Challenges Associated with Statistical Analysis in the Presence of Sparse Data and Applications to Alternative Tobacco Product Research

Thesis (Master's)--University of Washington, 2013Rarely observed covariate combinations, or "sparsity" is a phenomenon associated with research concerning the health risks of alternative-use (non-combusted tobacco products (AUPs)). Of particular concern is sparsity relating to AUP users who do not currently or formerly use other tobacco products. This thesis aims to identify reasons why sparsity is a concern, the effect that sparsity can have on statistical inference, and potential appropriate approaches in the presence of sparsity. Special attention will be paid to scenarios in which sparsity can lead to inference that results in estimates of the AUP effect that are in the opposite direction of the true effect (e.g. found to be harmful when truly beneficial) and to be in an opposite direction related to the cigarette effect (e.g. found to be less harmful than cigarettes when truly more harmful). The impact of sparsity will be assessed primarily by constructing examples from both case-control and cohort studies and investigating the results from common statistical modeling methods under sparse and non-sparse conditions. These examples will include hypothetical examples constructed to approximate real world study design as well as data from a published study of an AUP. These examples will focus on issues of sparsity in relation to interaction assumptions and model scale assumptions. Conditional parameter estimates can vary widely from the marginal estimates for that parameter. Data sets with few subjects who use AUPs without also using cigarettes have reduced power to detect interaction. When scale or interaction assumptions are violated estimation of incidence rate or parameter values can be biased. This bias can be such that conclusions from analysis of sparse data sets can be misleading. These issues can cause AUP use to be estimated as beneficial when it is in truth harmful, or as less harmful than cigarettes when in truth it is more harmful. These issues are of such severity that we, if it is not possible to oversample the sparse categories, recommend restricting analysis to subgroups in which sparsity is unlikely to be a concern

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: A randomised, open-label, crossover trial

Background: Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. Methods: MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16–21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. Findings: From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17–19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. Interpretation: Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences

Dedicated IT infrastructure for Smart Levee Monitoring and Flood Decision Support

Smart levees are being increasingly investigated as a flood protection technology. However, in large-scale emergency situations, a flood decision support system may need to collect and process data from hundreds of kilometers of smart levees; such a scenario requires a resilient and scalable IT infrastructure, capable of providing urgent computing services in order to perform frequent data analyses required in decision making, and deliver their results in a timely fashion. We present the ISMOP IT infrastructure for smart levee monitoring, designed to support decision making in large-scale emergency situations. Most existing approaches to urgent computing services in decision support systems dealing with natural disasters focus on delivering quality of service for individual, isolated subsystems of the IT infrastructure (such as computing, storage, or data transmission). We propose a holistic approach to dynamic system management during both urgent (emergency) and normal (non-emergency) operation. In this approach, we introduce a Holistic Computing Controller which calculates and deploys a globally optimal configuration for the entire IT infrastructure, based on cost-of-operation and quality-of-service (QoS) requirements of individual IT subsystems, expressed in the form of Service Level Agreements (SLAs). Our approach leads to improved configuration settings and, consequently, better fulfilment of the system’s cost and QoS requirements than would have otherwise been possible had the configuration of all subsystems been managed in isolation

Dedicated IT infrastructure for Smart Levee Monitoring and Flood Decision Support

Smart levees are being increasingly investigated as a flood protection technology. However, in large-scale emergency situations, a flood decision support system may need to collect and process data from hundreds of kilometers of smart levees; such a scenario requires a resilient and scalable IT infrastructure, capable of providing urgent computing services in order to perform frequent data analyses required in decision making, and deliver their results in a timely fashion. We present the ISMOP IT infrastructure for smart levee monitoring, designed to support decision making in large-scale emergency situations. Most existing approaches to urgent computing services in decision support systems dealing with natural disasters focus on delivering quality of service for individual, isolated subsystems of the IT infrastructure (such as computing, storage, or data transmission). We propose a holistic approach to dynamic system management during both urgent (emergency) and normal (non-emergency) operation. In this approach, we introduce a Holistic Computing Controller which calculates and deploys a globally optimal configuration for the entire IT infrastructure, based on cost-of-operation and quality-of-service (QoS) requirements of individual IT subsystems, expressed in the form of Service Level Agreements (SLAs). Our approach leads to improved configuration settings and, consequently, better fulfilment of the system’s cost and QoS requirements than would have otherwise been possible had the configuration of all subsystems been managed in isolation

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma

Background and Rationale Bortezomib (PS- 341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m 2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib. © Springer Science+Business Media, LLC 2010

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

BackgroundYoung women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence.MethodsIn this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews.ResultsNinety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits.ConclusionThe dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents