Risk Prediction In Cardiovascular Epidemiology: Considerations for Modeling Composite Endpoints

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

RACIAL/ETHNIC VARIABILITY IN THE EFFECT OF RADIATION ON SECOND PRIMARY THYROID CANCER IN CHILDREN: ANALYSIS USING SURVEILLANCE EPIDEMIOLOGY AND END RESULTS DATA

Increases in pediatric thyroid cancer incidence could be partly due to previous clinical intervention. This retrospective cohort study used 1973-2012 data from the Surveillance Epidemiology and End Results program to assess the association between previous radiation therapy exposure in development of second primary thyroid cancer (SPTC) among 0-19-year-old children. Statistical analysis included the calculation of summary statistics and univariable and multivariable logistic regression analysis. Relative to no previous radiation therapy exposure, cases exposed to radiation had 2.46 times the odds of developing SPTC (95% CI: 1.39-4.34). After adjustment for sex and age at diagnosis, Hispanic children who received radiation therapy for a first primary malignancy had 3.51 times the odds of developing SPTC compared to Hispanic children who had not received radiation therapy, [AOR=3.51, 99% CI: 0.69-17.70, p=0.04]. These findings support the development of age-specific guidelines for the use of radiation based interventions among children with and without cancer.

Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes

INTRODUCTION: Invasive aspergillosis (IA) is a fungal infection that particularly affects immunocompromised hosts. Recently, several studies have indicated a high incidence of IA in intensive care unit (ICU) patients. However, few data are available on the epidemiology and outcome of patients with IA in this setting.

Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources

How epidemiology has challenged 3 prevailing concepts about atopic dermatitis

We challenge 3 prevailing concepts in understanding atopic dermatitis using data from epidemiologic studies. First, we show that although atopy is associated with atopic dermatitis to some degree, its importance is not likely to be a simple causeand- effect relationship, especially at a population level. Our epidemiologic data do not exclude a contributory role for IgEmediated immunologic processes, especially in those with existing and severe disease. Second, evidence is presented that does not support a straightforward inverse relationship between infections and atopic dermatitis risk. A link, if present, is likely to be more complex, depending critically on the timing and type of infectious exposure. Third, recent evidence suggests that the risk of subsequent childhood asthma is not increased in children with early atopic dermatitis who are not also early wheezers, suggesting a comanifestation of phenotypes rather than a progressive atopic march. Collectively, these observations underline the importance of epidemiologic studies conducted at a population level to gain a more balanced understanding of the enigma of atopic dermatitis.

Epidemiology of injuries in female high school soccer players.

Background: Sport is a compulsory activity in schools in South Africa. Female learners participating in soccer are more vulnerable to injuries than males. Objective: This study determined the epidemiology of injuries in female high school soccer players. Methods: A cross sectional survey captured the epidemiology of injuries in the players. The population included 200 players from 27 high schools in one district between the ages of 14 to 19 years. A self-administered questionnaire was used to collect data. Results: Only 85 scholars from 8 schools participated. From the 85 respondents, 31 (36.5%) sustained injuries. Only 61 injuries were reported by the injured players. The injury prevalence for the season was 36.5%. The rate of injury was 90 per 1000 athlete exposure hours during the season. The defenders and midfielders sustained the most injuries. Most injuries reported were contact in nature. More injuries occurred during training than during matches. The lower extremity (77.8%) was injured more than the upper extremity (22.2%). The knee (22.2%) and ankle (15.9%) were the most frequently injured body parts. Muscle injury was the most commonly reported followed by bruising. Conclusion: Prevalence of injuries was high with the lower limb, specifically the knee and ankle being commonly injured.

PLAGUE. Un editor visual para PDDL

Plague es un editor de archivos escritos en lenguajes de planificación como STRIPS y PDDL, que permite lanzar el algoritmo GrahPlan a partir de los archivos de dominio y problema editados y encontrar una solución al problema planteado. El objetivo del editor es eminentemente pedagógico: su uso es muy simple y viene con variados ejemplos de ambos lenguajes de planificación, de modo que el usuario pueda aprenderlos de forma paulatina. Además, la salida de la ejecución permite ir viendo paso a paso el desarrollo del algoritmo GraphPlan: los operadores que se van ejecutando, los no-ops que se han seguido, los mutex que se han aplicado en cada nivel y el tiempo empleado, además de la solución final al problema si se alcanza. El programa hace uso de dos utilidades que permiten compilar el código STRIPS o PDDL que son JavaGP y PDDL4J. Una vez ejecutado el problema de planificación, se obtiene la salida en pantalla y también se puede imprimir el problema completo incluida la solución. El objetivo ha sido crear un programa que permita al usuario editar rápidamente archivos STRIPS y PDDL, los pueda compilar velozmente y obtener el resultado en un solo sitio, con una salida mucho más clara, organizada y entendible y se evite el problema de tener que usar editores externos y una ventana de línea de comando para ejecutar GraphPlan. Plague is a text editor for files written in action languages, such as STRIPS and PDDL, which allows running the GraphPlan algorithm from the domain archives and edited problems, and finding a solution to the proposed problem. The goal of the editor is primarily for pedagogical purposes: it is simple to use and comes equipped with a variety of examples in both action languages, so that the user can gradually learn. In addition, as the editor runs it allows the user to observe the step by step development of the GraphPlan algorithm: the operators being executed, the no-ops that have been followed, the mutex applied at each level and the time spent, as well as the final answer to the problem, if reached. The program uses two utilities allowing the STRIPS or PDDL code to be compiled: JavaGP and PDDL4J. Once the planning problem has been executed, the result is shown on screen and the complete problem can also be printed, including the solution. The objective has been to create a program that allows the user to quickly edit STRIPS and PDDL archives, to compile them swiftly and obtain the solution in a single place, with a result that is clear, organised and understandable, thus avoiding the problem of having to use external editors and command prompts to execute GraphPlan.

Tuberculosis epidemiology in islands: insularity, hosts and trade

Because of their relative simplicity and the barriers to gene flow, islands are ideal systems to study the distribution of biodiversity. However, the knowledge that can be extracted from this peculiar ecosystem regarding epidemiology of economically relevant diseases has not been widely addressed. We used information available in the scientific literature for 10 old world islands or archipelagos and original data on Sicily to gain new insights into the epidemiology of the Mycobacterium tuberculosis complex (MTC). We explored three nonexclusive working hypotheses on the processes modulating bovine tuberculosis (bTB) herd prevalence in cattle and MTC strain diversity: insularity, hosts and trade. Results suggest that bTB herd prevalence was positively correlated with island size, the presence of wild hosts, and the number of imported cattle, but neither with isolation nor with cattle density. MTC strain diversity was positively related with cattle bTB prevalence, presence of wild hosts and the number of imported cattle, but not with island size, isolation, and cattle density. The three most common spoligotype patterns coincided between Sicily and mainland Italy. However in Sicily, these common patterns showed a clearer dominance than on the Italian mainland, and seven of 19 patterns (37%) found in Sicily had not been reported from continental Italy. Strain patterns were not spatially clustered in Sicily. We were able to infer several aspects of MTC epidemiology and control in islands and thus in fragmented host and pathogen populations. Our results point out the relevance of the intensity of the cattle commercial networks in the epidemiology of MTC, and suggest that eradication will prove more difficult with increasing size of the island and its environmental complexity, mainly in terms of the diversity of suitable domestic and wild MTC hosts.

Epidemiology and Emergence of Schmallenberg Virus Part 2: Pathogenesis and Risk of Viral Spread

Schmallenberg virus (SBV) is a novel Orthobunyavirus causing mild clinical signs in cows and malformations in aborted and neonatal ruminants in Europe. SBV belongs to the family Bunyaviridae and is transmitted by biting midges. This new virus was identified for the first time in blood samples of cows in the city of Schmallenberg in North-Rhine Westphalia in November 2011. Since then, the virus spread to several European countries. Here, we describe the pathogenesis and the risk of viral spread in the Portuguese territory.