OBJECTIVES: The objective of this thesis is to explore the effectiveness and safety of common pharmacotherapeutic options used for the management of patent ductus arteriosus (PDA) in preterm infants. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance, article 1 develops the protocol to conduct the systematic review and network meta-analysis to answer the research question. Article 2 details the actual methods implemented to conduct the network meta-analysis and presents the results in the form of network plots, league tables, rank heat maps, rankograms and forest plots. RESULTS: Article 1 suggests the need to conduct a Bayesian random-effects network meta-analysis of randomized controlled trials (RCTs) as the analysis would involve multiple treatments with potentially both direct and indirect comparisons. Article 1 also a priori defines potential effect modifiers and statistical strategies to control for the same. In article 2, the results of the meta-analysis show that in 68 RCTs that included 4802 infants, 14 different variations of indomethacin, ibuprofen or acetaminophen were used. Oral high-dose ibuprofen was associated with a significantly higher odds of PDA closure compared with standard-dose intravenous ibuprofen (Odds Ratio [OR], 3.59; 95% Credible Interval [CrI],1.64-8.17) and intravenous indomethacin (OR, 2.35; 95% CrI,1.08-5.31). Oral high-dose ibuprofen ranked the best option for PDA closure (SUCRA [surface under the cumulative ranking curve],0.89 [SD, 0.12]) and to prevent surgical PDA ligation (SUCRA,0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis or intra-ventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. CONCLUSION: This thesis suggests that oral high-dose ibuprofen could be the best treatment option for closure of a hemodynamically significant PDA. Placebo or no treatment for a hemodynamically significant PDA may not increase morbidity and mortality. / Thesis / Master of Science (MSc) / The following thesis explores the effectiveness and safety of commonly used drugs for the treatment of a heart condition in premature infants called the patent ductus arteriosus (PDA). Article 1 outlines the protocol for the systematic review and network meta-analysis designed to evaluate the effectiveness and safety of indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. Article 2 provides in detail the results of the network meta-analysis that examined all eligible randomized controlled trials that compared intravenous or oral formulations of indomethacin, ibuprofen or acetaminophen compared against to other or placebo for the treatment of a PDA that may be harmful for a premature infant based on certain clinical and echocardiographic criteria set by the clinicians and researchers. Overall, this body of work suggests that a higher dose of oral ibuprofen is the best treatment for PDA in premature infants.

Systematic reviews (SR) and meta-analysis (MA) of randomised controlled trials (RCT) are the trustworthy sources of evidence. However, most systematic reviews focus on pair-wise comparisons. Network-meta-analysis (NMA) offers quantitative methods of integrating data from all the available comparisons of many different treatments for each outcome. In a systematic review of interventions, Summary of Findings (SoF) tables present the main findings of a review in a transparent and simple form. However, it is unknown how to present NMA findings in a tabular format. Moreover, systematic reviews and meta-analysis of interventions can summarize bodies of evidence from randomized and non-randomized studies (NRS). Integrating both sources of evidence in a single study can be challenging particularly in the context of assessing the certainty of the evidence, as well as presenting findings of both RCTs and NRS sources of evidence. In our study, we described how 276 NMA were conducted and how authors reported their main findings. We also conducted 32 interviews with users of NMAs and we designed two final NMA-SoF tables. Furthermore, we conducted two systematic reviews that included RCTs and NRS to address methodological challenges. Based on our results, we developed two NMA-SoF table formats to report the main findings of NMAs. The final format was appealing for users and allowed them to better understand NMA findings. Assessment of quality of individual NRS remains challenging and further research is needed to increase its appropriateness in systematic reviews of NRS. We determined that quality assessment of individual NRS was particularly challenging to implement due to the complexity of NRS evaluation tools. Our evaluation revealed that effect estimates of RCTs and NRS were better presented separately. / Thesis / Doctor of Philosophy (PhD) / Systematic reviews (SR) are a summary of studies that address a particular clinical question. Frequently, SRs are complemented with a statistical aggregation of results of individual studies to produce a single estimate. Summary of findings (SoF) tables are designed to present the most relevant information of systematic reviews and meta-analysis. However, it is unknown how to present network meta-analysis (NMA) findings in SoF tables. Another challenge relates to the integration of randomized controlled trials (RCTs) and non-randomized (NRS) studies. Methodological challenges in systematic reviews need to be addressed through careful research. In our study, we appraised how NMA were conducted, and how they presented their main findings. We designed two versions of SoF tables to present NMA findings. Moreover, we conducted two systematic reviews that included RCTs and NRS to address potential challenges in analyzing and presenting their findings.

The relationship between human health and nutrition is complex and limited widely accepted guidance on proper methods of evidence synthesis is available for nutritional issues. While concepts and methods of evidence synthesis in pharmacological treatments can be mostly applied to nutritional interventions, characteristics unique to the nutrition- and dietetics-related topics can lead to distinct challenges that may not be encountered in evidence synthesis of traditional medical interventions. In addition to traditional methods for pooling the results, state-of-the-art methodologies such as GRADE or network meta-analysis, while being widely used in many medical fields, their use in the field of nutrition and food science is surprisingly rare. This thesis begins with the assessment of methodological quality of available public health guidelines on sugar intake to determine the extent to which nutritional guidelines follow currently available guidance in evidence synthesis and making practice recommendations. Subsequently, we present two examples of proper implementation of evidence synthesis methods in standard pairwise meta-analysis and indirect treatment comparison and handling of relevant challenges including applications of GRADE approach. Further, this thesis presents a network meta-analysis in the field of nutrition and child health in which the challenges of conducting multiple treatment comparison are tackled and a new approach for presenting and making conclusion from network meta-analysis results is proposed. / Thesis / Doctor of Philosophy (PhD)

Network meta-analysis (NMA) synthesizes all available direct (head-to-head) and indirect evidence on the comparative effectiveness of at least three treatments and provides coherent estimates of their relative effects. Ranking probabilities are commonly used to summarize these estimates and provide comparative rankings of treatments. However, the reliability of ranking probabilities as summary measures has not been formally established and treatments are often ranked for each outcome separately. This thesis aims to address methodological gaps and limitations in current literature by providing alternative methods for evaluating the robustness of treatment ranks, establishing comparative rankings, and integrating ranking probabilities across multiple outcomes. These novel tools, addressing three specific objectives, are developed in three papers. The first paper presents a conceptual framework for quantifying the robustness of treatments ranks and for elucidating potential sources of lack of robustness. Cohen’s kappa is proposed for quantifying the agreement between two sets of ranks based on NMAs of the full data and a subset of the data. A leave one-study-out strategy was used to illustrate the framework with empirical data from published NMAs, where ranks based on the surface under the cumulative ranking curve (SUCRA) were considered. Recommendations for using this strategy to evaluate sensitivity or robustness to concerning evidence are given. When two or more cumulative ranking curves cross, treatments with large probabilities of ranking the best, second best, third best, etc. may rank worse than treatments with smaller corresponding probabilities based on SUCRA. This limitation of SUCRA is addressed in the second paper through the proposal of partial SUCRA (pSUCRA) as an alternative measure for ranking treatments. pSUCRA is adopted from the partial area under the receiver operating characteristic curve in diagnostic medicine and is derived to summarize relevant regions of the cumulative ranking curve. Knowledge users are often faced with the challenge of making sense of large volumes of NMA results presented across multiple outcomes. This may be further complicated if the comparative rankings on each outcome contradict each other, leading to subjective final decisions. The third paper addresses this limitation through a comprehensive methodological framework for integrating treatments’ ranking probabilities across multiple outcomes. The framework relies on the area inside spie charts representing treatments’ performances on all outcomes, while also incorporating the outcomes’ relative importance. This approach not only provides an objective measure of the comparative ranking of treatments across multiple outcomes, but also allows graphical presentation of the results, thereby facilitating straightforward interpretation. All contributions in this thesis provide objective means to improve the use of comparative treatment rankings in NMA. Further extensive evaluations of these tools are required to assess their validity in empirical and simulated networks of different size and sparseness. / Thesis / Doctor of Philosophy (PhD) / Decisions on how to best treat a patient should be informed by all relevant evidence comparing the benefits and harms of available options. Network meta-analysis (NMA) is a statistical method for combining evidence on at least three treatments and produces a coherent set of results. Nevertheless, NMA results are typically presented separately for each health outcome (e.g., length of hospital stay, mortality) and the volume of results can be overwhelming to a knowledge user. Moreover, the results can be contradictory across multiple outcomes. Statistics that facilitate the ranking of treatments may aid in easing this interpretative burden while limiting subjectivity. This thesis aims to address methodological gaps and limitations in current ranking approaches by providing alternative methods for evaluating the robustness of treatment ranks, establishing comparative rankings, and integrating ranking probabilities across multiple outcomes. These contributions provide objective means to improve the use of comparative treatment rankings in NMA.

The vast and complex wealth of information available to researchers often leads to a systematic review, which involves a detailed and comprehensive plan and search strategy with the goal of identifying, appraising, and synthesizing all relevant studies on a particular topic. A meta–analysis, conducted ideally as part of a comprehensive systematic review, statistically synthesizes evidence from multiple independent studies to produce one overall conclusion. The increasingly widespread use of meta–analysis has led to growing interest in meta–analytic methods for rare events and sparse data. Conventional approaches tend to perform very poorly in such settings. Recent work in this area has provided options for sparse data, but these are still often hampered when heterogeneity across the available studies differs based on treatment group. Heterogeneity arises when participants in a study are more correlated than participants across studies, often stemming from differences in the administration of the treatment, study design, or measurement of the outcome. We propose several new exact methods that accommodate this common contingency, providing more reliable statistical tests when such patterns on heterogeneity are observed. First, we develop a permutation–based approach that can also be used as a basis for computing exact confidence intervals when estimating the effect size. Second, we extend the permutation–based approach to the network meta–analysis setting. Third, we develop a new exact confidence distribution approach for effect size estimation. We show these new methods perform markedly better than traditional methods when events are rare, and heterogeneity is present.

Economic evaluations and network meta-analyses (NMAs) are complex methodologies. Increasing their transparency and accessibility could enhance confidence in the legitimacy of policy decisions informed by these analyses. Four systematic reviews were conducted to understand policymakers’ informational needs and to determine what guidance researchers have on how to present economic evaluations and NMAs. Qualitative interviews were conducted with Canadian policymakers, i.e., knowledge users, to understand barriers and facilitators to using and communicating economic evaluations and NMAs and with individuals in international health technology assessment organizations, i.e. knowledge producers, to explore current approaches to communicating economic evaluations and NMAs. A toolkit for NMAs and economic evaluations was proposed based on an integrated review of these findings and guided by the Knowledge-to-Action framework. Examples of tools were developed and applied to an economic evaluation and NMA of osteoporosis therapies. Systematic reviews and qualitative interviews found that communication approaches that provide robust content, identify contextual factors relevant to policy decisions and enhance clarity were valued. Twelve tools were proposed that enhance communication, education and access to resources for policymakers. Two of these tools were developed: Economic Guidance for Researchers and NMA Guidance for Researchers.

There is little head-to-head evidence comparing interventions available for juvenile idiopathic arthritis (JIA). This review involved a series of systematic reviews and network meta-analyses (NMAs) to evaluate the comparative efficacy and safety of pharmacological and non-pharmacological interventions among patients with JIA. Outcomes were the American College of Rheumatology Pediatric 30 (ACR Pedi 30) (disease response), its six composite outcomes, pain relief, health-related quality of life, and physical and emotional functioning. There was some evidence that etanercept had greater reduction in the number of joints with active arthritis compared to abatacept for polyarticular-course JIA and that canakinumab had improved ACR Pedi 30 over rilonacept. Non-pharmacological interventions showed no significant results for efficacy but were safe overall. Most included studies were low-quality and many were excluded from analysis because of unclear reporting or no results for outcomes of interest. As more studies are conducted this will improve the estimates from the NMAs.

Pancreatic cancer is the fourth leading cause of cancer death in Canada. Significant advancements in chemotherapy for advanced pancreatic cancer have resulted in the need for a quantitative comparison between these treatments on a relative scale. Therefore, a systematic review and Bayesian network meta-analysis of randomized clinical trials was conducted using gemcitabine, the standard treatment, as the reference comparator. Based on results from the network meta-analysis, in which optimal treatments were identified and side effects of each treatment evaluated, an Internet-based patient decision aid was developed in order to present the benefits and risks of each therapy option: (1) Best supportive care (2) gemcitabine (3) FOLFIRINOX. The objective of the decision aid was to guide patients through the decision-making process based on their individual preferences and values. The decision aid was deemed to be acceptable and feasible based on results from a pilot study conducted at The Ottawa Hospital Cancer Centre.

Aging and age-related frailty are important public health problems. There is a need to develop rehabilitation interventions to reduce the prevalence and disabling effects of frailty. This thesis reports the rationale and design of two studies and findings of three studies aimed to optimize health outcomes of frail older adults and their caregivers. The second chapter describes the protocol of the first network meta-analysis to determine the comparative effect of interventions targeting the prevention or treatment of frailty. In the third chapter, the results of frailty network meta-analysis were presented and 89 RCTs were included. The review shows that physical activity and medication management are the most effective frailty interventions. The fourth chapter describes a protocol of pilot randomized controlled trial (RCT) to examine a preoperative multi-modal frailty intervention in pre-frail/frail older adults undergoing elective joint replacements. The fifth chapter describes the results of a subgroup analysis of a RCT examining the effect of complex primary care intervention to support caregivers of frail older adults. There were no differences between caregivers of frail older adults and non-caregivers in quality of life, social support, hospitalization, and emergency department visits. The sixth chapter examines the construct validity and discriminative properties of the fracture rating scale (FRS) (a tool designed for fracture risk assessment in long term care (LTC)). The FRS is a valid tool for identifying LTC residents at different risk levels for hip fracture in three Canadian provinces. The work presented in this thesis is proposing and examining the comparative effect of frailty interventions, a preoperative frailty intervention/ model, a primary care intervention to identify and support caregivers, and a predictive tool to optimize care planning of LTC residents. These findings will support the rehabilitation and care program for older adults and their caregivers and improve their health outcomes. / Thesis / Doctor of Philosophy (PhD) / There is a need to develop rehabilitation interventions to reduce the prevalence and disabling effects of frailty. This thesis reports the rationale and design of two studies and findings of three studies aimed to improve health outcomes of frail older adults and their caregivers. The second and third chapters of this thesis describe the protocol and results of a review aims to identify the effect of interventions targeting frailty, the review found that physical activity and medication management are the most effective frailty interventions. The fourth chapter describes a study examining the possibility of comparing a complex intervention to usual care in frail older adults undergoing joint replacements. The fifth chapter showed that a primary care intervention did not improve the caregivers’ health outcome. The sixth chapter presents the fracture rating scale, a valid tool for identifying Long-term care residents at risk of hip fracture in three Canadian provinces. These findings aim to improve the care for older adults and their caregivers.

The potential that telemedicine interventions may have in effectively delivering remote specialized cardiovascular care to large numbers of patients with heart diseases has recently come under question. In the first phase of this thesis, a systematic review and meta-analysis was conducted to compare the impact of a basic form of telemedicine that is regular patient follow-up by telephone, with usual care for individuals with coronary artery disease following their discharge. In the second phase of this thesis, a network meta-analysis, using Bayesian methods for multiple treatment comparisons, was conducted to compare the more complex forms of telemedicine for patients with heart failure. In the third and final phase of this thesis, a randomized controlled trial was designed to compare the impact of two forms of telemedicine, identified in the earlier two phases as being the most promising, on clinical outcomes, cardiac risk factors and patient reported outcomes.