Aim: To develop an outcome measure to identify “responders” for patients who had a clinically important improvement in lupus disease activity with treatment. Methods: The outcome measure derived was based on the commonly used disease activity measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose. SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months. Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30 days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50 Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months. Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial, ≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent outcome measure of improvement in patients with SLE.

Since the publication of the Framingham algorithm for heart disease, tools that predict disease risk have been increasingly integrated into standards of practice. The utility of algorithms at the population level can serve several purposes in health care decision-making and planning. A population-based risk prediction tool for Diabetes Mellitus (DM) can be particularly valuable for public health given the significant burden of diabetes and its projected increase in the coming years. This thesis addresses various aspects related to diabetes risk in addition to incorporating methodologies that advance the practice of epidemiology. The goal of this thesis is to demonstrate and inform the methods of population-based diabetes risk prediction. This is studied in three components: (I) development and validation of a diabetes population risk tool, (II) measurement and (III) obesity risk. Analytic methods used include prediction survival modeling, simulation, and multilevel growth modeling. Several types of data were analyzed including population healthy survey, health administrative, simulation and longitudinal data. The results from this thesis reveal several important findings relevant to diabetes, obesity, population-based risk prediction, and measurement in the population setting. In this thesis a model (Diabetes Population Risk Tool or DPoRT) to predict 10-year risk for diabetes, which can be applied using commonly-collected national survey data was developed and validated. Conclusions drawn from the measurement analysis can inform research on the influence of measurement properties (error and type) on modeling and statistical prediction. Furthermore, the use of new modeling strategies to model change of body mass index (BMI) over time both enhance our understanding of obesity and diabetes risk and demonstrate an important methodology for future epidemiological studies. Epidemiologists are in need of innovative and accessible tools to assess population risk making these types of risk algorithms an important scientific advance. Population-based prediction models can be used to improve health planning, explore the impact of prevention strategies, and enhance our understanding of the distribution of diabetes in the population. This work can be extended to future studies which develop tools for disease planning at the population level in Canada and to enrich the epidemiologic literature on modeling strategies.

The total number of births among immigrants is on the rise and currently exceeds one fifth of live births within industrialized countries. The relation between adverse birth outcomes and migration remains unclear. The objectives of this thesis are to undertake a literature review to clarify the relation between migration and adverse birth outcomes, and to examine the interplay between duration of residence, maternal country of origin, and the residential environment using data on immigrants to Ontario Census Metropolitan Areas. The findings indicate that: a) Analyzing disparities in birth outcomes by migrant status with migrants defined as a single category is not informative. Rather, ethnicity and country of origin are important predictors of birth outcomes among immigrants. b) Duration of residence is linearly associated with low infant birth weight and preterm birth, mainly driven by decreases in gestational age with prolonged stay in Canada. c) The detrimental effects of long duration of residence on preterm birth are modestly attenuated, but not prevented, among immigrants living in urban neighbourhoods characterized by low material deprivation. d) Neighbourhood material deprivation has little, if any, influence on birth outcomes of recent immigrants, and only becomes influential after 15 years of stay in Canada. Maternal world region of origin constitutes a stronger predictor of adverse birth outcomes among recent immigrants. These findings stress the importance of the maternal country of birth and duration of residence as key predictors of immigrants’ health. They also support further research aimed at clarifying the nature of the association between time spent in Canada after migration and decreases in gestational age at delivery, and the identification of immigrant groups at high risk of adverse birth outcomes, based on these two key predictors.

Aim: To develop an outcome measure to identify “responders” for patients who had a clinically important improvement in lupus disease activity with treatment. Methods: The outcome measure derived was based on the commonly used disease activity measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose. SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months. Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30 days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50 Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months. Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial, ≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent outcome measure of improvement in patients with SLE.

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.

Hepatitis C is the most common blood-borne viral illness in the North America. Chronic hepatitis C infection may lead to cirrhosis of the liver, liver failure and liver cancer. In North America, injection drug use is the most important risk factor for infection and substance abusing populations are disproportionately affected by the disease. Antiviral therapy exists and approximately 50% of infected individuals can be cured. The aim of this thesis was to provide information to help clinicians and policy-makers minimize the impact of hepatitis C in substance abusers. The thesis is comprised of three studies. The first assessed the rate of progression to cirrhosis for those acquiring infection through injection drug use, using a meta-analysis of 44 studies from the published literature. We estimated that fibrosis progression occurs at a rate of 8.1 per 1000 person-years (95% Credible Region (CR), 3.9 to 14.7) corresponding to a 20-year cirrhosis prevalence of 14.8% (95% CR, 7.5 to 25.5). The second study measured the association between successful antiviral therapy and quality of life. We demonstrated that sustained responders to therapy had higher scores on the hepatitis-specific Medical Outcomes Survey Short-Form-36 (SF-36), Health Utilities Index Mark 2/3 (HUI2/3), and time-tradeoff (TTO) than treatment failures, an average of 3.7 years following antiviral therapy. The third study assessed rates of adherence to antiviral therapy and rates of sustained response in current or former iii substance abusers on methadone maintenance. We demonstrated that while use of illicit substances prior to therapy negatively affected adherence, rates of sustained response were comparable to non-substance abusing populations. Our work indicates the future burden of disease in current and former substance abusers, demonstrates that antiviral therapy can be successful in this population, and indicates that the benefits of successful therapy may extend beyond decreased disease burden to improved quality of life.

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.

Our knowledge of a drug’s potential for harm is incomplete at the time of drug licensing leaving residual questions about the long-term safety and effectiveness of drugs in the ‘real world’. Pharmacoepidemiologic research can contribute to the study of the unintended effects of drugs. The central aims of this dissertation were to create new knowledge about drug-related harm in the postmarketing environment using pharmacoepidemiologic methods and larged linked databases, and understand how various types of design and analytic strategies can be applied to reduce bias and threats to internal validity when studying drug harm. The aims of the thesis were achieved by performing three studies. The first study examined elderly individuals hospitalized with bradycardia and identified an association with recent initiation of cholinesterase inhibitor therapy (adjusted odds-ratio 2.13, 95% confidence interval 1.29 to 3.51). The second study examined the measurement properties of administrative diagnostic codes for subtrochanteric and femoral shaft fractures and found the positive predictive value and sensitivity of the codes to be reasonably good (90% and 81%, respectively). This study was linked to the third study which explored the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in postmenopausal women and found an increased risk of these unusual fractures in women with greater than 5 years of bisphosphonate use. The research performed as part of this thesis provides an example of the types of new knowledge about drug-related harm that can be generated using pharmacoepidemiologic designs and analytic strategies. The pharmacoepidemiologic studies will play an important and dynamic role in the larger evolving focus on post-marketing drug safety and effectiveness as new data sources become increasingly available and and the methods within the pharmacoepidemiologic discipline become more sophisticated and refined.

Hepatitis C is the most common blood-borne viral illness in the North America. Chronic hepatitis C infection may lead to cirrhosis of the liver, liver failure and liver cancer. In North America, injection drug use is the most important risk factor for infection and substance abusing populations are disproportionately affected by the disease. Antiviral therapy exists and approximately 50% of infected individuals can be cured. The aim of this thesis was to provide information to help clinicians and policy-makers minimize the impact of hepatitis C in substance abusers. The thesis is comprised of three studies. The first assessed the rate of progression to cirrhosis for those acquiring infection through injection drug use, using a meta-analysis of 44 studies from the published literature. We estimated that fibrosis progression occurs at a rate of 8.1 per 1000 person-years (95% Credible Region (CR), 3.9 to 14.7) corresponding to a 20-year cirrhosis prevalence of 14.8% (95% CR, 7.5 to 25.5). The second study measured the association between successful antiviral therapy and quality of life. We demonstrated that sustained responders to therapy had higher scores on the hepatitis-specific Medical Outcomes Survey Short-Form-36 (SF-36), Health Utilities Index Mark 2/3 (HUI2/3), and time-tradeoff (TTO) than treatment failures, an average of 3.7 years following antiviral therapy. The third study assessed rates of adherence to antiviral therapy and rates of sustained response in current or former iii substance abusers on methadone maintenance. We demonstrated that while use of illicit substances prior to therapy negatively affected adherence, rates of sustained response were comparable to non-substance abusing populations. Our work indicates the future burden of disease in current and former substance abusers, demonstrates that antiviral therapy can be successful in this population, and indicates that the benefits of successful therapy may extend beyond decreased disease burden to improved quality of life.

Our knowledge of a drug’s potential for harm is incomplete at the time of drug licensing leaving residual questions about the long-term safety and effectiveness of drugs in the ‘real world’. Pharmacoepidemiologic research can contribute to the study of the unintended effects of drugs. The central aims of this dissertation were to create new knowledge about drug-related harm in the postmarketing environment using pharmacoepidemiologic methods and larged linked databases, and understand how various types of design and analytic strategies can be applied to reduce bias and threats to internal validity when studying drug harm. The aims of the thesis were achieved by performing three studies. The first study examined elderly individuals hospitalized with bradycardia and identified an association with recent initiation of cholinesterase inhibitor therapy (adjusted odds-ratio 2.13, 95% confidence interval 1.29 to 3.51). The second study examined the measurement properties of administrative diagnostic codes for subtrochanteric and femoral shaft fractures and found the positive predictive value and sensitivity of the codes to be reasonably good (90% and 81%, respectively). This study was linked to the third study which explored the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in postmenopausal women and found an increased risk of these unusual fractures in women with greater than 5 years of bisphosphonate use. The research performed as part of this thesis provides an example of the types of new knowledge about drug-related harm that can be generated using pharmacoepidemiologic designs and analytic strategies. The pharmacoepidemiologic studies will play an important and dynamic role in the larger evolving focus on post-marketing drug safety and effectiveness as new data sources become increasingly available and and the methods within the pharmacoepidemiologic discipline become more sophisticated and refined.