Many important variables in biomedical studies of HIV/AIDS are ordered categorical. A few examples include WHO clinical stage, level of education, frequency of douching, stage of cervical lesions, self- reported condom use, and biallelic genotypes. Although ordinal variables are common, statistical methods that account for their ordered nature are lacking, particularly when the ordinal variable is a predictor variable. Most standard methods either treat the ordinal predictor as categorical (ignoring the order information) or continuous (making linearity assumptions). This proposal develops statistical methods that account for the ordered nature of ordinal variables without making linearity assumptions. The methods address situations when a predictor variable (X) is ordered categorical;the outcome variable (Y) is continuous, discrete, counts, time-to-event, or repeated measures;and there are multiple covariates (Z). The general approach is to fit appropriate regression models of Y on Z, and X on Z, and then to test for correlation between the residuals from these two models. The methods therefore rely on a new definition of residual for ordered categorical data. Statistical properties of this residual are evaluated, as well as its use in model diagnostics. Asymptotic properties of the residual- based test statistics are computed, relationships with other methods are derived, user-friendly software that implements these methods is developed, and the advantages of the new methods are studied using simulated and real data. The methods are applied to two HIV studies: The first assesses the effect of the frequency of douching on sexually transmitted infections among a cohort of adolescent females using marginal structural models. The second data application looks for human genetic polymorphisms associated with drug plasma levels, virologic failure, and toxicities for patients initiating an efavirenz- or abacavir-based antiretroviral regimen.

Public Health Relevance

The new methods are put into computer software and applied to studies of 1) the effect of douching on sexually transmitted infections among adolescent females, and 2) which patients may be able to better respond to specific HIV-treatments based on genetic patterns.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Gezmu, Misrak
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Vanderbilt University Medical Center
Biostatistics & Other Math Sci
Schools of Medicine
United States
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Shepherd, Bryan E; Liu, Qi; Mercaldo, Nathaniel et al. (2016) Comparing results from multiple imputation and dynamic marginal structural models for estimating when to start antiretroviral therapy. Stat Med 35:4335-4351
Blevins, Meridith; Wehbe, Firas H; Rebeiro, Peter F et al. (2016) Interactive Data Visualization for HIV Cohorts: Leveraging Data Exchange Standards to Share and Reuse Research Tools. PLoS One 11:e0151201
Shepherd, Bryan E; Rebeiro, Peter F; Caribbean, Central, South America network for HIV epidemiology (CCASAnet) (2016) Assessing and interpreting the association between continuous covariates and outcomes in observational studies of HIV using splines. J Acquir Immune Defic Syndr :
Ray, Wayne A; Liu, Qi; Shepherd, Bryan E (2015) Performance of time-dependent propensity scores: a pharmacoepidemiology case study. Pharmacoepidemiol Drug Saf 24:98-106
Wanga, Valentine; Venuto, Charles; Morse, Gene D et al. (2015) Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics 25:450-61
Shepherd, Bryan E; Blevins, Meridith; Vaz, Lara M E et al. (2013) Impact of definitions of loss to follow-up on estimates of retention, disease progression, and mortality: application to an HIV program in Mozambique. Am J Epidemiol 178:819-28
Gilbert, Peter B; Shepherd, Bryan E; Hudgens, Michael G (2013) Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials. J Am Stat Assoc 108:
Antiretroviral Therapy Cohort Collaboration (ART-CC); Shepherd, Bryan E; Jenkins, Cathy A et al. (2013) Higher rates of AIDS during the first year of antiretroviral therapy among migrants: the importance of tuberculosis. AIDS 27:1321-9
Shepherd, Bryan E; Shaw, Pamela A; Dodd, Lori E (2012) Using audit information to adjust parameter estimates for data errors in clinical trials. Clin Trials 9:721-9
Li, Chun; Shepherd, Bryan E (2012) A new residual for ordinal outcomes. Biometrika 99:473-480

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