TY - JOUR

T1 - Recurrent events modelling of haemophilia bleeding events

AU - Titman, Andrew

AU - Wolfsegger, Martin J.

AU - Jaki, Thomas

N1 - This is the peer reviewed version of the following article: Titman, A.C., Wolfsegger, M.J. and Jaki, T.F. (2021), Recurrent events modelling of haemophilia bleeding events. J R Stat Soc Series C, 70: 351-371. https://doi.org/10.1111/rssc.12462 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/rssc.12462 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - A pharmacokinetic–pharmacodynamic (PK-PD) approach is developed for modelling the recurrent bleeding events in patients with severe haemophilia to investigate the relationship between factor VIII plasma activity level and the instantaneous risk of a bleed. The model incorporates patient-level pharmacokinetic (PK) information obtained through measurements taken prior to the study which are used to fit a non-linear mixed-effects two-compartment PK model. Dosing times within the study are combined with the PK model to provide the estimated factor VIII plasma level for all patients, which is used as a time-dependent covariate within the recurrent events model. Methods are developed to correct the attenuation in covariate effects that would otherwise arise due to the discrepancy between estimated and true factor VIII. In contrast to existing methods proposed for such data, such as count data regression or time-to-event analysis, the new method allows all the bleeding times to be used to investigate the relationship between current factor VIII and risk of a bleed. The performance of the proposed estimators are assessed via simulation and found to outperform the naive estimator, which treats the estimated factor VIII levels as if they were measured without error, both in terms of bias and mean squared error.

AB - A pharmacokinetic–pharmacodynamic (PK-PD) approach is developed for modelling the recurrent bleeding events in patients with severe haemophilia to investigate the relationship between factor VIII plasma activity level and the instantaneous risk of a bleed. The model incorporates patient-level pharmacokinetic (PK) information obtained through measurements taken prior to the study which are used to fit a non-linear mixed-effects two-compartment PK model. Dosing times within the study are combined with the PK model to provide the estimated factor VIII plasma level for all patients, which is used as a time-dependent covariate within the recurrent events model. Methods are developed to correct the attenuation in covariate effects that would otherwise arise due to the discrepancy between estimated and true factor VIII. In contrast to existing methods proposed for such data, such as count data regression or time-to-event analysis, the new method allows all the bleeding times to be used to investigate the relationship between current factor VIII and risk of a bleed. The performance of the proposed estimators are assessed via simulation and found to outperform the naive estimator, which treats the estimated factor VIII levels as if they were measured without error, both in terms of bias and mean squared error.

KW - haemophilia

KW - measurement error

KW - pharmacodynamics

KW - pharmacokinetics

KW - PK/PD modelling

KW - recurrent events

U2 - 10.1111/rssc.12462

DO - 10.1111/rssc.12462

M3 - Journal article

VL - 70

SP - 351

EP - 371

JO - Journal of the Royal Statistical Society: Series C (Applied Statistics)

JF - Journal of the Royal Statistical Society: Series C (Applied Statistics)

SN - 0035-9254

IS - 2

ER -