Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress

REV3, the catalytic subunit of translesion polymerase zeta (polζ), is commonly associated with DNA damage bypass and repair. Despite sharing accessory subunits with replicative polymerase δ, very little is known about the role of polζ in DNA replication. We previously demonstrated that inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. To reveal determinants of this sensitivity and obtain insights into the cellular function of REV3, we performed whole human genome RNAi library screens aimed at identification of synthetic lethal interactions with REV3 in A549 lung cancer cells. The top confirmed hit was RRM1, the large subunit of ribonucleotide reductase (RNR), a critical enzyme of de novo nucleotide synthesis. Treatment with the RNR-inhibitor hydroxyurea (HU) synergistically increased the fraction of REV3-deficient cells containing single stranded DNA (ssDNA) as indicated by an increase in replication protein A (RPA). However, this increase was not accompanied by accumulation of the DNA damage marker γH2AX suggesting a role of REV3 in counteracting HU-induced replication stress (RS). Consistent with a role of REV3 in DNA replication, increased RPA staining was confined to HU-treated S-phase cells. Additionally, we found genes related to RS to be significantly enriched among the top hits of the synthetic sickness/lethality (SSL) screen further corroborating the importance of REV3 for DNA replication under conditions of RS.

Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit.

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking. This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any "hardcore" smoker who finds it difficult to quit with standard approaches.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.Leukemia advance online publication, 26 February 2016; doi:10.1038/leu.2016.20.

Evaluating the impact of vertical integration on health system peformance

Vertical integration is grounded in economic theory as a corporate strategy for reducing cost and enhancing efficiency. There were three purposes for this dissertation. The first was to describe and understand vertical integration theory. The review of the economic theory established vertical integration as a corporate cost reduction strategy in response to environmental, structural and performance dimensions of the market. The second purpose was to examine vertical integration in the context of the health care industry, which has greater complexity, higher instability, and more unstable demand than other industries, although many of the same dimensions of the market supported a vertical integration strategy. Evidence on the performance of health systems after integration revealed mixed results. Because the market continues to be turbulent, hybrid non-owned integration in the form of alliances have increased to over 40% of urban hospitals. The third purpose of the study was to examine the application of vertical integration in health care and evaluate the effects. The case studied was an alliance formed between a community hospital and a tertiary medical center to facilitate vertical integration of oncology services while maintaining effectiveness and preserving access. The economic benefits for 1934 patients were evaluated in the delivery system before and after integration with a more detailed economic analysis of breast, lung, colon/rectal, and non-malignant cases. A regression analysis confirmed the relationship between the independent variables of age, sex, location of services, race, stage of disease, and diagnosis, and the dependent variable, cost. The results of the basic regression model, as well as the regression with first-order interaction terms, were statistically significant. The study shows that vertical integration at an intermediate health care system level has economic benefits. If the pre-integration oncology group had been treated in the post-integration model, the expected cost savings from integration would be 31.5%. Quality indicators used were access to health care services and research treatment protocols, and access was preserved in the integrated model. Using survival as a direct quality outcome measure, the survival of lung cancer patients was statistically the same before and after integration. ^

Smoke free restaurant ordinance, compliance with the regulation to reduce exposure to environmental tobacco smoke while dining at local restaurants in San Antonio, Texas

This study is a secondary analysis of a survey developed by Dr. Jimmy Perkins and administered by San Antonio/Bexar County Metropolitan Health District. The survey was developed subsequent to the implementation of the city smoking ordinance effective January 1, 2004. The survey had a multi-purpose plan to establish the number of restaurants having smoke free status prior to and following the ordinance, determine compliance as it relates to a necessary smoking section and proper signage, and expose the rationale for restaurants to become smoke free. The data resulting from the survey was presented to the San Antonio/Bexar County Metropolitan Health District. The summary presented the types of establishments surveyed, smoking status of the establishment, reasons for the establishment becoming smoke free, compliance with smoking sections, compliance with signage requirements, awareness of ordinance, and chain status of the establishment. ^ The results of this study display the relationships among the variables previously mentioned. The following relationships have been examined and the outcomes have determined whether each is significant. After careful analysis, knowledge translates into compliance with signage regulations, which then translate into ordinance compliance. Size does matter as it relates to an establishment's number of employees and seating capacity. The smaller the establishment the more likely the establishment is to have become smoke free before the ordinance went into effect. Restaurants, rather than fast food establishments most commonly cited their reason for becoming smoke free was to comply with the ordinance and only ten percent of restaurants gave policy as the main reason for becoming smoke free. ^ This study is important for public health because the negative health effects of environmental tobacco smoke (ETS) are still an overwhelming problem in the United States (3). ETS is a Known Human Group A Carcinogen (5). The Environmental Protection Agency (EPA) has estimated that around 3,000 non-smoking Americans die every year from lung cancer caused by ETS (6). This information illustrates the importance of providing smoke free establishments, especially to non-smoking patrons. ^

Environmental tobacco smoke exposure, respiratory and cardiovascular health in restaurant and bar workers in Mexico

Environmental tobacco smoke (ETS) is a well established health hazard, being causally associated to lung cancer and cardiovascular disease. ETS regulations have been developed worldwide to reduce or eliminate exposure in most public places. Restaurants and bars constitute an exception. Restaurants and bar workers experience the highest ETS exposure levels across several occupations, with correspondingly increased health risks. In Mexico, previous exposure assessment in restaurants and bars showed concentrations in bars and restaurants to be the highest across different public and workplaces. Recently, Mexico developed at the federal level the General Law for Tobacco Control restricting indoors smoking to separated areas. AT the local level Mexico City developed the Law for the Protection of Non-smokers Health, completely banning smoking in restaurants and bars. Studies to assess ETS exposure in restaurants and bars, along with potential health effects were required to evaluate the impact of these legislative changes and to set a baseline measurement for future evaluations.^ A large cross-sectional study conducted in restaurants and bars from four Mexican cities was conducted from July to October 2008, to evaluate the following aims: Aim 1) Explore the potential impact of the Mexico City ban on ETS concentrations through comparison of Mexico City with other cities. Aim 2). Explore the association between ETS exposure, respiratory function indicators and respiratory symptoms. Aim 3). Explore the association between ETS exposure and blood pressure and heart rate.^ Three cities with no smoking ban were selected: Colima (11.5% smoking prevalence), Cuernavaca (21.5% smoking prevalence) and Toluca (27.8% smoking prevalence). Mexico City (27.9% smoking prevalence), the only city with a ban at the time of the study, was also selected. Restaurants and bars were randomly selected from municipal records. A goal of 26 restaurants and 26 bars per city was set, 50% of them under 100 m2. Each establishment was visited during the highest occupancy shift, and managers and workers answered to a questionnaire. Vapor-phase nicotine was measured using passive monitors, that were activated at the beginning and deactivated at the end of the shift. Also, workers participated at the beginning and end of the shift in a short physical evaluation, comprising the measurement of Forced Expiratory Volume in the first second (FEV1) and Peak Expiratory Flow (PEF), as well as blood pressure and heart rate.^ A total of 371 establishments were invited, 219 agreed to participate for a 60.1% participation rate. In them, 828 workers were invited, 633 agreed to participate for a 76% participation rate. Mexico City had at least 4 times less nicotine compared to any of the other cities. Differences between Mexico City and other cities were not explained by establishment characteristics, such as ventilation or air extraction. However, differences between cities disappeared when ban mechanisms, such as policy towards costumer's smoking, were considered in the models. An association between ETS exposure and respiratory symptoms (cough OR=1.27, 95%CI=1.04, 1.55) and respiratory illness (asthma OR=1.97, 95%CI=1.20, 3.24; respiratory illness OR=1.79, 95%CI=1.10, 2.94) was observed. No association between ETS and phlegm, wheezing or respiratory infections was observed. No association between ETS and any of the spirometric indicators was observed. An association between ETS exposure and increased systolic and diastolic blood pressure at the end of the shift was observed among non-smokers (systolic blood pressure beta=1.51, 95%CI=0.44, 2.58; diastolic blood pressure beta=1.50, 95%CI=0.72, 2.28). The opposite effect was observed in heavy smokers, were increased ETS exposure was associated with lower blood pressure at the end of the shift (systolic blood pressure beta=1.90, 95%CI=-3.57, -0.23; diastolic blood pressure beta=-1.46, 95%CI=-2.72, -0.02). No association in light smokers was observed. No association for heart rate was observed. ^ Results from this dissertation suggest Mexico City's smoking ban has had a larger impact on ETS exposure. Ventilation or air extraction, mechanisms of ETS control suggested frequently by tobacco companies to avoid smoking bans were not associated with ETS exposure. This dissertation suggests ETS exposure could be linked to changes in blood pressure and to increased respiratory symptoms. Evidence derived from this dissertation points to the potential negative health effects of ETS exposure in restaurants and bars, and provides support for the development of total smoking bans in this economic sector. ^

A cohort study of occupational asbestos-exposure related neoplasms in Texas Gulf Coast area

A cohort study was conducted in Texas and Louisiana Gulf Coast area on individual workers who have been exposed to asbestos for 15 years or more. Most of these workers were employed in petrochemical industries. Of the 15,742 subjects initially selected for the cohort study, 3,258 had positive chest X-ray findings believed to be related to prolonged asbestos exposure. These subjects were further investigated. Their work out included detailed medical and occupational history, laboratory tests and spirometry. One thousand eight-hundred and three cases with positive chest X-ray findings whose data files were considered complete at the end of May 1986 were analyzed and their findings included in this report.^ The prevalence of lung cancer and cancer of the following sights: skin, stomach, oropharyngeal, pancreas and kidneys were significantly increased when compared to data from Connecticut Tumor Registry. The prevalence of other chronic conditions such as hypertension, emphysema, heart disease and peptic ulcer was also significantly high when compared to data for the U.S. and general population furnished by the National Center for Health Statistics (NCHS). In most instances the occurrence of cancer and the chronic ailment previously mentioned appeared to follow 15-25 years of exposure to asbestos. ^

Genetic epidemiologic methods in risk determination in Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is characterized by a variety of neoplasms occurring at a young age with an apparent autosomal dominant transmission. Individuals in pedigrees with LFS have high incidence of second malignancies. Recently LFS has been found to be associated with germline mutations of a tumor-suppressor gene, p53. Because LFS is rare and indeed not a clear-cut disease, it is not known whether all cases of LFS are attributable to p53 germline mutations and how p53 plays in cancer occurrence in such cancer syndrome families. In the present study, DNAs from constitutive cells of two-hundred and thirty-three family members from ten extended pedigrees were screened for p53 mutations. Six out of the ten LFS families had germline mutations at the p53 locus, including point and deletion mutations. In these six families, 55 out of 146 members were carriers of p53 mutations. Except one, all mutations occurred in exons 5 to 8 (i.e., the "hot spot" region) of the p53 gene. The age-specific penetrance of cancer was estimated after the genotype for each family member at risk was determined. The penetrance was 0.15, 0.29, 0.35, 0.77, and 0.91 by 20, 30, 40, 50 and 60 year-old, respectively, in male carriers; 0.19, 0.44, 0.76, and 0.90 by 20, 30, 40, and 50 year-old, respectively, in female carriers. These results indicated that one cannot escape from tumorigenesis if one inherits a p53 mutant allele; at least ninety percent of p53 carriers will develop cancer by the age of 60. To evaluate the possible bias due to the unexamined blood-relatives in LFS families, I performed a simulation analysis in which a p53 genotype was assigned to each unexamined person based on his cancer status and liability to cancer. The results showed that the penetrance estimates were not biased by the unexamined relatives. I also determined the sex, site, and age-specific penetrance of breast cancer in female carriers and lung cancer in male carriers. The penetrance of breast cancer in female carriers was 0.81 by age 45; the penetrance of lung cancer in male carriers was 0.78 by age 60, indicating that p53 play a key role for tumorigenesis in common cancers. ^

A comparative analysis of Texas and Louisiana Oil-field NORM Waste Policy

NORM (Naturally Occurring Radioactive Material) Waste Policies for the nation's oil and gas producing states have been in existence since the 1980's, when Louisiana was the first state to develop a NORM regulatory program in 1989. Since that time, expectations for NORM Waste Policies have evolved, as Health, Safety, Environment, and Social responsibility (HSE & SR) grows increasingly important to the public. Therefore, the oil and gas industry's safety and environmental performance record will face challenges in the future, about its best practices for managing the co-production of NORM wastes. ^ Within the United States, NORM is not federally regulated. The U.S. EPA claims it regulates NORM under CERCLA (superfund) and the Clean Water Act. Though, there are no universally applicable regulations for radium-based NORM waste. Therefore, individual states have taken responsibility for developing NORM regulatory programs, because of the potential radiological risk it can pose to man (bone and lung cancer) and his environment. This has led to inconsistencies in NORM Waste Policies as well as a NORM management gap in both state and federal regulatory structures. ^ Fourteen different NORM regulations and guidelines were compared between Louisiana and Texas, the nation's top two petroleum producing states. Louisiana is the country's top crude oil producer when production from its Federal offshore waters are included, and fourth in crude oil production, behind Texas, Alaska, and California when Federal offshore areas are excluded. Louisiana produces more petroleum products than any state but Texas. For these reasons, a comparative analysis between Louisiana and Texas was undertaken to identify differences in their NORM regulations and guidelines for managing, handling and disposing NORM wastes. Moreover, this analysis was undertaken because Texas is the most explored and drilled worldwide and yet appears to lag behind its neighboring state in terms of its NORM Waste Policy and developing an industry standard for handling, managing and disposing NORM. As a result of this analysis, fourteen recommendations were identified.^

Design and Optimization of Four-dimensional Cone-beam Computed Tomography in Image-guided Radiation Therapy

The influence of respiratory motion on patient anatomy poses a challenge to accurate radiation therapy, especially in lung cancer treatment. Modern radiation therapy planning uses models of tumor respiratory motion to account for target motion in targeting. The tumor motion model can be verified on a per-treatment session basis with four-dimensional cone-beam computed tomography (4D-CBCT), which acquires an image set of the dynamic target throughout the respiratory cycle during the therapy session. 4D-CBCT is undersampled if the scan time is too short. However, short scan time is desirable in clinical practice to reduce patient setup time. This dissertation presents the design and optimization of 4D-CBCT to reduce the impact of undersampling artifacts with short scan times. This work measures the impact of undersampling artifacts on the accuracy of target motion measurement under different sampling conditions and for various object sizes and motions. The results provide a minimum scan time such that the target tracking error is less than a specified tolerance. This work also presents new image reconstruction algorithms for reducing undersampling artifacts in undersampled datasets by taking advantage of the assumption that the relevant motion of interest is contained within a volume-of-interest (VOI). It is shown that the VOI-based reconstruction provides more accurate image intensity than standard reconstruction. The VOI-based reconstruction produced 43% fewer least-squares error inside the VOI and 84% fewer error throughout the image in a study designed to simulate target motion. The VOI-based reconstruction approach can reduce acquisition time and improve image quality in 4D-CBCT.

DEVELOPMENT OF A BEAM-SPECIFIC PLANNING TARGET VOLUME AND A ROBUST PLAN ANALYSIS TOOL FOR PROTON THERAPY

Proton therapy is growing increasingly popular due to its superior dose characteristics compared to conventional photon therapy. Protons travel a finite range in the patient body and stop, thereby delivering no dose beyond their range. However, because the range of a proton beam is heavily dependent on the tissue density along its beam path, uncertainties in patient setup position and inherent range calculation can degrade thedose distribution significantly. Despite these challenges that are unique to proton therapy, current management of the uncertainties during treatment planning of proton therapy has been similar to that of conventional photon therapy. The goal of this dissertation research was to develop a treatment planning method and a planevaluation method that address proton-specific issues regarding setup and range uncertainties. Treatment plan designing method adapted to proton therapy: Currently, for proton therapy using a scanning beam delivery system, setup uncertainties are largely accounted for by geometrically expanding a clinical target volume (CTV) to a planning target volume (PTV). However, a PTV alone cannot adequately account for range uncertainties coupled to misaligned patient anatomy in the beam path since it does not account for the change in tissue density. In order to remedy this problem, we proposed a beam-specific PTV (bsPTV) that accounts for the change in tissue density along the beam path due to the uncertainties. Our proposed method was successfully implemented, and its superiority over the conventional PTV was shown through a controlled experiment.. Furthermore, we have shown that the bsPTV concept can be incorporated into beam angle optimization for better target coverage and normal tissue sparing for a selected lung cancer patient. Treatment plan evaluation method adapted to proton therapy: The dose-volume histogram of the clinical target volume (CTV) or any other volumes of interest at the time of planning does not represent the most probable dosimetric outcome of a given plan as it does not include the uncertainties mentioned earlier. Currently, the PTV is used as a surrogate of the CTV’s worst case scenario for target dose estimation. However, because proton dose distributions are subject to change under these uncertainties, the validity of the PTV analysis method is questionable. In order to remedy this problem, we proposed the use of statistical parameters to quantify uncertainties on both the dose-volume histogram and dose distribution directly. The robust plan analysis tool was successfully implemented to compute both the expectation value and its standard deviation of dosimetric parameters of a treatment plan under the uncertainties. For 15 lung cancer patients, the proposed method was used to quantify the dosimetric difference between the nominal situation and its expected value under the uncertainties.

THE NATURAL AND ORTHOGONAL INTERACTION (NOIA) MODELS FOR QUANTITATIVE TRAITS (QTs) AND COMPLEX DISEASES

My dissertation focuses on developing methods for gene-gene/environment interactions and imprinting effect detections for human complex diseases and quantitative traits. It includes three sections: (1) generalizing the Natural and Orthogonal interaction (NOIA) model for the coding technique originally developed for gene-gene (GxG) interaction and also to reduced models; (2) developing a novel statistical approach that allows for modeling gene-environment (GxE) interactions influencing disease risk, and (3) developing a statistical approach for modeling genetic variants displaying parent-of-origin effects (POEs), such as imprinting. In the past decade, genetic researchers have identified a large number of causal variants for human genetic diseases and traits by single-locus analysis, and interaction has now become a hot topic in the effort to search for the complex network between multiple genes or environmental exposures contributing to the outcome. Epistasis, also known as gene-gene interaction is the departure from additive genetic effects from several genes to a trait, which means that the same alleles of one gene could display different genetic effects under different genetic backgrounds. In this study, we propose to implement the NOIA model for association studies along with interaction for human complex traits and diseases. We compare the performance of the new statistical models we developed and the usual functional model by both simulation study and real data analysis. Both simulation and real data analysis revealed higher power of the NOIA GxG interaction model for detecting both main genetic effects and interaction effects. Through application on a melanoma dataset, we confirmed the previously identified significant regions for melanoma risk at 15q13.1, 16q24.3 and 9p21.3. We also identified potential interactions with these significant regions that contribute to melanoma risk. Based on the NOIA model, we developed a novel statistical approach that allows us to model effects from a genetic factor and binary environmental exposure that are jointly influencing disease risk. Both simulation and real data analyses revealed higher power of the NOIA model for detecting both main genetic effects and interaction effects for both quantitative and binary traits. We also found that estimates of the parameters from logistic regression for binary traits are no longer statistically uncorrelated under the alternative model when there is an association. Applying our novel approach to a lung cancer dataset, we confirmed four SNPs in 5p15 and 15q25 region to be significantly associated with lung cancer risk in Caucasians population: rs2736100, rs402710, rs16969968 and rs8034191. We also validated that rs16969968 and rs8034191 in 15q25 region are significantly interacting with smoking in Caucasian population. Our approach identified the potential interactions of SNP rs2256543 in 6p21 with smoking on contributing to lung cancer risk. Genetic imprinting is the most well-known cause for parent-of-origin effect (POE) whereby a gene is differentially expressed depending on the parental origin of the same alleles. Genetic imprinting affects several human disorders, including diabetes, breast cancer, alcoholism, and obesity. This phenomenon has been shown to be important for normal embryonic development in mammals. Traditional association approaches ignore this important genetic phenomenon. In this study, we propose a NOIA framework for a single locus association study that estimates both main allelic effects and POEs. We develop statistical (Stat-POE) and functional (Func-POE) models, and demonstrate conditions for orthogonality of the Stat-POE model. We conducted simulations for both quantitative and qualitative traits to evaluate the performance of the statistical and functional models with different levels of POEs. Our results showed that the newly proposed Stat-POE model, which ensures orthogonality of variance components if Hardy-Weinberg Equilibrium (HWE) or equal minor and major allele frequencies is satisfied, had greater power for detecting the main allelic additive effect than a Func-POE model, which codes according to allelic substitutions, for both quantitative and qualitative traits. The power for detecting the POE was the same for the Stat-POE and Func-POE models under HWE for quantitative traits.

Development and implementation of a dynamic heterogeneous proton equivalent anthropomorphic thorax phantom for the assessment of scanned proton beam therapy

DEVELOPMENT AND IMPLEMENTATION OF A DYNAMIC HETEROGENEOUS PROTON EQUIVALENT ANTHROPOMORPHIC THORAX PHANTOM FOR THE ASSESSMENT OF SCANNED PROTON BEAM THERAPY by James Leroy Neihart, B.S. APPROVED: ______________________________David Followill, Ph.D. ______________________________Peter Balter, Ph.D. ______________________________Narayan Sahoo, Ph.D. ______________________________Kenneth Hess, Ph.D. ______________________________Paige Summers, M.S. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston DEVELOPMENT AND IMPLEMENTATION OF A DYNAMIC HETEROGENEOUS PROTON EQUIVALENT ANTHROPOMORPHIC THORAX PHANTOM FOR THE ASSESSMENT OF SCANNED PROTON BEAM THERAPY A THESIS Presented to the Faculty of The University of Texas Health Science Center at Houston andThe University of TexasMD Anderson Cancer CenterGraduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE by James Leroy Neihart, B.S. Houston, Texas Date of Graduation August, 2013 Acknowledgments I would like to acknowledge my advisory committee members, chair David Followill, Ph.D., Peter Balter, Ph.D, Narayan Sahoo, Ph.D., Kenneth Hess, Ph.D., Paige Summers M.S. and, for their time and effort contributed to this project. I would additionally like to thank the faculty and staff at the PTC-H and the RPC who assisted in many aspects of this project. Falk Pӧnisch, Ph.D. for his breath hold proton therapy treatment expertise, Matt Palmer and Jaques Bluett for proton dosimetry assistance, Matt Kerr for verification plan assistance, Carrie Amador, Nadia Hernandez, Trang Nguyen, Andrea Molineu, Lynda McDonald for TLD and film dosimetry assistance. Finally, I would like to thank my wife and family for their support and encouragement during my research and studies. Development and implementation of a dynamic heterogeneous proton equivalent anthropomorphic thorax phantom for the assessment of scanned proton beam therapy By: James Leroy Neihart, B.S. Chair of Advisory Committee: David Followill, Ph.D Proton therapy has been gaining ground recently in radiation oncology. To date, the most successful utilization of proton therapy is in head and neck cases as well as prostate cases. These tumor locations do not suffer from the resulting difficulties of treatment delivery as a result of respiratory motion. Lung tumors require either breath hold or motion tracking, neither of which have been assessed with an end-to-end phantom for proton treatments. Currently, the RPC does not have a dynamic thoracic phantom for proton therapy procedure assessment. Additionally, such a phantom could be an excellent means of assessing quality assurance of the procedures of proton therapy centers wishing to participate in clinical trials. An eventual goal of this phantom is to have a means of evaluating and auditing institutions for the ability to start clinical trials utilizing proton therapy procedures for lung cancers. Therefore, the hypothesis of this study is that a dynamic anthropomorphic thoracic phantom can be created to evaluate end-to-end proton therapy treatment procedures for lung cancer to assure agreement between the measured and calculated dose within 5% / 5 mm with a reproducibility of 2%. Multiple materials were assessed for thoracic heterogeneity equivalency. The phantom was designed from the materials found to be in greatest agreement. The phantom was treated in an end-to-end treatment four times, which included simulation, treatment planning and treatment delivery. Each treatment plan was delivered three times to assess reproducibility. The dose measured within the phantom was compared to that of the treatment plan. The hypothesis was fully supported for three of the treatment plans, but failed the reproducibility requirement for the most aggressive treatment plan.

BAYESIAN STATISTICAL METHODS IN GENE-ENVIRONMENT AND GENE-GENE INTERACTION STUDIES

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of complex diseases. In the past decade, thanks to the increasing computational capabilities and novel statistical developments, Bayesian methods have been widely applied in the genetics/genomics researches and demonstrating superiority over some regular approaches in certain research areas. Gene-environment and gene-gene interaction studies are among the areas where Bayesian methods may fully exert its functionalities and advantages. This dissertation focuses on developing new Bayesian statistical methods for data analysis with complex gene-environment and gene-gene interactions, as well as extending some existing methods for gene-environment interactions to other related areas. It includes three sections: (1) Deriving the Bayesian variable selection framework for the hierarchical gene-environment and gene-gene interactions; (2) Developing the Bayesian Natural and Orthogonal Interaction (NOIA) models for gene-environment interactions; and (3) extending the applications of two Bayesian statistical methods which were developed for gene-environment interaction studies, to other related types of studies such as adaptive borrowing historical data. We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions (epistasis) and gene by environment interactions in the same model. It is well known that, in many practical situations, there exists a natural hierarchical structure between the main effects and interactions in the linear model. Here we propose a model that incorporates this hierarchical structure into the Bayesian mixture model, such that the irrelevant interaction effects can be removed more efficiently, resulting in more robust, parsimonious and powerful models. We evaluate both of the 'strong hierarchical' and 'weak hierarchical' models, which specify that both or one of the main effects between interacting factors must be present for the interactions to be included in the model. The extensive simulation results show that the proposed strong and weak hierarchical mixture models control the proportion of false positive discoveries and yield a powerful approach to identify the predisposing main effects and interactions in the studies with complex gene-environment and gene-gene interactions. We also compare these two models with the 'independent' model that does not impose this hierarchical constraint and observe their superior performances in most of the considered situations. The proposed models are implemented in the real data analysis of gene and environment interactions in the cases of lung cancer and cutaneous melanoma case-control studies. The Bayesian statistical models enjoy the properties of being allowed to incorporate useful prior information in the modeling process. Moreover, the Bayesian mixture model outperforms the multivariate logistic model in terms of the performances on the parameter estimation and variable selection in most cases. Our proposed models hold the hierarchical constraints, that further improve the Bayesian mixture model by reducing the proportion of false positive findings among the identified interactions and successfully identifying the reported associations. This is practically appealing for the study of investigating the causal factors from a moderate number of candidate genetic and environmental factors along with a relatively large number of interactions. The natural and orthogonal interaction (NOIA) models of genetic effects have previously been developed to provide an analysis framework, by which the estimates of effects for a quantitative trait are statistically orthogonal regardless of the existence of Hardy-Weinberg Equilibrium (HWE) within loci. Ma et al. (2012) recently developed a NOIA model for the gene-environment interaction studies and have shown the advantages of using the model for detecting the true main effects and interactions, compared with the usual functional model. In this project, we propose a novel Bayesian statistical model that combines the Bayesian hierarchical mixture model with the NOIA statistical model and the usual functional model. The proposed Bayesian NOIA model demonstrates more power at detecting the non-null effects with higher marginal posterior probabilities. Also, we review two Bayesian statistical models (Bayesian empirical shrinkage-type estimator and Bayesian model averaging), which were developed for the gene-environment interaction studies. Inspired by these Bayesian models, we develop two novel statistical methods that are able to handle the related problems such as borrowing data from historical studies. The proposed methods are analogous to the methods for the gene-environment interactions on behalf of the success on balancing the statistical efficiency and bias in a unified model. By extensive simulation studies, we compare the operating characteristics of the proposed models with the existing models including the hierarchical meta-analysis model. The results show that the proposed approaches adaptively borrow the historical data in a data-driven way. These novel models may have a broad range of statistical applications in both of genetic/genomic and clinical studies.

Estudio experimental sobre la efectividad y la viabilidad de distintas soluciones constructivas para reducir la concentración de gas radón en edificaciones

El trabajo de investigación desarrollado que ha dado lugar a la realización de esta Tesis, aborda la protección de los edificios frente a la entrada de gas radón y su acumulación en los espacios habitados. Dicho gas (isótopo del radón Rn-222) es un elemento radiactivo que se genera, principalmente, en terrenos con altos contenidos de radio (terrenos graníticos por ejemplo). Su alto grado de movilidad permite que penetre en los edificios a través de los materiales de cerramiento del mismo (porosidad de los materiales, fisuras, grietas y juntas) y se acumule en su interior, donde puede ser inhalado en altas concentraciones. La Organización Mundial de la Salud, califica al radón como agente cancerígeno de grado 1. Según este Organismo, el radón es la segunda causa de contracción de cáncer pulmonar detrás del tabaco. Como respuesta a esta alarma, distintos estados ya han elaborado normativas en las que se proponen soluciones para que los niveles de concentración de radón no superen los valores recomendados por los organismos internacionales responsables de la protección radiológica. En España aún no existe normativa de protección frente a este agente cancerígeno causante de numerosas muertes, y es por tal motivo evidente la necesidad de aportar documentación técnica que ayude a las administraciones nacionales y locales a desarrollar dicha normativa para ajustarse a las recomendaciones europeas e internacionales sobre los niveles que no se deben superar y que, por otro lado, ya han contemplado una gran cantidad de países. Como principal aportación de este trabajo se muestran los resultados de reducción de concentración de gas radón de distintas soluciones constructivas enfocadas a frenar la entrada de gas radón al interior de los edificios haciendo uso de técnicas y materiales habituales en el ámbito de la construcción en España. Para ello, se han estudiado las efectividades de dichas soluciones, en lo referente a su capacidad para frenar la inmisión de radón, en un prototipo de vivienda construido al efecto en un terreno con altas concentraciones de radón. Las soluciones propuestas y ensayadas han sido el resultado de una labor de optimización de los sistemas estudiados en la bibliografía con el fin de adaptar las técnicas a los sistemas constructivos habituales en España y en concreto a la situación real del prototipo de vivienda construido en un lugar con contenidos de radón en terreno muy elevados. El trabajo incluye un capítulo inicial con los conceptos básicos necesarios para entender la problemática que supone habitar en espacios con altos contenidos de radón. ABSTRACT The research developed, which has led to the completion of this thesis, deal with the protection of buildings against entry of radon gas and its accumulation in the ocupated spaces. This gas (radon isotope Rn-222) is a radioactive element generated, mainly, in areas with high levels of radio (granitic terrain for example). Its high mobility allows entering in buildings through the enclosure materials of it (porosity of materials, cracks, crevices and joints) and accumulates inside, where it can be inhaled in high concentrations. The World Health Organization describes radon gas as a carcinogen agent in level 1. According to this Agency, radon is the second leading cause of lung cancer behind tobacco. In response to this alarm, some states have developed regulations that propose solutions to reduce radon concentration levels for not exceeding the values recommended by international agencies responsible in radiation protection. In Spain there is still no legislation to protect against this carcinogen element that cause numerous deaths, and for that reason it is evident the need to provide technical documentation to help the national and local governments to develop legislation for reaching the European and international levels recommendations. As the main contribution of this work are the results of reducing radon concentration using different constructive solutions aimed to stop radon entry in buildings, with techniques and materials common in Spain. To do this, effectiveness of such solutions, have been studied in terms of its ability to stop radon entry in a housing prototype built for this purpose in an area with high radon levels. The solutions proposed and tested have been the result of a process of optimization of systems studied in the literature in order to adapt the techniques to Spanish building material and, specifically, to the actual situation of housing prototype built in a place with high contents of radon in soil. The work includes an initial chapter with the basic concepts needed to understand the problem of living in areas with high levels of radon.