Dealing with time-dependent exposures and confounding when defining and estimating attributable fractions-Revisiting estimands and estimators.

The population-attributable fraction (PAF) is commonly interpreted as the proportion of events that can be ascribed to a certain exposure in a certain population. Its estimation is sensitive to common forms of time-dependent bias in the face of a time-dependent exposure. Predominant estimation approaches based on multistate modeling fail to fully eliminate such bias and, as a result, do not permit a causal interpretation, even in the absence of confounding. While recently proposed multistate modeling approaches can successfully eliminate residual time-dependent bias, and moreover succeed to adjust for time-dependent confounding by means of inverse probability of censoring weighting, inadequate application, and misinterpretation prevails in the medical literature. In this paper, we therefore revisit recent work on previously proposed PAF estimands and estimators in settings with time-dependent exposures and competing events and extend this work in several ways. First, we critically revisit the interpretation and applied terminology of these estimands. Second, we further formalize the assumptions under which a causally interpretable PAF estimand can be identified and provide analogous weighting-based representations of the identifying functionals of other proposed estimands. This representation aims to enhance the applied statistician's understanding of different sources of bias that may arise when the aim is to obtain a valid estimate of a causally interpretable PAF. To illustrate and compare these representations, we present a real-life application to observational data from the Ghent University Hospital ICUs to estimate the fraction of ICU deaths attributable to hospital-acquired infections.

On estimation and cross-validation of dynamic treatment regimes with competing risks.

The optimal moment to start renal replacement therapy in a patient with acute kidney injury (AKI) remains a challenging problem in intensive care nephrology. Multiple randomized controlled trials have tried to answer this question, but these contrast only a limited number of treatment initiation strategies. In view of this, we use routinely collected observational data from the Ghent University Hospital intensive care units (ICUs) to investigate different prespecified timing strategies for renal replacement therapy initiation based on time-updated levels of serum potassium, pH, and fluid balance in critically ill patients with AKI with the aim to minimize 30-day ICU mortality. For this purpose, we apply statistical techniques for evaluating the impact of specific dynamic treatment regimes in the presence of ICU discharge as a competing event. We discuss two approaches, a nonparametric one - using an inverse probability weighted Aalen-Johansen estimator - and a semiparametric one - using dynamic-regime marginal structural models. Furthermore, we suggest an easy to implement cross-validation technique to assess the out-of-sample performance of the optimal dynamic treatment regime. Our work illustrates the potential of data-driven medical decision support based on routinely collected observational data.

Timing of dialysis in acute kidney injury using routinely collected data and dynamic treatment regimes.

BACKGROUND AND OBJECTIVES: Defining the optimal moment to start renal replacement therapy (RRT) in acute kidney injury (AKI) remains challenging. Multiple randomized controlled trials (RCTs) addressed this question whilst using absolute criteria such as pH or serum potassium. However, there is a need for identification of the most optimal cut-offs of these criteria. We conducted a causal analysis on routinely collected data (RCD) to compare the impact of different pre-specified dynamic treatment regimes (DTRs) for RRT initiation based on time-updated levels of potassium, pH, and urinary output on 30-day ICU mortality. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients in the ICU of Ghent University Hospital were included at the time they met KDIGO-AKI-stage ≥ 2. We applied inverse-probability-of-censoring-weighted Aalen-Johansen estimators to evaluate 30-day survival under 81 DTRs prescribing RRT initiation under different thresholds of potassium, pH, or persisting oliguria. RESULTS: Out of 13,403 eligible patients (60.8 ± 16.8 years, SOFA 7.0 ± 4.1), 5622 (63.4 ± 15.3 years, SOFA 8.2 ± 4.2) met KDIGO-AKI-stage ≥ 2. The DTR that delayed RRT until potassium ≥ 7 mmol/l, persisting oliguria for 24-36 h, and/or pH < 7.0 (non-oliguric) or < 7.2 (oliguric) despite maximal conservative treatment resulted in a reduced 30-day ICU mortality (from 12.7% [95% CI 11.9-13.6%] under current standard of care to 10.5% [95% CI 9.5-11.7%]; risk difference 2.2% [95% CI 1.3-3.8%]) with no increase in patients starting RRT (from 471 [95% CI 430-511] to 475 [95% CI 342-572]). The fivefold cross-validation benchmark for the optimal DTR resulted in 30-day ICU mortality of 10.7%. CONCLUSIONS: Our causal analysis of RCD to compare RRT initiation at different thresholds of refractory low pH, high potassium, and persisting oliguria identified a DTR that resulted in a decrease in 30-day ICU mortality without increase in number of RRTs. Our results suggest that the current criteria to start RRT as implemented in most RCTs may be suboptimal. However, as our analysis is hypothesis generating, this optimal DTR should ideally be validated in a multicentric RCT.

The importance of the urinary output criterion for the detection and prognostic meaning of AKI.

Most reports on AKI claim to use KDIGO guidelines but fail to include the urinary output (UO) criterion in their definition of AKI. We postulated that ignoring UO alters the incidence of AKI, may delay diagnosis of AKI, and leads to underestimation of the association between AKI and ICU mortality. Using routinely collected data of adult patients admitted to an intensive care unit (ICU), we retrospectively classified patients according to whether and when they would be diagnosed with KDIGO AKI stage ≥ 2 based on baseline serum creatinine (Screa) and/or urinary output (UO) criterion. As outcomes, we assessed incidence of AKI and association with ICU mortality. In 13,403 ICU admissions (62.2% male, 60.8 ± 16.8 years, SOFA 7.0 ± 4.1), incidence of KDIGO AKI stage ≥ 2 was 13.2% when based only the SCrea criterion, 34.3% when based only the UO criterion, and 38.7% when based on both criteria. By ignoring the UO criterion, 66% of AKI cases were missed and 13% had a delayed diagnosis. The cause-specific hazard ratios of ICU mortality associated with KDIGO AKI stage ≥ 2 diagnosis based on only the SCrea criterion, only the UO criterion and based on both criteria were 2.11 (95% CI 1.85-2.42), 3.21 (2.79-3.69) and 2.85 (95% CI 2.43-3.34), respectively. Ignoring UO in the diagnosis of KDIGO AKI stage ≥ 2 decreases sensitivity, may lead to delayed diagnosis and results in underestimation of KDIGO AKI stage ≥ 2 associated mortality.