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Stepped Wedge Cluster Randomized Trials
Nicole SolomonBIOS 790
December 14, 2015
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Cluster Randomized Trials
Groups (clusters) of individuals are randomizedMotivation:
logisticstatisticalfinancialethical
Primary use:evaluate effectiveness of delivery of (preventive) health services,especially intervention which previously demonstrated efficacy
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Motivating example: GHIS
Gambia Hepatitis Intervention Study (GHIS)
large-scale study to evaluate effectiveness of HepB vaccine inliver disease preventionEpidemiological studies identified positive association betweenHepB and liver diseaseFollow-up on liver disease outcomes over 30-40 years (ongoing)Phased randomization was implemented by geographical regionRandomization intervals were 10-12 weeks apart
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Motivating example: GHIS II
Design considerations:
Vaccine price and limited availabilityComparison groups available from the same time periodDesirable to have vaccine available nationwide with deliverysystem in place by study’s endSerious logistic difficulties for individual randomization:
large cohort (> 61,000 children)large number of immunization teamscomplicated vaccination: 4 doses per childquestionably ethical
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
CRTs
Experimental units (randomized): clustersObservational units (measured): individualsStatistical implications: correlated observations within clusters
inflated Type I errorbiased treatment effect
Design types:1. parallel2. crossover (stepped wedge)
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
CRT Designs I
Common features (between parallel and crossover):
2-arm studyRandomize 1x (order of treatment in crossover)2I clusters
Differences:
Parallel CrossoverDesign 1 trt both trt
Analysis (paired) t-testGEE, random effects paired t-test
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
CRT Designs II
ParallelTime
Cluster
11 12 13 04 0
CrossoverTime
Cluster
1 21 1 02 1 03 0 14 0 1
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Crossover Implications
fewer clusters neededlonger trialdemands short follow-up period
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Stepped Wedge Design
unidirectional crossover: control to treatmentcrossover occurs at different times for different clusterstiming of crossover is randomized
Stepped WedgeTime
Cluster
1 2 3 4 51 0 1 1 1 12 0 0 1 1 13 0 0 0 1 14 0 0 0 0 1
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Strengths & Weaknesses of SWD
Strengths:Smaller fraction of clusters at a time [logistic]All clusters receive intervention [ethical]Intervention is never removed once implemented [ethical]Less sensitive to ICC
Weaknesses:same as crossover designs (longer trial length)cannot estimate treatment effect solely from within-clustercomparisons
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Assumptions
cross-sectional designN: number individuals sampled per cluster per time interval(k = 1, . . . ,N)I: number of clusters; assumed independent (i = 1, . . . , I)T = I + 1: number of time intervals (fixed) (j = 1, . . . ,T − 1)full treatment effect is realized in single time interval
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Notation
µij = µ+ αi + βj + Xijθ: expected response in cluster i at timejµ: overall meanαi ∼ N(0, τ2): random cluster effectβj : fixed time effect (βT = 0 for identifiability)Xij : indicator for administered treatment in cluster i at time jθ: treatment effect
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Model
Individual level responses:Yijk : response of individual k in cluster i at time jYijk = µij + eijk
eijkiid∼ N(0, σ2
e )V(Yijk) = τ2 + σ2
e
Cluster level responses:Yij = 1
N∑
k Yijk : mean response of cluster i at time jLinear Mixed Model (LMM):
Yij = µij + eij (1)
eij = 1N
∑k eijk
iid∼ N(0, σ2), σ2 = σ2e/N
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Cluster Variability
Variance of the cluster-level response = sum of between andwithin cluster variability:
V(Yij) = τ2 + σ2
= τ2 + σ2e
N [1 + (N − 1)ρ]
= τ2
N1ρVIF
where ρ = τ2
τ2+σ2e
= ICC
Increase in V(Yij) due to clustering captured by:Variance Inflation Factor: VIF = 1 + (N − 1)ρCoefficient of Variation: CV = τ
µ
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Analysis Methods I
Fixed effects: η = (µ, β1, . . . , βT−1, θ)
1. τ2, σ2 known: use weighted least squares (WLS)η̂ = (Z′V−1Z)−1(Z′V−1Y)
whereZITx(T+1) is the design matrix corresponding to ηVITxIT block diagonal matrix where each TxT block describescorrelation structure between cluster means across timeV(η̂) = (Z′V−1Z)−1
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Analysis Methods II
2. τ2, σ2 unknown:a. Approximately equal cluster sizes (cluster level analysis):
empirical Bayes approach to estimate η and variance components(Laird & Ware, 1982)
b. Unequal cluster sizes (and non-normal responses):conduct individual level analysis w/GEE or GLMM
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
GLMM & GEE
GLMM is to LMM as GLM is to LMlink functionoutcome from exponential familyautomatically applies proper weights when cluster sizes vary
GEE can handle normal or non-normal datautilizes “sandwich" type variance estimatestends to be more robust to variance structure misspecificationautomatically adjusts for unequal cluster sizestends to give inflated α rates when I is small
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Analysis Comparison
LMM, GEE, and GLMM theories rely on asymptotics so caremust be taken when I, T is smallGEE, GLMM preferred for binary responseJackknife estimate of variance needed to maintain α rate forGEE, GLMM analysisComparisons:
Equal cluster sizes: LMM barely superior in power to GEEwhich in turn is superior to GLMMUnequal cluster sizes: GEE and GLMM dominate LMM
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Power
Test: H0 : θ = 0 vs H1 : θ = θA
power = Φ
θA√V(θ̂)
− Z1−α/2
where θ̂ = θ̂WLS
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
SWD Power Trends
Insensitive to variations in CVNonlinear relationship with ICC: (Hemming 2014)
smaller ICC values: power decreases with increasing ICClarger ICC values: power increases with increasing ICC
Fewer time intervals leads to reduced powerOptimal when each cluster randomized in a unique time interval
Sensitive to delayed treatment effectpartly recoverable if additional measurement intervals included
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Cross-sectional vs Cohort Designs
Cross-sectional: different population at each time pointCohort: same population measured repeatedlyImplications of choosing a cohort design:
blinding of treatment allocation is not possible with individualrecruitment → selection biastwo-level hierarchical models may be modified to fit cohortdesign (Hemming 2015)
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
Recommendations
Ensure time intervals long enough to fully realize outcomeMaximize number time intervalsOnly use within-cluster analyses if no significant fluctuationsexpected over time (βj = 0)Use individual level analyses when cluster sizes varyconsiderablyUse jackknife variance estimate to maintain α rate with GEE,GLMM analyses
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials
CRT ReferencesEldridge S & Kerry S. A Practical Guide to Cluster Randomised Trials inHealth Services Research. Wiley & Sons, 2nd ed, 2012.
Hemming K, Lilford R, & Girling A. (2014). Stepped-wedge clusterrandomised controlled trials: a generic framework including parallel andmultiple-level designs. Stat in Med, 34: 181-96.
Hemming K, Haines T, Chilton P, et al. (2015). The stepped wedgecluster randomised trial: rationale, design, analysis, and reporting. BMJ,350: h391.
Hussey M & Hughes J. (2007). Design and analysis of stepped wedgecluster randomized trials. Contemp Clin Trials, 28: 182-91.
Laird N & Ware J. (1982). Random-effects models for longitudinal data.Biometrics, 38: 963-74.
The Gambia Hepatitis Study Group. (1987). The Gambia HepatitisIntervention Study. Cancer Res, 47: 5782-7.
Torgerson D. (2001). Contamination in trials: is cluster randomisation theanswer? BMJ, 322: 355-7.
Nicole SolomonBIOS 790 Stepped Wedge Cluster Randomized Trials