Elucidating vaccine efficacy using a correlate of protection, demographics, and logistic regression.

BACKGROUND: Vaccine efficacy (VE) assessed in a randomized controlled clinical trial can be affected by demographic, clinical, and other subject-specific characteristics evaluated as baseline covariates. Understanding the effect of covariates on efficacy is key to decisions by vaccine developers and public health authorities. METHODS: This work evaluates the impact of including correlate of protection (CoP) data in logistic regression on its performance in identifying statistically and clinically significant covariates in settings typical for a vaccine phase 3 trial. The proposed approach uses CoP data and covariate data as predictors of clinical outcome (diseased versus non-diseased) and is compared to logistic regression (without CoP data) to relate vaccination status and covariate data to clinical outcome. RESULTS: Clinical trial simulations, in which the true relationship between CoP data and clinical outcome probability is a sigmoid function, show that use of CoP data increases the positive predictive value for detection of a covariate effect. If the true relationship is characterized by a decreasing convex function, use of CoP data does not substantially change positive or negative predictive value. In either scenario, vaccine efficacy is estimated more precisely (i.e., confidence intervals are narrower) in covariate-defined subgroups if CoP data are used, implying that using CoP data increases the ability to determine clinical significance of baseline covariate effects on efficacy. CONCLUSIONS: This study proposes and evaluates a novel approach for assessing baseline demographic covariates potentially affecting VE. Results show that the proposed approach can sensitively and specifically identify potentially important covariates and provides a method for evaluating their likely clinical significance in terms of predicted impact on vaccine efficacy. It shows further that inclusion of CoP data can enable more precise VE estimation, thus enhancing study power and/or efficiency and providing even better information to support health policy and development decisions.

Covariate adjustment in randomized controlled trials: General concepts and practical considerations.

There has been a growing interest in covariate adjustment in the analysis of randomized controlled trials in past years. For instance, the US Food and Drug Administration recently issued guidance that emphasizes the importance of distinguishing between conditional and marginal treatment effects. Although these effects may sometimes coincide in the context of linear models, this is not typically the case in other settings, and this distinction is often overlooked in clinical trial practice. Considering these developments, this article provides a review of when and how to use covariate adjustment to enhance precision in randomized controlled trials. We describe the differences between conditional and marginal estimands and stress the necessity of aligning statistical analysis methods with the chosen estimand. In addition, we highlight the potential misalignment of commonly used methods in estimating marginal treatment effects. We hereby advocate for the use of the standardization approach, as it can improve efficiency by leveraging the information contained in baseline covariates while remaining robust to model misspecification. Finally, we present practical considerations that have arisen in our respective consultations to further clarify the advantages and limitations of covariate adjustment.

Propensity Score Analysis With Baseline and Follow-Up Measurements of the Outcome Variable.

A common feature in cohort studies is when there is a baseline measurement of the continuous follow-up or outcome variable. Common examples include baseline measurements of physiological characteristics such as blood pressure or heart rate in studies where the outcome is post-baseline measurement of the same variable. Methods incorporating the propensity score are increasingly being used to estimate the effects of treatments using observational studies. We examined six methods for incorporating the baseline value of the follow-up variable when using propensity score matching or weighting. These methods differed according to whether the baseline value of the follow-up variable was included or excluded from the propensity score model, whether subsequent regression adjustment was conducted in the matched or weighted sample to adjust for the baseline value of the follow-up variable, and whether the analysis estimated the effect of treatment on the follow-up variable or on the change from baseline. We used Monte Carlo simulations with 750 scenarios. While no analytic method had uniformly superior performance, we provide the following recommendations: first, when using weighting and the ATE is the target estimand, use an augmented inverse probability weighted estimator or include the baseline value of the follow-up variable in the propensity score model and subsequently adjust for the baseline value of the follow-up variable in a regression model. Second, when the ATT is the target estimand, regardless of whether using weighting or matching, analyze change from baseline using a propensity score that excludes the baseline value of the follow-up variable.

Modeling unmeasured baseline information in observational time-to-event data subject to delayed study entry.

Unmeasured baseline information in left-truncated data situations frequently occurs in observational time-to-event analyses. For instance, a typical timescale in trials of antidiabetic treatment is "time since treatment initiation", but individuals may have initiated treatment before the start of longitudinal data collection. When the focus is on baseline effects, one widespread approach is to fit a Cox proportional hazards model incorporating the measurements at delayed study entry. This has been criticized because of the potential time dependency of covariates. We tackle this problem by using a Bayesian joint model that combines a mixed-effects model for the longitudinal trajectory with a proportional hazards model for the event of interest incorporating the baseline covariate, possibly unmeasured in the presence of left truncation. The novelty is that our procedure is not used to account for non-continuously monitored longitudinal covariates in right-censored time-to-event studies, but to utilize these trajectories to make inferences about missing baseline measurements in left-truncated data. Simulating times-to-event depending on baseline covariates we also compared our proposal to a simpler two-stage approach which performed favorably. Our approach is illustrated by investigating the impact of baseline blood glucose levels on antidiabetic treatment failure using data from a German diabetes register.

Matching in cluster randomized trials using the Goldilocks Approach.

In group or cluster-randomized trials (GRTs), matching is a technique that can be used to improve covariate balance. When baseline data are available, we suggest a strategy that can be used to achieve the desired balance between treatment and control groups across numerous potential confounding variables. This strategy minimizes the overall within-pair Mahalanobis distance; and involves iteratively: 1) making pairs that minimize the distance between pairs of clusters with respect to potentially confounding variables; 2) visually assessing the potential effects of these pairs and resulting possible randomizations; and 3) reweighting variables of selecting weights to make pairs of clusters. In step 2, we plot the between-arm differences with a parallel-coordinates plot. Investigators can compare plots of different weighting schemes to determine the one that best suits their needs prior to the actual, final, randomization. We demonstrate application of the approach with the Mupirocin-Iodophor Swap Out trial. A webapp is provided.