The Impact of Cardiovascular Disease Risk Factors on Late Graft Outcome Disparities in Adult African American Kidney Transplant Recipients

Introduction: Although outcome disparities for non-Hispanic Black (NHB) kidney transplant recipients are well known and documented, there is paucity in the data assessing the impact of cardiovascular disease (CVD) risk factors and risk control on racial disparities in kidney transplantation. Methods: Longitudinal study of a national cohort of veteran kidney recipients transplanted between Jan 2001 and Dec 2007 (follow up through Dec 2010) with the aim of determining the prevalence and impact of CVD risk factor and control, compared between NHB and non-Hispanic White (NHW) recipients, on death-censored graft loss (DCGL), overall graft loss and mortality. Data included comprehensive baseline characteristics acquired through the USRDS with detailed follow up clinical, laboratory and medication regimen information acquired through linkage to the VA electronic health records. Analyses were conducted using sequential multivariable modeling (Cox regression), incorporating blocks of variables into iterative nested models. Results: 3,139 patients with complete data were included (2,095 NHW [66.7%] and 1,044 NHBs [33.3%]). At five years post-transplant, NHBs had a higher prevalence of hypertension (100% vs. 99.2%, p\u3c0.01) and post-transplant diabetes (58.9% vs. 53.3%, p\u3c0.01) with reduced control of hypertension (BP \u3c140/90, 60% vs. 69% p\u3c0.01), diabetes (A1c \u3c7%, 35% vs. 47%, p\u3c0.01) and LDL (\u3c100 mg/dL, 55% vs. 61%, p\u3c0.01), when compared to NHWs. Adherence to several medication classes used to manage CVD risk factors was significantly lower in NHBs, as compared to NHWs. The unadjusted risk of DCGL was two-fold higher in NHBs, when compared to NHWs (HR 2.00, 95% CI 1.61-2.49). After adjustment for recipient sociodemographics, donor criteria, transplant characteristics, CVD risk factors and control and post-transplant events, the adjusted independent risk of DCGL was substantially reduced (HR 1.49, 1.11-1.99). CVD risk factors and risk control reduced the influence of NHB race on DCGL by 8.7-17.5%. Similar trends were noted for the outcomes of overall graft loss and mortality and were consistent in multiple sensitivity analyses. Conclusion: These results demonstrate that NHB kidney transplant recipients have substantially higher rates of CVD risk factors and reduced CVD risk control, as compared to NHWs. These issues may be partly related to medication non-adherence and meaningfully contribute to disparities for graft outcomes within NHBs

Clinical and economic impact of immunosuppressive therapy in the treatment and management of adult renal and liver transplantation

World wide the number of people living with renal or liver transplants is growing due to the increase in prevalence of end stage renal disease and end stage liver disease which neccesitate transplantation. Life long immunosuppression is needed for transplant recipients to prevent graft rejection and or death. Whilst the immunosuppression can significantly improve patient and graft survival it comes at a cost to the healthcare services. It is therefore, important that the immunosuppression used in clinical practice is supported by both clinical and cost effectiveness evidence. The aim of this thesis is to evaluate the clinical and economic impact of immunosuppression therapy in the treatment and management of adult renal and liver transplant recipients based on author's published research. Healthcare systems across the world are now placing greater importance on optimising their finite resources in demonstrating clinical and cost effectiveness of treatments. A number of health authorities such as the United Kingdom(UK), National Institute of Health and Care Excellence (NICE) have implemented methodologies guiding resource allocation decisions through formal health technology assessment (HTA). Clinical and economic evidence generation and synthesis reflecting current clinical practice can help to inform HTA decisions which impacts patients access to medicines. This thesis presents and critically appraise eight peer reviewed publications to demonstrate the clinical and economic impact of immunosuppression therapy in adult renal and liver transplant recipients. Each publication updated and or contributed to new knowledge in the field. The thesis highlights how the eight publications formed a cohesive body of evidence which can be used by policy makers to inform the development and or updating of clinical and reimbursemsent guidelines which ultimately impact product adoption and patient accesss to immunosuppressive medicines. The clinical effectiveness of immunosuppression was explored through systematic literature reviews, meta-analysis and indirect treatment comparison to establish the efficacy and safety of the different interventions used in post renal and liver transplant. The outputs from the clinical effectiveness together with relevant data from other sources was used to develop economic models to assess the cost effectiveness of immunosuppression. An assessment of the budget impact of immunosuppression in post renal transplant was also examined. Based on this research prolonged release tacrolimus was shown to be clinically and economically more effective than immediate release tacrolimus the current standard of care. The thesis concluded that tacrolimus remains the cornerstone of renal and liver post transplant immunosuppression while also highlighting the strengths and limitations of the current research and making recommendations for future studies

Risk stratification in cardiac surgery: Algorithms and applications

The aims of this research was to compare different risk score algorithms with regard to their validity to predict 30-day and one-year mortality after open-heart surgery, to evaluate if the preoperative risk stratification model EuroSCORE predicts the different components of resource utilization in cardiac surgery, and to systematically evaluate the accuracy and performance of artificial neural networks (ANNs) to select and rank the most important risk factors for operative mortality in open-heart surgery. Preoperative evaluation of the surgical risk is an important component in cardiac surgery. Risk stratification can give patients and their relatives insight into the existent risk of complications and mortality, and aid in the selection of cases for surgery versus alternative, non-surgical therapies. It may also predict the need for hospital care resources and improve the quality of care. A few comparative studies of different risk algorithms exist, but the relative performance of the risk scoring systems currently used is unclear, and it still remains difficult to risk-stratify individual patients. The present work identified four cardiac surgical risk models with a superior performance, with the EuroSCORE algorithm performing best. Though the algorithms were originally designed to predict early mortality, the one-year mortality prediction was also reasonably accurate. The additive EuroSCORE algorithm was also shown to be useful to predict intensive care unit (ICU) cost and an ICU stay more than two days after open-heart surgery. In an attempt to improve the mortality prediction further, a machine-learning technique, ANNs, was used. This identified mortality risk factors in a ranked order and defined a minimal set of risk variables resulting in a superior mortality prediction, compared with previously developed algorithms

Mining Medical Data: Bridging the Knowledge Divide

Due to the signi¯cant amount of data generated by modern medicine there is a growing reliance on tools such as data mining and knowledge discovery to help make sense and comprehend such data. The success of this process requires collaboration and interaction between such methods and medical professionals. Therefore an important question is: How can we strengthen the relationship between two traditionally separate fields (technology and medicine) in order to work simultaneously towards enhancing knowledge in modern medicine. To address this question, this study examines the application of data mining techniques to a large asthma medical dataset. A discussion introducing various methods for a smooth approach, straying from the `jack of all trades, master of none' to a modular cooperative approach for a successful outcome is pro-posed. The results of this study support the use of data mining as a useful tool and highlight the advantages on a global scale of closer relations between the two distinct fields. The exploration of CRISP methodology suggests that a `one methodology fits all approach' is not appropriate, but rather combines to create a hybrid holistic approach to data mining

Some epidemiological aspects of liver cirrhosis and hepatocellular carcinoma in Sweden

Background: Contemporary epidemiological studies examining incidence rates (IR) of cirrhosis and hepatocellular carcinoma (HCC) in Swedish populations are scarce. Cirrhosis and HCC are associated with a significant burden of health inequity and stigma. The importance of socioeconomic status (SES) in cirrhosis survival has scarcely been studied in Sweden. The impact of SES on HCC incidence and prognosis had never been investigated in Sweden. Aim: The overall aim of this thesis was to describe the contemporary epidemiology of cirrhosis and HCC in Swedish settings. We also aimed to improve the understanding of the importance of sociodemographic and clinical characteristics for the clinical course and early identification of cirrhosis and HCC. Methods: We used population-based medical registries to identify adult patients diagnosed with cirrhosis in the region of Halland between 2011 and 2018. Annual crude IR of cirrhosis were calculated (Paper I). Patients were followed-up until date of liver transplantation, death, moving from Halland, or until December 31st, 2019; whichever occurred first. Cox regression models were employed to estimate unadjusted and adjusted hazard ratios (HR and aHR) for several clinical and sociodemograhic variables (Paper II). The nationwide quality register for liver cancer was used to identify all adult patients diagnosed with HCC in Sweden between 2012 and 2018. Poisson regression was used to estimate IRs of HCC across several populations of interest (Paper III). Data extracted from the quality register were cross-linked to data from other nationwide registers. Multivariable logistic regression models were employed to identify factors associated with an increased likelihood for having unrecognized cirrhosis, or late-stage HCC at diagnosis. Patients were followed-up until the date of death, emigration from Sweden, or until December 31st, 2020; whichever occurred first. Cox regression modelling was used for the estimation of HRs and aHRs for several clinical variables (Paper IV). IRs of HCC were estimated for the whole adult population of Sweden and stratified by HCC etiologies (Paper V). Patients were stratified into those with non-alcoholic fatty liver disease (NAFLD) associated HCC and those with non-NAFLD-HCC. Furthermore, those with NAFLD-HCC were divided into those with and without underlying cirrhosis. Results: We identified a total of 598 patients with cirrhosis. The IR of cirrhosis in adults in Halland was estimated at 30 per 100,000 person-years, 39 for men, and 22 for women (Paper I). Patients with a low SES, defined as a low occupational skill level, had more advanced cirrhosis at diagnosis, lower mean survival, and higher mortality risk when compared to patients with high SES (Paper II). A total of 3,473 adult patients with HCC were identified and 68% were diagnosed with a late-stage HCC. Sex, country of birth, and individual- and contextual level SES were associated with the IRs of HCC. Men with a low household income and/or living in the most deprived neighborhoods had the highest IR of HCC (Paper III). Among patients with HCC, 2670 (77%) had underlying cirrhosis. Cirrhosis was unrecognized in 39% of all patients with underlying cirrhosis. Unrecognized cirrhosis was associated with more advanced HCC at diagnosis and worse survival (Paper IV). Among the 3,473 patients with HCC, 21% had underlying NAFLD, which also was the second-leading cause of HCC and the fastest- increasing cause of HCC (Paper V). Conclusions: The IRs of cirrhosis may be higher than previously estimated. Low SES was associated with a worse prognosis in cirrhosis, higher IRs of HCC, and increased risk of unrecognized cirrhosis in HCC. NAFLD is an increasing cause of cirrhosis and has become a leading cause of HCC. NAFLD is also associated with an increased risk of cirrhosis unrecognition in HCC