Patient-related barriers may reduce the effectiveness of screening for depression. This study aimed to explore perceived barriers to participation in a Screening Program for Depression by hemodialysis patients. In a cross-sectional study of hemodialysis patients, the Perceived Barriers to Psychological Treatment questionnaire was used to measure barriers to the Screening Program. Of 160 participants, 73.1% perceived at least one barrier (95% CI, 66.2% to 80.0%). The most common barriers were concerns about the side effects of antidepressant medications (40%), concerns about having more medications (32%), feeling that the problem is not severe enough (23%), and perceiving no risk of depression (23%). A high depression score was an independent predictor of barriers related to perceiving no benefit of the Screening Program and psychological, social, and practical barriers. We believe that patient-related barriers need to be addressed before implementing any case identification and treatment program for depression.

DKK1, SFRP1, WIF-1, and Wnt5a encode Wnt pathway genes that are frequently silenced by promoter hypermethylation in colorectal cancer. Despite attractive biological consequences of these events, it is unclear whether they contribute to patient prognostication or may influence tumour cell biology within distinct patient subsets. I sought to determine the prognostic roles of these methylation events in a large cohort of colorectal carcinomas from Ontario and Newfoundland. Methylation was quantified and associated with patient clinicopathlogical features. Methylation was present in cancer tissue. DKK1, Wnt5a, and SFRP1 were strongly and independently associated with tumour subtype in a manner that suggested subtype-specific activity of Wnt signaling. Methylation of DKK1 was a borderline prognosticator of favourable outcome. These results offer intriguing insight into subtype-specific biology and lead to a proposed model whereby methylation-induced Wnt bias may contribute to patient outcome.

Colorectal cancer (CRC) is common in Ontario. This study described the processes of care following CRC resection, and identified CRC relapse from administrative data. Methods: CRC patients aged 18-80 from 1996-2001 with a colorectal resection were identified from the Ontario Cancer Registry. Linked discharge abstracts and physician billings were examined for physician visits, body imaging and endoscopy over the 5 year follow-up period. Administrative codes suggesting disease relapse were compared with patient charts. Results: Overall, 12,804 patients were identified and 8,804 had no evidence of relapse. Most (96.2%) patients had general practitioner follow-up, while 49.3% had medical oncology and 80.4% had general surgery follow-up. Greater than 90% of patients received endoscopy, while only 68.7% of patients received body imaging. Detecting disease relapse was 87.5% sensitive and 93.0% specific. Conclusions: There is potential for improving post-resectional follow-up in CRC patients. It is possible to detect relapse through administrative databases.

Occupational skin and respiratory symptoms, and disease, are common problems. Workers can develop new disease or aggravate existing disease as a result of exposures at work. Many workers are exposed to chemicals that can cause both respiratory and skin responses and there is evidence that some workers experience symptoms in both systems. There is also evidence that skin exposure may lead to sensitization and the development of respiratory disease. There is very little research that has examined both airborne and skin exposures together with lung and skin outcomes. The purpose of this thesis was to further investigate the relationships between occupational exposures, skin symptoms and disease, and respiratory symptoms and disease. Four studies were undertaken to improve our understanding of these complex relationships. Results from a study of clinical patch test data determined that seven of the ten most common occupational contact allergens are also capable of causing occupational asthma and that these common occupational exposures may not be recognized as sensitizers in common reference materials. Exposure-response relationships for skin symptoms were modeled in bakery workers and auto body shop workers using historical data; significant exposure-response relationships were found for auto body workers. In two separate studies of concurrent skin and respiratory symptoms, workers did report concurrent skin and respiratory symptoms. In predictive models, subjects reporting a history of eczema were more likely to report concurrent skin and respiratory symptoms. Overall, the results from this thesis provide more evidence that the skin and respiratory systems are associated. This body of work suggests that: (1) several common occupational exposures can cause disease in both the skin and respiratory system; (2) a portion of workers report both skin and respiratory symptoms; and (3) exposure-response relationships do exist for skin symptoms, both work-related and non-work-related. Future studies need to gather detailed information about exposure and response in both systems in order to better determine the role of exposure(s) in the development of skin and respiratory symptoms. Improved understanding of these relationships will allow for more targeted and effective exposure prevention strategies and will ultimately reduce the burden of occupational disease.

The ultimate success of bypass surgery depends on the construction of a technically perfect bypass graft to an appropriate coronary vessel using a conduit which will remain durable for the lifetime of the patient. This thesis explores methods to improve coronary surgery by enhancing intraoperative imaging and conduit selection in the operating room. It is known that technical errors in graft construction cause failure of up to 12% of coronary bypass grafts in the operating room. We performed investigations of a new technique of intraoperative fluorescence angiography using indocyanine green dye to determine graft patency. We developed optimal methods of obtaining images and preliminary investigations revealed the technique was highly reproducible. In a follow-up trial, we demonstrated that over 80% of technical errors which would otherwise have been missed were identifiable with indocyanine green angiography, while only 25% of these errors were identified by transit-time ultrasonic flow measurement, the current clinical standard. We also determine that coronary surgery with indocyanine green angiographic graft patency verification was associated with less perioperative myocardial injury than bypass surgery without graft patency assessment. The long term graft patency of saphenous vein grafts is sub-optimal, with over 40% of such grafts totally occluded and a further 30% significantly diseased at ten years. We attempted to improve these outcomes by increasing the use of arterial grafts, which are less prone to intimal hyperplasia. In a multicentre clinical trial, we demonstrated a 40% relative risk reduction in graft occlusion at one year when radial arteries were used as bypass conduits versus saphenous veins. We identified that women and patients with small coronary vessels maximally benefited from radial artery bypass grafts. Conversely, in settings of less severe target vessel stenosis or concomitant peripheral vascular disease, saphenous veins performed as well as radial arteries. We have demonstrated that high quality imaging to identify technical errors during the operation, increased use of radial artery grafts and careful consideration of individual patient and target vessel characteristics can all improve graft patency. Future studies will be aimed at identifying the role of intraoperative imaging and arterial grafting in improving long-term clinical outcomes.

Background: The use of meta-analysis to combine the results of observational studies is controversial. Despite its common use, methodological work in this area is lacking. Because of the diversity of study designs, exposure and outcome measures, and differential adjustment for confounding variables, the identification of sources of heterogeneity among study effect estimates is particularly important when combining data from observational studies. This thesis presents the results of a study that examines the relative ability of individual participant data (IPD) meta-analysis (which was considered a “gold standard”) and traditional aggregate data (AD) meta-analysis to identify sources of heterogeneity among studies examining mechanical exposure and low back pain (LBP) in workers. Materials and Methods: A systematic literature search was conducted to identify relevant articles. The corresponding author of each article was contacted to request their individual-level data. Because the outcome definitions and exposure measures were not uniform across studies, two sub-studies were conducted 1) to identify sets of outcome definitions that could be combined in a meta-analysis and 2) to develop methods to translate mechanical exposure onto a common metric. IPD analyses were conducted using generalized estimating equation (GEE) regression to identify variables that acted as strong confounders and effect modifiers. Traditional AD meta-analysis was also conducted and potential sources of heterogeneity were tested using meta-regression. Key Findings: (1) Overall, we found an association between both forces and postures on LBP, although the magnitude varied depending on the exposure-outcome combination. Among the outcomes, the ORs tended to be highest for sick leave due to LBP. (2) There was very little evidence of strong confounders in the relationship between mechanical exposure and LBP; thus differential adjustment for confounders in studies would not likely be an important source of heterogeneity in an AD meta-analysis. (3) AD meta-analysis was able to identify the same study-level effect modifiers as IPD meta-analysis, but did not consistently identify individual-level effect modifiers. Both individual-level characteristics (older age and being male), and study-level characteristics (population-based studies and self-reported mechanical exposure), were associated with an increased OR for many of the LBP outcome and mechanical exposure combinations. Conclusion: AD meta-analysis is likely sufficient to detect heterogeneity for study-level factors but is not sufficient to identify individual-level effect modifiers. When the primary source of evidence in a research area is observational studies and when there is controversy despite several systematic reviews, IPD meta-analysis can be used to better understand sources of heterogeneity and provide context

Rationale/Objective: Excess lung cancer risks associated with exposure to inhaled radon decay products among uranium miners has well been established. Although ingestion is also a potentially important route of exposure, the relationship between ingested radon decay products and gastrointestinal cancer risks are not well examined. The objective of this study is to determine the relationship between exposure to radon decay products and the incidence and mortality of gastrointestinal (esophagus, stomach, and colorectal) cancer among men employed as uranium miners in Ontario. Secondly, to determine whether the duration of exposure (dose rate), years since last exposure and age at first exposure modify these associations. Methods: A cohort of miners who had ever worked in an Ontario uranium mine between 1954 and 1996 was created using the Mining Master File and the National Dose Registry. Cumulative radon exposures measured in Working Level Months (WLM) were previously estimated for each miner. Cancer diagnoses (1964-2004) and cancer deaths (1954-2004) occurring in Ontario were determined by probabilistic record linkage with the Ontario Cancer Registry. To calculate person-years at risk, non-cancer deaths were also ascertained from the Ontario mortality file for the period between 1954 and 2004. Poisson regression methods for grouped data were used to estimate the relative risks (RR) and 95% Confidence Intervals (CI) by exposure level. Results/Conclusions: The final cohort consisted of 28,273 Ontario uranium miners. By the end of 2004, 34 miners had been diagnosed with esophageal cancer, 86 with stomach cancer, and 359 with colorectal cancer. There were 40 deaths due to esophageal cancer, 69 from stomach cancer, and 176 from colorectal cancer. When comparing the highest cumulative exposure category (>40 WLM) to the referent group (0 WLM), significant increases in both stomach (RRIncidence= 2.30, 95% CI;1.02-5.17 and RRMortality=2.90, 95% CI;1.11-7.63) and colorectal cancers (RRIncidence =1.56, 95% CI;1.07-2.27 and RRMortality =1.74, 95% CI;1.01-2.99) after adjusting for age at risk and period effects. However, no relationships were observed for esophageal cancer. Suggestive evidence of modifying effects of these associations by duration of employment (dose rate) and years since last exposure for colorectal cancer was also observed.

Striking differences exist between countries in the incidence of breast cancer, with rates higher in the West than in Asian countries. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The objective of this thesis was to compare established breast cancer risk factors, physical activity, and diet in three groups of postmenopausal women at substantially different risks of developing breast cancer – Caucasians (N = 413), Chinese born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants, 99% of whom coming from urban China (N = 421). In this cross-sectional study, information on risk factors and diet were collected by telephone, and physical activity and anthropometric data were obtained at a home visit. Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, and less often had a family history of breast cancer or a benign breast biopsy. Estimating 5-year absolute breast cancer risks using the Gail Model showed that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the variables in the Gail Model. Compared to Caucasians, recent Chinese migrants had lower average total physical activity over lifetime, and also spent less time on moderate- and vigorous-intensity activity. Compared to Caucasians, recent Chinese migrants consumed per day on average 175 fewer calories, 6 more grams of energy-adjusted protein, 16 more grams of energy-adjusted carbohydrates, and 5 fewer grams of energy-adjusted fat. Also, recent Chinese migrants consumed higher amounts of grains, fruits, vegetables, fish, and soy products, and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western born Chinese and early Chinese migrants had values intermediate between the other two groups for most of the variables. These results suggest that in addition to the established risk factors, some dietary factors may also contribute to the lower breast cancer risk in urban Chinese women.

Genetic studies of lung disease in Cystic Fibrosis are faced with the challenge of identifying a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. This thesis uses data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies (CGS), Johns Hopkins University Twins and Siblings Study (TSS), and University of North Carolina/Case Western Reserve University Gene Modifier Study (GMS)), to calculate two novel phenotypes using age-specific CF percentile values of FEV1 (Forced Expiratory Volume in 1 second), with adjustment for CF age-specific mortality. The normalized residual, mortality adjusted (NoRMA) was designed for population based samples, while KNoRMA, using Kulich percentiles, is robust to sample ascertainment; both account for the effects of age-related disease progression and mortality attrition. NoRMA was computed for 2122 patients representing the Canadian CF population. KNoRMA was computed for these 2122 patients and also 1137 extreme phenotype patients in the GMS study and 1323 patients from multiple CF sib families in the TSS study. Phenotype was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype was highly correlated with the previously recommended mixed model phenotype1; 2, but computationally much easier and suited to studies with limited follow up time. As an example of its use, KNoRMA was used to test the association between locus variants in a previously published candidate gene, Transforming Growth Factor β1(TGFβ1), and lung function in CF, in an attempt to provide insight into discrepant results in the literature. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible interpolation distortions.

Background: The relationship between average alcohol consumption and heart disease is well researched, showing a substantial cardioprotective association. This dissertation examined the epidemiological evidence for an effect of heavy episodic drinking (HED) over and above the effect of average alcohol consumption on heart disease. Methods: Electronic databases were systematically searched for epidemiological studies on the effect of HED on heart disease and identified articles were quantitatively summarized in a meta-analysis. Meta-regression models were used to examine the effect of characteristics of primary studies. Using individual-level data, semi-parametric Cox regression models were used to investigate HED exposure within narrow categories of average alcohol consumption in a US national population sample (n = 9,937) in relation to heart disease mortality in an 11-22 year follow-up. Frequency of heavy drinking episodes was used to identify latent classes of drinking history using growth mixture modeling in a sub-sample of this US cohort. Retrieved classes were used as independent variables in Cox regression models with heart disease mortality as the outcome event. Results: A pooled relative risk of 1.45 (95% confidence interval (CI): 1.24-1.70) for HED compared with non-HED drinkers with average alcohol consumption between 0.1-60 g/day was derived in a meta-analysis. A strong and consistent association with HED was found among current drinkers consuming an average of 1-2 drinks per day in the US cohort. There was no evidence of increased heart disease mortality resulting from the frequency of heavy drinking episodes before the age of forty. Conclusions: There is reasonable and consistent evidence for an association of HED and heart disease in current drinkers, negating any beneficial effect from alcohol consumption on heart health. History of frequency of heavy drinking episodes, however, showed no evidence for such an effect modification.