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Optimal design problems for the bivariate Emax model
Stockholm University, Faculty of Social Sciences, Department of Statistics.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Finding a suitable dose is among the most difficult tasks during clinical development of a new drug. In early phases dose finding studies usually focus on finding a safe dose. Safety variables are thus of main interest. In later phases the focus is shifted towards efficacy. Typically a primary efficacy variable is defined and modeled. Various dose-response models have been suggested. For continuous responses among the most successful ones is the Emax model. Here both efficacy and safety are considered simultaneously and the Emax model is extended to a model with a bivariate response, one response being a primary efficacy variable and one being a primary safety variable. This model is referred to as the bivariate Emax model. The focus is on locally c-optimal designs for the bivariate Emax model and a simplified version of it. More specifically the locallyc-optimal designs minimize the asymptotic variance for the estimate of the dose that maximizes the patient's utility. The utility is a function of the efficacy and safety variables and referred to as the Clinical Utility Index (CUI).

Keyword [en]
bivariate Emax model, Clinical Utility Index (CUI), c-optimal design, dose-response studies
National Category
Probability Theory and Statistics
Research subject
Statistics
Identifiers
URN: urn:nbn:se:su:diva-102867OAI: oai:DiVA.org:su-102867DiVA: diva2:713850
Available from: 2014-04-24 Created: 2014-04-23 Last updated: 2014-04-24
In thesis
1. Estimation and optimal designs for multi-response Emax models
Open this publication in new window or tab >>Estimation and optimal designs for multi-response Emax models
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis concerns optimal designs and estimation approaches for a class of nonlinear dose response models, namely multi-response Emax models. These models describe the relationship between the dose of a drug and two or more efficacy and/or safety variables. In order to obtain precise parameter estimates it is important to choose efficient estimation approaches and to use optimal designs to control the level of the doses administered to the patients in the study.

We provide some optimal designs that are efficient for estimating the parameters, a subset of the parameters, and a function of the parameters in multi-response Emax models. The function of interest is an estimate of the best dose to administer to a group of patients. More specifically the dose that maximizes the Clinical Utility Index (CUI) which assesses the net benefit of a drug taking both effects and side-effects into account. The designs derived in this thesis are locally optimal, that is they depend upon the true parameter values. An important part of this thesis is to study how sensitive the optimal designs are to misspecification of prior parameter values.

For multi-response Emax models it is possible to derive maximum likelihood (ML) estimates separately for the parameters in each dose response relation. However, ML estimation can also be carried out simultaneously for all response profiles by making use of dependencies between the profiles (system estimation). In this thesis we compare the performance of these two approaches by using a simulation study where a bivariate Emax model is fitted and by fitting a four dimensional Emax model to real dose response data. The results are that system estimation can substantially increase the precision of parameter estimates, especially when the correlation between response profiles is strong or when the study has not been designed in an efficient way.

Place, publisher, year, edition, pages
Stockholm: Department of Statistics, Stockholm University, 2014. 38 p.
Keyword
multi-response Emax models, Clinical Utility Index (CUI), optimal designs, system estimation, dose-response studies.
National Category
Probability Theory and Statistics
Research subject
Statistics
Identifiers
urn:nbn:se:su:diva-102888 (URN)978-91-7447-909-6 (ISBN)
Public defence
2014-05-30, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 1: Manuscript; Paper 2: Manuscript; Paper 3: Manuscript; Paper 4: Manuscript.

Available from: 2014-05-08 Created: 2014-04-24 Last updated: 2014-05-05Bibliographically approved

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CiteExportLink to record
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Citation style
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