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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

The design phase of a randomized controlled clinical trial is critical to its success. With many non-adaptive designs and an explosive number of adaptive designs introduced to the research community, the number of designs from which a statistician can select has the potential to be overwhelming. At times, a statistician may be uncertain how a newer adaptive design will perform in a particular setting of interest. While regulatory agencies have originally treated adaptive designs with resistance, recent years have seen more acceptance if there is extensive simulation work that shows good control of Type I error.

There are many adaptive designs, and it is important to understand and compare characteristics of competing designs before implementation. However, the overall lack of understanding of the performance of adaptive designs with regard to several design characteristics and the lack of an effective tool to measure overall design quality may have led to clinical trial statisticians implementing traditional designs rather than adopting more innovative methods. Yet adaptive designs have many appealing features that can benefit both the clinical trial sponsor, who funds the trial, and the clinical trial subjects. These strengths include early completion of a trial due to overwhelming efficacy and minimizing the number of subjects assigned to an inferior treatment arm.

The aim of this dissertation is to introduce methodology that provides statisticians and other clinical trial stakeholders with a tool that can measure the overall quality of a design and thereby facilitate comparison across competing designs. The methodology utilizes desirability functions to measure various statistical and non-statistical features that contribute to the quality of a design. Specifically, individual desirability functions evaluate a library of components including statistical considerations, such as treatment group size imbalance, probability of covariate imbalance, accidental bias, control for chronological bias, Type I error and power, and ethical considerations, such as minimizing the expected number of failures and total sample size needed in the whole trial. The proposed strategy is to compute an overall desirability score for each design, use it to rank the clinical trial designs of interest, and select the most relevant and efficient design for the trial's various objectives. To facilitate use of the proposed methodology, the project includes the development of an online interactive tool for the user to incorporate input before desirability functions are generated to help the user select the most appropriate design for the trial.

    Cover page: Evaluation of Clinical Trial Design Quality Using Desirability Functions
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2013)
    Despite current consensus guidelines recommending intensive cardiovascular risk factor management for peripheral artery disease (PAD), patients suffering from PAD continue to experience significant morbidity and mortality. This excess morbid burden is at least partially related to impaired vascular function and systemic inflammation. Interventions bridging this gap are critical. Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to improve endothelial function and reduce inflammation in different cohorts, as well as to decrease cardiovascular events in secondary prevention trials in patients with coronary artery disease. Their effects in the PAD population are, however, less well understood. The OMEGA-PAD trial is a double-blinded, randomized, placebo-controlled trial that examines the impact of a high-dose, short-duration dietary oral supplementation of n-3 PUFA on vascular function and inflammation in patients with established PAD. The purpose of this article is to provide a detailed description of the design and methods of the OMEGA-PAD trial, and a summary of baseline characteristics of the cohort.
      Cover page: n-3 Polyunsaturated fatty acids supplementation in peripheral artery disease: the OMEGA-PAD trial
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2018)

      Background

      Chronic immune activation is a harbinger of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), yet the underlying basis is unclear. Microbial translocation, the passage of microbial components from the gastrointestinal tract into the systemic circulation, is a source of systemic immune activation in HIV infection and may be an important contributor to chronic B-cell activation and subsequent AIDS-NHL development.

      Method

      We measured biomarkers of microbial translocation including bacterial receptors/antibodies, intestinal barrier proteins, and macrophage activation-associated cytokines/chemokines, in serum from 200 HIV-infected men from the Multicenter AIDS Cohort Study prior to their AIDS-NHL diagnosis (mean = 3.9 years; SD = 1.6 years) and 200 controls. Controls were HIV-infected men who did not develop AIDS-NHL, individually matched to cases on CD4 T-cell count, prior antiretroviral drug use, and recruitment year into the cohort.

      Results

      Biomarkers of bacterial translocation and intestinal permeability were significantly increased prior to AIDS-NHL. Lipopolysaccharide-binding protein (LPB), fatty acid-binding protein 2 (FABP2), and soluble CD14 were associated with 1.6-fold, 2.9-fold, and 3.7-fold increases in AIDS-NHL risk for each unit increase on the natural log scale, respectively. Haptoglobin had a 2.1-fold increase and endotoxin-core antibody a 2.0-fold decrease risk for AIDS-NHL (fourth versus first quartile). Biomarkers of macrophage activation were significantly increased prior to AIDS-NHL: B-cell activation factor (BAFF), IL18, monocyote chemoattractant protein-1 (MCP1), tumor necrosis factor-α (TNFα), and CCL17 had 2.2-fold, 2.0-fold, 1.6-fold, 2.8-fold, and 1.7-fold increases in risk for each unit increase on the natural log scale, respectively.

      Conclusion

      These data provide evidence for microbial translocation as a cause of the systemic immune activation in chronic HIV infection preceding AIDS-NHL development.
        Cover page: A prospective study of serum microbial translocation biomarkers and risk of AIDS-related non-Hodgkin lymphoma
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2014)

        Background

        Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening, and increased vascular inflammation.

        Methods

        Five healthy subjects (four men and one woman) underwent 5 d of bed rest (BR) to simulate inactivity. Measurements of vascular function (flow-mediated vasodilation to evaluate endothelial function; applanation tonometry to assess arterial resistance), inflammation, and metabolism were made before BR, daily during BR, and 2 d after BR recovery period. Subjects maintained an isocaloric diet throughout.

        Results

        BR led to significant decreases in brachial artery and femoral artery flow-mediated vasodilation (brachial: 11 ± 3% pre-BR versus 9 ± 2% end-BR, P = 0.04; femoral: 4 ± 1% versus 2 ± 1%, P = 0.04). The central augmentation index increased with BR (-4 ± 9% versus 5 ± 11%, P = 0.03). Diastolic blood pressure increased (58 ± 7 mm Hg versus 62 ± 7 mm Hg, P = 0.02), whereas neither systolic blood pressure nor heart rate changed. 15-Hydroxyeicosatetraenoic acid, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged.

        Conclusions

        Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased diastolic blood pressure, and an increase in 15-hydroxyeicosatetraenoic acid. We speculate that inactivity promotes a vascular "deconditioning" state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored.
          Cover page: Short-term physical inactivity impairs vascular function
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