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Most distribution free nonparametric methods depend on the ranks or orderings of the individual observations. This dissertation develops methods for the situation when there is only partial information about the ranks available. A random-linear-extension exact test and an empirical version of the random-linear-extension test are proposed as a new way to compare groups of data with partial orders. The basic computation procedure is to generate all possible permutations constrained by the known partial order using a randomization method similar in nature to multiple imputation. This random-linear-extension test can be simply implemented using a Gibbs Sampler to generate a random sample of complete orderings. Given a complete ordering, standard nonparametric methods, such as the Wilcoxon rank-sum test, can be applied, and the corresponding test statistics and rejection regions can be calculated. As a direct result of our new method, a single p-value is replaced by a distribution of p-values. This is related to some recent work on Fuzzy P-values, which was introduced by Geyer and Meeden in Statistical Science in 2005. A special case is to compare two groups when only two objects can be compared at a time. Three matching schemes, random matching, ordered matching and reverse matching are introduced and compared between each other. The results described in this dissertation provide some surprising insights into the statistical information in partial orderings. / Statistics

Study design of a randomized-controlled trial investigating the effects of probiotic supplementation on induction of prediabetes remission to normoglycemia in adults with prediabetes. / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to implement at the population level. Recently, the role of gut microbiota has emerged as a possible link to metabolic disease. The modulation of the gut microbiota in individuals with prediabetes through probiotic supplementation may improve metabolic dysfunction and induce remission of prediabetes to normoglycemia. OBJECTIVES: The primary objective of this trial is to determine the effect of 900 billion CFU/day of VSL#3®, a multi-strain probiotic supplement for 20 weeks, on induction of drug-free remission to normoglycemia (HbA1c<6.0%) in adults with prediabetes compared to placebo 20 weeks post-randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will undergo a 2-week run-in after which they will be randomly allocated to 20 weeks of either 900 billion CFUs of VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal relative abundance of bacteria will be measured from baseline at week 20 and 32. Exploratory regression analyses will involve a multiple logistic regression model to assess whether the change in relative abundance of the Rosburia genus from baseline at week 20 is an independent predictor of drug-free prediabetes remission at week 20. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of microbiota in metabolic processes presents the potential for therapeutic applications of probiotics. If successful, probiotics would offer a therapeutic option for reversing prediabetes to normoglycemia that is simple, cheap and easy to incorporate into standard clinical care. / Thesis / Master of Science (MSc) / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to apply at the population level. Recently, the role of gut bacteria has emerged as a possible link to metabolic disease. Changing the gut microbiota in people with prediabetes through probiotic supplements may improve metabolic function and result in remission of prediabetes to normal glucose control. OBJECTIVES: The primary objective of this study is to determine the effect of VSL#3®, a probiotic supplement, for 20 weeks, on induction of drug-free remission to normal glucose control in adults with prediabetes compared to placebo, 20 weeks after randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will be randomly assigned to 20 weeks of either VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal bacteria will be measured from baseline at week 20 and 32. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of gut bacteria in metabolic health presents the potential for probiotics to be therapy options. If successful, probiotics would be simple, cheap and easy to incorporate into standard clinical care.

Background: Many randomized controlled trials (RCTs) and meta-analyses include analyses of effect modification (also known as subgroup, interaction, or moderation analyses). Methodologists have widely acknowledged the challenges in deciding whether an apparent effect modification is credible or likely the result of chance or bias. Various sets of credibility criteria are available (Chapter 2 provides an example) but are inconsistent, vague in wording, lack guidance for deciding on overall credibility, and have not been systematically tested. Objective: To systematically develop a formal instrument to assess the credibility of effect modification analyses (ICEMAN) in RCTs and meta-analyses of RCTs. Methods: Key steps in the development process included 1) a systematic survey of the literature to identify available criteria, rationales, and previous instruments, 2) a formal consensus study among 10 leading experts, and 3) a formal user-testing study to refine the instrument based on interviews with trial investigators, systematic reviewer authors, and journal editors who applied drafts of the instrument to published claims of effect modification. Results: The systematic survey identified 150 relevant publications, 36 candidate credibility criteria with associated rationales, and 30 existing checklists (Chapter 3). The consensus study consisted of two main video conferences and multiple rounds of written discussion. The user-testing involved 17 users (including systematic review authors, trial investigators, and journal editors) who suggested substantial improvements based on detailed interviews. The final instrument provides separate versions for RCTs (five core questions) and meta-analyses (eight core questions) with explicit response options, and an overall credibility rating ranging from very low to high credibility. A detailed manual provides rationales, supporting references, examples from the literature, and suggestions for use in combination with other quality appraisal tools and reporting (Chapter 4). Discussion: ICEMAN is a rigorously developed instrument to evaluate claims of effect modification and addresses the main limitations of previous approaches. / Thesis / Doctor of Philosophy (PhD) / Randomized controlled trials and meta-analyses provide the best available evidence to evaluate whether effects of a therapy vary among individual patients. Efforts to decide whether treatment effects differ across patients are important and frequently done but difficult to interpret. The fundamental challenge is to decide whether apparent differences in effect are real or due to chance. To aid this decision, experts have suggested various sets of credibility criteria, all with important limitations. This thesis documents how we systematically addressed the limitations of previous approaches. Key steps were a systematic survey of the available credibility criteria, a consensus study among leading methodologists, and a formal user-testing study. The result is a new instrument for assessing the credibility of effect modification analyses (ICEMAN).

Background: Low health literacy and increased sugar-sweetened beverage (SSB) consumption are two broad public health concerns facing the United States. For example, it is estimated that 90 million Americans have insufficient literacy skills (IOMC, 2004) and low health literacy is associated with poorer health outcomes (Berkman et. al., 2011). Furthermore, SSBs contribute about 80% of added sugars in the diet (Nielsen & Popkin, 2004) and have been associated with poor health outcomes, including obesity, type II diabetes, bone fractures, dental caries, and coronary heart disease. Despite these findings, there is limited research related to how to effectively decrease SSB intake among adults. Additionally, there have been few studies investigating health literacy interventions that target health behaviors in community settings (Allen et.al, 2011). Objective: As guided by the Theory of Planned Behavior (TPB) and constructs of health literacy, this 5-week, 2-arm randomized controlled pilot trial, used mixed methods to examine the effects of an intervention to decrease SSB (SipSmartER), as compared to a matched-contact control condition targeting physical activity (Move More). The primary aims of this pilot project were to evaluate participant's feedback through process and summative evaluation as well as evaulate intervention content and/or delivery through process evaluation by staff tracking for quality improvements. Secondary aims included the assessment of changes in theorized mediating variables and health behaviors among participants. Methods: Twenty-five participants (mean age = 42±14 years, mean BMI = 34.3±7.5 kg/m₂, 19 females, 12 African Americans, 9 (high school education) residing in Roanoke, VA were randomized to either SipSmartER (n=14) or Move More (n=11) to begin the 5-week intervention. Inclusion criteria consisted of participants being 18 years of age or older, English speaking, consuming greater than 200 kcal/day of SSB, and being without medical conditions in which physical activity would be contraindicated. Both 5-week interventions included two interactive small group sessions (Weeks 1 & 5) and three support telephone calls (Weeks 2, 3 & 4). Pre-post data was obtained using previously validated instruments including Beverage Intake Questionnaire (Bev-Q), Theory of Planned Behavior constructs addressing SSB and physical activity, media literacy, subjective numeracy, Stanford Leisure-Time Activity Categorical Item (L-CAT), and quality of life. Descriptive statistics, ANOVA, and regression models were used in data analysis. Results: Although SSB consumption decreased more among the SipSmartER participants (-257±622.6 kcal/day) than Move More (-200±404.6 kcal/day) there were no significant group by time differences. However, among all participants, changes in TPB constructs significantly predicted changes in SSB (R²=0.592; F=2.485; p=0.080) and physical activity behaviors (R2=0.621; F=2.813; p=0.056). Participant and staff feedback were very positive, ranging from 4.2-5.0 on a 5-point likert scale that included questions about intervention organization, flow, effectiveness, engagement, and enjoyment. Favorite themes that emerged with SipSmartER participants when asking about small group sessions included, realizing how much sugar is found in SSBs, understanding the health risks associated with drinking too much sugar, realizing how much sugar was being consumed during the day, and learning about better alternatives. Conclusion: Findings suggest promise for the piloted intervention to reduce SSB consumption through targeted TPB and health literacy strategies. This pilot study has allowed further refinement and execution of a larger trial that includes a larger sample and longer study duration (i.e. 6-months) and follow-up period (i.e. 18-months). / Master of Science

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Purpose: Transitioning into retirement may be a suitable period to help adults establish an active lifestyle. One innovative approach to promote PA may be through multimedia-based programs. This experiment aimed to explore the feasibility DVD and videogame-based exercise programs in promoting physical activity (PA) in adults transitioning into retirement. Underlying motivations, functional fitness, quality of life, and elicited beliefs from participating in the exercise programs were also explored. Methods: Twenty-seven adults were randomized into either a nine-week exercise DVD (n = 9), exergame (n = 9), or waitlisted control group (n = 9). Main outcomes include adherence was based on attendance during the in-lab component and participant logs during the in-home component. PA levels were measured through accelerometery and assessed at baseline, four-, nine- and 12-weeks. Secondary outcomes related to motivation were assessed at baseline, three- and nine-weeks. Tertiary outcomes such as physiological/functional fitness and quality of life outcomes were assessed at pre- and post-intervention. Results: During the in-lab portion, t-tests showed that adherence was slightly higher in the exergame group than the DVD group (t16 = -0.06, p = .96; d = .31). Repeated measures of analysis showed that the group x time interaction for moderate-to-vigorous physical activity (MVPA) (F2,24 = 0.87, p = .52; η2 = .05), while overall PA saw negligible changes (F2,24 = 0.16, p = .85; η2 = .01). At the end of the intervention, overall adherence was similar between both exercise groups (t16 = -0.06, p = .96; d = .03). The group by time interaction effect yielded a moderate effect size for MVPA (F2,24 = 1.07, p = .36; η2 = .08) and overall PA (F2,24 = 1.11, p = .35; η2 = .08). Overall PA only increased in the exergame group (d = .74). The exergame group saw major decreases in instrumental attitude (d = .64), injunctive norm (d = .79), perceived behavioural control (d = .40) and intention (d = .90). Both exercise groups enhanced strength, mobility, and aerobic endurance outcomes (d = .33-.98), as well as several quality of life domains (d = .32-.89). At the post-intervention follow-up, both exercise groups were more active than the control group (d = .49-1.03). Two-thirds of the DVD group adopted DVD-based exercise, while a third of exergame group adopted videogame-based exercise. Conclusions: With a high adoption rate, DVD-based exercise programs may be a feasible and acceptable approach to promote PA levels. Participants in both groups were generally satisfied, indicating that the exercise program was enjoyable, comprehensive, and a simple and convenient way to exercise at home. Improvements to important functional and quality of life domains were also identified. Further research will be required to fully test the effectiveness of exercise DVDs and exergames on adherence and PA behaviour in adults transitioning into retirement. / Graduate / 0384 / christopher.yao7@gmail.com

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Typescript. Bibliography: leaves 82-110.

In cluster randomized trials (CRTs), groups of participants are randomized as opposed to individual participants. This design is often chosen to minimize treatment arm contamination or to enhance compliance among participants. In CRTs, we cannot assume independence among individuals within the same cluster because of their similarity, which leads to decreased statistical power compared to individually randomized trials. The intracluster correlation coefficient (ICC) is crucial in the design and analysis of CRTs, and measures the proportion of total variance due to clustering. Missing data is a common problem in CRTs and should be accommodated with appropriate statistical techniques because they can compromise the advantages created by randomization and are a potential source of bias. In three papers, I investigate statistical approaches for handling missing data in CRTs. In the first paper, I carry out a systematic review evaluating current practice of handling missing data in CRTs. The results show high rates of missing data in the majority of CRTs, yet handling of missing data remains suboptimal. Fourteen (16%) of the 86 reviewed trials reported carrying out a sensitivity analysis for missing data. Despite suggestions to weaken the missing data assumption from the primary analysis, only five of the trials weakened the assumption. None of the trials reported using missing not at random (MNAR) models. Due to the low proportion of CRTs reporting an appropriate sensitivity analysis for missing data, the second paper aims to facilitate performing a sensitivity analysis for missing data in CRTs by extending the pattern mixture approach for missing clustered data under the MNAR assumption. I implement multilevel multiple imputation (MI) in order to account for the hierarchical structure found in CRTs, and multiply imputed values by a sensitivity parameter, k, to examine parameters of interest under different missing data assumptions. The simulation results show that estimates of parameters of interest in CRTs can vary widely under different missing data assumptions. A high proportion of missing data can occur among CRTs because missing data can be found at the individual level as well as the cluster level. In the third paper, I use a simulation study to compare missing data strategies to handle missing cluster level covariates, including the linear mixed effects model, single imputation, single level MI ignoring clustering, MI incorporating clusters as fixed effects, and MI at the cluster level using aggregated data. The results show that when the ICC is small (ICC ≤ 0.1) and the proportion of missing data is low (≤ 25\%), the mixed model generates unbiased estimates of regression coefficients and ICC. When the ICC is higher (ICC > 0.1), MI at the cluster level using aggregated data performs well for missing cluster level covariates, though caution should be taken if the percentage of missing data is high.