On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models.

Autor:	Savel H; Department of Public Health, Inserm Bordeaux Population Health Research Centre, U1219, University of Bordeaux, Bordeaux, France.; Ipsen Innovation, Les Ulis, France.; Inria, SISTM, Talence, France., Barbier S; Ipsen Innovation, Les Ulis, France., Proust-Lima C; Department of Public Health, Inserm Bordeaux Population Health Research Centre, U1219, University of Bordeaux, Bordeaux, France.; University of Bordeaux, INSERM, CHU de Bordeaux, Institut Bergonié, CIC-EC 1401, Bordeaux, France., Rondeau V; Department of Public Health, Inserm Bordeaux Population Health Research Centre, U1219, University of Bordeaux, Bordeaux, France., Thiébaut R; Department of Public Health, Inserm Bordeaux Population Health Research Centre, U1219, University of Bordeaux, Bordeaux, France.; Inria, SISTM, Talence, France.; University of Bordeaux, INSERM, CHU de Bordeaux, Institut Bergonié, CIC-EC 1401, Bordeaux, France., Meyer-Losic F; Ipsen Innovation, Les Ulis, France., Richert L; Department of Public Health, Inserm Bordeaux Population Health Research Centre, U1219, University of Bordeaux, Bordeaux, France.; Inria, SISTM, Talence, France.; University of Bordeaux, INSERM, CHU de Bordeaux, Institut Bergonié, CIC-EC 1401, Bordeaux, France.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Jan 26; Vol. 3 (1), pp. 140-147. Date of Electronic Publication: 2023 Jan 26 (Print Publication: 2023).
DOI:	10.1158/2767-9764.CRC-22-0238
Abstrakt:	In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models. Mixed and joint models were compared in a real MCT ( N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR). In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm 3 )/week for mixed model vs. -0.02 [-0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model. Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths. Significance: This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models. Competing Interests: H. Savel reports other from Ipsen during the conduct of the study; other from Ipsen outside the submitted work. F. Meyer-Losic reports other from Ipsen during the conduct of the study. L. Richert reports grants from Ipsen during the conduct of the study. No disclosures were reported by the other authors. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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