Dataset Information

Monte Carlo Simulations for the Analysis of Non-linear Parameter Confidence Intervals in Optimal Experimental Design.

ABSTRACT: Especially in biomanufacturing, methods to design optimal experiments are a valuable technique to fully exploit the potential of the emerging technical possibilities that are driving experimental miniaturization and parallelization. The general objective is to reduce the experimental effort while maximizing the information content of an experiment, speeding up knowledge gain in R&D. The approach of model-based design of experiments (known as MBDoE) utilizes the information of an underlying mathematical model describing the system of interest. A common method to predict the accuracy of the parameter estimates uses the Fisher information matrix to approximate the 90% confidence intervals of the estimates. However, for highly non-linear models, this method might lead to wrong conclusions. In such cases, Monte Carlo sampling gives a more accurate insight into the parameter's estimate probability distribution and should be exploited to assess the reliability of the approximations made through the Fisher information matrix. We first introduce the model-based optimal experimental design for parameter estimation including parameter identification and validation by means of a simple non-linear Michaelis-Menten kinetic and show why Monte Carlo simulations give a more accurate depiction of the parameter uncertainty. Secondly, we propose a very robust and simple method to find optimal experimental designs using Monte Carlo simulations. Although computational expensive, the method is easy to implement and parallelize. This article focuses on practical examples of bioprocess engineering but is generally applicable in other fields.

SUBMITTER: Krausch N

PROVIDER: S-EPMC6543167 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Monte Carlo Simulations for the Analysis of Non-linear Parameter Confidence Intervals in Optimal Experimental Design.

Krausch Niels N Barz Tilman T Sawatzki Annina A Gruber Mathis M Kamel Sarah S Neubauer Peter P Cruz Bournazou Mariano Nicolas MN

Frontiers in bioengineering and biotechnology 20190524

Especially in biomanufacturing, methods to design optimal experiments are a valuable technique to fully exploit the potential of the emerging technical possibilities that are driving experimental miniaturization and parallelization. The general objective is to reduce the experimental effort while maximizing the information content of an experiment, speeding up knowledge gain in R&D. The approach of model-based design of experiments (known as MBDoE) utilizes the information of an underlying mathe ...[more]

PMID: 31179278

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Project description:This work seeks to develop exact confidence interval estimators for figures of merit that describe the performance of linear observers, and to demonstrate how these estimators can be used in the context of x-ray computed tomography (CT). The figures of merit are the receiver operating characteristic (ROC) curve and associated summary measures, such as the area under the ROC curve. Linear computerized observers are valuable for optimization of parameters associated with image reconstruction algorithms and data acquisition geometries. They provide a means to perform assessment of image quality with metrics that account not only for shift-variant resolution and nonstationary noise but that are also task-based.We suppose that a linear observer with fixed template has been defined and focus on the problem of assessing the performance of this observer for the task of deciding if an unknown lesion is present at a specific location. We introduce a point estimator for the observer signal-to-noise ratio (SNR) and identify its sampling distribution. Then, we show that exact confidence intervals can be constructed from this distribution. The sampling distribution of our SNR estimator is identified under the following hypotheses: (i) the observer ratings are normally distributed for each class of images and (ii) the variance of the observer ratings is the same for each class of images. These assumptions are, for example, appropriate in CT for ratings produced by linear observers applied to low-contrast lesion detection tasks.Unlike existing approaches to the estimation of ROC confidence intervals, the new confidence intervals presented here have exactly known coverage probabilities when our data assumptions are satisfied. Furthermore, they are applicable to the most commonly used ROC summary measures, and they may be easily computed (a computer routine is supplied along with this article on the Medical Physics Website). The utility of our exact interval estimators is demonstrated through an image quality evaluation example using real x-ray CT images. Also, strong robustness is shown to potential deviations from the assumption that the ratings for the two classes of images have equal variance. Another aspect of our interval estimators is the fact that we can calculate their mean length exactly for fixed parameter values, which enables precise investigations of sampling effects. We demonstrate this aspect by exploring the potential reduction in statistical variability that can be gained by using additional images from one class, if such images are readily available. We find that when additional images from one class are used for an ROC study, the mean AUC confidence interval length for our estimator can decrease by as much as 35%.We have shown that exact confidence intervals can be constructed for ROC curves and for ROC summary measures associated with fixed linear computerized observers applied to binary discrimination tasks at a known location. Although our intervals only apply under specific conditions, we believe that they form a valuable tool for the important problem of optimizing parameters associated with image reconstruction algorithms and data acquisition geometries, particularly in x-ray CT.

Dataset Information

Monte Carlo Simulations for the Analysis of Non-linear Parameter Confidence Intervals in Optimal Experimental Design.

Publications

Monte Carlo Simulations for the Analysis of Non-linear Parameter Confidence Intervals in Optimal Experimental Design.

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