

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Scientific Justification (1)

• Investigation of a large number of conditions in
  one study
• Exposure information collected prior to
  development of disease
• Measurement of blood based molecular and
  proteomic factors using samples collected prior
  to onset
• Genetic information available for all cases
  regardless of severity

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Scientific Justification (2)

• A framework for nested case / control studies
• Potential to identify families within the cohort
  and augment the basic cohort with relatives
• Potential for collecting additional continuous
  phenotype data from a sub cohort
• A resource where investigation of unforeseen
  outcomes and relationships is possible
• Providing a research resource which builds up a
  mass of unique and valuable data

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The scientific criticisms

• Sibling rivalry - BBs got our money!
• Case-control studies are more efficient
• Existing cohorts are adequate
• Biobank is too small
• Family studies are what is needed
• Phenotype/exp data will be inadequate
• endpoints unreliable
• intermediate phenotypes

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Exposures and endpoints

• Baseline biochemistry / environmental exposures
• Continuous monitoring of routine data
• Resurvey of all participants at 5 years for
  self-reported health and exposures
• Validation of endpoints from source clinical
  records using standard definitions
• Linkage to area-referenced environment data
• Participants can be re-approached at any time for
  further investigation

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Intensive Phenotyping

• Questionnaire a) Detailed analysis of
  occupational exposure, diet, family history,
  socio- economic status, physical activity
• b) Anxiety questionnaire
• Personality questionnaire
• Fatigue questionnaire
• Reading test
• Verbal memory
• Examination Skinfold thickness
• Bioimpedence
• BP x3
• Anklebrachial pressure
• EC6
• Spirometry
• Hearing and visual acuity
• Dexa
• Analysis Glucose
• Insulin, GTT, HOMA
• Lipids

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Continuing design questions

• Can we collect some continuous vascular/
  metabolic endpoints as well as binary endpoints?
• What level of active follow up could be
  undertaken?
• How much validation of endpoints is required
  routinely?
• Repeat measurements early / 2 years /
• 5 years?

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Preliminary Survey Results
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Ethics and Governance

• Public consultation early and continuing
• Interim Advisory Group established
• Draft Ethics and Governance Framework published
• Independent Ethics and Governance Council to be
  appointed

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Public Consultation Conclusions

• Proposal accepted in principle
• Broad acceptance of use of material for
• medical research
• Misinformation and misunderstanding
• of genetics research
• Consent is crucial
• Communication is essential
• Public ownership important

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UK Biobank Ethical and Governance Framework

• Volunteers can withdraw at anytime
• Data security confidentiality assured
• Samples not released to others
• Full access for appropriate purposes
• Internal and external review of science and
  ethics
• Independent Ethics and Governance Council

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Features of UK Biobank

• A powerful multipotent resource for the future
• Long term
• Specific questions unknown at the outset
• International project
• UK is well placed to do this work

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Requirements

• Wisdom, leadership and diplomacy
• Scientific rigour
• Consistently high standards of practice
• Industrial scale processes
• Trust and respect from the public

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