Kernel Methods in Computer-Aided Constructive Drug Design

A drug is typically a small molecule that interacts with the binding site of some target protein. Drug design involves the optimization of this interaction so that the drug effectively binds with the target protein while not binding with other proteins (an event that could produce dangerous side effects). Computational drug design involves the geometric modeling of drug molecules, with the goal of generating similar molecules that will be more effective drug candidates. It is necessary that algorithms incorporate strategies to measure molecular similarity by comparing molecular descriptors that may involve dozens to hundreds of attributes. We use kernel-based methods to define these measures of similarity. Kernels are general functions that can be used to formulate similarity comparisons. The overall goal of this thesis is to develop effective and efficient computational methods that are reliant on transparent mathematical descriptors of molecules with applications to affinity prediction, detection of multiple binding modes, and generation of new drug leads. While in this thesis we derive computational strategies for the discovery of new drug leads, our approach differs from the traditional ligandbased approach. We have developed novel procedures to calculate inverse mappings and subsequently recover the structure of a potential drug lead. The contributions of this thesis are the following: 1. We propose a vector space model molecular descriptor (VSMMD) based on a vector space model that is suitable for kernel studies in QSAR modeling. Our experiments have provided convincing comparative empirical evidence that our descriptor formulation in conjunction with kernel based regression algorithms can provide sufficient discrimination to predict various biological activities of a molecule with reasonable accuracy. 2. We present a new component selection algorithm KACS (Kernel Alignment Component Selection) based on kernel alignment for a QSAR study. Kernel alignment has been developed as a measure of similarity between two kernel functions. In our algorithm, we refine kernel alignment as an evaluation tool, using recursive component elimination to eventually select the most important components for classification. We have demonstrated empirically and proven theoretically that our algorithm works well for finding the most important components in different QSAR data sets. 3. We extend the VSMMD in conjunction with a kernel based clustering algorithm to the prediction of multiple binding modes, a challenging area of research that has been previously studied by means of time consuming docking simulations. The results reported in this study provide strong empirical evidence that our strategy has enough resolving power to distinguish multiple binding modes through the use of a standard k-means algorithm. 4. We develop a set of reverse engineering strategies for QSAR modeling based on our VSMMD. These strategies include: (a) The use of a kernel feature space algorithm to design or modify descriptor image points in a feature space. (b) The deployment of a pre-image algorithm to map the newly defined descriptor image points in the feature space back to the input space of the descriptors. (c) The design of a probabilistic strategy to convert new descriptors to meaningful chemical graph templates. The most important aspect of these contributions is the presentation of strategies that actually generate the structure of a new drug candidate. While the training set is still used to generate a new image point in the feature space, the reverse engineering strategies just described allows us to develop a new drug candidate that is independent of issues related to probability distribution constraints placed on test set molecules

Public healthcare financing and provision in Hong Kong : a public-private partnership approach

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Measurement invariance of the Functional Assessment of Cancer Therapy—Colorectal quality-of-life instrument among modes of administration

OBJECTIVES: To test for the measurement invariance of the Functional Assessment of Cancer Therapy—Colorectal (FACT-C) in patients with colorectal neoplasms between two modes of administration (self- and interviewer administrations). It is important to establish the measurement invariance of the FACT-C across different modes of administration to ascertain whether it is valid to pool FACT-C data collected by different modes or to assess each group separately. METHODS: A cross-sectional sample of 391 Chinese patients with colorectal neoplasms was recruited from specialist outpatient clinics between September 2009 and July 2010. Confirmatory factor analysis (CFA) was used to test the original five-factor model of the FACT-C on data collected by self- and interviewer administrations in single-group analysis. Multiple-group CFA was then used to compare the factor structure between the two modes of administration using chi-square tests and other goodness-of-fit statistics. RESULTS: The hypothesized five-factor model of FACT-C demonstrated good fit in each group. Configural invariance and metric invariance were fully supported in multiple-group CFA. Some item intercepts and their corresponding error variances were not identical between administration groups, suggesting evidence of partial strict factorial invariance. CONCLUSIONS: Our results confirmed that the five-factor structure of FACT-C was invariant in Chinese patients using both self- and interviewer administrations. It is appropriate to pool or compare data in the emotional well-being and colorectal cancer subscale scores collected by both administrations. Measurement invariance in three items, one from each of the other subscales, may be contaminated by response bias between modes of administration

A Gramaticalização do Verbo Ir e a Variação de Formas para Expressar o Futuro do Presente: uma Fotografia Capixaba

Esta pesquisa verifica o estágio do processo de gramaticalização do verbo IR, que tem assumido a função de auxiliar em construções perifrásticas para expressar tempo. Para isso, investiga-se a variação entre as formas sintética e perifrástica com IR para expressão do futuro do presente. Temos por hipótese que a forma perifrástica já atinge todos os gêneros das duas modalidades da língua, uma vez que já se especializou para codificar tempo. São examinados dois gêneros, tomando-os como prototípicos do continuun oral/escrito: entrevistas com informantes universitários e editoriais de jornal. Partindo de uma orientação teórica Funcionalista, num quadro mais geral, concebe-se a língua como flexível ao uso, passível de influências cognitivas, sociais e também individuais, embora haja nela forças que atuam no sentido de regularizar a estrutura. Seguindo algumas pesquisas que têm se mostrado frutíferas, o modelo funcionalista estará em diálogo com outro modelo que procura dar conta da heterogeneidade estruturada da língua e de seus processos de mudança: a Teoria Variacionista. Num quadro mais específico, os fundamentos que orientam a pesquisa são os da Gramaticalização. Os dados extraídos dos gêneros selecionados serão submetidos ao programa computacional GOLDVARB 2001 e, em seguida, interpretados à luz das teorias lingüísticas que fundamentam esta pesquisa

Hong Kong Renal Registry Report 2012

SummaryThis report examined the characteristics and trends of dialysis and renal transplant patients among the resident population of Hong Kong who were managed by hospitals or dialysis centers of the Hospital Authority, and accounted for approximately 95% of all patients receiving renal replacement therapies (RRTs) in the territory. Patients receiving RRTs solely in the private sector were not included in this report. Data trends from 1996 to 2011 are presented. In 2011, 1115 new patients were accepted into RRT programs, and the incident rate was 157 patients per million populations (pmp). An increasing trend was noted. The incident rate was 95.1 pmp at the commencement of the annual report in 1996. The point prevalence on December 31, 2012 was 8197 with a prevalence rate of 1152.5 pmp. Overall, there were 3573 patients (43.6%) on peritoneal dialysis (PD) and 1246 patients (15.2%) on hemodialysis (HD), and 3378 patients (41.2%) were living with a functioning renal transplant. The PD/HD ratio was 74.2:25.8. The “PD First” policy was continued. The overall mortality rate among RRT patients was 9.95 patients per 100 patient-years exposed. There was a decreasing trend in mortality among PD patients. Infection and cardiovascular complications were the most common causes of death. Renal transplant was the modality with the best survival rates. The 5 years cumulative patient survival rate for patients on transplant treatment was 89.6%, whereas the corresponding patient survival rates for PD and HD patients were 50.7% and 55.7%, respectively. More than 70% of RRT patients with reports on rehabilitation were active and had normal daily activities

Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues

Current available tissue clearing techniques are mostly used for rodent tissues. Here, the authors develop OPTIClear solution for fresh and archival human brain tissue clearing and establish associated protocols for three-dimensional histological investigations