Development, validation and uncertainty analysis of quantitative structure and activity relationship models for Log P of disinfection by -products

Hydrophobicity as measured by Log P is an important molecular property related to toxicity and carcinogenicity. With increasing public health concerns for the effects of Disinfection By-Products (DBPs), there are considerable benefits in developing Quantitative Structure and Activity Relationship (QSAR) models capable of accurately predicting Log P. In this research, Log P values of 173 DBP compounds in 6 functional classes were used to develop QSAR models, by applying 3 molecular descriptors, namely, Energy of the Lowest Unoccupied Molecular Orbital (ELUMO), Number of Chlorine (NCl) and Number of Carbon (NC) by Multiple Linear Regression (MLR) analysis. The QSAR models developed were validated based on the Organization for Economic Co-operation and Development (OECD) principles. The model Applicability Domain (AD) and mechanistic interpretation were explored. Considering the very complex nature of DBPs, the established QSAR models performed very well with respect to goodness-of-fit, robustness and predictability. The predicted values of Log P of DBPs by the QSAR models were found to be significant with a correlation coefficient R2 from 81% to 98%. The Leverage Approach by Williams Plot was applied to detect and remove outliers, consequently increasing R 2 by approximately 2% to 13% for different DBP classes. The developed QSAR models were statistically validated for their predictive power by the Leave-One-Out (LOO) and Leave-Many-Out (LMO) cross validation methods. Finally, Monte Carlo simulation was used to assess the variations and inherent uncertainties in the QSAR models of Log P and determine the most influential parameters in connection with Log P prediction. The developed QSAR models in this dissertation will have a broad applicability domain because the research data set covered six out of eight common DBP classes, including halogenated alkane, halogenated alkene, halogenated aromatic, halogenated aldehyde, halogenated ketone, and halogenated carboxylic acid, which have been brought to the attention of regulatory agencies in recent years. Furthermore, the QSAR models are suitable to be used for prediction of similar DBP compounds within the same applicability domain. The selection and integration of various methodologies developed in this research may also benefit future research in similar fields.

Mitigating inconsistencies by coupling data cleaning, filtering, and contextual data validation in wireless sensor networks

With the advent of peer to peer networks, and more importantly sensor networks, the desire to extract useful information from continuous and unbounded streams of data has become more prominent. For example, in tele-health applications, sensor based data streaming systems are used to continuously and accurately monitor Alzheimer's patients and their surrounding environment. Typically, the requirements of such applications necessitate the cleaning and filtering of continuous, corrupted and incomplete data streams gathered wirelessly in dynamically varying conditions. Yet, existing data stream cleaning and filtering schemes are incapable of capturing the dynamics of the environment while simultaneously suppressing the losses and corruption introduced by uncertain environmental, hardware, and network conditions. Consequently, existing data cleaning and filtering paradigms are being challenged. This dissertation develops novel schemes for cleaning data streams received from a wireless sensor network operating under non-linear and dynamically varying conditions. The study establishes a paradigm for validating spatio-temporal associations among data sources to enhance data cleaning. To simplify the complexity of the validation process, the developed solution maps the requirements of the application on a geometrical space and identifies the potential sensor nodes of interest. Additionally, this dissertation models a wireless sensor network data reduction system by ascertaining that segregating data adaptation and prediction processes will augment the data reduction rates. The schemes presented in this study are evaluated using simulation and information theory concepts. The results demonstrate that dynamic conditions of the environment are better managed when validation is used for data cleaning. They also show that when a fast convergent adaptation process is deployed, data reduction rates are significantly improved. Targeted applications of the developed methodology include machine health monitoring, tele-health, environment and habitat monitoring, intermodal transportation and homeland security.

Blood-brain barrier in vitro model: A tissue engineering approach and validation

This dissertation evaluated the feasibility of using commercially available immortalized cell lines in building a tissue engineered in vitro blood-brain barrier (BBB) co-culture model for preliminary drug development studies. Mouse endothelial cell line and rat astrocyte cell lines purchased from American Type Culture Collections (ATCC) were the building blocks of the co-culture model. An astrocyte derived acellular extracellular matrix (aECM) was introduced in the co-culture model to provide a novel in vitro biomimetic basement membrane for the endothelial cells to form endothelial tight junctions. Trans-endothelial electrical resistance (TEER) and solute mass transport studies were engaged to quantitatively evaluate the tight junction formation on the in-vitro BBB models. Immuno-fluorescence microscopy and Western Blot analysis were used to qualitatively verify the in vitro expression of occludin, one of the earliest discovered tight junction proteins. Experimental data from a total of 12 experiments conclusively showed that the novel BBB in vitro co-culture model with the astrocyte derived aECM (CO+aECM) was promising in terms of establishing tight junction formation represented by TEER values, transport profiles and tight junction protein expression when compared with traditional co-culture (CO) model setups and endothelial cells cultured alone. Experimental data were also found to be comparable with several existing in vitro BBB models built from various methods. In vitro colorimetric sulforhodamine B (SRB) assay revealed that the co-cultured samples with aECM resulted in less cell loss on the basal sides of the insert membranes than that from traditional co-culture samples. The novel tissue engineering approach using immortalized cell lines with the addition of aECM was proven to be a relevant alternative to the traditional BBB in vitro modeling.

Chlorine contribution to quantitative structure and activity relationship models of disinfection by -products' quantum chemical descriptors and toxicities

Quantitative Structure-Activity Relationship (QSAR) has been applied extensively in predicting toxicity of Disinfection By-Products (DBPs) in drinking water. Among many toxicological properties, acute and chronic toxicities of DBPs have been widely used in health risk assessment of DBPs. These toxicities are correlated with molecular properties, which are usually correlated with molecular descriptors. The primary goals of this thesis are: (1) to investigate the effects of molecular descriptors (e.g., chlorine number) on molecular properties such as energy of the lowest unoccupied molecular orbital (E LUMO) via QSAR modelling and analysis; (2) to validate the models by using internal and external cross-validation techniques; (3) to quantify the model uncertainties through Taylor and Monte Carlo Simulation. One of the very important ways to predict molecular properties such as ELUMO is using QSAR analysis. In this study, number of chlorine (NCl ) and number of carbon (NC) as well as energy of the highest occupied molecular orbital (EHOMO) are used as molecular descriptors. There are typically three approaches used in QSAR model development: (1) Linear or Multi-linear Regression (MLR); (2) Partial Least Squares (PLS); and (3) Principle Component Regression (PCR). In QSAR analysis, a very critical step is model validation after QSAR models are established and before applying them to toxicity prediction. The DBPs to be studied include five chemical classes: chlorinated alkanes, alkenes, and aromatics. In addition, validated QSARs are developed to describe the toxicity of selected groups (i.e., chloro-alkane and aromatic compounds with a nitro- or cyano group) of DBP chemicals to three types of organisms (e.g., Fish, T. pyriformis, and P.pyosphoreum) based on experimental toxicity data from the literature. The results show that: (1) QSAR models to predict molecular property built by MLR, PLS or PCR can be used either to select valid data points or to eliminate outliers; (2) The Leave-One-Out Cross-Validation procedure by itself is not enough to give a reliable representation of the predictive ability of the QSAR models, however, Leave-Many-Out/K-fold cross-validation and external validation can be applied together to achieve more reliable results; (3) E LUMO are shown to correlate highly with the NCl for several classes of DBPs; and (4) According to uncertainty analysis using Taylor method, the uncertainty of QSAR models is contributed mostly from NCl for all DBP classes.

Engineering Analysis in Imprecise Geometric Models

Engineering analysis in geometric models has been the main if not the only credible/reasonable tool used by engineers and scientists to resolve physical boundaries problems. New high speed computers have facilitated the accuracy and validation of the expected results. In practice, an engineering analysis is composed of two parts; the design of the model and the analysis of the geometry with the boundary conditions and constraints imposed on it. Numerical methods are used to resolve a large number of physical boundary problems independent of the model geometry. The time expended due to the computational process are related to the imposed boundary conditions and the well conformed geometry. Any geometric model that contains gaps or open lines is considered an imperfect geometry model and major commercial solver packages are incapable of handling such inputs. Others packages apply different kinds of methods to resolve this problems like patching or zippering; but the final resolved geometry may be different from the original geometry, and the changes may be unacceptable. The study proposed in this dissertation is based on a new technique to process models with geometrical imperfection without the necessity to repair or change the original geometry. An algorithm is presented that is able to analyze the imperfect geometric model with the imposed boundary conditions using a meshfree method and a distance field approximation to the boundaries. Experiments are proposed to analyze the convergence of the algorithm in imperfect models geometries and will be compared with the same models but with perfect geometries. Plotting results will be presented for further analysis and conclusions of the algorithm convergence

Mitigating Inconsistencies by Coupling Data Cleaning, Filtering, and Contextual Data Validation in Wireless Sensor Networks

With the advent of peer to peer networks, and more importantly sensor networks, the desire to extract useful information from continuous and unbounded streams of data has become more prominent. For example, in tele-health applications, sensor based data streaming systems are used to continuously and accurately monitor Alzheimer's patients and their surrounding environment. Typically, the requirements of such applications necessitate the cleaning and filtering of continuous, corrupted and incomplete data streams gathered wirelessly in dynamically varying conditions. Yet, existing data stream cleaning and filtering schemes are incapable of capturing the dynamics of the environment while simultaneously suppressing the losses and corruption introduced by uncertain environmental, hardware, and network conditions. Consequently, existing data cleaning and filtering paradigms are being challenged. This dissertation develops novel schemes for cleaning data streams received from a wireless sensor network operating under non-linear and dynamically varying conditions. The study establishes a paradigm for validating spatio-temporal associations among data sources to enhance data cleaning. To simplify the complexity of the validation process, the developed solution maps the requirements of the application on a geometrical space and identifies the potential sensor nodes of interest. Additionally, this dissertation models a wireless sensor network data reduction system by ascertaining that segregating data adaptation and prediction processes will augment the data reduction rates. The schemes presented in this study are evaluated using simulation and information theory concepts. The results demonstrate that dynamic conditions of the environment are better managed when validation is used for data cleaning. They also show that when a fast convergent adaptation process is deployed, data reduction rates are significantly improved. Targeted applications of the developed methodology include machine health monitoring, tele-health, environment and habitat monitoring, intermodal transportation and homeland security.

Chlorine Contribution to Quantitative Structure and Activity Relationship Models of Disinfection By-Products' Quantum Chemical Descriptors and Toxicities

Quantitative Structure-Activity Relationship (QSAR) has been applied extensively in predicting toxicity of Disinfection By-Products (DBPs) in drinking water. Among many toxicological properties, acute and chronic toxicities of DBPs have been widely used in health risk assessment of DBPs. These toxicities are correlated with molecular properties, which are usually correlated with molecular descriptors. The primary goals of this thesis are: 1) to investigate the effects of molecular descriptors (e.g., chlorine number) on molecular properties such as energy of the lowest unoccupied molecular orbital (ELUMO) via QSAR modelling and analysis; 2) to validate the models by using internal and external cross-validation techniques; 3) to quantify the model uncertainties through Taylor and Monte Carlo Simulation. One of the very important ways to predict molecular properties such as ELUMO is using QSAR analysis. In this study, number of chlorine (NCl) and number of carbon (NC) as well as energy of the highest occupied molecular orbital (EHOMO) are used as molecular descriptors. There are typically three approaches used in QSAR model development: 1) Linear or Multi-linear Regression (MLR); 2) Partial Least Squares (PLS); and 3) Principle Component Regression (PCR). In QSAR analysis, a very critical step is model validation after QSAR models are established and before applying them to toxicity prediction. The DBPs to be studied include five chemical classes: chlorinated alkanes, alkenes, and aromatics. In addition, validated QSARs are developed to describe the toxicity of selected groups (i.e., chloro-alkane and aromatic compounds with a nitro- or cyano group) of DBP chemicals to three types of organisms (e.g., Fish, T. pyriformis, and P.pyosphoreum) based on experimental toxicity data from the literature. The results show that: 1) QSAR models to predict molecular property built by MLR, PLS or PCR can be used either to select valid data points or to eliminate outliers; 2) The Leave-One-Out Cross-Validation procedure by itself is not enough to give a reliable representation of the predictive ability of the QSAR models, however, Leave-Many-Out/K-fold cross-validation and external validation can be applied together to achieve more reliable results; 3) ELUMO are shown to correlate highly with the NCl for several classes of DBPs; and 4) According to uncertainty analysis using Taylor method, the uncertainty of QSAR models is contributed mostly from NCl for all DBP classes.