arXiv subjects

Henrik Ravn

Publications and source records attributed to Henrik Ravn.

7 recordsLinked to original sources

arXiv2026

Estimation of treatment effects in presence of differential use of post-randomization concomitant medication with time-to-event outcomes

In placebo-controlled randomized trials, the post-randomization use of concomitant medications may be higher in the placebo arm than in the treatment arm. This may dilute the full benefits of the randomized drug as estimated by the intention-to-treat analysis. We focus on cardiovascular outcomes trials in type-2 diabetes patients of glucose-lowering treatments where patients in the placebo arm are more likely to add other glucose-lowering agents with established cardio-protective properties. As a supplement to the intention-to-treat analysis, we propose a class of estimands within a causal framework that isolates the specific impact of the treatment being studied from that of concomitant treatment use. These estimands are defined under time-dependent treatment interventions to balance exposure to additional medications across intervention arms. We advocate for specific stochastic interventions to achieve this balance while minimizing positivity violations, which arise when certain treatment combinations or characteristics are not sufficiently represented in the data. We employ targeted minimum loss-based estimation (TMLE) to optimize the estimation procedure for our estimands while allowing for flexible adjustments for time-dependent covariates from follow-up visits. Finally, we demonstrate the application of the methods through a simulation study and a real-world example from the LEADER cardiovascular outcomes trial, which assessed cardiovascular risk for liraglutide versus placebo.

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arXiv2026

A non-parametric approach for estimating the correlation between log-rank test statistics with applications to a conjunctive power calculation

We present a method for estimating the correlation between log-rank test statistics evaluating separate null hypotheses for two time-to-event endpoints. The correlation is estimated using subject-level data by a non-parametric approach based on the independent and identically distributed (iid) decomposition of the log-rank test statistic under any alternative. Using the iid decomposition, we are able to make an assumption-lean estimation of the correlation. A motivating example using the developed approach is provided. Here, we illustrate how the suggested approach can be used to give a realistic quantification of expected conjunctive power that can guide the design of a new randomized clinical trial using historical data. Finally, we investigate the method's finite sample properties via a simulation study that confirms unbiased and consistent behavior of the proposed approach. In addition, the simulation study gives insight into the effects of censoring on the correlation between the log-rank test statistics.

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arXiv2025

Improving precision of cumulative incidence estimates in randomized controlled trials with external controls

Augmenting the control arm in clinical trials with external data can improve statistical power for demonstrating treatment effects. In many time-to-event outcome trials, participants are subject to truncation by death. Direct application of methods for competing risks analysis on the joint data may introduce bias, for example, due to covariate shifts between the populations. In this work, we consider transportability of the conditional cause-specific hazard of the event of interest under the control treatment. Under this assumption, we derive semiparametric efficiency bounds of causal cumulative incidences. This allows for quantification of the theoretical efficiency gain from incorporating the external controls. We propose triply robust estimators that can achieve the efficiency bounds, where the trial controls and external controls are made comparable through time-specific weights in a martingale integral. We conducted a simulation study to show the precision gain of the proposed fusion estimators compared to their counterparts without utilizing external controls. As a real data application, we used two cardiovascular outcome trials conducted to assess the safety of glucagon-like peptide-1 agonists. Incorporating the external controls from one trial into the other, we observed a decrease in the standard error of the treatment effects on adverse non-fatal cardiovascular events with all-cause death as the competing risk.

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arXiv2025

Proximal indirect comparison

We consider the problem of indirect comparison, where a treatment arm of interest is absent by design in one randomized controlled trial but available in the other. The former is the target trial, and the latter is the source trial. The identifiability of the target population average treatment effect often relies on conditional transportability assumptions. However, it is a common concern whether all relevant effect modifiers are measured and controlled for. We give a new proximal identification result in the presence of shifted, unobserved effect modifiers based on proxies: an adjustment proxy in both trials and an additional reweighting proxy in the source trial. We propose an estimator which is doubly-robust against misspecifications of the so-called bridge functions and asymptotically normal under mild consistency of estimators for the bridge functions. We use two weight management trials as a context to illustrate selection of proxies and apply our method to compare the weight loss effect of active treatments from these trials.

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arXiv2025

Efficient estimation of the target population average treatment effect from multi-source data

We consider estimation of the target population average treatment effect (TATE) when outcome information is unavailable. Instead, we observe the outcome in multiple source populations and wish to combine the treatment effects therein to make inference on the TATE. In contrast to existing works that assume transportability on the conditional distribution of potential outcomes or conditional treatment-specific means, we work under a weaker form of effect transportability. Following the framework for causally interpretable meta-analysis, we assume transportability of conditional average treatment effects across multiple populations, which may hold with fewer standardization variables. Under this assumption, we derive the semiparametric efficiency bound of the TATE and characterize a class of doubly robust and asymptotically linear estimators. Within this class, an efficient estimator assigns optimal weights to observations from different data sources. Additionally, we suggest estimators of a low-dimensional summary of effect heterogeneity in the target population. We illustrate the use of the proposed estimators on a multicentre weight management clinical trial for semaglutide, a glucagon-like peptide-1 receptor agonist, on overweight or obese patients. Using outcome information from other regions, we estimate the weight loss effect of semaglutide in the United States subgroup.

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arXiv2023

A Causal Roadmap for Hybrid Randomized and Real-World Data Designs: Case Study of Semaglutide and Cardiovascular Outcomes

Introduction: Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: 1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), 2) a single RCT, and 3) a hybrid randomized-external data study. Methods: The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient-time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. Results: In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient-time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). Conclusions: The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.

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arXiv2023

A Causal Roadmap for Generating High-Quality Real-World Evidence

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized controlled trials with outcomes assessed using RWD to fully observational studies. Yet many RWE study proposals lack sufficient detail to evaluate adequacy, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to pre-specify analytic study designs; it addresses a wide range of guidance within a single framework. By requiring transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on pre-specified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers, with companion papers demonstrating application of the Causal Roadmap for specific use cases.

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