PurposeThis work investigates improved utilization of ADAS-cog data (the primary outcome in Alzheimer’s disease (AD) trials of mild and moderate AD) by combining pharmacometric modeling and item response theory (IRT).MethodsA baseline IRT model characterizing the ADAS-cog was built based on data from 2,744 individuals. Pharmacometric methods were used to extend the baseline IRT model to describe longitudinal ADAS-cog scores from an 18-month clinical study with 322 patients. Sensitivity of the ADAS-cog items in different patient populations as well as the power to detect a drug effect in relation to total score based methods were assessed with the IRT based model.ResultsIRT analysis was able to describe both total and item level baseline ADAS-cog data. Longitudinal data were also well described. Differences in the information content of the item level components could be quantitatively characterized and ranked for mild cognitively impairment and mild AD populations. Based on clinical trial simulations with a theoretical drug effect, the IRT method demonstrated a significantly higher power to detect drug effect compared to the traditional method of analysis.ConclusionA combined framework of IRT and pharmacometric modeling permits a more effective and precise analysis than total score based methods and therefore increases the value of ADAS-cog data.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-014-1315-5) contains supplementary material, which is available to authorized users.
Purpose: This manuscript aims to precisely describe the natural disease progression of Parkinson's disease (PD) patients and evaluate approaches to increase the drug effect detection power.Methods: An item response theory (IRT) longitudinal model was built to describe the natural disease progression of 423 de novo PD patients followed during 48 months while taking into account the heterogeneous nature of the MDS-UPDRS scale. Clinical trial simulations were then used to compare drug effect detection power from IRT and sum of item scores based analysis under different analysis endpoints and drug effects.
Results:The IRT longitudinal model accurately describes the evolution of patients with and without PD medications while estimating different progression rates for the subscales. When comparing analysis methods, the IRT-based one consistently provided the highest power.
Conclusion:IRT is a powerful tool which enables to capture the heterogeneous nature of the MDS-UPDRS.IRT as a tool to describe a heterogeneous clinical scale 2
Composite assessments aim to combine different aspects of a disease in a single score and are utilized in a variety of therapeutic areas. The data arising from these evaluations are inherently discrete with distinct statistical properties. This tutorial presents the framework of the item response theory (IRT) for the analysis of this data type in a pharmacometric context. The article considers both conceptual (terms and assumptions) and practical questions (modeling software, data requirements, and model building).
Non-linear mixed effect models (NLMEMs) are widely used for the analysis of longitudinal data. To design these studies, optimal design based on the expected Fisher information matrix (FIM) can be used instead of performing time-consuming clinical trial simulations. In recent years, estimation algorithms for NLMEMs have transitioned from linearization toward more exact higher-order methods. Optimal design, on the other hand, has mainly relied on first-order (FO) linearization to calculate the FIM. Although efficient in general, FO cannot be applied to complex non-linear models and with difficulty in studies with discrete data. We propose an approach to evaluate the expected FIM in NLMEMs for both discrete and continuous outcomes. We used Markov Chain Monte Carlo (MCMC) to integrate the derivatives of the log-likelihood over the random effects, and Monte Carlo to evaluate its expectation w.r.t. the observations. Our method was implemented in R using Stan, which efficiently draws MCMC samples and calculates partial derivatives of the log-likelihood. Evaluated on several examples, our approach showed good performance with relative standard errors (RSEs) close to those obtained by simulations. We studied the influence of the number of MC and MCMC samples and computed the uncertainty of the FIM evaluation. We also compared our approach to Adaptive Gaussian Quadrature, Laplace approximation, and FO. Our method is available in R-package MIXFIM and can be used to evaluate the FIM, its determinant with confidence intervals (CIs), and RSEs with CIs.
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