study design and sample size hrb revised 130910 design and... · 23 measured endpoints in follow-up...
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Study DesignandSample Size
Professor Leslie Daly9th Sept, 2010
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If only I had a centfor every time I was asked
How many patientsdo I need for my study?
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Advice to a StatisticalConsultant:
There is no such thing as a sample size problem.Sample size is but one aspect of study design. Whenyou are asked to help determine the sample sizea lot of questions must be asked and answeredbefore you get to that one…….You may often end upnever discussing sample size because there areother matters that override it in importance.
Russell Lenth (2001)
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It seems an easy question, like
How much moneyshould I take on my holidays?
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Why is the Sample SizeImportant?
Ethical reasons:–Proper use of scarce resources–You don’t want a study that won’t show anything because it’s too small
–You don’t want a study that is too big when a smaller one would have done
Funding agencies require it
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How many?
Use a similar number to previous researchin the same area–Maybe a guideline–But much research is under-powered
Use a scientific approach, but remember–Sample size calculations are not a substitute for
careful study planning
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Sample Size
Scientific Validity:Sample Size Formulae
Reality: resources
n
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Resources
Number of available patientsLaboratory resources
–Diagnostic tests etc. - if needed
Time you have available–Set by funding agency–Set by your career trajectory
Funds and personnel
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Study Timelines
Set-up,Ethicalapproval
etc.
Patientrecruitment
Duration ofFollow-up(minimum)
Analysis,Write-up
Last patientrecruited
Last patientFollow-upcompleted
SAMPLESIZE
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Non-influences on Sample Size
Sample size required does NOT depend onthe population size
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Influences on Sample Size
Study objectivesStudy designEndpointType of samplingType of statistical analysis
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Influences on Sample Size:Study Objectives
Prevalence study–To estimate a mean or percentage–No comparisons
Comparative Study–Superiority study
•To show differences between groups/treatments
–Equivalence or non-inferiority study•To show that groups/treatments are similar
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Influences on Sample SizeStudy Design
Cross-sectional prevalence surveyComparative study design
–Cross-sectional or follow-up–Number of groups
•Reduce to two groups for simplicity
–Independent, paired or matched groups•Parallel or cross-over designs•Matched control groups
–Other designs•Factorial and sequential designs
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Influences on Sample SizeEndpoints
Must relate to your objectivesMust be measurable and well defined
–Preferable standardized–Don’t reinvent the wheel
Mean or percentage of something usually–Sample sizes tend to be smaller for means than
percentages
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Endpoints
Need prior estimates of variability–Requires estimates of standard deviation and
expected percentage–Pilot study or literature review
If you can’t decide on a single important endpoint you will have to calculate a samplesize for each and take the biggest
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Sample Size for PrevalenceStudies
No comparisons involved–Just an estimation in a cross-sectional survey
How precise do we want our answer to be?–Want the percentage of CF patients with liver
disease to ± 3%–Want the mean serum cholesterol to within ±0.5
mmol/L
Use the 95% confidence interval–Easy formulae available
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Precision-based Sample Size
Need prior estimate (rough idea) of–Standard deviation (σ) when estimating a mean–Where the percentage (p) might be when
estimating a percentage
Use pilot study or published data
nx
96.1
npp
p)1(
96.1
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Precision goes up by√n
Doubling n reduces CI width by 30%Multiplying n by 4 reduces CI width by 50%
SampleSize
95% CI given by*
50 ±12.7%100 ±9.0%500 ±4.0%1000 ±2.8%
*For estimating a percentage around 30%
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Superiority Studies:Looking for Differences between Groups
At a particular significance level–Usually set to 5% 2-sided–P < 0.05
A statistically significantresult is one not likely tobe due to chance
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Superiority Studies:Looking for Differences between Groups
Looking for a difference in what?–If there is no follow-up the endpoint is a measure
taken at the time of the study–If there is follow-up the endpoint is likely to
relate to a measure at end of follow-up•Survival / mortality
–Need special methods
•Biochemical or measured–Absolute levels or changes in levels
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Measured Endpointsin Follow-up Studies (1)
Absolute levels at follow-up–Ignores baseline differences–May be valid for a RCT
Average change (% change) from baseline–Calculate change for each person and average
changes in each group•Measure change or ask about change?
–Difficult to get prior estimates of variability
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Measured Endpointsin Follow-up Studies (2)
Analyse absolute levels at follow-up–Adjusting for baseline measures using ANCOVA–Most efficient
•You can allow for it in getting sample size
Replicate measures pre and post treatment–Can reduce sample size–Useful for RCTs–For biochemical endpoint–Requires efficient statistical analysis
•ANCOVA rather than mean change from baseline
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Measured Endpointsin Follow-up Studies (3)
Your sample size is the number of patientsNOT the number of replicates–Increase patients and reduce replicates
•10 measures on 100 patients is better than 100measures on 10 patients
Reduce number of replicate measurements–Relevant if the measurement is the expensive or
limiting factor
If you are measuring response over time–Fewer samples needed when value is stable–Analyse summary end point not values at each
time
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Superiority Studies:Looking for Differences between Groups
How big a difference?–The ‘minimal worthwhile difference’–A clinical question not a statistical one–‘What would you like to find?’–The effect size
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The Effect Size for theEndpoint ()
If the difference (the effect) is really this big:–I don’t want to miss it–I want to get a significant result–I want a good chance of getting a significant
result
If the effect is smaller:–I don’t mind missing it–I don’t mind a smaller chance of getting a
significant result
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Power of a study (1 - )
is the chance of not getting a significantresult when the real effect is as big aspostulated–Chance of a Type II error–Often set at 4 x (significance level)
The chance of getting a significant resultwhen the real effect is as big as postulated–1 - –Set at 80% for 5% significance–Set at 95% for 1% significance
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Sample Sizes for SuperiorityStudies: Inter-relationships
n
1-
Sample size
Significance level
Effect size
Power
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Other Calculations
Can calculate power for required differenceand fixed sample size (and significance)–Give consequences of going ahead–Formulae difficult–use software
Can calculate detectable difference forgiven sample size, power and significance–May help decision on an appropriate level to set
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Sample Size for ComparingGroups increases with 1/2
Halving effect size multiplies sample size by 4
Samplesize in each
group
To detect adifference between
groups of
Difference tobe detected
()*20 60% versus 20% 40%50 60% versus 33% 27%
100 60% versus 41% 19%500 60% versus 51% 9%
*Power 80%; 2-sided 5% significance
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Free Sample Size Software
Epi Info–http://www.cdc.gov/Epiinfo/
WinPepi–http://www.brixtonhealth.com/pepi4windows.html
Power and Sample Size–http://biostat.mc.vanderbilt.edu/wiki/Main
/PowerSampleSize
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“Power and Sample Size”
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“WinPepi”
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Using Software (or Formulae)
Check whether it is the total sample size orthe sample size in each group–Common error
Try software or formula against an answeryou know–One of the tables in this presentation–Use two different programmes
Allow for non-response/loss to follow-upPlay around with your calculations
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Usual Formulae are for EqualSample Sizes
Designing a study with equal sample sizesin two comparison groups is most efficient
When might you have unequal n?–Cross-sectional survey
•Comparing smokers to non-smokers
–Limited availability of patients•Use up to 4 controls per case in a case-control study
–Cost issues•More expensive to recruit into one of your groups
Easy adjustment of ‘equal n’ calculation
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Equivalent Sample Sizes(giving same power to detect a given difference)
Ratio A:B Sample sizein group A
Sample sizein Group B
TotalSample Size
1:1 100 100 2001:2 75 150 2251:3 67 198 2651:4 62 259 3211:5 60 300 360
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Influences on Sample Size
Study objectives–Prevalence, Superiority or Equivalence
Study design–Cross-sectional or follow-up; Matched or
independent; Factorial or sequential designs
EndpointType of samplingType of statistical analysis
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Factorial Designs–Two for the Price of One
Comparing two treatments and a placebo–Three groups is inefficient
Treatment A Treatment B Placebo
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Factorial Designs–Two for the Price of One
Comparing two treatments and a placebo–Use four groups–Two independent comparisons
•Unless there are interactions
–Total sample size that of a two-group study
Treatment A Treatment Aonly
Treatment Bonly
Treatment B
Placebo
Treatment A Treatment Aonly
Treatment Bonly
Treatment B
Placebo
Treatment A Treatment Aonly
Treatment Bonly
Treatment B
Placebo
‘A’ versus ‘No A’‘B’ versus ‘No B’
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Equivalence / Non-inferiorityStudies
When trying to show two groups (treatments)are the same–‘Non-significance’ is not the same as ‘no difference’
•Absence of evidence is not the same as evidence ofabsence
–‘Non-significance’ is ambiguous•There might be a difference or there might not be
–Do you want•Equivalence or non-inferiority?
–Easier to show a difference than sameness•Easier to disprove something than prove it
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Equivalence or Non-inferiority Studies
Must set a non-inferiority margin(equivalence limit)–The largest difference (between the treatments)
that is clinically acceptable so that a differencebigger than this would matter in practice
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Endpoint of BP Difference(BP on Treatment B minus BP on A)
Treatment A betterTreatment B better
BP Difference
0
Treatment A statistically superior to B
Treatment A clinically equivalent to B
Treatment A clinically non-inferior to B
For a significant resultthe 95% CI for BP difference must lie totally within the red bars
- +
±defines the equivalence/non-inferiority limits
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Equivalence /Non-inferiorityStudies: Issues
Setting equivalence/non-inferiority limit isdifficult
For non-inferiority trials there arearguments about use of one or two-sidedsignificance levels
Sample sizes tend to be very largeSoftware is not widely available
–And is very difficult to use or understand
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Influences on Sample Size
Study objectivesStudy designEndpointType of samplingType of statistical analysis
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Infleuences on Sample Size:Type of Sampling
Theory:–Our patients are a random
sample from a population
Reality:–We rarely work with
random samples anyway–Either we assume we have
OR–We adjust for sampling
method
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Complex Sampling
Cluster sampling or cluster randomisation–Sampling unit is a ‘group’ of subjects
•Randomising general practices•Sampling school children by class
Stratified samplingSample size estimation
–Can adjust usual formula with a ‘design effect’ or ‘variance inflation factor’•Usually extremely difficult to determine
–Often educated guess-work dressed up inscientific language
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Accounting for StatisticalAnalysis Methods
Interim analyses–increases sample size
Using regression to adjust for confounders–Variance inflation/deflation factors are available
•But usually require unobtainable prior estimates•No agreement on acceptable approach
–Standard two-group sample size methodsusually used•Probably the best practical solution at the moment
Using ANCOVA to adjust for initial levels–Can reduce sample size required
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Influences on Sample Size
Study objectivesStudy designEndpointType of samplingType of statistical analysis
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A Final Rule:Maximise Use of Available Patients
Increase response rate and avoid missingvalues–Avoid invasive procedures–Shorten your questionnaire–Spend time on the recruitment process
A small sample with a high response rate orfew missing values is better than–A large sample with a low response rate or a lot
of missing data
Use all available patients–Perform some measures on a subset of patients
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The Final Word
The question of the most appropriate study sizeis not a technical decision to be determinedby calculation, but a judgement to be determinedby experience, intuition and insight
Modern Epidemiology, Ken Rothman - 1986
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Resources
Steven Julious–Statistics in Medicine 2004: 23:1921-1956–Sample sizes for clinical trials with Normal data
65 page articleFormulae for every situation
–Comparing means only