Consistent Bayesian meta-analysis on subgroup specific effects and interactions

Commonly, clinical trials report effects not only for the full study population but also for patient subgroups. Meta-analyses of subgroup-specific effects and treatment-by-subgroup interactions may be inconsistent, especially when trials apply different subgroup weightings. We show that meta-regression can, in principle, with a contribution adjustment, recover the same interaction inference regardless of whether interaction data or subgroup data are used. Our Bayesian framework for subgroup-data interaction meta-analysis inherently (i) adjusts for varying relative subgroup contribution, quantified by the information fraction (IF) within a trial; (ii) is robust to prevalence imbalance and variation; (iii) provides a self-contained, model-based approach; and (iv) can be used to incorporate prior information into interaction meta-analyses with few studies.The method is demonstrated using an example with as few as seven trials of disease-modifying therapies in relapsing-remitting multiple sclerosis. The Bayesian Contribution-adjusted Meta-analysis by Subgroup (CAMS) indicates a stronger treatment-by-disability interaction (relapse rate reduction) in patients with lower disability (EDSS <= 3.5) compared with the unadjusted model, while results for younger patients (age < 40 years) are unchanged.By controlling subgroup contribution while retaining subgroup interpretability, this approach enables reliable interaction decision-making when published subgroup data are available.Although the proposed CAMS approach is presented in a Bayesian context, it can also be implemented in frequentist or likelihood frameworks.

Utilizing subgroup information in random-effects meta-analysis of few studies

Random-effects meta-analyses are widely used for evidence synthesis in medical research. However, conventional methods based on large-sample approximations often exhibit poor performance in case of very few studies (e.g., 2 to 4), which is very common in practice. Existing methods aiming to improve small-sample performance either still suffer from poor estimates of heterogeneity or result in very wide confidence intervals. Motivated by meta-analyses evaluating surrogate outcomes, where units nested within a trial are often exploited when the number of trials is small, we propose an inference approach based on a common-effect estimator synthesizing data from the subgroup-level instead of the study-level. Two DerSimonian-Laird type heterogeneity estimators are derived using the subgroup-level data, and are incorporated into the Henmi-Copas type variance to adequately reflect variance components. We considered t-quantile based intervals to account for small-sample properties and used flexible degrees of freedom to reduce interval lengths. A comprehensive simulation is conducted to study the performance of our methods depending on various magnitudes of subgroup effects as well as subgroup prevalences. Some general recommendations are provided on how to select the subgroups, and methods are illustrated using two example applications.

A studentized permutation test for the treatment effect in individual participant data meta-analysis

Meta-analysis is a well-established tool used to combine data from several independent studies, each of which usually compares the effect of an experimental treatment with a control group. While meta-analyses are often performed using aggregated study summaries, they may also be conducted using individual participant data (IPD). Classical meta-analysis models may be generalized to handle continuous IPD by formulating them within a linear mixed model framework. IPD meta-analyses are commonly based on a small number of studies. Technically, inference for the overall treatment effect can be performed using Student-t approximation. However, as some approaches may not adequately control the type I error, Satterthwaite's or Kenward-Roger's method have been suggested to set the degrees-of-freedom parameter. The latter also adjusts the standard error of the treatment effect estimator. Nevertheless, these methods may be conservative. Since permutation tests are known to control the type I error and offer robustness to violations of distributional assumptions, we propose a studentized permutation test for the treatment effect based on permutations of standardized residuals across studies in IPD meta-analysis. Also, we construct confidence intervals for the treatment effect based on this test. The first interval is derived from the percentiles of the permutation distribution. The second interval is obtained by searching values closest to the effect estimate that are just significantly different from the true effect. In a simulation study, we demonstrate satisfactory performance of the proposed methods, often producing shorter confidence intervals compared with competitors.

Meta-analytic-predictive priors based on a single study

Meta-analytic-predictive (MAP) priors have been proposed as a generic approach to deriving informative prior distributions, where external empirical data are processed to learn about certain parameter distributions. The use of MAP priors is also closely related to shrinkage estimation (also sometimes referred to as dynamic borrowing). A potentially odd situation arises when the external data consist only of a single study. Conceptually this is not a problem, it only implies that certain prior assumptions gain in importance and need to be specified with particular care. We outline this important, not uncommon special case and demonstrate its implementation and interpretation based on the normal-normal hierarchical model. The approach is illustrated using example applications in clinical medicine.

ISCB46 - 2025 Conference