Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is a strong independent predictor of cardiovascular morbidity and mortality, while its regression is associated with an improved clinical prognosis. It is, therefore, vital to elucidate and fully comprehend the mechanisms that contribute to LVH development and to identify markers that indicate a strong predisposition to the development of severe cardiac hypertrophy, before its occurrence. Hypertrophic cardiomyopathy (HCM) serves as a model to investigate LVH development. This primary cardiac disease is characterised by LVH in the absence of increased external loading conditions and is caused by defective sarcomeric proteins, as a result of mutations within the genes encoding these proteins. However, the hypertrophic phenotype of HCM is largely complex, as we see strong variability in the extent and distribution of LVH in HCM, even in individuals with the same disease-causing mutation from the same family; this points toward the involvement of additional genetic and environmental modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) influence LVH indirectly, through their key role in blood pressure regulation, but also directly, due to the direct cellular hypertrophic effects of some RAAS components. Previous genetic association studies aimed at investigating the contribution of RAAS variants to LVH were largely centred on a subset of polymorphisms within the genes encoding the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor genes, while the renin section and RAAS components downstream from ACE remained largely neglected. In addition, most previous studies have reported relatively small individual effects for a small subset of RAAS variants on LVH. In the present study we, therefore, employ a family-based genetic association analysis approach to investigate the contribution of the entire RAAS to this complex hypertrophic phenotype by exploring both the individual as well as the compound effects of 84 variants within 22 RAAS genes, in a cohort of 388 individuals from 27 HCM families, in which either of three HCM-founder mutations segregate. During the course of this explorative study, we identified a number of RAAS variants that had significant effects on hypertrophy in HCM, whether alone or within the context of a multi-variant haplotype. Through single variant association analyses, we identified variants within the genes encoding angiotensinogen, renin-binding protein, the mannose-6-phosphate receptor, ACE, ACE2, angiotensin receptors 1 and 2, the mineralocorticoid receptor, as well as the epithelial sodium channel and the Na+/K+-ATPase β-subunits, that contribute to hypertrophy in HCM. Using haplotype-based association analyses, we were able to identify haplotypes within the genes encoding for renin, the mannose-6-phosphate receptor, angiotensin receptor 1, the mineralocorticoid receptor, epithelial sodium channel and Na+/K+-ATPase α- and β subunits, as well as the CYP11B1/B2 locus, that contribute significantly to LVH. In addition, we found that some RAAS variants and haplotypes had statistically significantly different effects in the three HCM founder mutation groups. Finally, we used stepwise selection to identify a set of nine risk-alleles that together predicted a 127.80 g increase in left ventricular mass, as well as a 13.97 mm increase in maximum interventricular septal thickness and a 14.67 mm increase in maximum left ventricular wall thickness in the present cohort. In contrast, we show that a set of previously identified “pro-LVH” polymorphisms rather poorly predicted LVH in the present South African cohort. This is the first RAAS investigation, to our knowledge, to provide clear quantitative effects for a subset of RAAS variants indicative of a risk for LVH development that are representative of the entire pathway. Our findings suggest that the eventual hypertrophic phenotype of HCM is modulated by the compound effect of a number of RAAS modifier loci, where each polymorphism makes a modest contribution towards the eventual phenotype. Research such as that presented here provides a basis on which future studies can build improved risk profiles for LVH development within the context of HCM, and ultimately in all patients with a risk of cardiac hypertrophy. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is 'n sterk onafhanklike voorspeller van kardiovaskulêre morbiditeit en mortaliteit, terwyl LVH regressie verband hou met ‘n verbeterde kliniese voorspelling. Dit is dus noodsaaklik om die meganismes wat bydra to LVH ontwikkeling ten volle te verstaan en merkers wat 'n sterk geneigdheid tot die ontwikkeling van ernstige kardiale hipertrofie te identifiseer, voordat dit voorkom. Hipertrofiese kardiomiopatie (HKM) dien as 'n model om LVH ontwikkeling te ondersoek. Hierdie primêre hartsiekte word gekenmerk deur LVH en word meestal veroorsaak deur foutiewe sarkomeer proteïene as gevolg van mutasies binne die gene wat kodeer vir hierdie proteïene. Die hipertrofiese fenotipe van HKM is egter grootliks kompleks; ons sien, by voorbeeld, sterk veranderlikheid in die omvang en die verspreiding van LVH in HKM, selfs in individue met dieselfde siekte-veroorsakende mutasie binne dieselfde gesin, wat dui op die betrokkenheid van addisionele genetiese en omgewing modifiseerders. Komponente van die renien-angiotensien-aldosteroon sisteem (RAAS) beïnvloed LVH indirek, deur middel van hul belangrike rol in bloeddruk regulasie, maar ook direk, as gevolg van die direkte sellulêre hipertrofiese gevolge van sommige RAAS komponente. Vorige genetiese assosiasie studies wat daarop gemik was om die bydrae van RAAS variante LVH te ondersoek, was hoofsaaklik gesentreer op 'n groepie polimorfismes binne die gene wat kodeer vir die “angiotensin converting enzyme” (ACE) en angiotensien II tipe 1-reseptor gene, terwyl die renien gedeelte en RAAS komponente stroomaf van ACE meestal nie ondersoek was nie. Daarbenewens het die meeste vorige studies relatief klein individuele gevolge gerapporteer vir 'n klein groepie RAAS variante op LVH. In die huidige studie het ons dus 'n familie-gebaseerde genetiese assosiasie-analise benadering gebruik om die bydrae van die hele RAAS tot hierdie komplekse hipertrofiese fenotipe te ondersoek deur 'n studie van die individuele-, sowel as die saamgestelde effekte van 84 variante binne 22 RAAS gene, in 'n groep van 388 individue vanaf 27 HKM families, waarin een van drie HCM-stigter mutasies seggregeer. Gedurende die loop van hierdie studie het ons 'n aantal RAAS variante wat ‘n beduidende uitwerking op HKM hipertrofie geïdentifiseer, hetsy alleen of binne die konteks van' n multi-variant haplotipe. Deur middel van enkele variant assosiasie toetsing het ons variante geïdentifiseer binne die gene wat kodeer vir angiotensinogen, renien-bindende proteïen, die mannose-6-fosfaat reseptor, ACE, ACE2, angiotensien reseptore 1 en 2, die mineralokortikoïd reseptor, sowel as die epiteel natrium kanaal en Na+/ K+-ATPase β-subeenhede, wat bydra tot HKM hipertrofie. Deur die gebruik van haplotipe-gebaseerde assosiasie ontleding was ons in staat om haplotipes te identifiseer binne die gene wat kodeer vir renien, die mannose-6-fosfaat reseptor angiotensien reseptor 1, die mineralokortikoïd reseptor, epiteel natrium kanaal en die Na+/ K+-ATPase α-en β subeenhede, sowel as die CYP11B1/B2 lokus, wat aansienlik bydra tot LVH. Verder het ons bevind dat sommige RAAS variante en haplotipes statisties beduidende verskillende effekte gehad het in die drie HKM stigter mutasie groepe. Laastens, het ons stapsgewyse seleksie gebruik om 'n stel van nege risiko-allele wat saam' n toename van 127.80 g in linker ventrikulêre massa, sowel as 'n 13.97 mm toename in maksimum ventrikulêre septale dikte, en' n 14.67 mm verhoging in maksimum linker ventrikulêre wanddikte voorspel, te identifiseer in die huidige kohort. In teenstelling hiermee wys ons dat 'n stel van voorheen geïdentifiseerde "pro-LVH" polimorfismes swakker gevaar het as LVH-voorspellers in die huidige Suid-Afrikaanse kohort. Hierdie is die eerste RAAS ondersoek, tot ons kennis, wat ‘n duidelike kwantitatiewe gevolge vir 'n stel RAAS variante wat ‘n verhoogde risiko tot LVH ontwikkeling aandui, wat verteenwoordigend is van die hele RAAS. Ons bevindinge dui daarop dat die uiteindelike hipertrofiese fenotipe van HKM gemoduleer word deur die saamgestelde effek van 'n aantal RAAS wysiger loki, waar elke polimorfisme ' n beskeie bydrae maak tot die uiteindelike fenotipe. Navorsing soos dié wat hier aangebied word dien as 'n basis waarop toekomstige studies kan bou vir ‘n verbeterde risiko-profiel vir LVH ontwikkeling binne die konteks van die HKM, en uiteindelik in alle pasiënte met' n verhoogde risiko vir kardiale hipertrofie.

published_or_final_version / abstract / Statistics and Actuarial Science / Master / Master of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Asian Studies / Doctoral / Doctor of Philosophy

published_or_final_version / Public Health / Master / Master of Public Health

No description available.

This dissertation studies the adverse financial implications of "longevity risk" and "mortality risk", which have attracted the growing attention of insurance companies, annuity providers, pension funds, public policy decision-makers, and investment banks. Securitization of longevity/mortality risk provides insurers and pension funds an effective, low-cost approach to transferring the longevity/mortality risk from their balance sheets to capital markets. The modeling and forecasting of the mortality rate is the key point in pricing mortality-linked securities that facilitates the emergence of liquid markets. First, this dissertation introduces the discrete models proposed in previous literature. The models include: the Lee-Carter Model, the Renshaw Haberman Model, The Currie Model, the Cairns-Blake-Dowd (CBD) Model, the Cox-Lin-Wang (CLW) Model and the Chen-Cox Model. The different models have captured different features of the historical mortality time series and each one has their own advantages. Second, this dissertation introduces a stochastic diffusion model with a double exponential jump diffusion (DEJD) process for mortality time-series and is the first to capture both asymmetric jump features and cohort effect as the underlying reasons for the mortality trends. The DEJD model has the advantage of easy calibration and mathematical tractability. The form of the DEJD model is neat, concise and practical. The DEJD model fits the actual data better than previous stochastic models with or without jumps. To apply the model, the implied risk premium is calculated based on the Swiss Re mortality bond price. The DEJD model is the first to provide a closed-form solution to price the q-forward, which is the standard financial derivative product contingent on the LifeMetrics index for hedging longevity or mortality risk. Finally, the DEJD model is applied in modeling and pricing of life settlement products. A life settlement is a financial transaction in which the owner of a life insurance policy sells an unneeded policy to a third party for more than its cash value and less than its face value. The value of the life settlement product is the expected discounted value of the benefit discounted from the time of death. Since the discount function is convex, it follows by Jensen's Inequality that the expected value of the function of the discounted benefit till random time of death is always greater than the benefit discounted by the expected time of death. So, the pricing method based on only the life expectancy has the negative bias for pricing the life settlement products. I apply the DEJD mortality model using the Whole Life Time Distribution Dynamic Pricing (WLTDDP) method. The WLTDDP method generates a complete life table with the whole distribution of life times instead of using only the expected life time (life expectancy). When a life settlement underwriter's gives an expected life time for the insured, information theory can be used to adjust the DEJD mortality table to obtain a distribution that is consistent with the underwriter projected life expectancy that is as close as possible to the DEJD mortality model. The WLTDDP method, incorporating the underwriter information, provides a more accurate projection and evaluation for the life settlement products. Another advantage of WLTDDP is that it incorporates the effect of dynamic longevity risk changes by using an original life table generated from the DEJD mortality model table. / text

The purpose of this study was to investigate the impact of Medicare Part D coverage on medication adherence and health outcomes in dialysis patients. A retrospective analysis (2006-2010) using the United States Renal Data System was conducted for Medicare-eligible dialysis patients. Cardiovascular disease morbidity, healthcare utilization and expenditures, medication adherence, and mortality rates were compared, categorized based on patients’ Part D coverage in 2007 for those who: 1) did not reach the coverage gap (cohort 1); 2) reached the coverage gap but not catastrophic coverage (cohort 2); 3) reached catastrophic coverage (cohort 3); and 4) did not reach the coverage gap but received a low-income subsidy (cohort 4). Cox proportional hazards models, Kaplan-Meier methods, logistic regressions, generalized linear models, and generalized estimating equations were used. A total of 11,732 patients were included as meeting inclusion criteria: 1) cohort 1: 3,678 patients had out-of-pocket drug costs <$799; 2) cohort 2: 4,349 patients had out-of-pocket drug costs between $799 and $3,850; 3) cohort 3: 1,310 patients had out-of-pocket drug costs > $3,850; and 4) cohort 4: the remaining 2,395 patients had out-of-pocket drug costs <$799 but received a low-income subsidy. After adjusting for demographic and clinical factors, patients in cohort 2 and cohort 3 had 42 percent and 36 percent increased risk of cardiovascular disease (odds ratio (OR)=1.42, 95% confidence interval (CI):1.20-1.67; OR=1.38, 95% CI:1.10-1.72); and had 36 percent and 37 percent higher death rates compared to those in cohort 4, respectively (hazard ratio (HR)=1.36, 95% CI:1.27-1.44; HR=1.37, 95% CI:1.27-1.48). Patients in cohort 2 were more likely to be nonadherent to medications for diabetes (OR=1.72, 95% CI:1.48-1.99), hypertension (OR=1.69, 95% CI:1.54-1.85), hyperlipidemia (OR=2.01, 95% CI:1.76-2.29), hyperphosphatemia (OR=1.74, 95% CI:1.55-1.95), and hyperparathyroidism (OR=2.08, 95% CI:1.66-2.60) after reaching the coverage gap. These patients had total health care costs that were $2,644 higher due to increased rates of hospitalization and outpatient visits, despite $2,419 lower pharmacy costs compared to patients in cohort 4 after controlling for covariates (p<0.0001). Reaching the Part D coverage gap was associated with decreased medication adherence and unfavorable clinical and economic outcomes in dialysis patients. / text

近年來，許多專家學者廣泛探討偵測稀有疾病的發生率或稱為叢集上的空間或空間對時間的統計方法及模型。這些方法大部分都是處理個別資料或是只能偵測接近圓形的叢集。在這篇論文中，根據Choynowski在1959年所探討的方法，我們進一步提出針對整體資料去偵測非圓形叢集的方法，並且會將此方法與Nagarwalla’s Spatial Scan Statistic做比較。同時，我們會呈現模擬結果中的型一、型二誤差來衡量此方法的可行性。另外，我們也會將此方法實際應用到台灣的癌症死亡資料做探討。 / In recent years, many statistical methods have been proposed for detecting excesses of rare diseases, i.e., clusters, in space or in space-time. Most of these methods deal with case-event or individual-level data and can only detect clusters with shape close to circles. In this study, adapting Choynowski's (1959) idea, a simulation-based approach is proposed to detect non-circular clusters with aggregate or group-level data. The proposed cluster detection method will be used to compare with a frequently used method: Nagarwalla’s Spatial Scan Statistic. Computer simulation is used to illustrate the validity, with respect to Type-I and Type-II errors, of the proposed approach. In addition, the cancer mortality data in Taiwan area are also used as a demonstration of the proposed test.