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Multiple imputation with missing indicators as proxies for unmeasured variables: simulation studySperrin, Matthew; orcid: 0000-0002-5351-9960; email: firstname.lastname@example.org; Martin, Glen P. (BioMed Central, 2020-07-08)Abstract: Background: Within routinely collected health data, missing data for an individual might provide useful information in itself. This occurs, for example, in the case of electronic health records, where the presence or absence of data is informative. While the naive use of missing indicators to try to exploit such information can introduce bias, its use in conjunction with multiple imputation may unlock the potential value of missingness to reduce bias in causal effect estimation, particularly in missing not at random scenarios and where missingness might be associated with unmeasured confounders. Methods: We conducted a simulation study to determine when the use of a missing indicator, combined with multiple imputation, would reduce bias for causal effect estimation, under a range of scenarios including unmeasured variables, missing not at random, and missing at random mechanisms. We use directed acyclic graphs and structural models to elucidate a variety of causal structures of interest. We handled missing data using complete case analysis, and multiple imputation with and without missing indicator terms. Results: We find that multiple imputation combined with a missing indicator gives minimal bias for causal effect estimation in most scenarios. In particular the approach: 1) does not introduce bias in missing (completely) at random scenarios; 2) reduces bias in missing not at random scenarios where the missing mechanism depends on the missing variable itself; and 3) may reduce or increase bias when unmeasured confounding is present. Conclusion: In the presence of missing data, careful use of missing indicators, combined with multiple imputation, can improve causal effect estimation when missingness is informative, and is not detrimental when missingness is at random.