Statistical analysis
febrile illness
EVENT, RECRUITMENT, FEBRILE ILLNESS, REGRESSION, EVENTS, TYPHOID FEVER
Our primary summary measure of the effect is a rate ratio (RR), from which vaccine effectiveness can be expressed as (1 − RR) × 100%. This will be estimated using an individual-level analysis using Poisson regression that will account for time at risk with censoring at the last known follow-up time. This is expected to be less than 2 years when participants migrate out of the study area. We will present an adjusted RR from a regression model including, covariates, the randomisation strata, participant age, gender, and household size. We will also compute unadjusted RRs but the adjusted RR will be considered ‘primary’. A difference in rates will also be computed after fitting the regression model, by standardization [For measures of vaccine effectiveness which are described here as contrasts between vaccinated participants in vaccine clusters and unvaccinated participants in non-vaccine clusters, such as the total effect, we will use instrumental variable methods. Under this approach, while data from all participants are included in the analysis, we estimate the effect of vaccine only in those who would take it if available in their cluster (i.e. would ‘comply’). Although we do not observe this compliance in the non-vaccine arm, by randomisation we would expect the same proportion as in the vaccine arm, and this underlies the approach. The details of exactly how this will be done will be specified in subsequent versions of the statistical analysis plan.The time at risk for the overall effect will begin 28 days after vaccination is completed in all intervention clusters. For participants that move into a trial cluster from outside the trial area, time at risk for the overall effect will begin at recruitment. For the total effect, time at risk for non-vaccine clusters begins as for the overall effect. In vaccine clusters, this will begin 28 days after vaccination is completed across clusters or 28 days after an individual is vaccinated (whichever is later) and no risk-time is contributed by those unvaccinated. Time at risk ends at the study’s close, the time of an event (culture-confirmed typhoid fever), withdrawal from the study, or migration from the study area or within the area but between trial arms (whichever is earliest).The primary outcome might have missing data if a trial participant with a febrile illness visits a study-associated healthcare facility but refuses a blood culture. We will describe the frequency of such refusals by trial arm. We will multiply impute the blood culture results for these participants under the missing at random assumption and conduct sensitivity analyses to explore the impact on the total and overall vaccine effect estimates of making alternative assumptions.We do not have any plans for interim analyses of vaccine effectiveness, or subgroup analyses except that we will estimate the total effect in participants aged 1–14 years. We will conduct simple descriptive analyses of safety events in vaccinated participants, and of vaccine uptake in eligible vaccine arm participants.A first draft of a detailed statistical analysis plan has been created and will be finalised before analysis.