UK Biobank and biobank harmonization

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UK Biobank andbiobank harmonization

• Paul Burton
• Dept of Health Sciences
• Dept of Genetics
• University of Leicester

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Structure of talk

• What is UK Biobank?
• Scientific rationale?
• Statistical power of nested case-control studies
• Expected event rates in UK Biobank
• Biobank Harmonization
• Conclusions

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What is UK Biobank?
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Basic design features

• A prospective cohort study
• 500,000 adults across UK
• Middle aged (40-69 years)
• A population-based biobank
• Not disease or exposure based
• Recruitment via electronic GP lists
• Broad spectrum not fully representative
• Individuals not families
• MRC, Wellcome Trust, DH, Scottish Executive
• 61M

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Basic design features

• Longitudinal health tracking
• Nested case-control studies
• Long time-horizon
• Owned by the Nation
• Central Administration Manchester
• PI Prof Rory Collins - Oxford
• 6 collaborating groups of university scientists

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The Fosse Way
UK BIOBANK FOSSE WAY REGIONAL COLLABORATION
CENTRE Local Collection Centres B Birmingham E
Exeter L Leicester N Nottingham P
Plymouth S Sheffield T Truro W Warwick
S
N
L
B
W
E
P
T
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Scientific Rationale
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Justification for UK Biobank

• Primary justifications
• Roles that can best be fulfilled by a new large
  cohort study of the type represented by UK
  Biobank
• Secondary justifications
• Roles that could be provided by other types of
  study, but given that UK Biobank is to go ahead
  anyway these additional roles can be taken on at
  relatively low marginal cost

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A platform for research in biomedical science

• Studies of the joint effects of genes and
  environment/life-style
• Genotype-based studies
• The genetics of disease progression
• Direct association of genes with disease
• Universal controls
• Family-based studies

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Statistical powerand sample size
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Issues that are often ignored in standard power
calculations

• Multiple testing/low prior probability of
  association
• Interactions
• Unobserved frailty
• Misclassification
• Genotype
• Environmental determinant
• Case-control status
• Subgroup analyses
• Population substructure

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Power calculations

• Work with least powerful setting
• Binary disease, binary genotype, binary
  environmental exposure
• Logistic regression interactions departure
  from a multiplicative model
• Complexity

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Summarise power using MDORs calculated by
iterative simulation

• Estimate minimum ORs detectable with 80 power at
  stated level of statistical significance under
  specified scenario

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Whole genome scan

• Genetic main effect, plt10-7

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Summary

• 80 power for genotype frequency 0.1, (allele
  frequency ? 0.05 under dominant model)
• Genetic main effect ? 1.5, p10-4 ? 5,000 cases
• Genetic main effect ? 1.3, p10-4 ? 10,000 cases
• Genetic main effect ? 1.2, p10-4 ? 20,000 cases
• Genetic main effect ? 1.4, p10-7 ? 10,000 cases
• Genetic main effect ? 1.3, p10-7 ? 20,000 cases
• (allele frequency 0.1 ?
  10,000 cases)
• GE interaction with environmental exposure
• prevalance 0.2 ? 2.0, p10-4 ? 20,000
  cases

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Expected event ratesin UK Biobank
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Taking account of

• Age range at recruitment 40-69 years
• Recruitment over 5 years
• All cause mortality
• Disease incidence (healthy cohort effect)
• Migration overseas
• Comprehensive withdrawal (max 1/500 p.a.)
• Partial withdrawal (c.f. 1958 Birth Cohort)

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No need to contact subjects
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Smaller sample sizes
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Conclusions

• Having taken account of realistic bioclinical
  complexity, UK Biobank is just about large enough
  to be of great value as a stand-alone research
  infrastructure
• Its value will be greatly augmented if it proves
  possible to set up a coherent and scientifically
  harmonized international network of Biobanks and
  large cohort studies

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Harmonizing biobanks internationally
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Why harmonize?

• Investigate less common (but not rare) conditions
• UKBB Ca stomach 2,500 cases in 29 years
• 6 UKBB equivalents ? 10,000 cases in 20 years
• Investigate smaller ORs
• GME 1.5 ? 1.2 requires 5,000 ? 20,000
• 4 UKBB equivalents
• Analysis based on subsets homogeneous classes
  of phenotype, or e.g. by sex

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Why harmonize?

• Earlier analyses
• UKBB Alzheimers disease, 10,000 cases in 18 yrs
• 5 UKBB equivalents ? 9 years
• Events at younger ages
• Broad range of environmental exposures
• Aim for 4-6 UKBB equivalents
• 2M 3M recruits

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Harmonization initiatives

• Population Biobanks
• FP6 Co-ordination Action
• Camilla Stoltenberg, Paul Burton, Leena Peltonen,
  George Davey Smith ..
• GenomeEUhealth
• Proposed FP6 Integrated Project
• Leena Peltonen .
• Public Population Program in Genomics (P3G)
• Canada Europe
• Tom Hudson, Bartha Knoppers ..

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Extra slides
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Genetic main effects

• plt10-4

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Geneenvironment interaction

• 20,000 cases, plt10-4

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Rarer genotypes

• Genetic main effects

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Necessary to contact subjects
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Summarise power using MDORs calculated by
iterative simulation

• Want minimum ORs detectable with 80 power at
  stated level of statistical significance
• 1. Guess starting values for ORs
• 2. Simulate population under specified scenario
• 3. Sample required number of cases and controls
• 4. Analyse resultant case-control study in
  standard way
• 5. Repeat 2,3,4 1,000 times
• 6. Use empirical statistical power results from
  the 1,000 analyses to update ORs to new values
  expected to generate a power of 80
• Repeat 2-6 till all ORs have 80 power

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Proposed assessment visit model
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Hattersley AT, McCarthy MI. A question of
standards what makes a good genetic association
study? Lancet 2005 in press.