Background: The relative treatment effectiveness of surgery versus radiotherapy for early-stage prostate cancer is uncertain and randomized clinical trials are unlikely to be performed. This study describes the difference in cause-specific survival between patients treated with radiotherapy versus surgery, using a number of design and analytic steps to mitigate confounding by indication within an observational study. Methods: We conducted a population-based case-cohort study, sampling patients from the Ontario Cancer Registry who were treated or were candidates for cure by radiotherapy or surgery. Cases were those who died of prostate cancer within 10 years. Cause-specific survival was analyzed using Cox-proportional hazard regression, with variance adjustment for the case-cohort sampling. Analysis using intent to treat was compared to that using treatment received. Propensity scores were also calculated and Cox-proportional hazard regression was conducted within each propensity score quintile. We formed instrumental variable groups based on radiotherapy rates in Cancer Care Ontario Regions (CCORs) using the study population sampling frame and checked the instrumental variable assumption of equal distribution of covariates by comparing those covariates across these groups using data from the subcohort. Results: The adjusted hazard ratios for risk of prostate cancer death for radiotherapy compared to surgery were 1.44 (95% CI 0.86-2.40) and 1.84 (1.06-3.17) using intent to treat and treatment received respectively. Stratified hazard ratios comparing radiotherapy to surgery for death from prostate cancer from the lowest propensity quintile to the highest propensity quintile were 0.30 (0.04-2.28), 1.54 (0.35-6.77), 0.90 (0.29-2.82), 2.71 (1.01-7.31) and 1.08 (0.41-2.81). Differences among these hazard ratios were not statistically significant (p=0.13). The distributions of all prognostic indicators were statistically significantly different between instrumental variable groups. Conclusion: Analysis by intent to treat produced a hazard ratio closer to the null than analysis by treatment received, indicating that uncontrolled confounding toward more serious cases getting radiotherapy was present in the analysis by treatment received. Future studies should focus on obtaining enough numbers for subgroup analysis such as the stratification by risk groups. Caution should be used when using the instrumental variable approach in this population, as prognostic indicators were not as equally distributed as expected. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-09-24 17:54:09.955

The survival of any organismis determined by the mechanisms triggered in response to the inputs received. Underlying mechanisms are described by graphical networks that can be inferred from different types of data such as microarrays. Deriving robust and reliable networks can be complicated due to the microarray structure of the data characterized by a discrepancy between the number of genes and samples of several orders of magnitude, bias and noise. Researchers overcome this problem by integrating independent data together and deriving the common mechanisms through consensus network analysis. Different conditions generate different inputs to the organism which reacts triggering different mechanisms with similarities and differences. A lot of effort has been spent into identifying the commonalities under different conditions. Highlighting similarities may overshadow the differences which often identify the main characteristics of the triggered mechanisms. In this thesis we introduce the concept of study-specific mechanism. We develop a pipeline to semiautomatically identify study-specific networks called unique-networks through a combination of consensus approach, graphical similarities and network analysis. The main pipeline called UNIP (Unique Networks Identification Pipeline) takes a set of independent studies, builds gene regulatory networks for each of them, calculates an adaptation of the sensitivity measure based on the networks graphical similarities, applies clustering to group the studies who generate the most similar networks into study-clusters and derives the consensus networks. Once each study-cluster is associated with a consensus-network, we identify the links that appear only in the consensus network under consideration but not in the others (unique-connections). Considering the genes involved in the unique-connections we build Bayesian networks to derive the unique-networks. Finally, we exploit the inference tool to calculate each gene prediction-accuracy across all studies to further refine the unique-networks. Biological validation through different software and the literature are explored to validate our method. UNIP is first applied to a set of synthetic data perturbed with different levels of noise to study the performance and verify its reliability. Then, wheat under stress conditions and different types of cancer are explored. Finally, we develop a user-friendly interface to combine the set of studies by using AND and NOT logic operators. Based on the findings, UNIP is a robust and reliable method to analyse large sets of transcriptomic data. It easily detects the main complex relationships between transcriptional expression of genes specific for different conditions and also highlights structures and nodes that could be potential targets for further research.

Background: Health-Related Quality of Life (HRQOL) can be negatively affected in patients living with arrhythmias and many patients experience a pronounced symptom burden. The arrhythmia can cause both uncertainty and limitations, including interference with work, reluctance to perform and plan for leisure activities and leading to self-imposed restrictions in daily life situations. There are patients striving to find strategies to manage the arrhythmia and for some this can become the focus in their lives. Treatment options are often a choice between pharmaceuticals and radiofrequency ablation (RFA) where RFA is an option for many arrhythmia-patients to be cured. In the care of arrhythmia-patients it is of great importance to combine objective examinations with patient-reported outcomes (PROs) to achieve patient’s own experiences of treatment efficacy and arrhythmias interference in daily life situations. Aims: The overall aims of this thesis were to assess symptom burden and HRQOL in patients with arrhythmias and to develop and validate an arrhythmia-specific questionnaire, suitable for most arrhythmia-patients. Design and Methods: Studies I and II were single-centre studies including patients referred for RFA, with two different arrhythmia diagnoses. Assessments of patient-reported outcomes (PROs) concerning HRQOL were performed using two questionnaires, SF-36 and EQ-5D (I-II). Further, patients were asked some disease-specific questions (I). Study I describes assessments before the RFA treatment and Study II the follow-up assessments at three and twelve months after RFA. Patients’ scoring of HRQOL was compared to age and gender matched reference groups before and after RFA (I-II). Studies III and IV describe the development and validation of a disease-specific questionnaire ASTA (Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia) assessing symptom burden and HRQOL. Studies III and IV were multicentre studies. Patients planned for DC-conversion, AF patients seeking emergency care and those with different forms of arrhythmias referred for RFA were included. Results: Patients scored significantly lower HRQOL in seven of SF-36’s eight scales compared to the age and gender matched reference groups before RFA treatment. Frequent arrhythmia attacks had a great negative impact on HRQOL, and female gender and older age were factors contributing to worse HRQOL (I). Treatment with RFA restored the patients’ HRQOL. Most positive effects were seen at three months follow-up. One year after treatment patients and the matched reference group scored their HRQOL to a similar level, assessed with SF-36 and EQ-5D index (II). The validated ASTA questionnaire was found to have good psychometric properties. Construct validity was confirmed with sufficient levels of item-total correlations in the ASTA symptom burden scale and HRQOL scales. The dimensionality of the ASTA HRQOL scale was established with confirmatory factor analysis, supporting a physical and a mental subscale. The internal consistency, demonstrated with Cronbach’s alpha (α), was satisfactory for the ASTA symptom burden scale and the ASTA HRQOL scales, varying from α 0.79 to α 0.91 (III-IV). Conclusions and clinical implications: The studies in this thesis confirmed how negatively affected the arrhythmia-patients can be with a pronounced symptom burden and impaired HRQOL. Treatment with RFA was demonstrated to restore the patients HRQOL to an equal level of that of the matched reference group. PROs are important to take into consideration in the care of arrhythmia-patients, to achieve the patients’ subjective experiences of their daily life situation. To the best of our knowledge ASTA is the first arrhythmia-specific questionnaire assessing symptom burden and HRQOL, suitable for most arrhythmia forms. The newly validated ASTA questionnaire can be an important contribution to assessment of PROs in arrhythmia-patients.

Despite the existence of numerous knee-joint specific patient-reported outcome measures, the content contained within such instruments does not completely capture the spectrum of injury and impairments experienced by multi-ligament knee injured patients. Based on this shortcoming, the overall objective of the current study was to develop, and to test the reliability and validity of a novel disease-specific quality of life instrument for patients with multi-ligament knee injuries. The World Health Organization’s International Classification of Functioning, Disability, and Health was used to guide content development. Using a mixed methods approach (surveys, patient focus groups, expert interviews), the final Multi-ligament Quality of Life (MLQOL) instrument was comprised of 52 items distributed over 4 domains. This instrument demonstrated excellent content validity, test-retest reliability, and construct validity. Future work will evaluate the responsiveness of the MLQOL and will implement its use in randomized trials.

This study assesses generic and disease-specific Health-Related Quality of Life (HRQOL) in children and adolescents with Inflammatory Bowel Disease (IBD). More specifically, the purpose of the study is to address the relationship between disease- specific indicators, both on a symptom-by-symptom basis and as a whole, to overall HRQOL. Self- and proxy-report versions of the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales and the newly developed Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module were administered to 187 parent-child dyads at ten study sites across the United States. Disease-specific indicators included: stomach pain, stomach upset, trouble swallowing, heartburn and reflux, gas and bloating, constipation, and diarrhea. It was hypothesized that caregiver- and child-reported disease-specific HRQOL would be positively correlated with generic HRQOL, and that physical disease-specific indicators would contribute the greatest variance in total generic HRQOL scores, for both self and proxy report. Results confirmed the hypothesis that disease-specific HRQOL would be positively correlated with generic HRQOL for children and caregivers. Multivariate regression results revealed that the Stomach Pain and Hurt, Worry, Medicines, and Communication scales contributed the most variance to overall HRQOL scores for children. The same analysis performed for parent ratings yielded one statistically significant scale: Worry. In essence, intervention efforts aimed at reducing the influence of worry and anxiety may prove more effective in improving HRQOL outcomes than interventions targeting reduction of physical symptoms.

Despite the existence of numerous knee-joint specific patient-reported outcome measures, the content contained within such instruments does not completely capture the spectrum of injury and impairments experienced by multi-ligament knee injured patients. Based on this shortcoming, the overall objective of the current study was to develop, and to test the reliability and validity of a novel disease-specific quality of life instrument for patients with multi-ligament knee injuries. The World Health Organization’s International Classification of Functioning, Disability, and Health was used to guide content development. Using a mixed methods approach (surveys, patient focus groups, expert interviews), the final Multi-ligament Quality of Life (MLQOL) instrument was comprised of 52 items distributed over 4 domains. This instrument demonstrated excellent content validity, test-retest reliability, and construct validity. Future work will evaluate the responsiveness of the MLQOL and will implement its use in randomized trials.

One of the tools a clinician has in disease diagnosis and treatment is genetic testing. To generate value in genetic testing, the link between genetic variants and disease must be discovered, documented, and shared within the community. Working with two existing genomic variation tools, Kafeen and Cordova, a new set of features referred to as Variant-Curation and Database Instantiation (Variant-CADI) was identified, designed, implemented and integrated into the existing Cordova system to unite data collection, management and distribution into one cohesive tool accessible through user interfaces. This eliminates the user needing specialized knowledge of the underlying implementation, data pipeline or data management to collect desired disease specific genetic variations. Using this tool, new disease-specific variation database instances have been initialized and created as demonstrations of the utility of these applications.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13354号 / 論医博第2200号 / 新制||医||1044(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 木村 剛, 教授 羽賀 博典 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

archives@tulane.edu / 1 / Kimberly Michelle Koporc

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20788号 / 医博第4288号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 高橋 淳, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM