Stephen R Cole's research while affiliated with University of North Carolina at Chapel Hill and other places
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Publications (452)
In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz (EFV)-based regimen compared to an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly...
Protocol adherence may influence measured treatment effectiveness in randomized controlled trials. Using data from a multicenter trial from Europe and North and South America in 2002-2009 of children with HIV-1 randomized to initial protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens, we generated time-to-...
When estimating an effect of an action with a randomized or observational study, that study is often not a random sample of the desired target population. Instead, estimates from that study can be transported to the target population. However, transportability methods generally rely on a positivity assumption, such that all relevant covariate patte...
Importance:
Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes.
Objectives:
To estimate racial and ethnic differences in the prescription of I...
Background:
When accounting for misclassification, investigators make assumptions about whether misclassification is "differential" or "nondifferential." Most guidance on differential misclassification considers settings where outcome misclassification varies across levels of exposure, or vice versa. Here, we examine when covariate-differential mi...
Objective:
Hypertension is a critical cause of cardiovascular disease, and women with HIV have a higher prevalence of hypertension compared to women without HIV. The relationship between hypertension and mortality has not been well characterized in women with treated HIV. Here, we estimate the effect of hypertension on one-year risk of all-cause m...
Background: Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention.
Methods: The Limiting Ad...
Missing data are pandemic and a central problem for epidemiology. Missing data reduce precision and can cause notable bias. There remain too few simple published examples detailing types of missing data and illustrating their possible impact on results. Here we take an example randomized trial that was not subject to missing data and induce missing...
Background: Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention.
Methods: The Limiting Ad...
The IPOP trial demonstrated a reduced risk of severe small for gestational age among infants born to women with HIV who received weekly intramuscular 17 alpha-hydroxyprogesterone caproate. This secondary analysis examined the 17P treatment effect in subgroups of maternal BMI, parity, timing of antiretroviral therapy (ART) initiation, and ART regime...
A covariate-adjusted estimate of an exposure-outcome association may be biased if the exposure variable suffers measurement error. We propose an approach to correct for exposure measurement error in a covariate-adjusted estimate of the association between a continuous exposure variable and outcome of interest. Our proposed approach requires data fo...
Purpose
To demonstrate improvements in the precision of inverse probability-weighted estimators by use of auxiliary variables, i.e., determinants of the outcome that are independent of treatment, missingness or selection.
Methods
First with simulated data, and then with public data from the National Health and Nutrition Examination Survey (NHANES)...
Positivity, the assumption that every unique combination of confounding variables that occurs in a population has a non-zero probability of an action, can be further delineated as deterministic positivity and stochastic positivity. Here, we revisit this distinction, examine its relation to nonparametric identifiability and estimability, and discuss...
Objective:
To illustrate the difference between exposure effects and population attributable effects.
Methods:
We examined the effect of mid-pregnancy short cervical length (<25mm) on preterm birth using data from a prospective cohort of pregnant women in Lusaka, Zambia. Preterm birth was live birth or stillbirth before 37 weeks gestation. For e...
Comparisons of treatments or exposures are of central interest in epidemiology, but direct comparisons are not always possible due to practical or ethical reasons. Here, we detail a data fusion approach that allows bridged treatment comparisons across studies. The motivating example entails comparing the risk of the composite outcome of death, AIDS...
Selection bias remains a subject of controversy. Existing definitions of selection bias are ambiguous. To improve communication and the conduct of epidemiologic research focused on estimating causal effects, we propose to unify the various existing definitions of selection bias in the literature by considering any bias away from the true causal eff...
“Fusion” study designs combine data from different sources to answer questions that could not be answered (as well) by subsets of the data. Studies that augment main study data with validation data, as in measurement-error correction studies or generalizability studies, are examples of fusion designs. Fusion estimators, here solutions to standard s...
The union of distinct covariate sets, or the superset, is often used in proofs for identification or the statistical consistency of an estimator when multiple sources of bias are present. However, use of a superset can obscure important nuances. Here, we provide two illustrative examples: one in the context of missing data on outcomes, and one in w...
Background:
Ultrasound is indispensable to gestational age estimation and thus to quality obstetrical care, yet high equipment cost and the need for trained sonographers limit its use in low-resource settings.
Methods:
From September 2018 through June 2021, we recruited 4695 pregnant volunteers in North Carolina and Zambia and obtained blind ult...
M-estimation is a general statistical approach that simplifies and unifies estimation in a variety of settings. Here, we introduce delicatessen, a Python library that automates the tedious calculations of M-estimation. To highlight the utility of delicatessen for data analyses in life science research, we provide several illustrations: linear regre...
Comparative effectiveness evidence from randomized trials may not be directly generalizable to a target population of substantive interest when, as in most cases, trial participants are not randomly sampled from the target population. Motivated by the need to generalize evidence from two trials conducted in the AIDS Clinical Trials Group (ACTG), we...
Causal inference methods can be applied to estimate the effect of a point exposure or treatment on an outcome of interest using data from observational studies. When the outcome of interest is a count, the estimand is often the causal mean ratio, i.e., the ratio of the counterfactual mean count under exposure to the counterfactual mean count under...
Background:
Integrase strand transfer inhibitor (InSTI)-based regimens have been recommended as first-line antiretroviral therapy (ART) for adults with HIV. But data on long-term effects of InSTI-based regimens on virologic outcomes remain limited. Here we examined whether InSTI improved long-term virologic outcomes compared with efavirenz (EFV)....
Background:
A trial of progesterone to prevent preterm birth among HIV-infected Zambian women (IPOP) found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome compri...
Background
Mortality among adults with HIV remains elevated over mortality in the US general population even in the years after entry into HIV care. We explore whether the elevation in 5-year mortality would have persisted if all adults with HIV had initiated antiretroviral therapy within 3 months of entering care.
Methods
Among 82,766 adults ente...
Objective:
To assess differences in anal cancer incidence between racial/ethnic groups among a clinical cohort of men with HIV who have sex with men.
Design:
Clinical cohort study.
Methods:
We studied men who have sex with men (MSM) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who initiated antiretroviral the...
Background: Ultrasound is indispensable to gestational age estimation, and thus to quality obstetric care, yet high equipment cost and need for trained sonographers limit its use in low-resource settings.
Methods: From September 2018 through June 2021, we recruited 4,695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound...
Background:
Exposure to fine particulate matter (PM2.5) is an established risk factor for human mortality. However, previous US studies have been limited to select cities or regions or to population subsets (e.g., older adults).
Methods:
Here, we demonstrate how to use the novel geostatistical method Bayesian Maximum Entropy to obtain estimates...
During the COVID-19 pandemic, governments and public health authorities have used seroprevalence studies to estimate the proportion of persons within a given population who have antibodies to SARS-CoV-2. Seroprevalence is crucial for estimating quantities such as the infection fatality ratio, proportion of asymptomatic cases, and differences in inf...
The main purpose of many medical studies is to estimate the effects of a treatment or exposure on an outcome. However, it is not always possible to randomize the study participants to a particular treatment, therefore observational study designs may be used. There are major challenges with observational studies; one of which is confounding. Control...
Objectives:
To define a smoking cessation "cascade" among US women with and without HIV and examine differences by sociodemographic characteristics.
Design:
Observational cohort study using data from smokers participating in the Women's Interagency HIV Study between 2014 and 2019.
Methods:
We followed 1165 women smokers with and without HIV fr...
Noncompliance, a common problem in randomized clinical trials (RCTs), can bias estimation of the effect of treatment receipt using a standard intention-to-treat analysis. The complier average causal effect (CACE) measures the effect of an intervention in the latent subpopulation that would comply with their assigned treatment. Although several meth...
Results of randomized trials and observational studies can be difficult to communicate. Results are often presented as risk or survival functions stratified by the treatment or exposure (1, 2). However, a contrast between the stratified risk functions is often of primary interest. Here we propose a “twister” plot to visualize contrasts in risk over...
Background
Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV.
Methods
We did a randomised, double-blind, placebo-co...
Consider an observational study of the association between a continuous exposure and outcome, where the exposure variable of primary interest suffers classical measurement error (i.e., the measured exposures are distributed around the true exposure with independent error). In the absence of exposure measurement error, it is widely recognized that o...
Background:
Prior studies suggest neighborhood poverty and deprivation are associated with adverse health outcomes including death, but evidence is limited among persons with HIV, particularly women. We estimated changes in mortality risk from improvement in three measures of area-level socioeconomic context among participants of the Women's Inter...
Objective
Recently Doi et al. argued that risk ratios should be replaced with odds ratios in clinical research. We disagreed, and empirically documented the lack of portability of odds ratios, while Doi et al. defended their position. In this response we highlight important errors in their position.
Study Design and Setting
We counter Doi et al.’s...
Objectives: A recent paper by Doi et al. advocated completely replacing the relative risk (RR) with the odds ratio (OR) as the effect measure in clinical trials and meta-analyses with binary outcomes. Besides some practical advantages of RR over OR, Doi et al.’s key assumption that the OR is “portable” in the meta-analysis, i.e., study-specific ORs...
Background:
Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population.
Objective:
To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality...
The aim of this study was to identify viral exposure (VE) measures and their relationship to mortality risk among persons with HIV.Prospective multicenter observational study to compare VE formulae.Eligible participants initiated first combination antiretroviral therapy (cART) between March 1, 1995 and June 30, 2015. We included 1645 participants f...
Objective: Recently Doi et al. argued that risk ratios should be replaced with odds ratios in clinical research. We disagreed, and empirically documented the lack of portability of odds ratios, while Doi et al. defended their position. In this response we highlight important errors in their position. Study Design and Setting: We counter Doi et al.'...
Parameters representing adjusted treatment effects may be defined marginally or conditionally on covariates. The choice between a marginal or covariate-conditional parameter should be driven by the study question. However, an unappreciated benefit of marginal estimators is a reduction in susceptibility to finite-sample bias relative to the unpenali...
Efavirenz was associated with increased suicidal thoughts/behaviors in an analysis of randomized trials. However, analyses of observational data have found no evidence of increased hazard. To assess whether population differences explain this divergence we transported the effect of efavirenz from these trials to a specific target population. Using...
While randomized trials remain the best evidence for treatment effectiveness, lack of generalizability often remains an important concern. Additionally, when new treatments are compared against existing standards of care, the potentially small benefit of the new treatment may be difficult to detect in a trial without extremely large sample sizes an...
Objective:
Examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the US and Canada.
Design:
HIV clinical cohort consortium.
Methods:
We followed PWH ≥18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classificati...
Comparative effectiveness evidence from randomized trials may not be directly generalizable to a target population of substantive interest when, as in most cases, trial participants are not randomly sampled from the target population. Motivated by the need to generalize evidence from two trials conducted in the AIDS Clinical Trials Group (ACTG), we...
A simple example is used to show how the bias and standard error of an estimator depend in part on the type of estimator chosen from among parametric, nonparametric, and semiparametric candidates. We estimate the cumulative distribution function in the presence of missing data with and without an auxiliary variable. Simulation results mirror theore...
Objective:
We investigated the effect of maternal HIV and its treatment on spontaneous and provider-initiated preterm birth (PTB) in an urban African cohort.
Methods:
The Zambian Preterm Birth Prevention Study enrolled pregnant women at their first antenatal visit in Lusaka. Participants underwent ultrasound, laboratory testing, and clinical phe...
Background
Persons with HIV (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk.
Methods
In six US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by e...
The purpose of many health studies is to estimate the effect of an exposure on an outcome. It is not always ethical to assign an exposure to individuals in randomised controlled trials, instead observational data and appropriate study design must be used. There are major challenges with observational studies, one of which is confounding that can le...
Background: Randomized controlled trials are often used to inform policy and practice for broad populations. The average treatment effect (ATE) for a target population, however, may be different from the ATE observed in a trial if there are effect modifiers whose distribution in the target population is different that from that in the trial. Method...
Background
Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy.Metho...
Objectives:
A recent paper by Doi et al. advocated completely replacing the relative risk (RR) with the odds ratio (OR) as the effect measure used to report the association between a treatment and a binary outcome in clinical trials and meta-analyses. Besides some practical advantages of RR over OR and the well-known issue of the OR being non-coll...
Background:
Parametric g-computation is an analytic technique that can be used to estimate the effects of exposures, treatments and interventions; it relies on a different set of assumptions than more commonly used inverse probability weighted estimators. Whereas prior work has demonstrated implementations for binary exposures and continuous outco...
Suppose that an investigator wants to estimate an association between a continuous exposure variable and an outcome, adjusting for a set of confounders. If the exposure variable suffers classical measurement error, in which the measured exposures are distributed with independent error around the true exposure, then an estimate of the covariate-adju...
Meta-analyses are undertaken to combine information from a set of studies, often in settings where some of the individual study-specific estimates are based on relatively small study samples. Finite sample bias may occur when maximum likelihood estimates of associations are obtained by fitting logistic regression models to sparse data sets. We show...
Background
Black women have higher hormone receptor positive (HR+) breast cancer mortality than White women. Early recurrence rates differ by race, but little is known about genomic predictors of early recurrence among HR+ women.
Methods
Using data from the Carolina Breast Cancer Study (phase III, 2008-2013), we estimated associations between race...
Background:
Integrase strand transfer inhibitor (InSTI)-based regimens are now recommended as first-line antiretroviral therapy (ART) for adults with human immunodeficiency virus. But evidence on long-term clinical effectiveness of InSTI-based regimens remains limited. We examined whether InSTI-based regimens improved longer-term clinical outcomes...
Measures of information and surprise, such as the Shannon information (the $S$ value), quantify the signal present in a stream of noisy data. We illustrate the use of such information measures in the context of interpreting $P$ values as compatibility indices. $S$ values help communicate the limited information supplied by conventional statistics a...
Illustrations of the g-computation algorithm to evaluate population average treatment and intervention effects have been predominantly implemented in settings with complete exposure information. Thus, worked examples of approaches to handle missing data in this causal framework are needed to facilitate wider use of these estimators. We illustrate t...
Neighborhoods with high poverty rates have limited resources to support residents’ health. Using census data, we calculated the proportion of each Women’s Interagency HIV Study participant’s census tract (neighborhood) living below the poverty line. We assessed associations between neighborhood poverty and (1) unsuppressed viral load [VL] in HIV-se...
Introduction:
There are few methodologic examples of how multiple causes of death may be summarized in cause-specific mortality analyses to address limitations of attributing death to a single underlying cause. We propose a cause-of-death weighting approach to estimate the set of risk functions of specific causes of mortality using both underlying...
We consider scenarios in which the likelihood function for a semiparametric regression model factors into separate components, with an efficient estimator of the regression parameter available for each component. An optimal weighted combination of the component estimators, named an ensemble estimator, may be employed as an overall estimate of the r...
Background: Black women have higher breast cancer mortality than white women, particularly within the hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) clinical subtype. Interactions between tumor biology and treatment factors are complex and racial disparities in early events (such as 5-year recurrence risk)...
The Kaplan-Meier (KM) estimator of the survival function imputes event times for right-censored and left-truncated observations, but these imputations are hidden and therefore sometimes unrecognized by applied health scientists. Using a simple example data set and the redistribution algorithm, we illustrate how imputations are made by the KM estima...
The disease risk score (DRS) can be used to summarize a potentially large vector of covariates with a single variable. The DRS can be used to control for confounding by the covariates that went into estimation of the DRS and obtain a standardized estimate of an exposure's effect on disease. However, to-date, literature on the DRS has not addressed...
Measurement error is common in epidemiology, but few studies use quantitative methods to account for bias due to mismeasurement. One barrier may be that some intuitive approaches that readily combine with methods to account for other sources of bias, like multiple imputation for measurement error (MIME), rely on internal validation data, which are...
Background:
The cost of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) prompted many payers to restrict treatment to patients who met non-evidence-based criteria. These restrictions have implications for survival of people with HCV, especially for people with human immunodeficiency virus (HIV)/HCV coinfection who are at high risk for...
Misclassification of outcomes or event types is common in health sciences research and can lead to serious bias when estimating the cumulative incidence functions in settings with competing risks. Recent work has shown how to estimate nonparametric cumulative incidence functions in the presence of nondifferential outcome misclassification when the...
Objective:
To investigate first-year survival of infants born with spina bifida, and examine the association of maternal prepregnancy body mass index (BMI) with infant mortality.
Methods:
This is a retrospective cohort study of 1,533 liveborn infants with nonsyndromic spina bifida with estimated dates of delivery from 1998 to 2011 whose mothers...
Objective:
We aimed to investigate potential causes of higher risk of treatment interruptions within the multicountry Strategic Timing of AntiRetroviral Treatment (START) trial in 2015.
Methods:
We defined baseline as the date of starting antiretroviral therapy (ART) and a treatment interruption as discontinuing ART for at least 2 weeks. Partici...
Effect estimates from randomized trials and observational studies may not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a three-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the...
The disease risk score is a summary score that can be used to control for confounding with a potentially large set of covariates. While less widely used than the exposure propensity score, the disease risk score approach might be useful for novel or unusual exposures, when treatment indications or exposure patterns are rapidly changing, or when mor...
Background and objectives:
Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols.
Design, setting, participants, & measurements:
Using clinical data from a larg...
Nonparametric bounds for the risk difference are straightforward to calculate and make no untestable assumptions about unmeasured confounding or selection bias due to missing data (e.g., dropout). These bounds are often wide and communicate uncertainty due to possible systemic errors. An illustrative example is provided.
Background
To obtain optimal health outcomes, people living with HIV must be retained in clinical care. We examined the relationships between four possible combinations of two separate retention measures (missed visits and the Institute of Medicine (IOM) indicator) and all-cause mortality.
Methods
The sample included 4,162 antiretroviral therapy (...
In the absence of strong assumptions (e.g., exchangeability), only bounds for causal effects can be identified. We describe bounds for the risk difference of a binary exposure on a binary outcome under four common study settings: observational and randomized studies, each with and without simple random selection from the target population. Through...
Background
Each year, an estimated 15 million babies are born preterm, a global burden borne disproportionately by families in lower-income countries. Maternal HIV infection increases a woman’s risk of delivering prematurely, and antir