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.

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.

An Indexing Structure and Application Model for Vehicles Moving on Road Networks

Moving objects database systems are the most challenging sub-category among Spatio-Temporal database systems. A database system that updates in real-time the location information of GPS-equipped moving vehicles has to meet even stricter requirements. Currently existing data storage models and indexing mechanisms work well only when the number of moving objects in the system is relatively small. This dissertation research aimed at the real-time tracking and history retrieval of massive numbers of vehicles moving on road networks. A total solution has been provided for the real-time update of the vehicles’ location and motion information, range queries on current and history data, and prediction of vehicles’ movement in the near future. To achieve these goals, a new approach called Segmented Time Associated to Partitioned Space (STAPS) was first proposed in this dissertation for building and manipulating the indexing structures for moving objects databases. Applying the STAPS approach, an indexing structure of associating a time interval tree to each road segment was developed for real-time database systems of vehicles moving on road networks. The indexing structure uses affordable storage to support real-time data updates and efficient query processing. The data update and query processing performance it provides is consistent without restrictions such as a time window or assuming linear moving trajectories. An application system design based on distributed system architecture with centralized organization was developed to maximally support the proposed data and indexing structures. The suggested system architecture is highly scalable and flexible. Finally, based on a real-world application model of vehicles moving in region-wide, main issues on the implementation of such a system were addressed.

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.

Effect of enhanced pCO2 levels on the production of dissolved organic carbon and transparent exopolymer particles in short-term bioassay experiments

It has been proposed that increasing levels of pCO2 in the surface ocean will lead to more partitioning of the organic carbon fixed by marine primary production into the dissolved rather than the particulate fraction. This process may result in enhanced accumulation of dissolved organic carbon (DOC) in the surface ocean and/or concurrent accumulation of transparent exopolymer particles (TEPs), with important implications for the functioning of the marine carbon cycle. We investigated this in shipboard bioassay experiments that considered the effect of four different pCO2 scenarios (ambient, 550, 750 and 1000 µatm) on unamended natural phytoplankton communities from a range of locations in the northwest European shelf seas. The environmental settings, in terms of nutrient availability, phytoplankton community structure and growth conditions, varied considerably between locations. We did not observe any strong or consistent effect of pCO2 on DOC production. There was a significant but highly variable effect of pCO2 on the production of TEPs. In three of the five experiments, variation of TEP production between pCO2 treatments was caused by the effect of pCO2 on phytoplankton growth rather than a direct effect on TEP production. In one of the five experiments, there was evidence of enhanced TEP production at high pCO2 (twice as much production over the 96 h incubation period in the 750 ?atm treatment compared with the ambient treatment) independent of indirect effects, as hypothesised by previous studies. Our results suggest that the environmental setting of experiments (community structure, nutrient availability and occurrence of phytoplankton growth) is a key factor determining the TEP response to pCO2 perturbations.

Progenitor-Dependent Explosion Dynamics in Self-Consistent, Axisymmetric Simulations of Neutrino-Driven Core-Collapse Supernovae

We present self-consistent, axisymmetric core-collapse supernova simulations performed with the Prometheus-Vertex code for 18 pre-supernova models in the range of 11–28 M ⊙, including progenitors recently investigated by other groups. All models develop explosions, but depending on the progenitor structure, they can be divided into two classes. With a steep density decline at the Si/Si–O interface, the arrival of this interface at the shock front leads to a sudden drop of the mass-accretion rate, triggering a rapid approach to explosion. With a more gradually decreasing accretion rate, it takes longer for the neutrino heating to overcome the accretion ram pressure and explosions set in later. Early explosions are facilitated by high mass-accretion rates after bounce and correspondingly high neutrino luminosities combined with a pronounced drop of the accretion rate and ram pressure at the Si/Si–O interface. Because of rapidly shrinking neutron star radii and receding shock fronts after the passage through their maxima, our models exhibit short advection timescales, which favor the efficient growth of the standing accretion-shock instability. The latter plays a supportive role at least for the initiation of the re-expansion of the stalled shock before runaway. Taking into account the effects of turbulent pressure in the gain layer, we derive a generalized condition for the critical neutrino luminosity that captures the explosion behavior of all models very well. We validate the robustness of our findings by testing the influence of stochasticity, numerical resolution, and approximations in some aspects of the microphysics.

Coupling short-term (B2G model) and long-term (g-function) models for ground source heat exchanger simulation in TRNSYS. Application in a real installation

Ground-source heat pump (GSHP) systems represent one of the most promising techniques for heating and cooling in buildings. These systems use the ground as a heat source/sink, allowing a better efficiency thanks to the low variations of the ground temperature along the seasons. The ground-source heat exchanger (GSHE) then becomes a key component for optimizing the overall performance of the system. Moreover, the short-term response related to the dynamic behaviour of the GSHE is a crucial aspect, especially from a regulation criteria perspective in on/off controlled GSHP systems. In this context, a novel numerical GSHE model has been developed at the Instituto de Ingeniería Energética, Universitat Politècnica de València. Based on the decoupling of the short-term and the long-term response of the GSHE, the novel model allows the use of faster and more precise models on both sides. In particular, the short-term model considered is the B2G model, developed and validated in previous research works conducted at the Instituto de Ingeniería Energética. For the long-term, the g-function model was selected, since it is a previously validated and widely used model, and presents some interesting features that are useful for its combination with the B2G model. The aim of the present paper is to describe the procedure of combining these two models in order to obtain a unique complete GSHE model for both short- and long-term simulation. The resulting model is then validated against experimental data from a real GSHP installation.

Spectral analysis of four 'hypervariable' AGN: a micro-needle in the haystack?

We analyze four extreme AGN transients to explore the possibility that they are caused by rare, high-amplitude microlensing events. These previously unknown type-I AGN are located in the redshift range 0.6-1.1 and show changes of > 1.5 magnitudes in the g-band on a timescale of ~years. Multi-epoch optical spectroscopy, from the William Herschel Telescope, shows clear differential variability in the broad line fluxes with respect to the continuum changes and also evolution in the line profiles. In two cases a simple point-source, point-lens microlensing model provides an excellent match to the long-term variability seen in these objects. For both models the parameter constraints are consistent with the microlensing being due to an intervening stellar mass object but as yet there is no confirmation of the presence of an intervening galaxy. The models predict a peak amplification of 10.3/13.5 and an Einstein timescale of 7.5/10.8 years respectively. In one case the data also allow constraints on the size of the CIII] emitting region, with some simplifying assumptions, to to be ~1.0-6.5 light-days and a lower limit on the size of the MgII emitting region to be > 9 light-days (half-light radii). This CIII] radius is perhaps surprisingly small. In the remaining two objects there is spectroscopic evidence for an intervening absorber but the extra structure seen in the lightcurves requires a more complex lensing scenario to adequately explain.

REIT Capital Structure Choices: Preparation Matters

Sun, Titman, and Twite (2015) find that capital structure risks, namely high leverage and a high share of short-term debt, reduced the cumulative total return of US REITs in the 2007-2009 financial crisis. We find that mitigating capital structure risks ahead of the crisis by reducing leverage and extending debt maturity in 2006, was associated with a significantly higher cumulative total return 2007-2009, after controlling for the levels of those variables at the start of the financial crisis. We further identify two systematic cross-sectional differences between those REITs that reduced capital structure risks prior to the financial crisis and those that did not: the exposure to capital structure risks and the strength of corporate governance. On balance, our findings are consistent with the interpretation of risk-reducing adjustments to capital structure ahead of the crisis as a component of managerial skill and discipline with significant implications for firm value during the crisis.

Modelling and estimating models of physician labour supply and productivity

Ma thèse s’intéresse aux politiques de santé conçues pour encourager l’offre de services de santé. L’accessibilité aux services de santé est un problème majeur qui mine le système de santé de la plupart des pays industrialisés. Au Québec, le temps médian d’attente entre une recommandation du médecin généraliste et un rendez-vous avec un médecin spécialiste était de 7,3 semaines en 2012, contre 2,9 semaines en 1993, et ceci malgré l’augmentation du nombre de médecins sur cette même période. Pour les décideurs politiques observant l’augmentation du temps d’attente pour des soins de santé, il est important de comprendre la structure de l’offre de travail des médecins et comment celle-ci affecte l’offre des services de santé. Dans ce contexte, je considère deux principales politiques. En premier lieu, j’estime comment les médecins réagissent aux incitatifs monétaires et j’utilise les paramètres estimés pour examiner comment les politiques de compensation peuvent être utilisées pour déterminer l’offre de services de santé de court terme. En second lieu, j’examine comment la productivité des médecins est affectée par leur expérience, à travers le mécanisme du "learning-by-doing", et j’utilise les paramètres estimés pour trouver le nombre de médecins inexpérimentés que l’on doit recruter pour remplacer un médecin expérimenté qui va à la retraite afin de garder l’offre des services de santé constant. Ma thèse développe et applique des méthodes économique et statistique afin de mesurer la réaction des médecins face aux incitatifs monétaires et estimer leur profil de productivité (en mesurant la variation de la productivité des médecins tout le long de leur carrière) en utilisant à la fois des données de panel sur les médecins québécois, provenant d’enquêtes et de l’administration. Les données contiennent des informations sur l’offre de travail de chaque médecin, les différents types de services offerts ainsi que leurs prix. Ces données couvrent une période pendant laquelle le gouvernement du Québec a changé les prix relatifs des services de santé. J’ai utilisé une approche basée sur la modélisation pour développer et estimer un modèle structurel d’offre de travail en permettant au médecin d’être multitâche. Dans mon modèle les médecins choisissent le nombre d’heures travaillées ainsi que l’allocation de ces heures à travers les différents services offerts, de plus les prix des services leurs sont imposés par le gouvernement. Le modèle génère une équation de revenu qui dépend des heures travaillées et d’un indice de prix représentant le rendement marginal des heures travaillées lorsque celles-ci sont allouées de façon optimale à travers les différents services. L’indice de prix dépend des prix des services offerts et des paramètres de la technologie de production des services qui déterminent comment les médecins réagissent aux changements des prix relatifs. J’ai appliqué le modèle aux données de panel sur la rémunération des médecins au Québec fusionnées à celles sur l’utilisation du temps de ces mêmes médecins. J’utilise le modèle pour examiner deux dimensions de l’offre des services de santé. En premierlieu, j’analyse l’utilisation des incitatifs monétaires pour amener les médecins à modifier leur production des différents services. Bien que les études antérieures ont souvent cherché à comparer le comportement des médecins à travers les différents systèmes de compensation,il y a relativement peu d’informations sur comment les médecins réagissent aux changementsdes prix des services de santé. Des débats actuels dans les milieux de politiques de santé au Canada se sont intéressés à l’importance des effets de revenu dans la détermination de la réponse des médecins face à l’augmentation des prix des services de santé. Mon travail contribue à alimenter ce débat en identifiant et en estimant les effets de substitution et de revenu résultant des changements des prix relatifs des services de santé. En second lieu, j’analyse comment l’expérience affecte la productivité des médecins. Cela a une importante implication sur le recrutement des médecins afin de satisfaire la demande croissante due à une population vieillissante, en particulier lorsque les médecins les plus expérimentés (les plus productifs) vont à la retraite. Dans le premier essai, j’ai estimé la fonction de revenu conditionnellement aux heures travaillées, en utilisant la méthode des variables instrumentales afin de contrôler pour une éventuelle endogeneité des heures travaillées. Comme instruments j’ai utilisé les variables indicatrices des âges des médecins, le taux marginal de taxation, le rendement sur le marché boursier, le carré et le cube de ce rendement. Je montre que cela donne la borne inférieure de l’élasticité-prix direct, permettant ainsi de tester si les médecins réagissent aux incitatifs monétaires. Les résultats montrent que les bornes inférieures des élasticités-prix de l’offre de services sont significativement positives, suggérant que les médecins répondent aux incitatifs. Un changement des prix relatifs conduit les médecins à allouer plus d’heures de travail au service dont le prix a augmenté. Dans le deuxième essai, j’estime le modèle en entier, de façon inconditionnelle aux heures travaillées, en analysant les variations des heures travaillées par les médecins, le volume des services offerts et le revenu des médecins. Pour ce faire, j’ai utilisé l’estimateur de la méthode des moments simulés. Les résultats montrent que les élasticités-prix direct de substitution sont élevées et significativement positives, représentant une tendance des médecins à accroitre le volume du service dont le prix a connu la plus forte augmentation. Les élasticitésprix croisées de substitution sont également élevées mais négatives. Par ailleurs, il existe un effet de revenu associé à l’augmentation des tarifs. J’ai utilisé les paramètres estimés du modèle structurel pour simuler une hausse générale de prix des services de 32%. Les résultats montrent que les médecins devraient réduire le nombre total d’heures travaillées (élasticité moyenne de -0,02) ainsi que les heures cliniques travaillées (élasticité moyenne de -0.07). Ils devraient aussi réduire le volume de services offerts (élasticité moyenne de -0.05). Troisièmement, j’ai exploité le lien naturel existant entre le revenu d’un médecin payé à l’acte et sa productivité afin d’établir le profil de productivité des médecins. Pour ce faire, j’ai modifié la spécification du modèle pour prendre en compte la relation entre la productivité d’un médecin et son expérience. J’estime l’équation de revenu en utilisant des données de panel asymétrique et en corrigeant le caractère non-aléatoire des observations manquantes à l’aide d’un modèle de sélection. Les résultats suggèrent que le profil de productivité est une fonction croissante et concave de l’expérience. Par ailleurs, ce profil est robuste à l’utilisation de l’expérience effective (la quantité de service produit) comme variable de contrôle et aussi à la suppression d’hypothèse paramétrique. De plus, si l’expérience du médecin augmente d’une année, il augmente la production de services de 1003 dollar CAN. J’ai utilisé les paramètres estimés du modèle pour calculer le ratio de remplacement : le nombre de médecins inexpérimentés qu’il faut pour remplacer un médecin expérimenté. Ce ratio de remplacement est de 1,2.

Convex Optimization Algorithms and Statistical Bounds for Learning Structured Models

Thesis (Ph.D.)--University of Washington, 2016-08

Air Pollution and High Density Lipoprotein Structure and Function

Thesis (Ph.D.)--University of Washington, 2016-06

New statin use and left ventricular structure: estimating long-term associations in the Multi-Ethnic Study of Atherosclerosis (MESA)

Thesis (Master's)--University of Washington, 2016-08

Structure learning of context-specific graphical models

Abstract The ultimate problem considered in this thesis is modeling a high-dimensional joint distribution over a set of discrete variables. For this purpose, we consider classes of context-specific graphical models and the main emphasis is on learning the structure of such models from data. Traditional graphical models compactly represent a joint distribution through a factorization justi ed by statements of conditional independence which are encoded by a graph structure. Context-speci c independence is a natural generalization of conditional independence that only holds in a certain context, speci ed by the conditioning variables. We introduce context-speci c generalizations of both Bayesian networks and Markov networks by including statements of context-specific independence which can be encoded as a part of the model structures. For the purpose of learning context-speci c model structures from data, we derive score functions, based on results from Bayesian statistics, by which the plausibility of a structure is assessed. To identify high-scoring structures, we construct stochastic and deterministic search algorithms designed to exploit the structural decomposition of our score functions. Numerical experiments on synthetic and real-world data show that the increased exibility of context-specific structures can more accurately emulate the dependence structure among the variables and thereby improve the predictive accuracy of the models.

Improved models for estimating temporal changes in carbon sequestration in above-ground biomass of mixed-species environmental plantings

Plantings of mixed native species (termed 'environmental plantings') are increasingly being established for carbon sequestration whilst providing additional environmental benefits such as biodiversity and water quality. In Australia, they are currently one of the most common forms of reforestation. Investment in establishing and maintaining such plantings relies on having a cost-effective modelling approach to providing unbiased estimates of biomass production and carbon sequestration rates. In Australia, the Full Carbon Accounting Model (FullCAM) is used for both national greenhouse gas accounting and project-scale sequestration activities. Prior to undertaking the work presented here, the FullCAM tree growth curve was not calibrated specifically for environmental plantings and generally under-estimated their biomass. Here we collected and analysed above-ground biomass data from 605 mixed-species environmental plantings, and tested the effects of several planting characteristics on growth rates. Plantings were then categorised based on significant differences in growth rates. Growth of plantings differed between temperate and tropical regions. Tropical plantings were relatively uniform in terms of planting methods and their growth was largely related to stand age, consistent with the un-calibrated growth curve. However, in temperate regions where plantings were more variable, key factors influencing growth were planting width, stand density and species-mix (proportion of individuals that were trees). These categories provided the basis for FullCAM calibration. Although the overall model efficiency was only 39-46%, there was nonetheless no significant bias when the model was applied to the various planting categories. Thus, modelled estimates of biomass accumulation will be reliable on average, but estimates at any particular location will be uncertain, with either under- or over-prediction possible. When compared with the un-calibrated yield curves, predictions using the new calibrations show that early growth is likely to be more rapid and total above-ground biomass may be higher for many plantings at maturity. This study has considerably improved understanding of the patterns of growth in different types of environmental plantings, and in modelling biomass accumulation in young (<25. years old) plantings. However, significant challenges remain to understand longer-term stand dynamics, particularly with temporal changes in stand density and species composition. © 2014.