arXiv subjects

Ronald J. Bosch

Publications and source records attributed to Ronald J. Bosch.

4 recordsLinked to original sources

arXiv2025

Causal indirect effect of an HIV curative treatment: mediators subject to an assay limit and measurement error

Causal mediation analysis decomposes the total effect of a treatment on an outcome into the indirect effect, operating through the mediator, and the direct effect, operating through other pathways. One can estimate only the pure indirect effect/indirect effect relative to no treatment, rather than the total effect by combining a hypothesized treatment effect on the mediator with outcome data without treatment. Furthermore, the mediation formula holds for the pure indirect effect (or the organic indirect effect relative to no treatment) regardless of whether there is an interaction between the treatment and mediator in the outcome model. This methodology holds significant promise in selecting prospective treatments based on their indirect effect for further evaluation in randomized clinical trials. We apply this methodology to assess which of two measures of HIV persistence is a more promising target for future HIV curative treatments. We combine a hypothesized treatment effect on two mediators, and outcome data without treatment, to compare the indirect effect of treatments targeting these mediators. Some HIV persistence measurements fall below the assay limit, leading to left-censored mediators. We address this by assuming the outcome model extends to mediators below the assay limit and use maximum likelihood estimation. To address measurement error in the mediators, we adjust our estimates. Using data from completed ACTG studies, we estimate the pure or organic indirect effect of potential curative HIV treatments on viral suppression through weeks 4 and 8 after HIV medication interruption, mediated by HIV persistence measures.

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arXiv2023

The survival-incorporated median versus the median in the survivors or in the always-survivors: What are we measuring? And why?

Many clinical studies evaluate the benefit of a treatment based on both survival and other continuous/ordinal clinical outcomes, such as Quality of Life scores. In these studies, when subjects die before the follow-up assessment, the clinical outcomes become undefined and are truncated by death. Treating outcomes as "missing" or "censored" due to death can be misleading for treatment effect evaluation. We show that if we use the median in the survivors or in the always-survivors as estimands to summarize clinical outcomes, we may conclude that a trade-off exists between the probability of survival and good clinical outcomes, even in settings where both the probability of survival and the probability of any good clinical outcome are better for one treatment. Therefore, we advocate not always treating death as a mechanism through which clinical outcomes are missing, but rather as part of the outcome measure. To account for the survival status, we describe the survival-incorporated median as an alternative summary measure for outcomes in the presence of death. The survival-incorporated median is the threshold such that 50% of the population is alive with an outcome above that threshold. Through conceptual examples and an application to a prostate cancer treatment study, we show that the survival-incorporated median provides a simple and useful summary measure to inform clinical practice.

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arXiv2021

Causal mediation analysis with mediator values below an assay limit

Causal indirect and direct effects provide an interpretable method for decomposing the total effect of an exposure on an outcome into the effect through a mediator and the effect through all other pathways. When the mediator is a biomarker, values can be subject to an assay lower limit. The mediator is affected by the treatment and is a putative cause of the outcome, so the assay lower limit presents a compounded problem in mediation analysis. We propose three approaches to estimate indirect and direct effects with a mediator subject to an assay limit: 1. extrapolation 2. numerical optimization and integration of the observed likelihood and 3. the Monte Carlo Expectation Maximization (MCEM) algorithm. Since the described methods solely rely on the so-called Mediation Formula, they apply to most approaches to causal mediation analysis: natural, separable, and organic indirect and direct effects. A simulation study compares the estimation approaches to imputing with half the assay limit. Using HIV interruption study data from the AIDS Clinical Trials Group described in [Li et al. 2016, AIDS; Lok \& Bosch 2021, Epidemiology], we illustrate our methods by estimating the organic/pure indirect effect of a hypothetical HIV curative treatment on viral suppression mediated by two HIV persistence measures: cell-associated HIV-RNA (N = 124) and single copy plasma HIV-RNA (N = 96).

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arXiv2020

Causal organic indirect and direct effects: closer to Baron and Kenny, with a product method for binary mediators

Mediation analysis, which started with Baron and Kenny (1986), is used extensively by applied researchers. Indirect and direct effects are the part of a treatment effect that is mediated by a covariate and the part that is not. Subsequent work on natural indirect and direct effects provides a formal causal interpretation, based on cross-worlds counterfactuals: outcomes under treatment with the mediator set to its value without treatment. Organic indirect and direct effects (Lok 2016) avoid cross-worlds counterfactuals, using so-called organic interventions on the mediator while keeping the initial treatment fixed at treatment. Organic indirect and direct effects apply also to settings where the mediator cannot be set. In linear models where the outcome model does not have treatment-mediator interaction, both organic and natural indirect and direct effects lead to the same estimators as in Baron and Kenny (1986). Here, we generalize organic interventions on the mediator to include interventions combined with the initial treatment fixed at no treatment. We show that the product method holds in linear models for organic indirect and direct effects relative to no treatment even if there is treatment-mediator interaction. Moreover, we find a product method for binary mediators. Furthermore, we argue that the organic indirect effect relative to no treatment is very relevant for drug development. We illustrate the benefits of our approach by estimating the organic indirect effect of curative HIV-treatments mediated by two HIV-persistence measures, using ART-interruption data without curative HIV-treatments combined with an estimated/hypothesized effect of the curative HIV-treatments on these mediators.

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