Propensity score analysis is a popular method to control for confounding in observational studies. A challenge in propensity methods is missing values in confounders. Several strategies for handling missing values exist, but guidance in choosing the best method is needed. In this simulation study, we compared four strategies of handling missing covariate values in propensity matching and propensity weighting. These methods include: complete case analysis, missing indicator method, multiple imputation and combining multiple imputation and missing indicator method. Concurrently, we aimed to provide guidance in choosing the optimal strategy. Simulated scenarios varied regarding missing mechanism, presence of effect modification or unmeasured confounding. Additionally, we demonstrated how missingness graphs help clarifying the missing structure. When no effect modification existed, complete case analysis yielded valid causal treatment effects even when data were missing not at random. In some situations, complete case analysis was also able to partially correct for unmeasured confounding. Multiple imputation worked well if the data were missing (completely) at random, and if the imputation model was correctly specified. In the presence of effect modification, more complex imputation models than default options of commonly used statistical software were required. Multiple imputation may fail when data are missing not at random. Here, combining multiple imputation and the missing indicator method reduced the bias as the missing indicator variable can be a proxy for unobserved confounding. The optimal way to handle missing values in covariates of propensity score models depends on the missing data structure and the presence of effect modification. When effect modification is present, default settings of imputation methods may yield biased results even if data are missing at random.

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In epidemiological research it is common to encounter measurements affected by medication use, such as blood pressure lowered by antihypertensive drugs. When one is interested in the relation between the variables not affected by medication, ignoring medication use can cause bias. Several methods have been proposed, but the problem is often ignored or handled with generic methods, such as excluding individuals on medication or adjusting for medication use in the analysis. This study aimed to investigate methods for handling measurements affected by medication use when one is interested in the relation between the unaffected variables and to provide guidance for how to optimally handle the problem. We focused on linear regression and distinguish between the situation where the affected measurement is an exposure, confounder or outcome. In the Netherlands Epidemiology of Obesity study and in several simulated settings, we compared generic and more advanced methods, such as substituting or adding a fixed value to the treated values, regression calibration, censored normal regression, Heckman’s treatment model and multiple imputation methods. We found that often-used methods such as adjusting for medication use could result in substantial bias and that methods for handling medication use should be chosen cautiously.

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Measurement errors commonly occur in 24-h hormonal data and may affect the outcomes of such studies. Measurement errors often appear as outliers in such data sets; however, no well-established method is available for their automatic detection. In this study, we aimed to compare performances of different methods for outlier detection in hormonal serial data. Hormones (glucose, insulin, thyroid-stimulating hormone, cortisol, and growth hormone) were measured in blood sampled every 10 min for 24 h in 38 participants of the Leiden Longevity Study. Four methods for detecting outliers were compared: (1) eyeballing, (2) Tukey’s fences, (3) stepwise approach, and (4) the expectation-maximization (EM) algorithm. Eyeballing detects outliers based on experts’ knowledge, and the stepwise approach incorporates physiological knowledge with a statistical algorithm. Tukey’s fences and the EM algorithm are data-driven methods, using interquartile range and a mathematical algorithm to identify the underlying distribution, respectively. The performance of the methods was evaluated based on the number of outliers detected and the change in statistical outcomes after removing detected outliers. Eyeballing resulted in the lowest number of outliers detected (1.0% of all data points), followed by Tukey’s fences (2.3%), the stepwise approach (2.7%), and the EM algorithm (11.0%). In all methods, the mean hormone levels did not change materially after removing outliers. However, their minima were affected by outlier removal. Although removing outliers affected the correlation between glucose and insulin on the individual level, when averaged over all participants, none of the 4 methods influenced the correlation. Based on our results, the EM algorithm is not recommended given the high number of outliers detected, even where data points are physiologically plausible. Since Tukey’s fences is not suitable for all types of data and eyeballing is time-consuming, we recommend the stepwise approach for outlier detection, which combines physiological knowledge and an automated process.