Browsing by Subject "Experimental Design"
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Item Quantitative Modeling and Estimation in Systems Biology using Fluorescent Reporter Systems(2013-12-10) Bansal, LoveleenaBuilding quantitative models of biological systems is a challenging task as these models can consist of a very large number of components with complex interactions between them and the experimental data available for model validation is often sparse and noisy. The focus in this work is on modeling and parameter estimation of biological systems that are monitored using fluorescent reporter systems. Fluorescent reporter systems are widely used for various applications such as monitoring gene expression, protein localization and protein-protein interactions. This dissertation presents various techniques to facilitate modeling of biological systems containing fluorescent reporters with special attention given to challenges arising due to limited experimental data, simultaneous monitoring of multiple events and variability in the observed response due to phenotypic differences. First, an inverse problem is formulated to estimate the dynamics of transcription factors, a crucial molecule that initiates the transcription process, using data of fluorescence intensity profiles obtained from a fluorescent reporter system. The resulting inverse problem is ill-conditioned and it is solved with the aid of regularization techniques. The main contribution is that, with the presented technique, any complex dynamics of transcription factors can be estimated using limited data of fluorescence measurements. The technique has been evaluated using simulated data as well as experimental data of a GFP reporter system of STAT3. Second, an experimental design formulation is developed to facilitate the use of multiple fluorescent reporters, with overlapping emission spectra, in the same experiment. This work develops a criterion to select the fluorescent proteins for simultaneous use such that the accuracy in the estimated contributions of individual proteins to the overall observed intensity is maximized. This technique has been validated using mixtures of different E. coli strains which express different fluorescent proteins. Finally, a population balance model of a cell population containing a fluorescence reporter system is developed to describe the variability in the observed fluorescence in cells. Factors such as rate of fluorescent protein formation as well as partitioning of the fluorescent protein on cell division have been taken into account to describe the dynamics of fluorescence intensity distributions in the cell populations. The model has been used to obtain preliminary hypotheses to explain the difference in response of HeLa cells containing the Tet-on expression system on stimulation by different levels doxycycline. Thus, this work describes techniques for building robust predictive models of biological systems such as regularization for solving ill-posed estimation problems, experimental design techniques as well as using population balance modeling to model complex multi-scale dynamics. Moreover, while the examples discussed here are motivated for fluorescent reporter systems, the developed techniques can be used for different kinds of linear or non-linear dynamic biological systems.Item Reservoir characterization using experimental design and response surface methodology(Texas A&M University, 2004-09-30) Parikh, HarshalThis research combines a statistical tool called experimental design/response surface methodology with reservoir modeling and flow simulation for the purpose of reservoir characterization. Very often, it requires large number of reservoir simulation runs for identifying significant reservoir modeling parameters impacting flow response and for history matching. Experimental design/response surface (ED/RS) is a statistical technique, which allows a systematic approach for minimizing the number of simulation runs to meet the two objectives mentioned above. This methodology may be applied to synthetic and field cases using existing statistical software tools. The application of ED/RS methodology for the purpose of reservoir characterization has been applied for two different objectives. The first objective is to address the uncertainties in the identification of the location and transmissibility of flow barriers in a field in the Gulf of Mexico. This objective is achieved by setting up a simple full-factorial design. The range of transmissibility of the barriers is selected using a Latin Hypercube Sampling (LHS). An analysis of variance (ANOVA) gives the significance of the location and transmissibility of barriers and comparison with decline-type curve analysis which gives us the most likely scenarios of the location and transmissibility of the flow barriers. The second objective is to identify significant geologic parameters in object-based and pixel-based reservoir models. This study is applied on a synthetic fluvial reservoir, whose characteristic feature is the presence of sinuous sand filled channels within a background of floodplain shale. This particular study reveals the impact of uncertainty in the reservoir modeling parameters on the flow performance. Box-Behnken design is used in this study to reduce the number of simulation runs along with streamline simulation for flow modeling purposes. In the first study, we find a good match between field data and that predicted from streamline simulation based on the most likely scenario. This validates the use of ED to get the most likely scenario for the location and transmissibility of flow barriers. It can be concluded from the second study that ED/RS methodology is a powerful tool along with a fast streamline simulator to screen large number of reservoir model realizations for the purpose of studying the effect of uncertainty of geologic modeling parameters on reservoir flow behavior.