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Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (p. 89-97).

Systematic reviews have consistently found that moderate intensity physical activity levels at or above a threshold value of 150 minutes per week reliably deliver cardiovascular, metabolic and musculo-skeletal health benefits. As a result, this threshold value has been widely adopted as an aspirational, public health goal throughout the world. However, while epidemiological and laboratory studies have established clear links between physical activity and sleep outcomes, the evidence base does not yet provide guidelines on minimum levels of exercise likely to reduce insomnia symptoms and improve sleep quality. Such a guideline, if evidence based, could greatly clarify advice, and accelerate the use of physical activity goals to improve sleep outcomes in behavioural sleep medicine and public health. This thesis examined the current public-health recommendation of 150 minutes of moderate intensity activity per week in relation to sleep outcomes. To commence, it established a population-level pattern of the relationship between levels of physical activity and sleep quality by reviewing relevant epidemiological evidence. Exploratory analyses were then conducted using data from an ongoing longitudinal study of physical activity and health outcomes among older people (aged 65 years and above) in which respondents were classified as walking at or above, or below the recommended threshold of 150 minutes per week. In regression models controlling for health and demographic factors, these analyses showed that higher levels of walking were significantly and independently associated with a lower likelihood of either reporting insomnia symptoms (OR = 0.67 (95% CI = 0.45 0.91) p=0.04), or experiencing poor sleep efficiency (OR = 0.70 (95% CI = 0.52 0.94 p=0.02). Using the same data, the predictive validity of this activity threshold was then confirmed in a 27-year survival analysis which showed a significantly decreased all-cause mortality risk associated with the higher level of walking (HR = 0.75 (95% CI = 0.65 - 0.86) p<0.01). These findings offered proof of concept that physical activity-sleep relationships operated on a continuum, with sleep benefits possible even at relatively low levels of activity. Experimental evidence on the acute and sustained effects of physical activity on sleep quality was then analysed and discussed. Outcomes from this review, together with the preliminary analyses described above, were then used to inform the design of a randomised controlled trial to investigate the effects on sleep quality of increasing physical activity to currently recommended levels among sedentary people with insomnia. A total of 41 sedentary adults meeting DSM-IV criteria for insomnia (30 female; mean age 59.8??9.5) were randomised to a physical activity group (???150 minutes moderate intensity activity/week) or a waiting list control group. The principal outcome was Insomnia Severity Index (ISI) change 6 months post baseline; secondary outcomes were anxiety (using the State Trait Anxiety Inventory) and depression (Beck Depression Inventory II). Physical activity was assessed using Actigraph GTX3+ accelerometers. Outcomes were assessed in univariate general linear models, adjusted for baseline confounders. Activity and sleep assessments did not differ at baseline. At 6 months post baseline the intervention group engaged in 213 min/week of moderate intensity PA, compared to the control group (82 min/week). Compared to the control group, the intervention group showed significant improvement in the ISI score at 6 months F(1,28) = 5.16, p=0.03), adjusted means difference = 3.37, with an adjusted Cohen's d =.78 (95% CI 0.10 1.45). There was a significant improvement in trait anxiety, and depression outcomes post-intervention, F(6,28)=4.41, p=0.05, and F(6,28)=5.61, p=0.02, respectively. The results showed that increasing activity in line with current guidelines could deliver clinically significant improvements in sleep quality and mood outcomes among inactive adults with insomnia. While the effect sizes are modest, the pattern of results reported here allow for two conclusions with clear implications for public health: 1) measures to increase levels of physical activity above the currently recommended threshold of 150 minutes per week could usefully be added to other approaches to insomnia management; and 2) the likelihood of improved sleep quality should be routinely added to those evidence-based cardiovascular and metabolic benefits most frequently associated with increased physical activity in behaviour change initiatives.

In cluster randomized trials (CRTs), groups are randomized to treatment arms rather than individuals while the outcome is assessed on the individuals within each cluster. Individuals within clusters tend to be more similar than in a randomly selected sample, which poses issues with dependence, which may lead to underestimated standard errors if ignored. To adjust for the correlation between individuals within clusters, two main approaches are used to analyze CRTs: cluster-level and individual-level analysis. In a cluster-level analysis summary measures are obtained for each cluster and then the two sets of cluster-specific measures are compared, such as with a t-test of the cluster means. A mixed model which takes into account cluster membership is an example of an individual-level analysis. We used a simulation study to quantify and compare power and bias of these two methods. We further take into account the effect of missing data. Complete datasets were generated and then data were deleted to simulate missing completely at random (MCAR) and missing at random (MAR) data. A balanced design, with two treatment groups and two time points was assumed. Cluster size, variance components (including within-subject, within-cluster and between-cluster variance) and proportion of missingness were varied to simulate common scenarios seen in practice. For each combination of parameters, 1,000 datasets were generated and analyzed. Results of our simulation study indicate that cluster-level analysis resulted in substantial loss of power when data were MAR. Individual-level analysis had higher power and remained unbiased, even with a small number of clusters.

Breastfeeding is recommended as the optimal source of nutrition for newborns for the first 6 months of life and beyond with the addition of complementary foods. While breastfeeding initiation rates have been increasing, duration rates remain a concern as many women prematurely discontinue due to difficulties encountered rather than maternal choice. In addition, there is a sizable gap between rates of exclusive breastfeeding and current recommendations. Targeting modifiable variables that may be amenable to intervention is one strategy to improve breastfeeding outcomes. One such modifiable variable is breastfeeding self-efficacy. Although research has clearly shown that breastfeeding self-efficacy is predictive of breastfeeding duration and exclusivity, it is unknown whether it can be enhanced to improve breastfeeding outcomes. The purpose of this pilot randomized controlled trial was to examine the feasibility and compliance of a newly developed trial protocol and the acceptability of an intervention to increase breastfeeding self-efficacy in the immediate postpartum period. Secondary outcomes included determining whether there were any trends between groups related to breastfeeding self-efficacy, duration, and exclusivity. Participants included 150 primiparous mothers who were breastfeeding their healthy, full-term infants. Eligible and consenting mothers were randomized to either a control group (standard postpartum care) or an intervention group (standard postpartum care plus the self-efficacy intervention). Participants allocated to the intervention group received three individualized, self-efficacy enhancing sessions with the researcher; two sessions were conducted in hospital, and one was administered via telephone 1 week following hospital discharge. A research assistant blinded to group allocation collected outcome data at 4 and 8 weeks postpartum. The results suggested that the administration of the intervention was feasible and that there was a high degree of protocol compliance; the majority of participants reported that the intervention was beneficial. Secondary outcomes identified that there was a trend among participants in the intervention group to have improved breastfeeding outcomes, including higher rates of breastfeeding self-efficacy, duration, and exclusivity at 4 and 8 weeks postpartum. Preliminary evidence also suggested that the self-efficacy intervention may have assisted to decrease perceptions of insufficient milk supply among the intervention group participants. Overall, the findings from this pilot trial indicated that a larger trial is warranted.

Hyperacusis is a type of decreased sound tolerance where the individual has decreased loudness discomfort levels (LDL), normal hearing thresholds and is sensitive to ordinary environmental sounds. Persons with hyperacusis frequently seek help at audiological departments as they are often affected by other audiological problems. Regrettably, there is neither a consensus-based diagnostic procedure nor an evidence-based treatment for hyperacusis. The principal aim of this thesis was to gain knowledge about the clinical condition hyperacusis. The specific aim of Paper I was to compare hyperacusis measurement tools in order to determine the most valid measures for assessing hyperacusis. Items from a constructed clinical interview were compared with the LDL test, the Hyperacusis Questionnaire (HQ) and the Hospital Anxiety and Depression Scale (HADS). LDLs were significantly correlated with the anxiety subscale of the HADS. A third of the 62 investigated patients scored below the previously recommended cut-off for the HQ. The results suggest that HQ and HADS in combination with a clinical interview are useful as part of the assessment procedure in patients with hyperacusis. The aim of Paper II was to further investigate the patient group with respect to individual characteristics, psychiatric morbidity and personality traits. It was shown that anxiety disorders and anxiety-related personality traits were over-represented, which suggests common or cooperating mechanisms. Avoidance behaviour proved to be very common in the patient group, as was being unable to work due to hyperacusis. In Paper III it was investigated in a randomized controlled trial whether Cognitive Behaviour Therapy (CBT) could be helpful for patients with hyperacusis. The effect of CBT for hyperacusis was assessed with measures of LDLs, symptoms of hyperacusis and of anxiety and depression, fear of (re)injury due to exposure to sounds, and quality of life, compared to a waiting list control group. There were significant group effects for a majority of the measures with moderate and strong effect sizes within- and between groups. After assessment the waiting list group was also given CBT, and was then reassessed with similar effects. The results were maintained for 12 months, concluding CBT to be potentially helpful for these patients.

The general objective of this thesis was to improve understandings of design, conduct and analysis of randomized controlled trials (RCTs). The specific objective was to evaluate the methodological and statistical principles associated with conducting analyses of futility, a component of interim analysis, as part of the conduct of RCTs. This objective was addressed by first performing a systematic review, which included a detailed literature search, as well as data from a cohort of previously extracted studies. The systematic review was designed to identify futility analysis principles and methodologies in order to inform the design and conduct of retrospective futility analyses of two completed NCIC CTG trials. The results of these trials have been previously published; one trial met its stated endpoint and the other did not. Neither trial underwent an interim analysis of futility during its conduct. The retrospective futility analyses assessed the accuracy of frequently used methods, by comparing the results of each method to each other and to the original final analysis results. These assessments were performed at selected time points using both aggressive and conservative stopping rules. In order to increase the robustness of the comparisons, bootstrapping methods were applied. The results of this thesis demonstrate principles associated with the conduct of futility analyses and provide a basis for hypotheses-testing of optimum methodologies and their associated trade-offs. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-12-12 13:10:15.619

In this thesis we consider two sets of combinatorial structures defined on an Eulerian graph: the Eulerian orientations and Euler tours. We are interested in the computational problems of counting (computing the number of elements in the set) and sampling (generating a random element of the set). Specifically, we are interested in the question of when there exists an efficient algorithm for counting or sampling the elements of either set. The Eulerian orientations of a number of classes of planar lattices are of practical significance as they correspond to configurations of certain models studied in statistical physics. In 1992 Mihail and Winkler showed that counting Eulerian orientations of a general Eulerian graph is #P-complete and demonstrated that the problem of sampling an Eulerian orientation can be reduced to the tractable problem of sampling a perfect matching of a bipartite graph. We present a proof that this problem remains #Pcomplete when the input is restricted to being a planar graph, and analyse a natural algorithm for generating random Eulerian orientations of one of the afore-mentioned planar lattices. Moreover, we make some progress towards classifying the range of planar graphs on which this algorithm is rapidly mixing by exhibiting an infinite class of planar graphs for which the algorithm will always take an exponential amount of time to converge. The problem of counting the Euler tours of undirected graphs has proven to be less amenable to analysis than that of Eulerian orientations. Although it has been known for many years that the number of Euler tours of any directed graph can be computed in polynomial time, until recently very little was known about the complexity of counting Euler tours of an undirected graph. Brightwell and Winkler showed that this problem is #P-complete in 2005 and, apart from a few very simple examples, e.g., series-parellel graphs, there are no known tractable cases, nor are there any good reasons to believe the problem to be intractable. Moreover, despite several unsuccessful attempts, there has been no progress made on the question of approximability. Indeed, this problem was considered to be one of the more difficult open problems in approximate counting since long before the complexity of exact counting was resolved. By considering a randomised input model, we are able to show that a very simple algorithm can sample or approximately count the Euler tours of almost every d-in/d-out directed graph in expected polynomial time. Then, we present some partial results towards showing that this algorithm can be used to sample or approximately count the Euler tours of almost every 2d-regular graph in expected polynomial time. We also provide some empirical evidence to support the unproven conjecture required to obtain this result. As a sideresult of this work, we obtain an asymptotic characterisation of the distribution of the number of Eulerian orientations of a random 2d-regular graph.