[Methods for controlling time-varying confounding in pharmaco-epidemiological studies: a systematic reveiw].

Objective

To systematically review the application of methods for controlling time-varying confounding in pharmaco-epidemiological studies.

Methods

PubMed, Embase, CNKI, and Wanfang were searched for pharmaco-epidemiological studies involving time-varying confounding on June 15th, 2020. The basic characteristics, drug exposure and outcome, time-varying confounders and the application of methods to control these confounders were analyzed.

Results

A total of 298 articles were included. An increasing trend was observed in numbers of studies dealing with time-varying confounding in pharmaco-epidemiological studies in recent years. A total of 106 (35.6%) studies involved the safety or effectiveness of medication use in HIV/AIDS patients and 92 of them involved antiretroviral drugs. The most common outcome was mortality, while the most commonly concerned time-dependent confounders were laboratory examination results (179, 60.1%), comorbidities (136, 45.6%), and co-used medications (108, 36.2%). Marginal structure model (MSM) and inverse probability of treatment weighting (IPTW) were the most commonly used methods to control time-varying confounding factors (244, 81.9%). Compared with the results after properly controlling time-varying confounding, traditional methods adjusting only baseline confounders resulted in substantial bias (median 18.2%, interquartile range, 7.4%-40.8%). As for basic assumptions needed for causal methods controlling time-varying confounding, 28.9% and 64.8% of the included studies examined or discussed the assumptions of positivity and no unmeasured confounders, respectively.

Conclusions

At present, most of the fields of drug therapy for chronic diseases still pay insufficient attention to time-varying confoundings. Information collected in routine medical practice, such as laboratory tests, comorbidities, and co-used drugs, was the most commonly concerned time-varying confounder. MSM and IPTW were the most commonly applied methods for dealing with time-varying confounding.