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2.  Large sample randomization inference of causal effects in the presence of interference 
Recently, increasing attention has focused on making causal inference when interference is possible. In the presence of interference, treatment may have several types of effects. In this paper, we consider inference about such effects when the population consists of groups of individuals where interference is possible within groups but not between groups. A two stage randomization design is assumed where in the first stage groups are randomized to different treatment allocation strategies and in the second stage individuals are randomized to treatment or control conditional on the strategy assigned to their group in the first stage. For this design, the asymptotic distributions of estimators of the causal effects are derived when either the number of individuals per group or the number of groups grows large. Under certain homogeneity assumptions, the asymptotic distributions provide justification for Wald-type confidence intervals (CIs) and tests. Empirical results demonstrate the Wald CIs have good coverage in finite samples and are narrower than CIs based on either the Chebyshev or Hoeffding inequalities provided the number of groups is not too small. The methods are illustrated by two examples which consider the effects of cholera vaccination and an intervention to encourage voting.
PMCID: PMC3960089  PMID: 24659836
causal inference; confidence interval; interference; Normal mixture; randomization
3.  Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study 
Antiviral therapy  2014;19(6):587-595.
An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
PMCID: PMC4110187  PMID: 24464632
4.  Change-Point Models to Estimate the Limit of Detection 
Statistics in medicine  2013;32(28):4995-5007.
In many biological and environmental studies, measured data is subject to a limit of detection. The limit of detection is generally defined as the lowest concentration of analyte that can be differentiated from a blank sample with some certainty. Data falling below the limit of detection is left-censored, falling below a level that is easily quantified by a measuring device. A great deal of interest lies in estimating the limit of detection for a particular measurement device. In this paper we propose a change-point model to estimate the limit of detection using data from an experiment with known analyte concentrations. Estimation of the limit of detection proceeds by a two-stage maximum likelihood method. Extensions are considered that allow for censored measurements and data from multiple experiments. A simulation study is conducted demonstrating that in some settings the change-point model provides less biased estimates of the limit of detection than conventional methods. The proposed method is then applied to data from an HIV pilot study.
PMCID: PMC3858526  PMID: 23784922
change point; limit of detection; linear calibration curve; two-stage maximum likelihood
5.  A Peer-Educator Network HIV Prevention Intervention Among Injection Drug Users: Results of a Randomized Controlled Trial in St. Petersburg, Russia 
AIDS and behavior  2013;17(7):2510-2520.
We evaluated the efficacy of a peer-educator network intervention as a strategy to reduce HIV acquisition among injection drug users (IDUs) and their drug and/or sexual networks. A randomized controlled trial was conducted in St. Petersburg, Russia among IDU index participants and their risk network participants. Network units were randomized to the control or experimental intervention. Only the experimental index participants received training sessions to communicate risk reduction techniques to their network members. Analysis includes 76 index and 84 network participants who were HIV uninfected. The main outcome measure was HIV sero-conversion. The incidence rates in the control and experimental groups were 19.57 (95 % CI 10.74–35.65) and 7.76 (95 % CI 3.51–17.19) cases per 100 p/y, respectively. The IRR was 0.41 (95 % CI 0.15–1.08) without a statistically significant difference between the two groups (log rank test statistic X2 = 2.73, permutation p value = 0.16). Retention rate was 67 % with a third of the loss due to incarceration or death. The results show a promising trend that this strategy would be successful in reducing the acquisition of HIV among IDUs.
PMCID: PMC3950300  PMID: 23881187
Injection drug users; Russia; HIV prevention; Network
6.  Community Diarrhea Incidence Before and After Rotavirus Vaccine Introduction in Nicaragua 
We estimated the incidence of watery diarrhea in the community before and after introduction of the pentavalent rotavirus vaccine in León, Nicaragua. A random sample of households was selected before and after rotavirus vaccine introduction. All children < 5 years of age in selected households were eligible for inclusion. Children were followed every 2 weeks for watery diarrhea episodes. The incidence rate was estimated as numbers of episodes per 100 child-years of exposure time. A mixed effects Poisson regression model was fit to compare incidence rates in the pre-vaccine and vaccine periods. The pre-vaccine cohort (N = 726) experienced 36 episodes per 100 child-years, and the vaccine cohort (N = 826) experienced 25 episodes per 100 child-years. The adjusted incidence rate ratio was 0.60 (95% confidence interval [CI] 0.40, 0.91) during the vaccine period versus the pre-vaccine period, indicating a lower incidence of watery diarrhea in the community during the vaccine period.
PMCID: PMC3741244  PMID: 23817336
7.  Pooled Individual Data Analysis of 5 Randomized Trials of Infant Nevirapine Prophylaxis to Prevent Breast-Milk HIV-1 Transmission 
A pooled analysis of individual data from >5000 human immunodeficiency virus type 1 (HIV-1)–infected mothers and their infants from Africa and India who participated in 5 randomized trials shows that extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection.
Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission.
Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks.
Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%–80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%–69%; P < .001).
Conclusions. Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
PMCID: PMC3518881  PMID: 22997212
breast milk; HIV; nevirapine
9.  Sharpening Bounds on Principal Effects with Covariates 
Biometrics  2013;69(4):812-819.
Estimation of treatment effects in randomized studies is often hampered by possible selection bias induced by conditioning on or adjusting for a variable measured post-randomization. One approach to obviate such selection bias is to consider inference about treatment effects within principal strata, i.e., principal effects. A challenge with this approach is that without strong assumptions principal effects are not identifiable from the observable data. In settings where such assumptions are dubious, identifiable large sample bounds may be the preferred target of inference. In practice these bounds may be wide and not particularly informative. In this work we consider whether bounds on principal effects can be improved by adjusting for a categorical baseline covariate. Adjusted bounds are considered which are shown to never be wider than the unadjusted bounds. Necessary and sufficient conditions are given for which the adjusted bounds will be sharper (i.e., narrower) than the unadjusted bounds. The methods are illustrated using data from a recent, large study of interventions to prevent mother-to-child transmission of HIV through breastfeeding. Using a baseline covariate indicating low birth weight, the estimated adjusted bounds for the principal effect of interest are 63% narrower than the estimated unadjusted bounds.
PMCID: PMC4086842  PMID: 24245800
Bounds; Causal Effects; Partial Identifiability; Potential Outcomes; Principal Strata
10.  Assessing the component associations of the healthy worker survivor bias: occupational asbestos exposure and lung cancer mortality 
Annals of epidemiology  2013;23(6):334-341.
The healthy worker survivor bias is well-recognized in occupational epidemiology. Three component associations are necessary for this bias to occur: i) prior exposure and employment status; ii) employment status and subsequent exposure; and iii) employment status and mortality. Together, these associations result in time-varying confounding affected by prior exposure. We illustrate how these associations can be assessed using standard regression methods.
We use data from 2975 asbestos textile factory workers hired between January 1940 and December 1965 and followed for lung cancer mortality through December 2001.
At entry, median age was 24 years, with 42% female and 19% non-Caucasian. Over follow-up, 21% and 17% of person-years were classified as at work and exposed to any asbestos, respectively. For a 100 fiber-year/mL increase in cumulative asbestos, the covariate-adjusted hazard of leaving work decreased by 52% (95% confidence interval [CI], 46–58). The association between employment status and subsequent asbestos exposure was strong due to nonpositivity: 88.3% of person-years at work (95% CI, 87.0–89.5) were classified as exposed to any asbestos; no person-years were classified as exposed to asbestos after leaving work. Finally, leaving active employment was associated with a 48% (95% CI, 9–71) decrease in the covariate-adjusted hazard of lung cancer mortality.
We found strong associations for the components of the healthy worker survivor bias in these data. Standard methods, which fail to properly account for time-varying confounding affected by prior exposure, may provide biased estimates of the effect of asbestos on lung cancer mortality under these conditions.
PMCID: PMC3773512  PMID: 23683709
Epidemiologic methods; Occupational health; Healthy worker effect; Bias; Lung cancer; Mortality
11.  Protein Binding of Lopinavir and Ritonavir During Four Phases of Pregnancy: Implications for Treatment Guidelines 
To investigate the intraindividual pharmacokinetics of total (protein bound + unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100mg/25mg) can overcome any pregnancy-associated changes.
Prospective longitudinal pharmacokinetic (PK) study
HIV-infected pregnant antiretroviral therapy-naïve and experienced women receiving LPV/RTV 400mg/100mg tablets twice daily. Intensive PK evaluations were performed at 20–24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100mg/25mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4).
Twelve women completed pre-specified PK evaluations. Median (range) age was 28 (1–35) years and baseline BMI was 32 (19–41) kg/m2. During pregnancy, total area under the time concentration (AUC0–12hr) for LPV was significantly lower than postpartum [PK1, PK2 or PK3 vs. PK4, p= 0.005]. Protein unbound LPV AUC0–12hr remained unchanged during pregnancy [PK1: 1.6 (1.3–1.9) vs. PK2: 1.6 (1.3–1.9) µg*hr/mL, p=0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3–2.1) µg*hr/mL, p=0.5]. Protein unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08–0.15) vs. PK3: 0.12 (0.10–0.15) µg/mL, p=0.09]. Albumin and LPV AUC0–12h fraction unbound were correlated (rs=0.3, p=0.03).
Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.
PMCID: PMC3625477  PMID: 23221983
HIV; pregnancy; lopinavir/ritonavir; protein unbound; pharmacokinetics
12.  Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus 
Obesity (Silver Spring, Md.)  2013;21(11):2377-2386.
Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific mechanisms by which obesity and overweight impact the cellular immune response to pH1N1.
Design and Methods
We stimulated peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals ex vivo with live pH1N1 and then measured markers of activation and function using flow cytometry and cytokine secretion using cytometric bead array assays.
Our data indicate that CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, as well as, produced lower levels of interferon-γ and granzyme B, compared to healthy weight individuals, suggesting deficiencies in activation and function. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex-II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin-12.
The defects in CD4+ and CD8+ T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.
PMCID: PMC3695020  PMID: 23512822
Obesity; overweight; pH1N1 influenza; CD4+ T cells; CD8+ T cells; dendritic cells
13.  The Association of Parasitic Infections in Pregnancy and Maternal and Fetal Anemia: A Cohort Study in Coastal Kenya 
Relative contribution of these infections on anemia in pregnancy is not certain. While measures to protect pregnant women against malaria have been scaling up, interventions against helminthes have received much less attention. In this study, we determine the relative impact of helminthes and malaria on maternal anemia.
A prospective observational study was conducted in coastal Kenya among a cohort of pregnant women who were recruited at their first antenatal care (ANC) visit and tested for malaria, hookworm, and other parasitic infections and anemia at enrollment. All women enrolled in the study received presumptive treatment with sulfadoxine-pyrimethamine, iron and multi-vitamins and women diagnosed with helminthic infections were treated with albendazole. Women delivering a live, term birth, were also tested for maternal anemia, fetal anemia and presence of infection at delivery.
Principal Findings
Of the 706 women studied, at the first ANC visit, 27% had moderate/severe anemia and 71% of women were anemic overall. The infections with highest prevalence were hookworm (24%), urogenital schistosomiasis (17%), trichuria (10%), and malaria (9%). In adjusted and unadjusted analyses, moderate/severe anemia at first ANC visit was associated with the higher intensities of hookworm and P. falciparum microscopy-malaria infections. At delivery, 34% of women had moderate/severe anemia and 18% of infants' cord hemoglobin was consistent with fetal anemia. While none of the maternal infections were significantly associated with fetal anemia, moderate/severe maternal anemia was associated with fetal anemia.
More than one quarter of women receiving standard ANC with IPTp for malaria had moderate/severe anemia in pregnancy and high rates of parasitic infection. Thus, addressing the role of co-infections, such as hookworm, as well as under-nutrition, and their contribution to anemia is needed.
Author Summary
International guidelines recommend routine prevention and treatments which are safe and effective during pregnancy to reduce hookworm, malaria and other infections among pregnant women living in geographic areas where these infections are prevalent. Despite their effectiveness, programs to address common infections such as hookworm, schistosomiasis and malaria during pregnancy have not been widely adopted. Hookworm, malaria and other infections have been associated with anemia in children, but the studies on the impact of these infections on anemia in pregnancy have not been as clear. This study was undertaken to evaluate the prevalence of parasitic infections among women attending antenatal care which provided the nationally recommended malaria preventive treatment program in coastal Kenya. At the first ANC visit, more than 70% of women were anemic, nearly one-fourth had hookworm and about 10% had malaria. Women with high levels of hookworm or malaria infections were at risk of anemia.
PMCID: PMC3937317  PMID: 24587473
14.  Causal Inference for Vaccine Effects on Infectiousness 
The International Journal of Biostatistics  2012;8(2):10.2202/1557-4679.1354 /j/ijb.2012.8.issue-2/1557-4679.1354/1557-4679.1354.xml.
If a vaccine does not protect individuals completely against infection, it could still reduce infectiousness of infected vaccinated individuals to others. Typically, vaccine efficacy for infectiousness is estimated based on contrasts between the transmission risk to susceptible individuals from infected vaccinated individuals compared with that from infected unvaccinated individuals. Such estimates are problematic, however, because they are subject to selection bias and do not have a causal interpretation. Here, we develop causal estimands for vaccine efficacy for infectiousness for four different scenarios of populations of transmission units of size two. These causal estimands incorporate both principal stratification, based on the joint potential infection outcomes under vaccine and control, and interference between individuals within transmission units. In the most general scenario, both individuals can be exposed to infection outside the transmission unit and both can be assigned either vaccine or control. The three other scenarios are special cases of the general scenario where only one individual is exposed outside the transmission unit or can be assigned vaccine. The causal estimands for vaccine efficacy for infectiousness are well defined only within certain principal strata and, in general, are identifiable only with strong unverifiable assumptions. Nonetheless, the observed data do provide some information, and we derive large sample bounds on the causal vaccine efficacy for infectiousness estimands. An example of the type of data observed in a study to estimate vaccine efficacy for infectiousness is analyzed in the causal inference framework we developed.
PMCID: PMC3348179  PMID: 22499732
causal inference; principal stratification; interference; infectious disease; vaccine
15.  Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART 
PLoS Pathogens  2014;10(1):e1003872.
Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA+ cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies.
Author Summary
Antiretroviral therapy (ART) improves the quality of life for HIV infected individuals. However, ART is currently a lifelong commitment because HIV persists during treatment despite being suppressed below detection. If therapy is stopped, the HIV reappears. A concerted effort is ongoing to develop new eradication therapies to prevent virus rebound, but there are challenges to be overcome. Our work is a major step forward in this process. We measured persistent HIV throughout the body during ART using bone marrow/liver/thymus (BLT) humanized mice, a model validated to study HIV persistence. HIV infected BLT mice were treated with tenofovir, emtricitabine and raltegravir. Despite documented tissue penetration by these drugs, we found that HIV expression persists in cells isolated from all the tissues analyzed (bone marrow, thymus, spleen, lymph nodes, liver, lung, intestines and peripheral blood cells). We therefore complemented ART with an immunotoxin that specifically kills HIV expressing cells while leaving other cells untouched. Our results demonstrate a dramatic reduction in persistent HIV throughout the body resulting from the killing of virus producing cells. Thus, our study provides new insights into the locations of HIV persistence during ART and a demonstration that persistent HIV can be successfully targeted inside the body.
PMCID: PMC3887103  PMID: 24415939
16.  Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials 
Journal of the American Statistical Association  2013;108(503):10.1080/01621459.2013.786649.
Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal treatment effects in compliers, these methods do not apply to a common class of trials where a) the primary objective compares survival curves, b) it is inconceivable to assign participants to be adherent and event-free before adherence is measured, and c) the exclusion restriction assumption fails to hold. HIV vaccine efficacy trials including the recent RV144 trial exemplify this class, because many primary endpoints (e.g., HIV infections) occur before adherence is measured, and nonadherent subjects who receive some of the planned immunizations may be partially protected. Therefore, we develop methods for assessing per-protocol treatment efficacy for this problem class, considering three causal estimands of interest. Because these estimands are not identifiable from the observable data, we develop nonparametric bounds and semiparametric sensitivity analysis methods that yield estimated ignorance and uncertainty intervals. The methods are applied to RV144.
PMCID: PMC3811958  PMID: 24187408
As-treated; Bounds; Causal inference; Exclusion restriction; Ignorance region; Intention to treat; Principal stratification; Selection bias; Survival analysis
17.  The Effect of Cotrimoxazole Prophylactic Treatment on Malaria, Birth Outcomes, and Postpartum CD4 Count in HIV-Infected Women 
Background. Limited data exist on cotrimoxazole prophylactic treatment (CPT) in pregnant women, including protection against malaria versus standard intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp). Methods. Using observational data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy, low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression, respectively. We used linear regression to assess effect of CPT on CD4 count. Results. Data from 468 CPT-exposed and 768 CPT-unexposed women were analyzed. CPT was associated with protection against malaria versus IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After adjustment for time period this effect was not statistically significant (adjusted hazard ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT, rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar. CPT was associated with lower CD4 counts 24 weeks postpartum in women receiving (−77.6 cells/μL, 95% CI: −125.2, −30.1) and not receiving antiretrovirals (−33.7 cells/μL, 95% CI: −58.6, −8.8). Conclusions. Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.
PMCID: PMC3865641  PMID: 24363547
18.  Comparing competing risk outcomes within principal strata, with application to studies of mother-to-child transmission of HIV 
Statistics in medicine  2012;31(27):3406-3418.
In randomized trials to prevent breast milk transmission of human immunodeficiency virus (HIV) from mother to infant, investigators are often interested in assessing the effect of a treatment or intervention on the cumulative risk of HIV infection by time (age) t in infants who are alive and uninfected at a certain time point τ0 < t. Such comparisons are challenging for two reasons. First, infants are typically randomized at birth (time 0 < τ0) such that comparisons between trial arms among the subset of infants alive and uninfected at τ0 are subject to selection bias. Second, in most mother-to-child transmission (MTCT) trials competing risks are often present, such as death or cessation of breastfeeding prior to HIV infection. In this paper we present methods for assessing the causal effect of a treatment on competing risk outcomes within principal strata. In MTCT trials, the causal effect of interest is that of treatment on the risk of HIV infection by time t > τ0 within the principal stratum of infants who would be alive and uninfected by τ0 regardless of randomization assignment. Large sample non-parametric bounds and a semi-parametric sensitivity analysis model are developed for drawing inference about this causal effect. A simulation study is presented demonstrating that the proposed methods perform well in finite samples. The proposed methods are applied to a large, recent MTCT trial.
PMCID: PMC3494821  PMID: 22927321
Causal inference; Infectious diseases; Principal stratification; Sensitivity analysis
19.  Comparing Bounds for Vaccine Effects on Infectiousness 
Epidemiology (Cambridge, Mass.)  2012;23(6):931-932.
PMCID: PMC3482261  PMID: 23038122
Causal inference; infectious disease; infectiousness; interference; principal stratification; vaccine efficacy
20.  Expression of p16INK4a as a biomarker of T-cell aging in HIV-infected patients prior to and during antiretroviral therapy 
Aging cell  2012;11(5):916-918.
The p16INK4a tumor suppressor gene is a mediator of cellular senescence and has been suggested to be a biomarker of ‘molecular’ age in several tissues including T-cells. To determine the association of both active and suppressed HIV infection with T-cell aging, T-cell p16INK4a expression was compared between 60 HIV+ suppressed subjects, 23 HIV+ untreated subjects, and 18 contemporaneously collected HIV-negative controls, as well as 148 HIV-negative historical samples. Expression did not correlate with chronologic age in untreated HIV+ patients, consistent with an effect of active HIV replication on p16INK4a expression. In patients on cART with suppressed viral loads, however, p16INK4a levels were similar to uninfected controls and correlated with chronologic age, with a trend toward an inverse correlation with CD4 count. These data show that p16INK4a is a reliable biomarker of T cell aging in HIV+ patients with suppressed viral loads and suggest that poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16INK4a, a marker of cellular senescence.
PMCID: PMC3697001  PMID: 22738669
21.  Vaccine-Relevant Human Papillomavirus (HPV) Infections and Future Acquisition of High-Risk HPV Types in Men 
The Journal of Infectious Diseases  2012;206(5):669-677.
Background.Little is known about type-specific associations between prevalent human papillomavirus (HPV) infections and risk of acquiring other HPV types in men. Data on natural clustering of HPV types are needed as a prevaccine distribution to which postvaccine data can be compared.
Methods.Using data from a randomized controlled trial of male circumcision in Kisumu, Kenya, adjusted mean survival ratios were estimated for acquisition of any-HPV, high-risk (HR) HPV, and individual HR-HPV types among men uninfected as compared to those infected with vaccine-relevant HPV types 16, 18, 31, 45, 6, or 11 at baseline.
Results.Among 1097 human immunodeficiency virus–negative, uncircumcised men, 2303 incident HPV infections were detected over 2534 person-years of follow-up. Although acquisition of individual HR-HPV types varied by baseline HPV type, there was no clear evidence of shorter times to acquisition among men without vaccine-relevant HPV-16, -18, -31, -45, -6, or -11 infections at baseline, as compared to men who did have these infections at baseline.
Conclusions.These prospective data on combinations of HPV infections over time do not suggest the potential for postvaccination HPV type replacement. Future surveillance studies are needed to definitely determine whether elimination of HPV types by vaccination will alter the HPV type distribution in the population.
PMCID: PMC3491740  PMID: 22711906
22.  Raltegravir Pharmacokinetics in Treatment-Naive Patients Is Not Influenced by Race: Results from the Raltegravir Early Therapy in African-Americans Living with HIV (REAL) Study 
Racial differences in antiretroviral treatment responses remain incompletely explained and may be a consequence of differential pharmacokinetics (PK) associated with race. Raltegravir, an inhibitor of HIV-1 integrase, is commonly used in the treatment of HIV-infected patients, many of whom are African-American. However, there are few data regarding the PK of raltegravir in African-Americans. HIV-infected men and women, self-described as African-American and naive to antiretroviral therapy were treated with raltegravir (RAL) at 400 mg twice a day, plus a fixed dose of tenofovir-emtricitabine (TDF/FTC) at 300 mg/200 mg once daily. Intensive PK sampling was conducted over 24 h at week 4. Drug concentrations at two trough values of 12 and 24 h after dosing (C12 and C24), area under the concentration-curve values (AUC), maximum drug concentration (Cmax), and the time at which this concentration occurred (Tmax) in plasma were estimated with noncompartmental pharmacokinetic methods and compared to data from a subset of white subjects randomized to the RAL twice a day (plus TDF/FTC) arm of the QDMRK study, a phase III study of the safety and efficacy of once daily versus twice daily RAL in treatment naive patients. A total of 38 African-American participants were enrolled (90% male) into the REAL cohort with the following median baseline characteristics: age of 36 years, body mass index (BMI) of 23 kg/m2, and a CD4 cell count of 339/ml. Plasma HIV RNA levels were below 200 copies/ml in 95% of participants at week 4. The characteristics of the 16 white QDMRK study participants were similar, although fewer (69%) were male, the median age was higher (45 years), and BMI was lower (19 kg/m2). There was considerable interindividual variability in RAL concentrations in both cohorts. Median C12 in REAL was 91 ng/ml (range, 10 to 1,386) and in QDMRK participants was 128 ng/ml (range, 15 to 1,074). The Cmax median concentration was 1,042 ng/ml (range, 196 to 10,092) for REAL and 1,360 ng/ml (range, 218 to 9,701) for QDMRK. There were no significant differences in any RAL PK parameter between these cohorts of African-American and white individuals. Based on plasma PK, and with similar adherence rates, the performance of RAL among HIV-infected African-Americans should be no different than that of infected patients who are white.
PMCID: PMC3553727  PMID: 23183440
23.  Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys 
Science translational medicine  2011;3(81):81ra36.
The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was an about one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01–negative monkeys challenged with SIVsmE660, no CD8+ T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4+ T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanism of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.
PMCID: PMC3718279  PMID: 21543722
24.  Sexual behaviour and less frequent bathing are associated with higher human papillomavirus incidence in a cohort study of uncircumcised Kenyan men 
Sexually transmitted infections  2012;89(2):148-155.
Data on the acquisition of human papillomavirus (HPV) infection in men are limited, especially from developing regions including Africa. The objective of this study was to characterise and determine the risk factors of HPV acquisition among a cohort of uncircumcised men participating in a randomised controlled trial (RCT) of male circumcision in Kisumu, Kenya.
Penile exfoliated cell specimens were collected at baseline, 6- and 12-month follow-up visits from the glans/coronal sulcus and shaft of men enrolled in the control arm of the RCT between 2002 and 2005. All participants were HIV seronegative, aged 17–24 years at baseline and remained uncircumcised over follow-up. Specimens were tested with GP5+/6+ PCR to detect 44 HPV types. Parametric frailty models were used to assess risk factors of HPV incidence.
The median age of 966 participants was 20 years. The median follow-up time was 12.1 months. The incidence rate (IR) of any HPV infection was 49.3/1000 person-months with HPV16 having the highest IR (10.9/1000 person-months). The strongest risk factors for overall HPV incidence were bathing less frequently than daily (adjusted HR=2.6; 95% CI 1.0 to 6.5) and having ≥2 female sexual partners in the past year (adjusted HR=1.6; 95% CI 1.2 to 2.1).
HPV IRs were notably high in this cohort of high-risk, uncircumcised men from Kisumu, Kenya, with the number of sexual partners and bathing frequency being the strongest risk factors.
PMCID: PMC3700546  PMID: 22941862
25.  Group Testing for Case Identification with Correlated Responses 
Biometrics  2011;68(2):532-540.
This article examines group testing procedures where units within a group (or pool) may be correlated. The expected number of tests per unit (i.e., efficiency) of hierarchical- and matrix-based procedures is derived based on a class of models of exchangeable binary random variables. The effect on efficiency of the arrangement of correlated units within pools is then examined. In general, when correlated units are arranged in the same pool, the expected number of tests per unit decreases, sometimes substantially, relative to arrangements that ignore information about correlation.
PMCID: PMC3384753  PMID: 21950447
Composite sampling; Epitope mapping; Exchangeable binary random variables; Group testing; HIV; Matrix testing; Pooled testing

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