SURVIVAL PREDICTION FOR BRAIN TUMOR PATIENTS USING GENE EXPRESSION DATA

Brain tumor is one of the most aggressive types of cancer in humans, with an estimated median survival time of 12 months and only 4% of the patients surviving more than 5 years after disease diagnosis. Until recently, brain tumor prognosis has been based only on clinical information such as tumor grade and patient age, but there are reports indicating that molecular profiling of gliomas can reveal subgroups of patients with distinct survival rates. We hypothesize that coupling molecular profiling of brain tumors with clinical information might improve predictions of patient survival time and, consequently, better guide future treatment decisions. In order to evaluate this hypothesis, the general goal of this research is to build models for survival prediction of glioma patients using DNA molecular profiles (U133 Affymetrix gene expression microarrays) along with clinical information. First, a predictive Random Forest model is built for binary outcomes (i.e. short vs. long-term survival) and a small subset of genes whose expression values can be used to predict survival time is selected. Following, a new statistical methodology is developed for predicting time-to-death outcomes using Bayesian ensemble trees. Due to a large heterogeneity observed within prognostic classes obtained by the Random Forest model, prediction can be improved by relating time-to-death with gene expression profile directly. We propose a Bayesian ensemble model for survival prediction which is appropriate for high-dimensional data such as gene expression data. Our approach is based on the ensemble "sum-of-trees" model which is flexible to incorporate additive and interaction effects between genes. We specify a fully Bayesian hierarchical approach and illustrate our methodology for the CPH, Weibull, and AFT survival models. We overcome the lack of conjugacy using a latent variable formulation to model the covariate effects which decreases computation time for model fitting. Also, our proposed models provides a model-free way to select important predictive prognostic markers based on controlling false discovery rates. We compare the performance of our methods with baseline reference survival methods and apply our methodology to an unpublished data set of brain tumor survival times and gene expression data, selecting genes potentially related to the development of the disease under study. A closing discussion compares results obtained by Random Forest and Bayesian ensemble methods under the biological/clinical perspectives and highlights the statistical advantages and disadvantages of the new methodology in the context of DNA microarray data analysis.

Effects of early and late lesion of orbital frontal cortex on visual processing of faces in rhesus macaques (Macaca mulatta)

Many mental disorders disrupt social skills, yet few studies have examined how the brain processes social information. Functional neuroimaging, neuroconnectivity and electrophysiological studies suggest that orbital frontal cortex plays important roles in social cognition, including the analysis of information from faces, which are important cues in social interactions. Studies in humans and non-human primates show that damage to orbital frontal cortex produces social behavior impairments, including abnormal aggression, but these studies have failed to determine whether damage to this area impairs face processing. In addition, it is not known whether damage early in life is more detrimental than damage in adulthood. This study examined whether orbital frontal cortex is necessary for the discrimination of face identity and facial expressions, and for appropriate behavioral responses to aggressive (threatening) facial expressions. Rhesus monkeys (Macaca mulatta) received selective lesions of orbital frontal cortex as newborns or adults. As adults, these animals were compared with sham-operated controls on their ability to discriminate between faces of individual monkeys and between different facial expressions of emotion. A passive visual paired-comparison task with standardized rhesus monkey face stimuli was designed and used to assess discrimination. In addition, looking behavior toward aggressive expressions was assessed and compared with that of normal control animals. The results showed that lesion of orbital frontal cortex (1) may impair discrimination between faces of individual monkeys, (2) does not impair facial expression discrimination, and (3) changes the amount of time spent looking at aggressive (threatening) facial expressions depending on the context. The effects of early and late lesions did not differ. Thus, orbital frontal cortex appears to be part of the neural circuitry for recognizing individuals and for modulating the response to aggression in faces, and the plasticity of the immature brain does not allow for recovery of these functions when the damage occurs early in life. This study opens new avenues for the assessment of rhesus monkey face processing and the neural basis of social cognition, and allows a better understanding of the nature of the neuropathology in patients with mental disorders that disrupt social behavior, such as autism. ^

The cost of publicly financed dental care in relation to community water fluoridation in Texas

Dental caries lead to children being less ready to learn and results in diminished productivity in the classroom. Tooth decay causes pain and infection, leading to impaired chewing, speech, and facial expression, in addition to a loss in self-esteem. There have been many studies supporting the safety and efficacy of community water fluoridation in reducing dental caries. Water fluoridation has been identified by the Centers for Disease Control and Prevention as one of 10 great public health achievements of the 20th century. The decline in the prevalence and severity of tooth decay in the United States during the past 60 years has been attributed largely to the increased use of fluoride; in particular, the widespread utilization of community water fluoridation. However, in the decades since fluoridation was first introduced, reductions in dental caries have declined, most likely due to the presence of other sources of fluoride. Questions have been raised regarding the need to continue to fluoridate community water supplies in the face of possible excessive exposure to fluoride. Nevertheless, dental caries continue to be a significant public health burden throughout the world, including the United States, especially among low-income and disadvantaged populations. Although many poor children receive their dental care through Medicaid, the percentage of Texas children with untreated dental caries continues to exceed the U.S. average and is well above Healthy People 2010 goals, even as state Medicaid expenditures continue to rise. The objective of this study is to determine the relationship between Medicaid dental expenditures and community water fluoridation levels in Texas counties. By examining this relationship, the cost-effectiveness of community water fluoridation in the Texas pediatric Medicaid beneficiary population, as measured by publicly financed dental care expenditures, may be ascertained.^