A new strategy for meta-analysis of continuous covariates in observational studies

When several studies are available, a meta-analytic assessment of the effect of a risk or prognostic factor on an outcome is often required. We propose a new strategy, requiring individual participant data, to provide a summary estimate of the functional relationship between a continuous covariate and the outcome in a regression model, adjusting for confounding factors. Our procedure comprises three steps. First, we determine a confounder model. Ideally, the latter should include the same variables across studies, but this may be impossible. Next, we estimate the functional form for the continuous variable of interest in each study, adjusted for the confounder model. Finally, we combine the individual functions by weighted averaging to obtain a summary estimate of the function. Fractional polynomial methodology and pointwise weighted averaging of functions are the key components. In contrast to a pooled analysis, our approach can reflect more variability between functions from different studies and more flexibility with respect to confounders. We illustrate the procedure by using data from breast cancer patients in the Surveillance, Epidemiology, and End Results Program database, where we consider data from nine individual registries as separate studies. We estimate the functional forms for the number of positive lymph nodes and age. The former is an example where a strong prognostic effect has long been recognized, whereas the prognostic effect of the latter is weak or even controversial. We further discuss some general issues that are found in meta-analyses of observational studies.