Background: Stories may be an effective tool to communicate with and influence patients because of their ability to engage the reader. Objectives: To develop story booklets and evaluate their effectiveness compared to standard information sheets for parents of children attending the emergency department (ED) with a child with croup. Methods: A systematic process was followed to develop and pilot-test the story booklets. Parents were randomized to receive story booklets or standard information sheets during their ED visit. The primary outcome of change in anxiety during the ED visit was assessed using the State Trait Anxiety Inventory, which was completed upon recruitment and at discharge. Follow-up telephone interviews were conducted at 1 and 3 days post-ED visit to gather information on secondary outcomes: symptoms, expected anxiety for future croup, satisfaction, regret, knowledge, return for medical care, and resource use. Telephone interviews were conducted every other day until symptoms resolved or until day 9. Outcomes were compared using independent-groups t-tests, Mann Whitney tests, or Chi-square tests. Results: There was no significant difference in the primary outcome of change in parental anxiety between recruitment and ED discharge. The story group (n=129) showed significantly greater decision regret regarding their decision to go to the ED than the comparison group (n=126) (p<0.001). The story group reported quicker resolution of symptoms: median days to no symptoms 3 versus 5; the survival distributions were significantly different (p=0.032). There were no differences for the remaining outcomes. Conclusions: This study provides preliminary evidence regarding the use of stories in the ED for an acute, self-limiting condition and contributes to a growing evidence matrix identifying when, where, and for whom storytelling may be most effective. Reasons for lack of significance for the primary and other outcomes may relate to choice of outcome, timing of outcome assessment, or disconnect between the intervention and needs of the end-user. Further research is needed to corroborate the significant findings and examine their underlying mechanism. An examination of risk of bias in a sample of pediatric trials demonstrates that there is room for improvement in the design, conduct, and reporting of research related to child health and provides direction for future research.

Objectives: 1) To evaluate the quality of randomized clinical trials (RCTs) in rare diseases using Juvenile Idiopathic Arthritis (JIA) as an example, 2) to evaluate the time to treatment response in patients with rheumatic diseases, 3) to evaluate the power of the Randomized Placebo-Phase Design (RPPD) under various response time distributions, and 4) to examine the use of Value of Information (VOI) methodology in the optimal design of clinical trials for rare disease using hemophilia prophylaxis with factor VIII as an example. Methods. The methods include a systematic review, a secondary analysis of data from an RCT and from a patient registry, a computer simulation study, and an evaluation of hypothetical RCT scenarios with VOI methodology. Results. The quality of RCTs in JIA based on selected quality indicators was poor with some positive changes over time. In the data sets used for the assessment of hazard distributions, the response times followed mostly generalized gamma or lognormal distributions. The impact of time-to-event distribution on the power of RCTs was assessed in computer simulations. Based on the simulation results, the highest sample sizes were observed for response times following the exponential distribution. In most scenarios, the parallel groups RCT design had higher power than the RPPD. The conclusion of the VOI analyses indicated that at threshold values lower than 400,000 the current evidence supported the use of on-demand therapy. Threshold values higher than 1,000,000 supported the use of tailored or alternate day prophylaxis. At threshold values between 400,000 - 1,000,000 the optimal decision varied from on-demand to prophylaxis therapies. Conclusions. New, more powerful and acceptable designs should be developed for rare diseases. When time-to-event outcomes are used, investigators should use various sources of information to evaluate response time distributions before the new trial is designed, and consider this information in sample size calculation and analysis. VOI methodology should be used in the planning stage of studies to determine the relevant costs and benefits of future research, and to determine the optimal trial parameters that maximize the cost-benefit trade-off.

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Objectives: 1) To evaluate the quality of randomized clinical trials (RCTs) in rare diseases using Juvenile Idiopathic Arthritis (JIA) as an example, 2) to evaluate the time to treatment response in patients with rheumatic diseases, 3) to evaluate the power of the Randomized Placebo-Phase Design (RPPD) under various response time distributions, and 4) to examine the use of Value of Information (VOI) methodology in the optimal design of clinical trials for rare disease using hemophilia prophylaxis with factor VIII as an example. Methods. The methods include a systematic review, a secondary analysis of data from an RCT and from a patient registry, a computer simulation study, and an evaluation of hypothetical RCT scenarios with VOI methodology. Results. The quality of RCTs in JIA based on selected quality indicators was poor with some positive changes over time. In the data sets used for the assessment of hazard distributions, the response times followed mostly generalized gamma or lognormal distributions. The impact of time-to-event distribution on the power of RCTs was assessed in computer simulations. Based on the simulation results, the highest sample sizes were observed for response times following the exponential distribution. In most scenarios, the parallel groups RCT design had higher power than the RPPD. The conclusion of the VOI analyses indicated that at threshold values lower than 400,000 the current evidence supported the use of on-demand therapy. Threshold values higher than 1,000,000 supported the use of tailored or alternate day prophylaxis. At threshold values between 400,000 - 1,000,000 the optimal decision varied from on-demand to prophylaxis therapies. Conclusions. New, more powerful and acceptable designs should be developed for rare diseases. When time-to-event outcomes are used, investigators should use various sources of information to evaluate response time distributions before the new trial is designed, and consider this information in sample size calculation and analysis. VOI methodology should be used in the planning stage of studies to determine the relevant costs and benefits of future research, and to determine the optimal trial parameters that maximize the cost-benefit trade-off.

It is widely accepted that breast milk is the optimal source of infant nutrition. Despite the World Health Organization (WHO) recommendation of exclusive breastfeeding for the first 6 months of infant life, many women discontinue breastfeeding as a result of perceived difficulties. Nipple pain is a highly prevalent, significant reason for breastfeeding cessation. Among the numerous interventions for nipple pain, the application of lanolin is commonly recommended, with endorsement by Health Canada, The La Leche League, and International Board Certified Lactation Consultants. The few studies that have evaluated the effectiveness of lanolin on nipple pain have lacked methodologic rigor, and are thus not reliable or generalizable. As such, the purpose of this trial was to rigourously evaluate the effect of lanolin for the treatment of nipple pain among breastfeeding women. This single-site randomized controlled trial (RCT) compared the application of lanolin (treatment) to usual postpartum care (not applying lanolin) for the treatment of nipple pain. The primary outcome for this trial was the effect on pain severity, as measured by a numeric rating scale (NRS) at 4 days post-randomization. Of 186 participants, 93 were randomized to the treatment group and 93 to the usual care group. At 4 and 7 days post-randomization there were no statistically significant differences in pain scores between groups. It is noteworthy that by 7 days post-randomization there were clinically relevant decreases in nipple pain in both groups. However, there were no statistically significant differences between groups for other outcomes, including pain measured with the short-form McGill Pain Questionnaire, breastfeeding duration, breastfeeding exclusivity, and breastfeeding self-efficacy. Despite these findings, women in the treatment group were significantly more satisfied receiving lanolin for their nipple pain than those receiving usual care. Since the use of lanolin is no more effective than applying nothing to the nipples for the management of nipple pain, the widespread use of lanolin is questionable. Further research is required on the role of interventions to prevent nipple pain and damage, and the effect of anticipatory guidance on improving breastfeeding outcomes for those experiencing nipple pain in the early postpartum period.

The present thesis focuses on the design and analysis of randomized algorithms for accelerating several linear algebraic tasks. In particular, we develop simple, efficient, randomized algorithms for a plethora of fundamental linear algebraic tasks and we also demonstrate their usefulness and applicability to matrix computations and graph theoretic problems. The thesis can be divided into three parts. The first part concentrates on the development of randomized linear algebraic primitives, the second part demonstrates the application of such primitives to matrix computations, and the last part discusses the application of such primitives to graph problems. First, we present randomized approximation algorithms for the problems of matrix multiplication, orthogonal projection, vector orthonormalization and principal angles computation (a.k.a. canonical correlation analysis). Second, utilizing the tools developed in the first part, we present randomized and provable accurate approximation algorithms for the problems of linear regression and element-wise matrix sparsification. Moreover, we present an efficient deterministic algorithm for selecting a small subset of vectors that are in isotropic position. Finally, we exploit well-known interactions between linear algebra and spectral graph theory to develop and analyze graph algorithms. In particular, we present a near-optimal time deterministic construction of expanding Cayley graphs, an efficient deterministic algorithm for graph sparsification and a randomized distributed Laplacian solver that operates under the gossip model of computation.

The present thesis focuses on the design and analysis of randomized algorithms for accelerating several linear algebraic tasks. In particular, we develop simple, efficient, randomized algorithms for a plethora of fundamental linear algebraic tasks and we also demonstrate their usefulness and applicability to matrix computations and graph theoretic problems. The thesis can be divided into three parts. The first part concentrates on the development of randomized linear algebraic primitives, the second part demonstrates the application of such primitives to matrix computations, and the last part discusses the application of such primitives to graph problems. First, we present randomized approximation algorithms for the problems of matrix multiplication, orthogonal projection, vector orthonormalization and principal angles computation (a.k.a. canonical correlation analysis). Second, utilizing the tools developed in the first part, we present randomized and provable accurate approximation algorithms for the problems of linear regression and element-wise matrix sparsification. Moreover, we present an efficient deterministic algorithm for selecting a small subset of vectors that are in isotropic position. Finally, we exploit well-known interactions between linear algebra and spectral graph theory to develop and analyze graph algorithms. In particular, we present a near-optimal time deterministic construction of expanding Cayley graphs, an efficient deterministic algorithm for graph sparsification and a randomized distributed Laplacian solver that operates under the gossip model of computation.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Estimation of exposure-specific risks (ESRs) using estimates of the overall risk and relative risk of disease given exposure has been performed in previous studies, but the performance of such an estimator has not been assessed nor has a variance for such an estimate been proposed. In this project I evaluated the performance of a simple product-based ESR and its variance derived using the delta method. I used the variance to estimate the 95% confidence interval. I found that this point estimate was biased and that the accompanying 95% confidence interval did not attain 95% coverage. I also proposed a revised product-based estimator and found that this estimator was unbiased. I used the delta method to derive a variance for this estimator and estimated the 95% confidence interval. The coverage of this interval attained 95% coverage in most situations. According to the CONSORT statement, subgroup analyses in randomized controlled trials (RCTs) should be pre-planned and accompanied with a formal test of interaction. I considered the interaction between treatment and a dichotomous prognostic factor with a continuous outcome. I examined the impact of misspecifying the distribution of the prognostic factor on power and sample size for interaction effects. I found that power for the interaction test was decreased when the misspecification of the distribution of the prognostic factor was away from a balanced design. I also proposed three methods for improving the power under misspecifications. Quota sampling maintained the power at 80%, but trial completion may be delayed under misspecifications. Modified quota sampling improved the power, but results were related to the proportion of trials switching to the quota sampling procedure. Sample size re-estimation improved the power, but did not always attain 80% power. All three methods maintained appropriate type I error. Lastly, I examined the impact of unplanned cross-over on power and sample size for interaction effects in RCTs. Unplanned cross-over is common in surgical trials and can diminish the magnitude of the interaction effect. Due to this, the sample size re-estimation procedure performed better than quota sampling and modified quota sampling in the presence of unplanned cross-over. / 2031-01-02

Background: Cluster randomized control trials (cRCTs) are useful for asking about system-level interventions compared to other types of clinical research design, however they present unique challenges with conduct and delivery. Numerous cRCTs in hospitals have encountered challenges and time delays in enrolling hospitals and launching the trials which contributes to research waste. While each cRCT has unique barriers and enablers to their conduct, it is important to understand and explore these factors at the general level of the cRCT itself. Previous literature has documented factors associated with successful cRCTs, however, these studies focused primarily on the statistical aspect, while neglecting to evaluate the delivery of the trial. Objectives: The goal of this dissertation was to explore barriers and enablers to conducting cRCTs in hospitals, and to identify potential strategies that facilitate their delivery. This research was conducted to identify evidence and generate guidance for researchers aiming to conduct these trials. Specifically, the objectives were: 1) To explore the current knowledge and evidence surrounding the implementation of cRCTs in hospitals; 2) To explore from the perspective of the coordinating site, what influenced the delivery and hospital engagement of an ongoing cRCT, and what challenges were encountered; 3) To identify strategies to facilitate delivery of cRCTs in hospitals; 4) To systematically review reported recruitment strategies of healthcare facilities in cRCTs. Methods: The dissertation employed multiple research methods. To address the first objective, a scoping review was performed of current literature related to hospitals in cRCTs. The second objective was addressed with a qualitative case study. Semi-structured interviews were carried out with six key members of the team to understand their perceptions of the delivery of the trial. For the third objective, a tool matching two implementation concepts (the Consolidated Framework for Implementation Research (CFIR)- Expert Recommendations for Implementing Change (ERIC) matching tool) was used to identify strategies targeted to address barriers and enablers to cRCT conduct identified in the first two studies. Lastly, a systematic review was performed to address the fourth objective, to identify reported strategies used for hospital engagement in cRCTs. The thesis was guided and analyzed using an over-arching implementation framework, CFIR, and an implementation strategies list, the ERIC compilation. This was done to allow comparability and synthesis of results between methodologies from the dissertation, and between the results from the studies and previous literature. Results: Several key CFIR domains were identified in the literature in the scoping review that were determined to being influential for conducting the cRCTs in hospitals: the adaptability to tailor the trial to each site; the engagement of opinion leaders, champions and formally appointed implementation leaders in the cRCT process as facilitators to conducting the trial; the lack of a site perceiving a relative priority for the trial or tension for change for the clinical field presenting barriers to conducting the cRCT; and limited available resources can present barriers to conducting the cRCT. The qualitative case study identified similar CFIR domains and constructs as potentially influential for cRCT conduct, including the emphasis on adaptability of trial, the importance of tension for change in the sites for accepting inclusion in the trial, the availability of resources, and the engagement of leaders. The CFIR-ERIC matching study identified strategies that may be used to overcome barriers and target enablers for cRCT delivery from CFIR domains and constructs identified in the first two studies. A list of strategies was generated, ranked by the number of many determinants for which the strategy was listed as a Level 1 strategy, then by how many determinants for which the strategy was listed as a Level 2 strategy. The top ERIC strategies that were endorsed as a Level 1 strategy for any or multiple CFIR domains were: 1) Identify and prepare champions, 2) Conduct local needs assessment, 3) Conduct educational meetings, 4) Inform local opinion leaders, 5) Build a coalition, 6) Promote adaptability, 7) Develop a formal implementation blueprint, 8) Involve patients/consumers and family members, 9) Obtain and use patients/consumers and family feedback, 10) Develop educational materials, 11) Promote network weaving, 12) Distribute educational materials, 13) Access new funding, and 14) Develop academic partnerships. The systematic review identified literature reporting on the recruitment of healthcare facility sites into cRCTs. Numerous strategies for cRCT site recruitment were identified, and these were coded to the ERIC compilation. Strategies that were commonly cited were: involve executive boards, promote network weaving, conduct educational meetings, inform local opinion leaders, and centralize technical assistance. Conclusions: The results from the dissertation can contribute to the knowledge for facilitating cRCT delivery in hospitals while recognizing the critical limitations in the studies. Key concepts and strategies to facilitate the conduct and delivery of cRCTs in hospitals were identified. Future research should aim to empirically evaluate the identified strategies. Researchers should aim to address the reporting gap for cRCT delivery identified by this dissertation.

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