Application of Novel Statistical Methods for Biomarker Selection to HIV Infection Data

The past decade has seen an explosion in the availability and use of biomarker data as a result of innovative discoveries and recent development of new biological and molecular techniques. Biomarkers are essential for at least four key purposes in biomedical research and public health practice: they are used for disease detection, diagnosis, prognosis, to identify patients who are most likely to benefit from selected therapies, and to guide clinical decision making. Determining the predictive and diagnostic value of these biomarkers, singly or in combination, is essential to their being used effectively, and this has spurred the development of new statistical methodologies to assess the relationship between biomarkers and clinical outcomes. One active area of research is the development of variable importance measures, a class of estimators that could reliably capture the effect of a specific biomarker on a clinical outcome. The central question addressed in this dissertation is the following: Given a large set of biomarkers that potentially predict a clinical outcome, how can one make a determination as to which ones are the most important? In the first paper, we estimate a targeted variable importance measure through Van der Laan's theory of targeted maximum likelihood estimation in the point treatment setting and use the same objective function to compute an alternative measure of marginal variable importance based on weights from a flexible propensity score model. Covariate-adjusted targeted variable importance measures are compared to estimates from this alternative methodology and to incremental value estimates from partial ROC curves. In the second paper, we extend the applicability of the TMLE methodology to analyze longitudinal repeated measures data. It addresses the gap caused by the absence of a generally accepted approach for generating a longitudinal variable importance index by proposing an estimator involving both TMLE and computation of the area under or above the LOESS curve. A graphical method is proposed for visual assessment of the longevity of a biomarker in terms of its predictive power, information that could be used to determine when repeated measures of a biomarker should be taken. Finally, in the third paper we take right censoring in the outcome variable into consideration and achieve biomarker selection in the presence of confounding and potential informative censoring through the use of stabilized weights in a time-dependent Cox proportional hazards model. A dataset from the Hormonal Contraception and HIV Genital Shedding and Disease Progression Study that includes longitudinal HIV infection data on a sample of 306 HIV-infected adult women from Uganda and Zimbabwe was used to develop and evaluate the methods discussed in the three papers. This study collected information on a number of biomarkers related to HIV infection, including plasma viral load, HIV subtype, CD4 and CD8 lymphocyte counts, hemoglobin level, and herpes simplex virus 2 (HSV-2). The relationships of these biomarkers with changes in CD4 cell counts were considered in three different contexts: cross-sectional, longitudinal and survival. In short, baseline CD4 cell counts, HIV subtype, and HSV-2 were found to be important biomarkers for the outcome variable studied

Nurses' Attitudes Toward Patients with Sickle Cell Disease: A Worksite Comparison

Individuals with sickle cell disease (SCD) have reported being stigmatized when they seek care for pain. Nurse attitudes contribute to stigmatization and may affect patients' response to sickle cell cues, care-seeking, and ultimately patient outcomes

Participant characteristics associated with withdrawal from a large randomized trial of spermicide effectiveness

BACKGROUND: In most recent large efficacy trials of barrier contraceptive methods, a high proportion of participants withdrew before the intended end of follow-up. The objective of this analysis was to explore characteristics of participants who failed to complete seven months of planned participation in a trial of spermicide efficacy. METHODS: Trial participants were expected to use the assigned spermicide for contraception for 7 months or until pregnancy occurred. In bivariable and multivariable analyses, we assessed the associations between failure to complete the trial and 17 pre-specified baseline characteristics. In addition, among women who participated for at least 6 weeks, we evaluated the relationships between failure to complete, various features of their first 6 weeks of experience with the spermicide, and characteristics of the study centers and population. RESULTS: Of the 1514 participants in this analysis, 635 (42%) failed to complete the study for reasons other than pregnancy. Women were significantly less likely to complete if they were younger or unmarried, had intercourse at least 8 times per month, or were enrolled at a university center or at a center that enrolled fewer than 4 participants per month. Noncompliance with study procedures in the first 6 weeks was also associated with subsequent early withdrawal, but dissatisfaction with the spermicide was not. However, many participants without these risk factors withdrew early. CONCLUSIONS: Failure to complete is a major problem in barrier method trials that seriously compromises the interpretation of results. Targeting retention efforts at women at high risk for early withdrawal is not likely to address the problem sufficiently

Association Between Plasma Concentrations of Certolizumab Pegol and Endoscopic Outcomes of Patients With Crohn's Disease.

BACKGROUND & AIMS: Monitoring plasma concentrations of anti-tumor necrosis factor agents could optimize treatment of patients with Crohn's Disease (CD). In a post hoc analysis of data from a clinical trial, we compared the relationship between plasma concentrations of certolizumab pegol (CZP) and endoscopic and clinical responses and remission with CZP therapy in patients with moderate to severe ileocolonic CD. METHODS: We analyzed data from the Endoscopic Mucosal Improvement in Patients with Active CD Treated with CZP trial, from 89 adult patients with active endoscopic CD (ulceration in ≥ 2 intestinal segments and CD Endoscopic Index of Severity [CDEIS] scores of ≥ 8 points). Patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 and then every 4 weeks until week 52. Endoscopic evaluations were performed at weeks 0, 10, and 54. Blood samples were collected to measure CZP plasma concentrations at weeks 8 and 54. CZP quartiles at weeks 8 (n = 80) and 54 (n = 45) were correlated with endoscopic response (>5-point decrease in CDEIS from baseline) and remission (CDEIS, <6) at weeks 10 and 54, respectively. RESULTS: Higher concentrations of CZP at week 8 were associated with endoscopic response (P = .0016) and remission (P = .0302) at week 10 (n = 45). At week 54, the rates of endoscopic remission correlated with plasma concentrations of CZP (P = .0206). There was a significant inverse relationship between plasma concentrations of CZP and baseline levels of C-reactive protein and body weight (P = .0014 and P = .0373, respectively). CONCLUSIONS: Endoscopic response and remission are associated with higher plasma concentrations of CZP in patients with moderate to severe ileocolonic CD. These results support the need to consider the pharmacokinetics of anti-tumor necrosis factor agents and therapeutic drug monitoring to optimize treatment. Clinicaltrials.gov Number, NCT00297648