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Marginal Structural Models with Dose-Delay Joint-Exposure for Assessing Variations to Chemotherapy Intensity

Lancia, C; Spitoni, C; Anninga, J; Sydes, MR; Jovic, G; Fiocco, M; (2018) Marginal Structural Models with Dose-Delay Joint-Exposure for Assessing Variations to Chemotherapy Intensity. Statistical Methods in Medical Research 10.1177/0962280218780619. (In press). Green open access

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Abstract

Marginal Structural Models (MSMs) are causal models designed to adjust for time-dependent confounders in observational studies with dynamically-adjusted treatments. They are robust tools to assess causality in complex longitudinal data. In this paper a MSM is proposed with an innovative dose-delay joint-exposure model for Inverse-Probability-of-Treatment Weighted (IPTW) estimation of the causal effect of alterations to the therapy intensity. The model is motivated by a precise clinical question concerning the possibility of reducing dosages in a regimen. It is applied to data from a randomised trial of chemotherapy in osteosarcoma, an aggressive primary bone-tumour. Chemotherapy data are complex because their longitudinal nature encompasses many clinical details like composition and organisation of multi-drug regimens, or dynamical therapy adjustments. This manuscript focuses on the clinical dynamical process of adjusting the therapy according to the patient’s toxicity history, and the causal effect on the outcome of interest of such therapy modifications. Depending on patients’ toxicity levels, variations to therapy intensity may be achieved by physicians through the allocation of either a reduction or a delay of the next planned dose. Thus, a negative feedback is present between exposure to cytotoxic agents and toxicity levels, which acts as time-dependent confounders. The construction of the model is illustrated highlighting the high complexity and entanglement of chemotherapy data. Built to address dosage reductions, the model also shows that delays should not be introduced in the therapy administration. The last aspect makes sense from the cytological point of view, but it is seldom addressed in the literature.

Type: Article
Title: Marginal Structural Models with Dose-Delay Joint-Exposure for Assessing Variations to Chemotherapy Intensity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1177/0962280218780619
Publisher version: https://doi.org/10.1177/0962280218780619
Language: English
Additional information: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Keywords: Causal Inference, Marginal Structural Models, Bivariate Exposure, Osteosarcoma, Therapy delay
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1574611
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