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A popular modeling approach for competing risks analysis in longitudinal studies is the proportional subdistribution hazards model by Fine and Gray (1999. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association94, 496-509). This model is widely used for the analysis of continuous event times in clinical and epidemiological studies. However, it does not apply when event times are measured on a discrete time scale, which is a likely scenario when events occur between pairs of consecutive points in time (e.g., between two follow-up visits of an epidemiological study) and when the exact lengths of the continuous time spans are not known. To adapt the Fine and Gray approach to this situation, we propose a technique for modeling subdistribution hazards in discrete time. Our method, which results in consistent and asymptotically normal estimators of the model parameters, is based on a weighted ML estimation scheme for binary regression. We illustrate the modeling approach by an analysis of nosocomial pneumonia in patients treated in hospitals. [ABSTRACT FROM AUTHOR]

For large cohort studies with rare outcomes, the nested case-control design only requires data collection of small subsets of the individuals at risk. These are typically randomly sampled at the observed event times and a weighted, stratified analysis takes over the role of the full cohort analysis. Motivated by observational studies on the impact of hospital-acquired infection on hospital stay outcome, we are interested in situations, where not necessarily the outcome is rare, but time-dependent exposure such as the occurrence of an adverse event or disease progression is. Using the counting process formulation of general nested case-control designs, we propose three sampling schemes where not all commonly observed outcomes need to be included in the analysis. Rather, inclusion probabilities may be time-dependent and may even depend on the past sampling and exposure history. A bootstrap analysis of a full cohort data set from hospital epidemiology allows us to investigate the practical utility of the proposed sampling schemes in comparison to a full cohort analysis and a too simple application of the nested case-control design, if the outcome is not rare. [ABSTRACT FROM AUTHOR]

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit‐risk ratio. The statistical analysis of AEs is complicated by the fact that the follow‐up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow‐up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta‐analyses of AE data and sketch possible solutions. [ABSTRACT FROM AUTHOR]

The aim of this work is to shed some light on common issues in the statistical analysis of adverse events (AEs) in clinical trials, when the main outcome is a time-to-event endpoint. To begin, we show that AEs are always subject to competing risks. That is, the occurrence of a certain AE may be precluded by occurrence of the main time-to-event outcome or by occurrence of another (fatal) AE. This has raised concerns on 'informative' censoring. We show that, in general, neither simple proportions nor Kaplan-Meier estimates of AE occurrence should be used, but common survival techniques for hazards that censor the competing event are still valid, but incomplete analyses. They must be complemented by an analogous analysis of the competing event for inference on the cumulative AE probability. The commonly used incidence rate (or incidence density) is a valid estimator of the AE hazard assuming it to be time constant. An estimator of the cumulative AE probability can be derived if the incidence rate of AE is combined with an estimator of the competing hazard. We discuss less restrictive analyses using non-parametric and semi-parametric approaches. We first consider time-to-first-AE analyses and then briefly discuss how they can be extended to the analysis of recurrent AEs. We will give a practical presentation with illustration of the methods by a simple example. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Comparison of Statistical Approaches for Dealing with Immortal Time Bias in Drug Effectiveness Studies," by M. E. Karim et al. in the 2016 issue.

Research on hospital-acquired infections (HAIs) requires the highest methodological standards to minimize the risk of bias and to avoid misleading interpretation. There are two major issues related specifically to studies in this area, namely the timing of infection and the occurrence of so-called competing risks, which deserve special attention. Just as a patient who acquires a serious infection during hospital admission needs appropriate antibiotic treatment, data being collected in studies on hospital-acquired infections need appropriate statistical analysis. We illustrate the urgent need for appropriate statistical treatment of hospital-acquired infections with some examples from recently conducted studies.The considerations presented are relevant for investigations on risk factors for HAIs as well as for outcome studies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Many studies disregard the time dependence of nosocomial infection when examining length of hospital stay and the associated financial costs. This leads to the “time-dependent bias,” which biases multiplicative hazard ratios. We demonstrate the time-dependent bias on the additive scale of extra length of stay. Methods: To estimate the extra length of stay due to infection, we used a multistate model that accounted for the time of infection. For comparison we used a generalized linear model assuming a gamma distribution, a commonly used model that ignores the time of infection. We applied these two methods to a large prospective cohort of hospital admissions from Argentina, and compared the methods'' performance using a simulation study. Results: For the Argentina data the extra length of stay due to nosocomial infection was 11.23 days when ignoring time dependence and only 1.35 days after accounting for the time of infection. The simulations showed that ignoring time dependence consistently overestimated the extra length of stay. This overestimation was similar for different rates of infection and even when an infection prolonged or shortened stay. We show examples where the time-dependent bias remains unchanged for the true discharge hazard ratios, but the bias for the extra length of stay is doubled because length of stay depends on the infection hazard. Conclusions: Ignoring the timing of nosocomial infection gives estimates that greatly overestimate its effect on the extra length of hospital stay. [Copyright &y& Elsevier]

Epidemiologists often study the incidence density (ID; also known as incidence rate), which is the number of observed events divided by population-time at risk. Its computational simplicity makes it attractive in applications, but a common concern is that the ID is misleading if the underlying hazard is not constant in time. Another difficulty arises if competing events are present, which seems to have attracted less attention in the literature. However, there are situations in which the presence of competing events obscures the analysis more than nonconstant hazards do. The authors illustrate such a situation using data on infectious complications in patients receiving stem cell transplants, showing that a certain transplant type reduces the infection ID but eventually increases the cumulative infection probability because of its effect on the competing event. The authors investigate the extent to which IDs allow for a reasonable analysis of competing events. They suggest a simple multistate-type graphic based on IDs, which immediately displays the competing event situation. The authors also suggest a more formal summary analysis in terms of a best approximating effect on the cumulative event probability, considering another data example of US women infected with human immunodeficiency virus. Competing events and even more complex event patterns may be adequately addressed with the suggested methodology. [ABSTRACT FROM PUBLISHER]

Objective: Time-dependent bias occurs when future exposure status is analyzed as being known with start of observation. As this bias is common, we sought to determine whether it always leads to biased effect estimation. We also sought to determine the direction of the effect bias.Study Design and Setting: We derived an easy mathematical proof investigating the nature of time-dependent bias. We applied the general mathematical result to data from a prospective cohort study on the incidence of hospital infection in intensive care: Here, we investigated the effect of time-dependent hospital infection status on intensive care unit stay. The nature of time-dependent bias was also illustrated graphically.Results: Biased effect estimation is a mathematically inevitable consequence of time-dependent bias, because the number of individuals at risk of exposure is distorted over the course of time. In case of a time-dependent exposure that prolongs time until the study endpoint, the prolonging effect will be overestimated.Conclusion: Because time-dependent bias inevitably leads to erroneous findings, it is a major concern that it is common in the clinical literature. Time-dependent bias can be avoided by proper hazard-based analyses. [ABSTRACT FROM AUTHOR]