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1.  Statistical considerations for the HPTN 052 Study to evaluate the effectiveness of early versus delayed antiretroviral strategies to prevent the sexual transmission of HIV-1 in serodiscordant couples 
Contemporary clinical trials  2012;33(6):1280-1286.
The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1,763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: “immediate” (early) therapy with ART initiated upon enrollment plus HIV primary care, or “delayed” therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200–250 cells/mm3, or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015.
PMCID: PMC3468650  PMID: 22813645
Antiretroviral therapy; Durability; Multinational; Partner; Treatment-as-prevention
2.  Performance of Goodness-of-Fit Tests for the Cox Proportional Hazards Model with Time-Varying Covariates 
Lifetime data analysis  2013;20(3):355-368.
There are few readily-implemented tests for goodness-of-fit for the Cox proportional hazards model with time-varying covariates. Through simulations, we assess the power of tests by Cox (1972), Grambsch and Therneau (1994), and Lin et al (2006). Results show that power is highly variable depending on the time to violation of proportional hazards, the magnitude of the change in hazard ratio, and the direction of the change. Because these characteristics are unknown outside of simulation studies, none of the tests examined is expected to have high power in real applications. While all of these tests are theoretically interesting, they appear to be of limited practical value.
PMCID: PMC3918489  PMID: 23925703
Survival analysis; Lack of fit; Time-dependent covariates
3.  Proportional mean residual life model for right-censored length-biased data 
Biometrika  2012;99(4):995-1000.
To study disease association with risk factors in epidemiologic studies, cross-sectional sampling is often more focused and less costly for recruiting study subjects who have already experienced initiating events. For time-to-event outcome, however, such a sampling strategy may be length biased. Coupled with censoring, analysis of length-biased data can be quite challenging, due to induced informative censoring in which the survival time and censoring time are correlated through a common backward recurrence time. We propose to use the proportional mean residual life model of Oakes & Dasu (Biometrika 77, 409–10, 1990) for analysis of censored length-biased survival data. Several nonstandard data structures, including censoring of onset time and cross-sectional data without follow-up, can also be handled by the proposed methodology.
PMCID: PMC3635658  PMID: 23843676
Biased sampling; Bivariate survival data; Proportional hazards model; Renewal process
4.  Estimating Regression Parameters in an Extended Proportional Odds Model 
The proportional odds model may serve as a useful alternative to the Cox proportional hazards model to study association between covariates and their survival functions in medical studies. In this article, we study an extended proportional odds model that incorporates the so-called “external” time-varying covariates. In the extended model, regression parameters have a direct interpretation of comparing survival functions, without specifying the baseline survival odds function. Semiparametric and maximum likelihood estimation procedures are proposed to estimate the extended model. Our methods are demonstrated by Monte-Carlo simulations, and applied to a landmark randomized clinical trial of a short course Nevirapine (NVP) for mother-to-child transmission (MTCT) of human immunodeficiency virus type-1 (HIV-1). Additional application includes analysis of the well-known Veterans Administration (VA) Lung Cancer Trial.
PMCID: PMC3420072  PMID: 22904583
Counting process; Estimating function; HIV/AIDS; Maximum likelihood estimation; Semiparametric model; Time-varying covariate
5.  An imputation method for interval censored time-to-event with auxiliary information: analysis of the timing of mother-to-child transmission of HIV 
The timing of mother-to-child transmission (MTCT) of HIV is critical in understanding the dynamics of MTCT. It has a great implication to developing any effective treatment or prevention strategies for such transmissions. In this paper, we develop an imputation method to analyze the censored MTCT timing in presence of auxiliary information. Specifically, we first propose a statistical model based on the hazard functions of the MTCT timing to reflect three MTCT modes: in utero, during delivery and via breastfeeding, with different shapes of the baseline hazard that vary between infants. This model also allows that the majority of infants may be immuned from the MTCT of HIV. Then, the model is fitted by MCMC to explore marginal inferences via multiple imputation. Moreover, we propose a simple and straightforward approach to take into account the imperfect sensitivity in imputation step, and study appropriate censoring techniques to account for weaning. Our method is assessed by simulations, and applied to a large trial designed to assess the use of antibiotics in preventing MTCT of HIV.
PMCID: PMC3419597  PMID: 22905281
HIV/AIDS; mixture models; mother to child transmission of HIV; multiple imputation
6.  Semiparametric Regression in Size-Biased Sampling 
Biometrics  2009;66(1):149-158.
Size-biased sampling arises when a positive-valued outcome variable is sampled with selection probability proportional to its size. In this article, we propose a semiparametric linear regression model to analyze size-biased outcomes. In our proposed model, the regression parameters of the covariates are of major interest, while the distribution of random errors is unspecified. Under the proposed model, we discover that the regression parameters are invariant regardless of size-biased sampling. Following this invariance property, we develop a simple estimation procedure for inferences. Our proposed methods are evaluated in simulation studies and applied to two real data analyses.
PMCID: PMC2875362  PMID: 19432792
Biased sampling; Linear Regression model; Log transformation; Size-biased probability of selection
7.  Intrapartum Antibiotic Exposure and Early Neonatal Morbidity and Mortality in Africa 
Pediatrics  2009;124(1):e137-e144.
Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants.
To determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality.
Secondary analysis of data from a multi-site randomized placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intent-to-treat (ITT) analysis, infants born to women randomized to antibiotics or placebo were compared. Additionally, non-ITT analysis was performed because some women received non-study antibiotics for various clinical indications.
Overall, 2659 pregnant women were randomized. Of these, 2466 HIV-1-infected and -uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs. 8.6%, p=0.03) and more admissions to the Special Care Baby Unit (12.6% vs. 9.8%, p = 0.04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Further analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received non-study antibiotics than of mothers who received study antibiotics.
There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive non-study antibiotics.
PMCID: PMC2764263  PMID: 19564260
Antibiotic resistance; Antibiotics; Neonatal morbidity; Neonatal mortality; Neonatal sepsis
8.  Risk Factors for Late Postnatal Transmission of Human Immunodeficiency Virus Type 1 in Sub-Saharan Africa 
We conducted secondary data analyses of a clinical trial (HIVNET 024) to assess risk factors for late postnatal transmission (LPT) of HIV-1 through breastfeeding.
Data regarding live born, singleton infants of HIV-1-infected mothers were analyzed. The timing of HIV-1 transmission through 12 months after birth was defined as: in utero (positive HIV-1 RNA results at birth), perinatal/early postnatal (negative results at birth, positive at 4–6 week visit), or LPT (negative results through the 4–6 week visit, but positive assays thereafter through the 12 month visit). HIV-1-uninfected infants were those with negative HIV-1 enzyme immunoassay results at 12 months of age, or infants with negative HIV-1 RNA results throughout follow-up.
Of 2292 HIV-1-infected enrolled women, 2052 mother/infant pairs met inclusion criteria. Of 1979 infants with HIV-1 tests, 404 were HIV-1-infected, and 382 had known timing of infection (LPT represented 22% of transmissions). Further analyses of LPT included infants who were breastfeeding at the 4–6 week visit (with negative HIV-1 results at that visit) revealed 6.9% of 1317 infants acquired HIV-1 infection through LPT by 12 months of age. More advanced maternal HIV-1 disease at enrollment (lower CD4+ counts, higher plasma viral loads) were the factors associated with LPT in adjusted analyses.
In this breastfeeding population, 6.9% of infants uninfected at 6 weeks of age acquired HIV-1 infection by 12 months. Making interventions to decrease the risk of LPT of HIV-1 available and continuing research regarding the mechanisms of LPT (so as to develop improved interventions to reduce such transmission) remain essential.
PMCID: PMC2730543  PMID: 18277935
Breast feeding; mother-to-child transmission of HIV-1; risk factors; Sub-Saharan Africa

Results 1-8 (8)