TY - JOUR
T1 - Statistical power and validity of Ebola vaccine trials in Sierra Leone: a simulation study of trial design and analysis
AU - Bellan, Steven E
AU - Pulliam, Juliet R C
AU - Pearson, Carl A B
AU - Champredon, David
AU - Fox, Spencer J
AU - Skrip, Laura
AU - Galvani, Alison
AU - Gambhir, Manoj
AU - Lopman, Benjamin A
AU - Porco, Travis C
AU - Meyers, Lauren Ancel
AU - Dushoff, Jonathan
PY - 2015
Y1 - 2015
N2 - Background: Safe and effective vaccines could help to end the ongoing Ebola virus disease epidemic in parts of west Africa, and mitigate future outbreaks of the virus. We assess the statistical validity and power of randomised controlled trial (RCT) and stepped-wedge cluster trial (SWCT) designs in Sierra Leone, where the incidence of Ebola virus disease is spatiotemporally heterogeneous, and is decreasing rapidly. Methods: We projected district-level Ebola virus disease incidence for the next 6 months, using a stochastic model fitted to data from Sierra Leone. We then simulated RCT and SWCT designs in trial populations comprising geographically distinct clusters at high risk, taking into account realistic logistical constraints, and both individual-level and cluster-level variations in risk. We assessed false-positive rates and power for parametric and non-parametric analyses of simulated trial data, across a range of vaccine efficacies and trial start dates. Findings: For an SWCT, regional variation in Ebola virus disease incidence trends produced increased false-positive rates (up to 0?15 at a=0?05) under standard statistical models, but not when analysed by a permutation test, whereas analyses of RCTs remained statistically valid under all models. With the assumption of a 6-month trial starting on Feb 18, 2015, we estimate the power to detect a 90 effective vaccine to be between 49 and 89 for an RCT, and between 6 and 26 for an SWCT, depending on the Ebola virus disease incidence within the trial population. We estimate that a 1-month delay in trial initiation will reduce the power of the RCT by 20 and that of the SWCT by 49 . Interpretation: Spatiotemporal variation in infection risk undermines the statistical power of the SWCT. This variation also undercuts the SWCT s expected ethical advantages over the RCT, because an RCT, but not an SWCT, can prioritise vaccination of high-risk clusters. Funding: US National Institutes of Health, US National Science Foundation, and Canadian Institutes of Health Research.
AB - Background: Safe and effective vaccines could help to end the ongoing Ebola virus disease epidemic in parts of west Africa, and mitigate future outbreaks of the virus. We assess the statistical validity and power of randomised controlled trial (RCT) and stepped-wedge cluster trial (SWCT) designs in Sierra Leone, where the incidence of Ebola virus disease is spatiotemporally heterogeneous, and is decreasing rapidly. Methods: We projected district-level Ebola virus disease incidence for the next 6 months, using a stochastic model fitted to data from Sierra Leone. We then simulated RCT and SWCT designs in trial populations comprising geographically distinct clusters at high risk, taking into account realistic logistical constraints, and both individual-level and cluster-level variations in risk. We assessed false-positive rates and power for parametric and non-parametric analyses of simulated trial data, across a range of vaccine efficacies and trial start dates. Findings: For an SWCT, regional variation in Ebola virus disease incidence trends produced increased false-positive rates (up to 0?15 at a=0?05) under standard statistical models, but not when analysed by a permutation test, whereas analyses of RCTs remained statistically valid under all models. With the assumption of a 6-month trial starting on Feb 18, 2015, we estimate the power to detect a 90 effective vaccine to be between 49 and 89 for an RCT, and between 6 and 26 for an SWCT, depending on the Ebola virus disease incidence within the trial population. We estimate that a 1-month delay in trial initiation will reduce the power of the RCT by 20 and that of the SWCT by 49 . Interpretation: Spatiotemporal variation in infection risk undermines the statistical power of the SWCT. This variation also undercuts the SWCT s expected ethical advantages over the RCT, because an RCT, but not an SWCT, can prioritise vaccination of high-risk clusters. Funding: US National Institutes of Health, US National Science Foundation, and Canadian Institutes of Health Research.
UR - http://www.sciencedirect.com/science/article/pii/S1473309915701398
U2 - 10.1016/S1473-3099(15)70139-8
DO - 10.1016/S1473-3099(15)70139-8
M3 - Article
SN - 1473-3099
VL - 15
SP - 703
EP - 710
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 6
ER -
