Exploiting nonsystematic covariate monitoring to broaden the scope of evidence about the causal effects of adaptive treatment strategies.

In studies based on electronic health records (EHR), the frequency of covariate monitoring can vary by covariate type, across patients, and over time, which can limit the generalizability of inferences about the effects of adaptive treatment strategies. In addition, monitoring is a health intervention in itself with costs and benefits, and stakeholders may be interested in the effect of monitoring when adopting adaptive treatment strategies. This paper demonstrates how to exploit nonsystematic covariate monitoring in EHR-based studies to both improve the generalizability of causal inferences and to evaluate the health impact of monitoring when evaluating adaptive treatment strategies. Using a real world, EHR-based, comparative effectiveness research (CER) study of patients with type II diabetes mellitus, we illustrate how the evaluation of joint dynamic treatment and static monitoring interventions can improve CER evidence and describe two alternate estimation approaches based on inverse probability weighting (IPW). First, we demonstrate the poor performance of the standard estimator of the effects of joint treatment-monitoring interventions, due to a large decrease in data support and concerns over finite-sample bias from near-violations of the positivity assumption (PA) for the monitoring process. Second, we detail an alternate IPW estimator using a no direct effect assumption. We demonstrate that this estimator can improve efficiency but at the potential cost of increase in bias from violations of the PA for the treatment process.

Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/µl compared with 500 cells/µl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.

Identification of the joint effect of a dynamic treatment intervention and a stochastic monitoring intervention under the no direct effect assumption.

The management of chronic conditions is characterized by frequent re-assessment of therapy decisions in response to the patient's changing condition over the course of the illness. Evidence most suitable to inform care thus often concerns the contrast of adaptive treatment strategies that repeatedly personalize treatment decisions over time using the latest accumulated data available from the patient's previous clinic visits such as laboratory exams (e.g., hemoglobin A1c measurements in diabetes care). The frequency at which such information is monitored implicitly defines the causal estimand that is typically evaluated in an observational or randomized study of such adaptive treatment strategies. Analytic control of monitoring with standard estimation approaches for time-varying interventions can therefore not only improve study generalizibility but also inform the optimal timing of clinical surveillance. Valid inference with these estimators requires the upholding of a positivity assumption that can hinder their applicability. To potentially weaken this requirement for monitoring control, we introduce identifiability results that will facilitate the derivation of alternate estimators of effects defined by general joint treatment and monitoring interventions in the context of time-to-event outcomes. These results are developed based on the nonparametric structural equation modeling framework using a no direct effect assumption originally introduced in a prior paper that inspired this work. The relevance and scope of the results presented here are illustrated with examples in diabetes comparative effectiveness research.