BACKGROUND AND OBJECTIVES: Standard meta-analysis compares two treatments whereas network meta-analysis compares multiple treatments. In light of the increasing number of treatments available, we have seen a shift from using standard meta-analysis towards using network meta-analyses to support regulatory and reimbursement decisions. This thesis (composed of nine separate papers) applied network meta-analysis to a series of real world problems which simultaneously addressed many of these methodological issues while also supporting healthcare decision making. METHODS: In the first chapter, background information on network meta-analysis and outline the rationale for each of the subsequent chapters is provided. In Chapter 2, an applied example is presented where we use FDA Public Summary documents to populate a network meta-analysis of antithrombotic therapies for atrial fibrillation. In Chapter 3, the advantages and disadvantages of rapid network meta-analysis using ClinicalTrials.gov are investigated by re-doing Chapter 3 but only using data available in ClinicalTrials.gov and examining concordance. In Chapter 4, the application of network meta-analysis when events are rare are investigated using an illustrative example investigating the risk of serious infection in biologics. In Chapter 5, the application of network meta-analysis to a complex network – triptans for migraine – are presented where there are a large number of studies and treatments. In Chapter 6 a network meta-analysis which assesses both a benefit and harm and integrates findings using a benefit harm methodology is presented. In Chapter 7, methods to incorporate non-randomized studies into network meta-analysis are investigated using data on riskof myocardial infarction derived from the Mini-Sentinel distributed data network. FINDINGS AND CONCLUSION: Pragmatic research around methodological areas in network meta-analysis were conducted to address real world problems for decision makers. It is my hope that this thesis and the approaches used in this thesis for the application of network meta-analysis will be disseminated to enhance research capacity in conducting network meta-analysis in Canada.

Objective Postpartum hemorrhage (PPH) is a major cause of maternal mortality world-wide; misoprostol is a relatively cheap, easily administered, and an efficient medication to be given after the delivery of the baby to prevent PPH, thus posing it as a first choice in resource-poor communities. The aim of this study is to answer questions regarding the most appropriate dose (400 µg versus 600 µg), effect of labour settings (community or clinical), and management of labour on misoprostol effectiveness and safety in preventing PPH. Methods We developed a search strategy and conducted a search within five key databases. Two reviewers screened the articles for predefined inclusion/exclusion criteria, quality, and performed data extraction. Discrepancy was dealt with by reaching consensus. In article 1, we only included randomized controlled trials, we performed a random-effects Bayesian network meta-analysis comparing 400 µg to 600 µg misoprostol over five outcomes of interest: blood loss ≥500 ml, blood loss ≥1000 ml, using additional uterotonics, shivering, and pyrexia. In article 2, we included any experimental trial, we performed a random effects model meta-analysis, pooling the incidence of PPH from each misoprostol arm. Subsequently, a meta-regression model was performed on identified potential effect-modifiers, including clinical settings and labour management. Results Of 444 identified records, 46 trials met the inclusion/exclusion criteria in article 1, and 56 trials in article 2. The odds ratio (OR) of misoprostol 400 µg vs. 600 µg for bleeding ≥ 500 ml is 0.86 [95% Credible Intervals: 0.46 − 1.54], for bleeding ≥ 1000 ml the OR is 0.83 [95% CrI 0.54 – 1.26], for additional uterotonics is 0.75 [95% CrI 0.40 – 1.40], for pyrexia and shivering an OR of 0.57 [95% CrI 0.15 – 2.18] and 0.63 [95% CrI 0.29 – 1.31] respectively. The overall incidence of PPH was 6.62 per 100 pregnancies (95%CI 4.71 per 100 – 8.53 per 100). Labour settings and other aspects of active management of labour had no statistically significant effect on the incidence of post-partum hemorrhage. Conclusion We found no difference between the administration of misoprostol 400 µg or 600 µg for the prevention of PPH and side effects of misoprostol, as well as no effect of labour settings and management of labour on misoprostol effectiveness.

Intensive Behavioural Intervention (IBI) is one of the most widely used treatments for children with an autism spectrum disorder (ASD). While IBI has been recognized as the treatment of choice for very young children with an ASD, its sensible use among school age children is a matter of dispute. The aim of this thesis was to determine the clinical effectiveness of IBI, as compared with no treatment or treatment-as-usual, for the management of cognitive functioning and adaptive skills in preschool and school age children with an ASD, as well as to examine predictors of treatment response. Peer-reviewed, English language publications were identified using MEDLINE, EMBASE, PsychINFO, CINAHL, and ERIC from 1995 to September 1, 2014. Grey literature and reference lists of published papers were also searched for relevant records. Retrieved citations were screened by two independent reviewers, and data extraction was performed by a single reviewer with verification by a second reviewer. The methodological quality and procedural fidelity of included studies was assessed by one reviewer, and a subset of included studies were pooled in a random-effects meta-analysis using the standardized mean difference (SMD) effect size. A total of 24 unique studies were selected for inclusion in this review, comprising a total of 1,816 participants. Findings revealed that IBI improves full-scale IQ (SMD ES = 0.66, 95% CI 0.46 to 0.85, p<0.00001; 13 studies) and adaptive skills (SMD ES = 0.57, 95% CI 0.33 to 0.82, p<0.00001; 12 studies) in preschool and school age children with an ASD, with seemingly higher clinical benefits in children aged under 4 years at intake. Better outcomes with IBI are predicted by children’s relatively younger age, increased cognitive and adaptive ability, as well as a milder severity of symptoms at treatment entry. Results warrant careful interpretation in light of several methodological limitations and inadequate monitoring of procedural fidelity.

This study meta-analyzed relationships between proposed antecedents and both directions of work-family enrichment (i.e., work-to-family enrichment and family-to-work enrichment). Proposed antecedents, which were derived from three existing theoretical models on the positive interface between work and family, include contextual and personal characteristics from both work- and family-domains. Primary studies included in the meta-analyses were from both published and unpublished sources between 1990 and 2016. The results suggest that several contextual and personal characteristics are significantly related to work-family enrichment. Gender’s moderating effect on the relationship between contextual characteristics and work-family enrichment received little support. Comparisons between examined antecedents of work-family enrichment and antecedents of work-family conflict supported the notion that work-family enrichment and work-family conflict are distinct constructs; in other words, enrichment is not merely the opposite of conflict. Practical implications and suggestions on future research are discussed.

The movement towards the provision of evidence-based services has become increasingly important to psychological practice (CPA Task Force on Evidence-Based Practice of Psychological Treatments, 2012; Levant, 2005). One of the key components of this movement is the summarizing and dissemination of important findings to key stakeholders for interventions using techniques such as meta-analysis. Meta-analyses are typically based on reviews of the published literature on a particular topic, but increasingly researchers are acknowledging the importance of examining and including unpublished, grey literature in their reviews in presenting an accurate picture of a body of literature (Hopewell, McDonald, Clarke, & Egger, 2008; McAuley, Pham, Tugwell, & Moher, 2000). However, the inclusion of grey literature in meta-analyses and reviews remains controversial (Coad, Hardicre, & Devitt, 2006; Martin, Perez, Sacristan, & Alvarez, 2005; Seymour, 2010). A number of reviews of behavioural parenting interventions have been conducted. The body of literature in this area continues to grow quickly, and recent meta-analyses in this area have examined only subsets of the literature, thus necessitating an overall examination of all available literature in this area: published and unpublished. The present meta-analysis synthesized the results of 42 published and 6 unpublished behavioural parenting intervention studies conducted between 1966 and 2011. In the first manuscript, treatment efficacy was examined with respect to three different outcomes (parent behaviour, child behaviour, and parent adjustment). I also examined the differential effects of six moderator variables in two categories: child characteristics (child formal diagnostic status and child age) and methodological characteristics (overall quality, comparison group, experimenter allegiance, and publication status). In the second manuscript, I examined both the advantages and challenges of including grey literature in meta-analyses, and explored the use of an innovative search program. I also explored the influence of the inclusion of grey literature on outcomes, including whether effect sizes, sample homogeneity, and publication bias indices are affected by the inclusion of grey literature. Results of the present study confirm the efficacy of behavioural parenting interventions on parent behaviour, child behaviour, and parent adjustment outcomes. Further, I extend the knowledge base through the inclusion of recent reports, grey literature, searches of basic search engines such as Google and Yahoo, and the examination of previously unexplored moderator variables. My results underline the importance of consistent reporting practices in the field and their impact on the availability of evidence for policy-makers, administrators, researchers, clinicians and consumers. I also discuss the implications of these findings for the provision of evidence-based services for parents, knowledge translation, and grey literature.

Class of 2008 Abstract / Objectives: 1) To determine if data on weight change in the placebo arm of RCT's for weight loss were available, and 2) to conduct a pilot meta-analysis to estimate the average weight change in the placebo arm. Methods: Four randomized placebo controlled trials of rimonabant for weight loss were retrieved. A draft data extraction form was developed to record weight loss and demographic data. Potential for bias was assessed on design issues related to withdrawals, blinding, allocation procedure, adherence, and manufacturer influence. Based on available data, a forest plot was constructed and heterogeneity was assessed. The a priori alpha level was 0.05. Results: The placebo groups from all studies were similar. The pooled data indicated that individuals in the placebo arm lost an average of 3.3 kg, p < 0.001. One study had a significantly greater completion rate than the other studies. Participants were prescribed a hypocaloric diet and were instructed to increase physical activity but no data were reported on calories consumed or amount of physical activity. Weight loss of 5% ranged from 15-20% of participants. There was potential for bias relating to reported adherence, allocation concealment process, and manufacturer funding. Conclusions: Participants in the placebo arm of rimonabant trials lost an average of 3.3 kg, which was statistically significant. Little can be learned about weight loss in the placebo arm because no data on calories consumed, amount of exercise, or hunger were reported. Information from other RCT's is needed to provide additional data and to confirm the findings.

Randomised trials of complex interventions are typically designed, conducted, and analysed as if they are drug trials. Although there are many parallels there are also a number of important distinctions, which are seldom considered when designing individual trials. One of these concerns the involvement of therapists in delivering psychotherapy. Systematic reviews and meta-analyses provide an opportunity for exploring the full range and complexity of issues encountered in realistically complex situations. The first objective of the thesis was therefore to develop a conceptual framework for understanding the role of the therapist in trial designs. It was addressed by a review of the psychotherapy and statistical literatures structured according to the broad concepts of precision, internal and external validity and refined on the basis of a systematic methodological review of Cochrane reviews meta-analysing trials involving psychotherapy. The second objective was then to review, adapt, illustrate and compare methods for meta-analysing psychotherapy trials with nested designs. Methods for meta-analysing ICC estimates, absolute and standardised mean differences were adapted to allow for heteroscedasticity between treatments at the therapist- and patient- levels. These were illustrated using the example of counselling in primary care, with comparisons being made between aggregate and one-step approaches to the meta-analysis of individual-patient-data.It was argued that the therapist has two roles in randomised trials. Firstly, they are one component of a multi-component intervention, and are thus a potential treatment variable. Second, the nesting of patients within therapists creates an additional level in the design, so the therapist is also an experimental unit. The inability to conceal or randomise allocations leads to observational components within the trial design and to heteroscedasticity which deserves more attention. Characterising complex interventions, like psychotherapy, with more than one treatment variable could facilitate greater understanding of their components, how they interact, which are important, to what extent, and for whom. It also brings what is currently referred to as process research into the remit of trials, enabling a more complete evaluation of the causal effects. The broad concept of multiple experimental units makes cluster-randomised, longitudinal, multi-centre, crossover, therapist- and group-based intervention trials special cases of a more general class of multilevel trial. All involve clustering effects; their nature and the appropriate statistical model varying according to the design. Methods were proposed for the meta-analysis of continuous outcome data for two-level nested designs. A general approach was adopted, where possible, to incorporate methods covering cluster-randomised trials and the Behrens-Fisher problem. It was clear that this is a relatively untouched methodological area in need of further exploration. For the same reasons as it became necessary to summarise clinical research, it is recommended that systematic methodological reviews be carried out on a larger scale in future.

Organizational development and change (ODC) is a broad field because change occurs in all organizations, occurs at multiple organizational levels, consists of numerous interventions, and can impact multiple outcomes. Many ODC efforts attempt to examine the effectiveness of their initiatives, yet fail to account for the quality, or rigor of their methods. The purpose of this paper is to examine how methodological rigor and intervention implementation quality impact ODC outcomes. The results indicate that overall methodological rigor is not a significant predictor of organizational change outcomes; however, several individual rigor criteria exhibit predictive power. Implementation quality is a significant predictor of organizational outcomes, but in a negative direction.

The present meta-analytic study estimated the overall effectiveness of child therapy interventions using CCPT methodology and explored the relationships between study characteristics and treatment effects. Fifty-two studies between 1995 and the present were included based on the following criteria: (a) the use of CCPT methodology, (b) the use of control or comparison repeated measure design, (c) the use of standardized psychometric assessment, and (d) clear reports of effect sizes or sufficient information for effect size calculation. Hierarchical linear modeling (HLM) techniques were utilized to estimate the overall effect size for the collected studies and explore relationships between effect sizes and study characteristics. Dependent variable included 239 effect sizes, and independent variables included 22 study characteristics. The mean age of all child participants in the collected studies was 6.7. In 15 studies, the majority of participants were Caucasian. An equal number of studies were made up of non-Caucasian participants, including 3 with majority African American, 4 with majority Hispanic/Latino participants, 5 with majority Asian/Asian American participants, and 3 with other ethnic populations. Study collection included 33 studies with majority of boys and 11 studies with majority of girls. HLM analysis estimated a statistically significant overall effect size of 0.47 for the collected studies (p < 0.001). This result indicated that the overall improvement from pre to post treatment demonstrated by children in experimental groups was approximately 1/2 standard deviation better than by children in control groups. A statistically significant amount (49.2%) of between-study variance was found (p < 0.001), indicating the heterogeneity among the 52 studies Statistically significant relationships were found between effect sizes and study characteristics including child age, child ethnicity, clinical level of referral, treatment integrity, presenting issue, source of data, population, and caregiver involvement. Effect size findings for CCPT and its moderators should be interpreted in light of the specific, and perhaps more rigorous statistical analysis method (HLM) and effect size calculation formula used for the present study, particularly in comparison to previous meta-analytic findings. Overall findings support CCPT's beneficial treatment effect. Specifically, CCPT can be considered a developmentally and culturally responsive effective mental health intervention across presenting issues.

Orientadores: Andre Deeke Sasse, Carmen Silvia Passos Lima / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T13:13:47Z (GMT). No. of bitstreams: 1 Duarte_IgorLemos_M.pdf: 729678 bytes, checksum: 3da7b8934fdc3f3c7776ad13bc0dbd2b (MD5) Previous issue date: 2015 / Resumo: Pacientes com câncer de mama localmente avançado são de alto risco para recidiva após ressecção cirúrgica com intuito curativo. Muitos estudos têm sido realizados na tentativa de se descobrir alguma intervenção adjuvante capaz de reduzir este risco. No entanto, há, na literatura atual, controvérsias no que tange a melhor estratégia terapêutica neste cenário. Discordância entre intensidade de dose e densidade de dose ainda permeiam o tema. O objetivo desta revisão sistemática foi avaliar o exato papel da quimioterapia em dose densa nas pacientes portadoras de câncer de mama local. Foram comparados os efeitos da quimioterapia em dose densa com quimioterapia convencional em pacientes com câncer de mama localizado ou loco-regionalmente avançado. Os desfechos clínicos avaliados foram sobrevida global (SG), sobrevida livre de doença (SLD) e toxicidades severas. A análise dos dados extraídos foi realizada no programa estatístico Review Manager 5.0 (RevMan 5; Cochrane Collaboration Software). As diferentes estratégias de tratamento adjuvante foram avaliadas em conjunto e separadamente. Quatro estudos (3418 pacientes) foram incluídos. A metanálise demonstrou que quimioterapia em dose densa pode melhorar a sobrevida livre de doença (3356 pacientes; HR 0,83; 95% IC 0,73-0,95; p 0,0005), independente do status de expressão hormonal. Não houve benefício em sobrevida global (3356 pacientes, HR 0,86; IC 95% 0,73-1,01; p 0,006), independente do status de receptor hormonal (SG no subgrupo hormônio positivo HR 0,94; 95% IC 0,74-1,21; SG no subgrupo hormônio negativo HR 0,78; IC 95% 0,62-0,99; p 0,28). Regimes em dose densa causaram pequeno aumento em mucosite, porem sem impacto em eventos cardíacos, leucemia ou mielodisplasia. Em conclusão, a quimioterapia adjuvante em dose densa pode melhora sobrevida livre de doença em pacientes com câncer de mama localizado com pouco impacto na segurança. Entretanto não há claro benefício em sobrevida global. Novas pesquisas podem indicar se há algum impacto em sobrevida global, não verificada atualmente em função do tamanho da amostra, e possivelmente qual grupo de pacientes teria maior benefício / Abstract: Patients with locally advanced breast cancer are at high risk for recurrence after surgical resection with curative intent. Many studies have been conducted in an attempt to discover some adjuvant intervention can reduce this risk. However, there is, in the current literature, controversies regarding the best therapeutic strategy in this scenario. Disagreement between dose intensity and dose density still permeate the theme. The aim of this systematic review was to assess the exact role of dose dense chemotherapy in patients with local breast cancer. The effects of dose dense chemotherapy with conventional chemotherapy in patients with localized breast cancer or loco-regionally advanced were compared. The clinical endpoints were overall survival (OS), disease-free survival (DFS) and severe toxicities. The extracted data was performed in Review Manager 5.0 (RevMan 5, Cochrane Collaboration Software) statistical program. The different strategies of adjuvant treatment were evaluated together and separately. Four studies (3418 patients) were included. The meta-analysis showed that dose dense chemotherapy in improvements can free survival (3356 patients, HR 0,83, 95% CI 0,73 to 0,95, p 0,0005), regardless of the status of hormone expression. There was no benefit in overall survival with chemotherapy dose dense (3356 patients, HR 0,86, 95% CI 0,73 ? 1:01, p 0,006), independent of hormone receptor status d (SG subgroup hormone positive HR 0,94, 95% CI 0,74 ? 1:21, SG in the subgroup negative hormone HR 0,78, 95% CI 0,62 ? 0.99, p 0:28). Regimes in dense dose caused small increase in mucositis, however no impact on cardiac events, leukemia or myelodysplasia. DD adjuvant chemotherapy may improve disease-free survival in patients with early breast cancer with little impact on safety. However there is no clear benefit in overall survival. New research may indicate whether there is any impact on overall survival, not currently seen as a function of sample size, and that group of patients will benefit most / Mestrado / Clinica Medica / Mestre em Clinica Medica