Malaria is one of the most prevalent vector-borne infectious diseases with major morbidity and mortality in sub-Saharan Africa and Southeast Asia. Recent epidemiological studies have shown that co-occurrence of soil-transmitted helminth (STH) infections, or infection caused by parasitic worms, are associated with increased risk of malaria infection. However, studies of the association between STH and malaria, and the effect of antihelminth (deworming) treatments that are more commonly used in areas with high STH infection rates, are sparse. Therefore, we explored the relationship between STH and malaria infection in an Indonesian community (N=1997) with high prevalence of both STH and malaria while controlling for covariates and evaluating the role of deworming treatment as a covariate. Participants with STH infection and/or malaria infection were categorized as either infected or uninfected using PCR testing (cycle threshold count) at both baseline and end of study. Self-report, blood, and stool samples were used to assess overall STH and malaria infection from September 2008 to July 2010. Descriptive statistics were used to assess the impact of STH infection on malaria outcomes. To quantify these associations, robust Poisson regression models were used to assess the impact of baseline infections including STH infection on malaria while adjusting for age, sex, and the use of deworming treatment. Approximately 39.5% and 19.1% of all participants were infected with Plasmodium vivax and P. falciparum, respectively, at the start, while 18.0% and 9.96%, respectively, were infected at the end. A positive association was observed between Ascaris lumbricoides and P. vivax, and between Necator americanus and P. falciparum (PR = 1.04, 95% CI = 0.53 to 2.04; PR = 2.07, 95% CI = 1.00 to 4.29, respectively). While a negative association was observed between N. americanus and P. vivax, and between A. lumbricoides and P. falciparum (PR = 0.91, 95% CI = 0.44 to 1.89; PR = 0.66, 95% CI = 0.27 to 1.65, respectively). Overall, two of these models were significant (p = 0.062; p = 0.008; p = 0.030; p = 0.062, respectively). Similarly, there was a positive association observed between the use of albendazole treatment and STH and malaria outcomes.

Frailty is a multifaceted, geriatric syndrome that is associated with age-related declines in functional reserves resulting in increased risks of in-hospital death, readmissions and discharge to nursing homes. The risks associated with frailty highlights the need for providers to be able to quickly, and accurately, assess someone’s frailty level. Previous studies have shown that bedside clinician assessment is not a reliable or valid way to determine frailty, meaning that a more reliable, valid and concise method is needed. We developed a prediction model using discharge ICD-9/ICD-10 diagnostic codes and other demographic variables to predict Reported Edmonton Frail Scale scores. Participants were from the Baystate Frailty Study, a prospective cohort design study among elderly patients greater than 65 years old who were admitted to a single academic medical center between 2014 and 2016. Three different predictive models were completed utilizing the LASSO approach. The adjusted r-square increased across the three models indicating an increase in the predictive ability of the models. In this study of 762 hospitalized patients over the age of 65 years old, we found that a frailty prediction model that included ICD codes only had a poor prediction ability (adjusted r-square=0.10). The prediction ability improved 2-fold after adding demographic information, a comorbidity score and interaction terms (adjusted r-square=0.26). This study provided additional insights into the development of an automatic frailty assessment, something which is currently missing from clinical care.

Chronic non-cancer pain (CNCP) is a complex phenomenon that affects multiple dimensions of daily life. Optimal therapies for managing CNCP must, then, demonstrate clinically important benefits that go beyond reductions in pain and adverse events. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has recommended that clinical trialists who are evaluating treatments for chronic pain consider reporting treatment effects across nine patient-important outcome domains. This thesis begins with an investigation of the extent to which clinical trials evaluating the effects of opioids for CNCP report IMMPACT-recommended core outcome domains. Further, it explores optimal therapeutic strategies for specific CNCP conditions; specifically, it features a systematic review of randomized controlled trials of all pharmacological and non-pharmacological therapies for central post-stroke pain, as well as a plan for a network meta-analysis of all therapies for all chronic neuropathic pain syndromes. Chronic pain is also a common reason for disability, and this thesis concludes with a retrospective cohort study focused on identifying predictors of claim duration following acceptance for disability benefits among Canadian workers. / Thesis / Doctor of Philosophy (PhD)

Chronic kidney disease (CKD) is a complex and progressive condition with limited curative therapies and is associated with both physical comorbidity, impaired health-related quality of life, and financial strain on the healthcare system. Currently, CKD is defined by a fixed threshold of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, which coincides with approximately 60% of healthy kidney function, for ≥3 months regardless of age. However, this definition does not account for natural declines in kidney function with advanced age, leaving older individuals (ages >65 years) with naturally lower eGFR and without significant kidney damage being over-diagnosed with CKD. Conversely, there is also concern of underdiagnosis of CKD in younger adults (ages <40 years) with “modest” eGFR reductions (eGFR levels well above 60, but below age-expected values). Indeed, severe impairment is not detected in younger adults until they lose close to 50% of their healthy kidney function, precluding timely prevention of CKD progression and its associated complications (premature mortality, cardiovascular events, etc.). However, whether these “modest” eGFR reductions are associated with elevated clinical risk in younger adults is unknown. This thesis is based on a retrospective cohort study using linked healthcare administrative databases to examine the association of index eGFR categories with time to adverse outcomes, relative to age-specific referents. In the first manuscript, we compared associations with key adverse outcomes (all-cause mortality, cardiovascular events, and kidney failure) and patterns of healthcare utilization between younger (ages 18-39), middle-aged (40-49), and older adults (50-65 years). In the second manuscript, we examined associations with major cardiovascular events (cardiovascular mortality, acute coronary syndrome, ischemic stroke, heart failure) by age group. In both manuscripts, we noted significant elevations in risk of adverse outcomes at higher eGFR levels relative to age-specific referents in younger, compared to middle-aged and older adults. Despite this age-related vii disparity in clinical risk with modestly reduced eGFR, younger adults were least likely to obtain a repeated eGFR measure or be referred to a specialist during follow-up. Notably, these findings persisted for individual adverse events and in clinically important subgroups, as well as after various sensitivity analyses (adjusting for additional comorbidities, defining index eGFR using repeated measures, using common referents, and excluding individuals with different underlying mechanisms for reduced eGFR (pregnancy, acute kidney injury, etc.)). The current thesis presents evidence of elevated clinical risk with modest reductions in kidney function in younger adults, emphasizing the importance of risk-based eGFR thresholds that vary with age and considering modestly reduced eGFR as important cardiovascular risk factors worth monitoring in routine clinical practice.

<p><strong><em>Background and objectives</em></strong><strong> </strong></p> <p>Despite great statistical advances in meta-analysis methodology, most published meta-analyses make use of out-dated statistical methods and authors are unaware of the shortcomings associated with the widely employed methods. There is a need for statistical contributions to meta-analysis where: 1) improvements to current statistical practice in meta-analysis are conveyed at the level that most systematic review authors will be able to understand; and where: 2) current statistical methods that are widely applied in meta-analytic practice undergo thorough testing and examination. The objective of this thesis is to address some of this demand.</p> <p><strong><em>Methods</em></strong></p> <p>Four studies were conducted that would each meet one or both of the objectives. Simulation was used to explore the number of patients and events required to limit the risk of overestimation of intervention effects to ‘acceptable’ levels. Empirical assessment was used to explore the performance of the popular measure of heterogeneity, <em>I²</em>, and its associated 95% confidence intervals (CIs) as evidence accumulates. Empirical assessment was also used to compare inferential agreement between the widely used DerSimonian-Laird random-effects model and four alternative models. Lastly, a narrative review was undertaken to identify and appraise available methods for combining health related quality of life (HRQL) outcomes.</p> <p><strong><em>Results and conclusion</em></strong></p> <p>The information required to limit the risk of overestimation of intervention effects is typically close to what is known as the optimal information size (OIS, i.e., the required meta-analysis sample size). <em>I² </em>estimates fluctuate considerably in meta-analyses with less than 15 trials and 500 events; their 95% confidence intervals provide desired coverage. The choice of random-effects has ignorable impact on the inferences about the intervention effect, but not on inferences about the degree of heterogeneity. Many approaches are available for pooling HRQL outcomes. Recommendations are provided to enhance interpretability. Overall, each manuscript met at least one thesis objective.</p> / Doctor of Philosophy (PhD)

<p><strong>Background: </strong>Myocardial injury after noncardiac surgery (MINS) increases the risk of 30-day mortality. Intraoperative hemodynamic events (i.e., tachycardia, bradycardia, hypotension, and hypertension) may contribute to developing MINS.</p> <p><strong>Objectives: </strong>To determine if the addition of the duration spent within predefined intraoperative systolic blood pressure (BP; mmHg) (i.e.,160-199 and ≥200) and heart rate (HR; bpm) (i.e.,100-140 and >140) hemodynamic bands improved the prediction of Day 1 MINS (i.e., postoperative troponin T elevation ≥0.03 ng/ml within the first day after surgery) beyond preoperative risk model prediction.</p> <p><strong>Methods: </strong> Prospective observational data was used to developed a baseline risk model to predict Day 1 MINS. Preoperative HR, systolic BP, and hemoglobin as well as intraoperative duration spent within each predefined hemodynamic band were explored to identify optimal thresholds for the prediction of Day-1 MINS. Preoperative variables were added to the baseline risk model to create a preoperative model. Intraoperative variables were then added to the preoperative risk model to create the final model. Models were compared using discrimination (c-statistic) and net reclassification index (NRI).</p> <p><strong>Results: </strong>Adding preoperative hemoglobin ≤105 g/dL, systolic BP110 improved baseline model discrimination (0.783 to 0.792, p5min; HR >100 for >147min; systolic BP59min and systolic BP >160 for >42min further improved discrimination (0.8; p</p> <p><strong>Conclusion:</strong> Adding intraoperative hemodynamic durations significantly improved Day-1 MINS model discrimination and risk stratification compared to the baseline risk model.</p> / Master of Health Sciences (MSc)

<p><strong>Introduction:</strong> In Ontario alone, an estimated 6,700 people (3,000 women; 3,700 men) will die of lung cancer in 2011 (Canadian Cancer Society, 2011). A diagnosis of cancer is associated with complex decisions; the array of choices of cancer treatments brings about hope, but also anxiety over which treatment is best suited for the individual patient (Blank, Graves, Sepucha et al., 2006). The overall cancer experience depends on the quality of this decision (Blank et al., 2006). Clinical practice guidelines are knowledge translation tools to facilitate treatment decision-making. In Ontario, guidelines have been developed and disseminated with the purpose to inform clinical decisions, improve evidence based practice, and to reduce unwanted practice variation in the province. But has this been achieved? To study this issue, the purpose of the current study was to gain an in-depth understanding and develop a theoretical framework of how Ontario physicians are making treatment decisions with their non-small cell lung cancer patients. The following research questions guided the study: (a) How do physicians make treatment decisions with their stage II, stage IIIA and stage IIIB non-small cell lung cancer patients in Ontario? (b) How do knowledge translation tools, such as Cancer Care Ontario guidelines, influence the decision-making process?</p> <p><strong>Methods:</strong> A qualitative approach of grounded theory, following a social constructivist paradigm outlined by Kathy Charmaz (2006), was used in this study. 21 semi-structured interviews were conducted; 16 interviews with physicians and 5 with health care administrators. The method of analysis integrated grounded theory philosophy to identify the treatment decision-making process in non-small cell lung cancer, from the physician perspective.</p> <p><strong>Findings:</strong> The theory depicts the treatment decision-making process to involve five key “guides” (or factors) to inform the treatment-decision making process: the unique patient, the unique physician, the family, the clinical team, and the clinical evidence.</p> <p><strong>Conclusion:</strong> Decision-making roles in lung cancer are complex and nuanced. The use of evidence, such as, clinical practice guidelines, is one of many considerations. Information from a large number of sources and a wide array of factors, people, emotions, preferences, clinical expertise, experiences, and clinical evidence informs the dynamic process of treatment decision-making. This theory of the treatment decision-making process (from the physician perspective) has implications relevant to treatment decision-making research, theory development, and guideline development for non-small cell lung cancer.</p> / Master of Science (MSc)

Objectives. To investigate diabetes prevalence, incidence, mortality trends, the effects of hyperglycaemia and blood pressure, diabetes and hypertension treatment, and the effect of screening detection on total and cardiovascular disease (CVD), myocardial infarction (MI) and stroke incidence. Study population and methods. Between 1972 and 2001 all patients with diabetes, some detected clinically and some by case-finding procedures (screening), were entered in a diabetes register at Laxå Primary Health Care Center in Sweden. The register included information on medical treatment and laboratory data as well as information on mortality and morbidity from National Registers. The register was supplemented with five non-diabetic subjects, matched to each diabetes patients by age, sex, and year of detection. Results. During the study period 776 new diabetes cases was found, 36 type 1 diabetes mellitus and 740 type 2 diabetes mellitus. Age standardised incidence and prevalence rates for type 1 and type 2 diabetes did not increase over time. Diabetic patients had 17% higher mortality rate than non-diabetic persons, 22% in women and 13% in men. The corresponding over-mortality in CVD was 33%, 41% in women and 27% in men. CVD mortality decreased across time in non-diabetic subjects and in diabetic men but not in diabetic women. Results regarding coronary heart disease (CHD) were similar. CVD incidence increased with fasting blood glucose (FBG), body mass index (BMI), mean arterial blood pressure (MABP), and decreased with metformin treatment and sulfonylurea. Myocardial infarction incidence increased with FBG, BMI and MABP, and decreased with metformin treatment. Stroke incidence increased with MABP. There was no difference in prognoses between those detected by screening or clinically. Conclusions. Diabetes prevalence and incidence did not change over time. The over-mortality according to diabetes was moderate. CVD and MI during follow up were negatively affected by hypertension and hyperglycaemia, and positively by pharmacological diabetic treatment. For stroke no pharmacological protective effect was seen. Screening did not improve prognosis.

Human papillomavirus (HPV) infection currently stands as the most common sexually transmitted disease in the world. With an estimated lifetime probability of disease acquisition of 84.6% for females and 91.3% for males with at least one sexual partner, HPV is an aggressive and ubiquitous virus that affects people from all walks of life. The virus generally resolves on its own within 1 year, but successful disease progression leads to complications ranging from genital warts to anogenital cancers. Globally, there are 530,000 new cases of, and 274,000 deaths caused by, cervical cancer in females each year, 99.7% of which are caused by HPV and 70% of which are caused by HPV types 16 and 18. With high rates of infection and 85% of cervical cancer cases concentrated in developing countries, the virus presents an immense threat to public health and global equity. Prophylactic vaccines demonstrate high efficacy against common HPV-related diseases, including cervical cancer, but the high cost and multiple-dose administration of the vaccine limit its full disease-fighting potential. This proposal seeks to determine if a single-dose prophylactic vaccine targeting HPV-16 and -18, when administered in preadolescence, demonstrates long-term efficacy against cervical cancer. Vaccine-induced antibody responses will be measured using geometric mean titers obtained from blood samples, and efficacy of the vaccine will be evaluated by persistent high-risk HPV (HR-HPV) infection, measured through Pap smears and HPV DNA tests. The study will extend 22 years post-vaccination. The single-dose vaccine is expected to provide protection against HR-HPV infection at rates comparable to those of multiple-dose vaccines currently in practice, with the implications of increasing accessibility of the vaccine and, thus, decreasing the global burden of cervical cancer.

The internet has radically changed the way people obtain and interact with information about diseases, treatments, and conditions. Yet, our understanding of how people access and use health information to make decisions- in other words, their health literacy- has not progressed. The overall aim of this thesis is to assess the extent to which health literacy is a valid and useful construct for policy and practice related to online health resources. A mixed-methods research programme of five studies was undertaken, influenced by realist evaluation methodology. First, to ascertain engagement with user-generated online health content (UGC) in the UK, analysis of a large European survey was undertaken. Then, the uncertainty regarding the relationship between health literacy and outcomes was addressed by a systematic review and qualitative analysis of health literacy measures. Results of these two studies informed interviews carried out with 13 'key informants': policymakers and primary care clinicians in the UK with a particular interest in health literacy and/or online information. A systematic review, incorporating a traditional narrative review and a realist review, evaluated existing trials addressing how effects of online resources vary by health literacy level. Finally, data were analysed from a feasibility randomized controlled trial, comparing usage and outcomes of accessing a 'personal experiences'-based asthma website (representing curated user-generated content) versus a 'facts and figures'-based website. Participant health literacy was assessed using an index identified from the systematic review of measures, and website usage was tracked. Approximately 25% of UK internet users engage with UGC at least monthly. The most frequent users were younger, more likely to be male, and to be carers for someone with a long-term illness. Three themes were identified from health literacy measurement: 'appropriate health decisions', 'ability to obtain healthcare services', and 'confidence'. Key informants noted the lack of clarity about how health literacy influences outcomes, and suggested that personal preferences and digital access and skills may be more relevant than health literacy for policy and practice. Existing trials of online resources in which participant health literacy was measured were mostly at high risk of bias; some possible explanations of how these interventions should work in people with low health literacy were that they may experience higher data entry burden related to chronic diseases, and that they may prefer simulated face-to-face communication. Finally, there were no differences between health literacy groups in the feasibility trial regarding usage or outcomes related to either the 'facts and figures' or 'personal experiences' websites. Taken together, these results question the validity and appropriateness of health literacy as a key objective or consideration in the development or use of online resources. While health literacy has value as a general idea, this thesis demonstrates that it may no longer be the right construct to guide intervention development and implementation to improve health outcomes.