Association Between HIV and Prevalence and Manifestations of Asthma: Analysis of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.

BACKGROUND: The association between HIV and asthma prevalence and manifestations remains unclear, with few studies including women. SETTING: A retrospective observational cohort study from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. METHODS: Asthma was defined in 2 ways: (1) self-report and (2) robust criteria requiring all the following: lack of fixed airflow obstruction, presence of wheeze on the St. George's Respiratory Questionnaire (SGRQ), and report of asthma therapies. Estimates of asthma prevalence and asthma-related manifestations were compared by HIV serostatus. RESULTS: A total of 1815 men and 2122 women were included. Asthma prevalence did not differ between people with HIV (PWH) and people without HIV regardless of definition: self-report (men, 12.0% vs. 11.2%; women, 24.3% vs. 27.5%) and robust criteria (men, 5.0% vs. 3.4%; women, 12.8% vs. 13.2%). Among men with asthma, worse respiratory symptom burden was reported among those with HIV, regardless of asthma definition. Among women with self-reported asthma, those with HIV had less respiratory symptom burden. Regardless of serostatus, women with robust-defined asthma had similar respiratory symptoms across SGRQ domains and similar frequencies of phlegm, shortness of breath, and wheezing. CONCLUSIONS: Among PWH and people without HIV, asthma prevalence was 2-fold to 3-fold higher using self-reported definition rather than robust definition. In men and women, HIV was not associated with increased asthma prevalence. In men, HIV was associated with more respiratory symptoms when asthma was self-reported; the relationship was attenuated with the robust criteria. Further studies are needed to explore asthma phenotypes among PWH.

Thirteen Questions About Using Machine Learning in Causal Research (You Won't Believe the Answer to Number 10!).

Machine learning is gaining prominence in the health sciences, where much of its use has focused on data-driven prediction. However, machine learning can also be embedded within causal analyses, potentially reducing biases arising from model misspecification. Using a question-and-answer format, we provide an introduction and orientation for epidemiologists interested in using machine learning but concerned about potential bias or loss of rigor due to use of "black box" models. We conclude with sample software code that may lower the barrier to entry to using these techniques.

Defining and Identifying Per-protocol Effects in Randomized Trials.

In trials with noncompliance to assigned treatment, researchers might be interested in estimating a per-protocol effect-a comparison of two counterfactual outcomes defined by treatment assignment and (often time-varying) compliance with a well-defined treatment protocol. Here, we provide a general counterfactual definition of a per-protocol effect and discuss examples of per-protocol effects that are of either substantive or methodologic interest. In doing so, we seek to make more concrete what per-protocol effects are and highlight that one can estimate per-protocol effects that are more than just a comparison of always taking treatment in two distinct treatment arms. We then discuss one set of identifiability conditions that allow for identification of a causal per-protocol effect, highlighting some potential violations of those conditions that might arise when estimating per-protocol effects.

Adverse maternal and neonatal outcomes among women with preeclampsia with severe features <34 weeks gestation with versus without comorbidity.

OBJECTIVES: To determine adverse maternal and neonatal outcomes among women with preeclampsia with severe features who delivered <34 weeks comparing those with versus without a comorbid condition. STUDY DESIGN: A retrospective analysis from the U.S. Consortium on Safe Labor Study of deliveries <34 weeks with preeclampsia with severe features. We examined the association of each comorbid condition versus none with adverse maternal and neonatal outcomes. The comorbidities (not mutually exclusive) were chronic hypertension, pregestational diabetes, gestational diabetes, twin gestation, and fetal growth restriction. MAIN OUTCOMES: Maternal outcome: eclampsia, thromboembolism, ICU admission, and/or death; and neonatal outcome: intracranial/periventricular hemorrhage, hypoxic-ischemic encephalopathy/periventricular leukomalacia, stillbirth, and/or perinatal death. RESULTS: Among 2217 deliveries, 50% had a comorbidity, namely chronic hypertension (30%), pregestational diabetes (8%), gestational diabetes (8%), twin gestation (10%), and fetal growth restriction (7%). Adverse maternal and neonatal outcomes occurred in 10% and 12% of pregnancies, respectively. Pregnancies with preeclampsia with severe features delivered <34 weeks complicated by gestational diabetes (adjusted risk difference, aRD: -4.9%, 95%CI: -9.11 to -0.71), twin gestation (aRD: -5.1%, 95%CI: -8.63 to -1.73), and fetal growth restriction (aRD: -4.7%, 95%CI: -7.96 to -1.62) were less likely to result in adverse maternal outcome compared to pregnancies without comorbidity, but not chronic hypertension and pregestational diabetes. A pregnancy complicated by fetal growth restriction (aRD: 12.2%, 95%CI: 5.48 to 19.03) was more likely to result in adverse neonatal outcome, but not other comorbid conditions. CONCLUSIONS: Preeclampsia with severe features <34 weeks complicated by comorbidity was generally not associated with an increased risk of adverse maternal and neonatal outcomes, with the exception of fetal growth restriction.

Use of Intrauterine Devices and Risk of Human Immunodeficiency Virus Acquisition Among Insured Women in the United States.

Concerns have been raised about progestin-containing contraceptives and the risk of human immunodeficiency virus (HIV) acquisition. Based on health insurance data from women in the United States with intrauterine device (IUD) insertions during 2011-2018, there was no increased risk of incident HIV diagnosis for levonorgestrel-releasing IUDs versus copper IUDs.

Past-month cannabis use among U.S. individuals from 2002-2015: An age-period-cohort analysis.

BACKGROUND: Cannabis is the most commonly used illicit drug among U.S. adolescents and adults, but little is known about factors that drive trends in cannabis use prevalence. To better understand drivers of these trends, we aimed to estimate age, period, and cohort effects on past-month cannabis use among U.S. individuals age 12 and older from 2002 to 2015. METHODS: We conducted an age-period-cohort analysis on past-month cannabis use among participants ages 12 and older using the National Survey on Drug Use and Health (NSDUH), an annual cross-sectional nationally-representative survey of drug use. Additionally, we examined how age, period, and cohort effects differed across gender. Participants (n = 779,799) self-reported cannabis patterns using a computer-assisted telephone interview (CATI). RESULTS: Past-month cannabis use in this population increased from 6.0% in 2002 to 8.1% in 2015. Distinct age, period, and cohort effects were observed. Compared to participants ages 12-13, participants ages 18-21 (PR: 16.8, 95% CI: 15.6, 18.1) and 22-25 (PR: 13.2, 95% CI: 12.2, 14.4) had dramatically higher prevalence of past-month cannabis use. Compared to participants in 2002, participants in 2014 (PR: 1.2, 95% CI: 1.1, 1.4) and 2014 (PR: 1.2, 95% CI: 1.1, 1.4) had slightly higher prevalence of past-month cannabis use. Compared to the 1940s birth cohort, the 1950s birth cohort (PR: 1.8, 95% CI: 1.5, 2.2) had a higher prevalence of past-month cannabis use. CONCLUSIONS: Past-month cannabis use is prevalent and increasing among U.S. adults. Distinct age, period, and cohort effects are at play, though age effects are strongest.

Association of Household Opioid Availability and Prescription Opioid Initiation Among Household Members.

Importance: Increases in prescription opioid use in the United States have been attributed to changing prescribing guidelines and attitudes toward pain relief; however, the spread of opioid use within households through drug diversion may also be a contributing factor. Objective: To investigate whether individuals living in a household with a prescription opioid user are more likely to initiate prescription opioids themselves, compared with individuals in households with a prescription nonsteroidal anti-inflammatory drug (NSAID) user. Design, Setting, and Participants: This was a retrospective cohort study using administrative health care claims data from 2000 to 2014 of commercial insurance beneficiaries sharing a health plan with continuous prescription drug coverage, without opioid or NSAID use in the prior year. Enrollees were followed from the date of the first prescription filled by a household member for an eligible opioid or NSAID until initiation of prescription opioids, disenrollment, or administrative censoring after 1 year or the end of follow-up on December 31, 2014. Risk of opioid initiation was derived from inverse probability-weighted (IPW) Kaplan-Meier estimators that adjusted for potential confounders, prognostic factors, and predictors of censoring. Exposure: Outpatient pharmacy dispensing of a prescription opioid or prescription NSAID. Main Outcomes and Measures: Incident outpatient pharmacy fill for a prescription opioid by a household member. Results: From 2000 to 2014, 12 695 280 individuals were exposed to prescription opioids and 6 359 639 to prescription NSAIDS through an index prescription to a household member. The IPW estimated risk of opioid initiation in the subsequent year was 11.83% (95% CI, 11.81%-11.85%) among individuals exposed to prescription opioids in the household, compared with 11.11% (95% CI, 11.09%-11.14%) among individuals exposed to prescription NSAIDs, resulting in a risk difference of 0.71% (95% CI, 0.68%-0.74%). An unmeasured confounder that is modestly associated with the exposure (eg, prevalence difference = 0.9%) and the outcome (eg, risk difference = 0.9) after adjustment for all measured variables could explain our observed estimate of the overall risk difference (0.71%). Conclusions and Relevance: Living in a household with a prescription opioid user may increase risk of prescription opioid use, which may reflect both increased access to these products as well as shared risk factors, such as prescriber preference and prescription drug monitoring.

An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women.

OBJECTIVE AND DESIGN: Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data. METHODS: We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception. RESULTS: We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4. CONCLUSION: Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.

Brief Report: Estimating Differences and Ratios in Median Times to Event.

Time differences and time ratios are often more interpretable estimates of effect than hazard ratios for time-to-event data, especially for common outcomes. We developed a SAS macro for estimating time differences and time ratios between baseline-fixed binary exposure groups based on inverse probability-weighted Kaplan-Meier curves. The macro uses pooled logistic regression to calculate inverse probability of censoring and exposure weights, draws Kaplan-Meier curves based on the weighted data, and estimates the time difference and time ratio at a user-defined survival proportion. The macro also calculates the risk difference and risk ratio at a user-specified time. Confidence intervals are constructed by bootstrap. We provide an example assessing the effect of exclusive breastfeeding during diarrhea on the incidence of subsequent diarrhea in children followed from birth to 3 years in Vellore, India. The SAS macro provided here should facilitate the wider reporting of time differences and time ratios.

Reduction in diarrhoeal rates through interventions that prevent unnecessary antibiotic exposure early in life in an observational birth cohort.

BACKGROUND: Antibiotic treatment early in life is often not needed and has been associated with increased rates of subsequent diarrhoea. We estimated the impact of realistic interventions, which would prevent unnecessary antibiotic exposures before 6 months of age, on reducing childhood diarrhoeal rates. METHODS: In data from a prospective observational cohort study conducted in Vellore, India, we used the parametric g-formula to model diarrhoeal incidence rate differences contrasting the observed incidence of diarrhoea to the incidence expected under hypothetical interventions. The interventions prevented unnecessary antibiotic treatments for non-bloody diarrhoea, vomiting and upper respiratory infections before 6 months of age. We also modelled targeted interventions, in which unnecessary antibiotic use was prevented only among children who had already stopped exclusive breast feeding. RESULTS: More than half of all antibiotic exposures before 6 months (58.9%) were likely unnecessary. The incidence rate difference associated with removing unnecessary antibiotic use before 6 months of age was -0.28 (95% CI -0.46 to -0.08) episodes per 30 child-months. This implies that preventing unnecessary antibiotic exposures in just 4 children would reduce the incidence of diarrhoea by 1 from 6 months to 3 years of age. CONCLUSIONS: Interventions to reduce unnecessary antibiotic use among young children could result in an important reduction in diarrhoeal rates. This work provides an example application of statistical methods which can further the aim of presenting epidemiological findings that are relevant to public health practice.

Early Life Antibiotic Exposure Is Not Associated with Growth in Young Children of Vellore, India.

OBJECTIVES: To estimate the effects of antibiotic exposures in the first 6 months of life on short- and long-term growth. STUDY DESIGN: In a prospective observational cohort study of 497 children from Vellore, India, we estimated short-term effects of antibiotics during the first 6 months using longitudinal general linear regression to model weight-for-age, height-for-age, and weight-for-height z-scores in monthly intervals. To estimate long-term effects, we modeled growth from 6 months to 3 years as a function of antibiotic use in the first 6 months. We also estimated the effects of antibiotics on the monthly relative risks of underweight, stunting, and wasting in the first 6 months and to 3 years. RESULTS: Underweight, stunting, and wasting were common in this population: 31%, 32%, and 15% on average after 6 months of age, respectively. There was no association between antibiotic exposures before 6 months and growth during that period. From 6 months to 3 years, adjusted absolute differences in weight and height were small (approximately -100 g and no more than -2 mm overall, respectively) and not statistically significant. CONCLUSIONS: Antibiotic exposures early in life were not associated with increased or decreased growth. The combination of malnutrition and recurrent illness likely complicate the relationship between antibiotic exposures and growth among children in low and middle-income countries.

Antibiotic treatment of diarrhoea is associated with decreased time to the next diarrhoea episode among young children in Vellore, India.

BACKGROUND: Antibiotics are commonly given for the treatment of childhood diarrhoea, but are not indicated in most cases. Antibiotics modify the gastrointestinal microbiota, which may have unanticipated effects on the risk of subsequent diarrhoea. METHODS: In a prospective observational cohort study, we assessed the effect of caregiver-reported antibiotic treatment for diarrhoea on the timing of a child's next episode among 434 children followed from birth to 3 years of age in Vellore, India. We estimated median time differences and time ratios from inverse probability of exposure-weighted Kaplan-Meier curves for the time to next diarrhoea episode, comparing children who did and did not receive antibiotics for the previous episode. RESULTS: Study children had more than five diarrhoea episodes on average in the first 3 years of life, and more than a quarter of all episodes were treated with antibiotics. Children who received antibiotics for their first diarrhoea episode had their second episode on average 8 weeks earlier (median time difference: -8, 95% confidence interval: -10, -3) than children who did not receive antibiotics. The effects of antibiotics on subsequent diarrhoea were greatest at earlier episodes and younger ages, and cefixime had a slightly larger effect compared with cotrimoxazole. CONCLUSIONS: Antibiotic treatment of diarrhoea was associated with reduced time to a subsequent diarrhoea episode, especially among younger infants. Whereas rational use of antibiotics has been advocated to reduce antimicrobial resistance in populations, we show that overuse of antibiotics may also have a direct adverse effect on individual patients.

Commentary: Epidemiology in the era of big data.

Big Data has increasingly been promoted as a revolutionary development in the future of science, including epidemiology. However, the definition and implications of Big Data for epidemiology remain unclear. We here provide a working definition of Big Data predicated on the so-called "three V's": variety, volume, and velocity. From this definition, we argue that Big Data has evolutionary and revolutionary implications for identifying and intervening on the determinants of population health. We suggest that as more sources of diverse data become publicly available, the ability to combine and refine these data to yield valid answers to epidemiologic questions will be invaluable. We conclude that while epidemiology as practiced today will continue to be practiced in the Big Data future, a component of our field's future value lies in integrating subject matter knowledge with increased technical savvy. Our training programs and our visions for future public health interventions should reflect this future.

Epidemiology's continuing contribution to public health: The power of "Then and Now".

The 47th annual meeting of the Society for Epidemiologic Research hosted 17 invited speakers charged by the Executive Committee with presenting some of the many ways that epidemiologists have improved the health of the general population. There were 9 "Then and Now" sessions that were structured to focus on how early epidemiologists overcame research hurdles and advanced health through innovative strategies. For most topics, a longstanding expert was paired with an excellent contemporary epidemiologist working in the area, and both were given the freedom to deliver an integrated story about epidemiology's temporal role in protecting and promoting public health. Epidemiologic discoveries in cardiovascular, cancer, and perinatal epidemiology were discussed on day 1, followed by discussions of accomplishments in reducing exposures that adversely impact health (nutrition, environment/occupation, and tobacco use) on day 2. Topics with relevancy for many aspects of epidemiology were presented on day 3, including infectious diseases, social forces, and causal thinking in epidemiologic research. Given the large number of outstanding senior and junior epidemiologists that attended the meeting, choosing speakers was a unique challenge. What became evident from all sessions was the passion that epidemiologists have for population health, tempered with concerns for remaining true to epidemiologic principles, the timely adoption of innovative methods, and the responsible interpretation of research findings.

Effect of pregnancy and the postpartum period on adherence to antiretroviral therapy among HIV-infected women established on treatment.

: Among women who become pregnant after initiating highly active antiretroviral therapy (HAART), few data describe the effect of pregnancy and postpartum on adherence. We conducted a retrospective clinical cohort study among therapy-naive women (age, 18-45 years) initiating HAART in Johannesburg, South Africa. Among 7510 women in our analysis, 896 experienced a pregnancy after starting HAART. Compared with nonpregnant periods of follow-up, there was an increased risk of nonadherence during the postpartum period (weighted risk ratio: 1.46, 95% confidence interval: 1.17 to 1.82) but not during pregnancy itself (weighted risk ratio: 0.95, 95% confidence interval: 0.78 to 1.17).

Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence.

Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we identified 22 studies published by January 15, 2014 which met inclusion criteria; we classified thirteen studies as having severe methodological limitations, and nine studies as "informative but with important limitations". Overall, data do not support an association between use of oral contraceptives and increased risk of HIV acquisition. Uncertainty persists regarding whether an association exists between depot-medroxyprogesterone acetate (DMPA) use and risk of HIV acquisition. Most studies suggested no significantly increased HIV risk with norethisterone enanthate (NET-EN) use, but when assessed in the same study, point estimates for NET-EN tended to be larger than for DMPA, though 95% confidence intervals overlapped substantially. No data have suggested significantly increased risk of HIV acquisition with use of implants, though data were limited. No data are available on the relationship between use of contraceptive patches, rings, or hormonal intrauterine devices and risk of HIV acquisition. Women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition, and like all women at risk of HIV, should be empowered to access and use condoms and other HIV preventative measures. Programs, practitioners, and women urgently need guidance on how to maximize health with respect to avoiding both unintended pregnancy and HIV given inconclusive or limited data for certain HC methods.

Postnatal cytomegalovirus exposure in infants of antiretroviral-treated and untreated HIV-infected mothers.

HIV-1 and CMV are important pathogens transmitted via breastfeeding. Furthermore, perinatal CMV transmission may impact growth and disease progression in HIV-exposed infants. Although maternal antiretroviral therapy reduces milk HIV-1 RNA load and postnatal transmission, its impact on milk CMV load is unclear. We examined the relationship between milk CMV and HIV-1 load (4-6 weeks postpartum) and the impact of antiretroviral treatment in 69 HIV-infected, lactating Malawian women and assessed the relationship between milk CMV load and postnatal growth in HIV-exposed, breastfed infants through six months of age. Despite an association between milk HIV-1 RNA and CMV DNA load (0.39 log(10) rise CMV load per log(10) rise HIV-1 RNA load, 95% CI 0.13-0.66), milk CMV load was similar in antiretroviral-treated and untreated women. Higher milk CMV load was associated with lower length-for-age (-0.53, 95% CI: -0.96, -0.10) and weight-for-age (-0.40, 95% CI: -0.67, -0.13) Z-score at six months in exposed, uninfected infants. As the impact of maternal antiretroviral therapy on the magnitude of postnatal CMV exposure may be limited, our findings of an inverse relationship between infant growth and milk CMV load highlight the importance of defining the role of perinatal CMV exposure on growth faltering of HIV-exposed infants.