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3.  The Cerebrospinal Fluid HIV Risk Score for Assessing Central Nervous System Activity in Persons With HIV 
American Journal of Epidemiology  2014;180(3):297-307.
Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004–2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians.
doi:10.1093/aje/kwu098
PMCID: PMC4108039  PMID: 24966216
central nervous system; cerebrospinal fluid; cerebrospinal fluid human immunodeficiency virus risk score; human immunodeficiency virus; prediction model
4.  Childhood Social Disadvantage, Cardiometabolic Risk, and Chronic Disease in Adulthood 
American Journal of Epidemiology  2014;180(3):263-271.
Adverse social environments in early life are hypothesized to become biologically embedded during the first few years of life, with potentially far-reaching implications for health across the life course. Using prospective data from a subset of a US birth cohort, the Collaborative Perinatal Project, started in 1959–1966 (n = 566), we examined associations of social disadvantage assessed in childhood with cardiometabolic function and chronic disease status more than 40 years later (in 2005–2007). Social disadvantage was measured with an index that combined information on adverse socioeconomic and family stability factors experienced between birth and age 7 years. Cardiometabolic risk (CMR) was assessed by combining information from 8 CMR biomarkers; an index of chronic disease status was derived by assessing 8 chronic diseases. Poisson models were used to investigate associations between social disadvantage and CMR or chronic disease scores while adjusting for childhood covariates and potential pathway variables. A high level of social disadvantage was significantly associated with both higher CMR (incident rate ratio = 1.69, 95% confidence interval: 1.19, 2.39) and with a higher number of chronic diseases (incident rate ratio = 1.39, 95% confidence interval: 1.00, 1.92) in minimally adjusted models. Associations with CMR persisted even after accounting for childhood and adult covariates.
doi:10.1093/aje/kwu127
PMCID: PMC4108040  PMID: 24970845
biological markers; cardiometabolic risk; cohort studies; psychosocial factors; social disadvantage; social environment; socioeconomic status
5.  Individual Joblessness, Contextual Unemployment, and Mortality Risk 
American Journal of Epidemiology  2014;180(3):280-287.
Longitudinal studies at the level of individuals find that employees who lose their jobs are at increased risk of death. However, analyses of aggregate data find that as unemployment rates increase during recessions, population mortality actually declines. We addressed this paradox by using data from the US Department of Labor and annual survey data (1979–1997) from a nationally representative longitudinal study of individuals—the Panel Study of Income Dynamics. Using proportional hazards (Cox) regression, we analyzed how the hazard of death depended on 1) individual joblessness and 2) state unemployment rates, as indicators of contextual economic conditions. We found that 1) compared with the employed, for the unemployed the hazard of death was increased by an amount equivalent to 10 extra years of age, and 2) each percentage-point increase in the state unemployment rate reduced the mortality hazard in all individuals by an amount equivalent to a reduction of 1 year of age. Our results provide evidence that 1) joblessness strongly and significantly raises the risk of death among those suffering it, and 2) periods of higher unemployment rates, that is, recessions, are associated with a moderate but significant reduction in the risk of death among the entire population.
doi:10.1093/aje/kwu128
PMCID: PMC4108041  PMID: 24993734
business cycles; Cox model; macroeconomic conditions; mortality; proportional hazards model; recessions; unemployment
6.  The Thompson-McFadden Commission and Joseph Goldberger: Contrasting 2 Historical Investigations of Pellagra in Cotton Mill Villages in South Carolina 
American Journal of Epidemiology  2014;180(3):235-244.
As pellagra reached epidemic proportions in the United States in the early 20th century, 2 teams of investigators assessed its incidence in cotton mill villages in South Carolina. The first, the Thompson-McFadden Commission, concluded that pellagra was likely infectious. The second, a Public Health Service investigation led by Joseph Goldberger, concluded that pellagra was caused by a dietary deficiency. In this paper, we recount the history of the 2 investigations and consider how the differences between the 2 studies' designs, measurements, analyses, and interpretations led to different conclusions. Because the novel dietary assessment strategy was a key feature of the Public Health Service's study design, we incorporated simulated measurement error in a reanalysis of the Public Health Service's data to assess whether this specific difference affected the divergent conclusions.
doi:10.1093/aje/kwu134
PMCID: PMC4108042  PMID: 24966221
epidemiology in history; measurement; multilevel epidemiology; nutrition
7.  Changes in Body Weight and Health-Related Quality of Life: 2 Cohorts of US Women 
American Journal of Epidemiology  2014;180(3):254-262.
Studies have shown that body weight is a determinant of health-related quality of life (HRQoL). However, few studies have examined long-term weight change with changes in HRQoL. We followed 52,682 women aged 46–71 years in the Nurses' Health Study (in 1992–2000) and 52,587 women aged 29–46 years in the Nurses’ Health Study II (in 1993–2001). Body weight was self-reported, HRQoL was measured by the Medical Outcomes Study's 36-Item Short Form Health Survey, and both were updated every 4 years. The relationship between changes in weight and HRQoL scores was evaluated at 4-year intervals by using a generalized linear regression model with multivariate adjustment for baseline age, ethnicity, menopausal status, and changes in comorbidities and lifestyle factors. Weight gain of 15 lbs (1 lb = 0.45 kg) or more over a 4-year period was associated with 2.05-point lower (95% confidence interval: 2.14, 1.95) physical component scores, whereas weight loss of 15 lbs or more was associated with 0.89-point higher (95% confidence interval: 0.75, 1.03) physical component scores. Inverse associations were also found between weight change and physical function, role limitations due to physical problems, bodily pain, general health, and vitality. However, the relations of weight change with mental component scores, social functioning, mental health, and role limitations due to emotional problems were small.
doi:10.1093/aje/kwu136
PMCID: PMC4108043  PMID: 24966215
body weight; health-related quality of life; prospective cohort study; women
8.  Variation in the Association Between Colorectal Cancer Susceptibility Loci and Colorectal Polyps by Polyp Type 
American Journal of Epidemiology  2014;180(2):223-232.
We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24–79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs. Polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for associations between polyps and the colorectal cancer risk allele for each SNP under a log-additive model. Analyses included 781 controls, 489 cases with adenoma, 401 cases with serrated polyps, and 188 cases with both polyp types. The following SNPs were associated with advanced adenomas: rs10936599, rs10795668, rs16892766, and rs9929218 (P < 0.05). For nonadvanced adenomas and for serrated polyps overall, only rs961253 was statistically significant (P < 0.05). These associations were in the same directions as those in prior colorectal cancer GWAS. No SNP was significantly associated with hyperplastic polyps, and only rs6983267 was significantly associated with sessile serrated polyps, but this association was opposite of that found in colorectal cancer GWAS. Our results suggest that the association between colorectal cancer susceptibility SNPs and colorectal polyps varies by polyp type.
doi:10.1093/aje/kwu114
PMCID: PMC4082340  PMID: 24875374
adenoma; colorectal cancer; colorectal polyps; genome-wide association studies; serrated polyps; single-nucleotide polymorphisms
9.  Pooled Results From 5 Validation Studies of Dietary Self-Report Instruments Using Recovery Biomarkers for Energy and Protein Intake 
American Journal of Epidemiology  2014;180(2):172-188.
We pooled data from 5 large validation studies of dietary self-report instruments that used recovery biomarkers as references to clarify the measurement properties of food frequency questionnaires (FFQs) and 24-hour recalls. The studies were conducted in widely differing US adult populations from 1999 to 2009. We report on total energy, protein, and protein density intakes. Results were similar across sexes, but there was heterogeneity across studies. Using a FFQ, the average correlation coefficients for reported versus true intakes for energy, protein, and protein density were 0.21, 0.29, and 0.41, respectively. Using a single 24-hour recall, the coefficients were 0.26, 0.40, and 0.36, respectively, for the same nutrients and rose to 0.31, 0.49, and 0.46 when three 24-hour recalls were averaged. The average rate of under-reporting of energy intake was 28% with a FFQ and 15% with a single 24-hour recall, but the percentages were lower for protein. Personal characteristics related to under-reporting were body mass index, educational level, and age. Calibration equations for true intake that included personal characteristics provided improved prediction. This project establishes that FFQs have stronger correlations with truth for protein density than for absolute protein intake, that the use of multiple 24-hour recalls substantially increases the correlations when compared with a single 24-hour recall, and that body mass index strongly predicts under-reporting of energy and protein intakes.
doi:10.1093/aje/kwu116
PMCID: PMC4082341  PMID: 24918187
24-hour recall; attenuation factors; calibration equations; dietary measurement error; food frequency questionnaire; under-reporting
10.  Marginal Structural Cox Models for Estimating the Association Between β-Interferon Exposure and Disease Progression in a Multiple Sclerosis Cohort 
American Journal of Epidemiology  2014;180(2):160-171.
Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the “real-world” clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995–2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed “normalized stabilized” weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings.
doi:10.1093/aje/kwu125
PMCID: PMC4082342  PMID: 24939980
bias (epidemiology); causality; confounding factors (epidemiology); epidemiologic methods; inverse probability weighting; marginal structural Cox model; multiple sclerosis; survival analysis
11.  Genetic Variants Related to Height and Risk of Atrial Fibrillation 
American Journal of Epidemiology  2014;180(2):215-222.
Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥65 years) enrolled in 1989–1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10−8). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.
doi:10.1093/aje/kwu126
PMCID: PMC4082343  PMID: 24944287
atrial fibrillation; cardiovascular disease; genetics; risk factors; risk prediction
12.  Snippets From the Past: Cohort Analysis of Disease Rates—Another Piece in a Seemingly Still Incomplete Puzzle 
American Journal of Epidemiology  2014;180(2):189-196.
For almost a century, epidemiologists have stratified age-specific disease rates by year of birth to better understand the distribution of a disease in a population and its evolution across time. In the present article, I review the contributions of John Brownlee, Kristian Feyer Andvord, and Wade Hampton Frost and, to accentuate the similarities of their approaches, redraw their original graphs of age-specific death rates of tuberculosis organized either by year of death or year of birth. In addition, this article reports on an apparently universally forgotten publication in the American Journal of Hygiene published in 1929, which both upsets the conventional history of the earliest reports of disease rates stratified by birth cohorts and challenges the theory that Frost discovered cohort analysis independently and gave it its name.
doi:10.1093/aje/kwu131
PMCID: PMC4082344  PMID: 24920785
cohort analysis; tuberculosis; typhoid; vital statistics
13.  Accuracy of Self-Reported Versus Measured Weight Over Adolescence and Young Adulthood: Findings From the National Longitudinal Study of Adolescent Health, 1996–2008 
American Journal of Epidemiology  2014;180(2):153-159.
Many studies rely on self-reports to capture population trends and trajectories in weight gain over adulthood, but the validity of self-reports is often considered a limitation. The purpose of this work was to examine long-term trajectories of self-reporting bias in a national sample of American youth. With 3 waves of data from the National Longitudinal Study of Adolescent Health (1996–2008), we used growth curve models to examine self-reporting bias in trajectories of weight gain across adolescence and early adulthood (ages 13–32 years). We investigated whether self-reporting bias is constant over time, or whether adolescents become more accurate in reporting their weight as they move into young adulthood, and we examined differences in self-reporting bias by sex, race/ethnicity, and attained education. Adolescent girls underreported their weight by 0.86 kg on average, and this rate of underreporting increased over early adulthood. In contrast, we found no evidence that boys underreported their weight either in adolescence or over the early adult years. For young men, self-reports of weight were unbiased estimates of measured weight among all racial/ethnic and educational subpopulations over adolescence and early adulthood.
doi:10.1093/aje/kwu133
PMCID: PMC4082345  PMID: 24944288
adolescence; bias; measurement; self-report; trajectories; weight; youth
14.  Design and Analysis for Studying microRNAs in Human Disease: A Primer on -Omic Technologies 
American Journal of Epidemiology  2014;180(2):140-152.
microRNAs (miRNAs) are fundamental to cellular biology. Although only approximately 22 bases long, miRNAs regulate complex processes in health and disease, including human cancer. Because miRNAs are highly stable in circulation when compared with several other classes of nucleic acids, they have generated intense interest as clinical biomarkers in diverse epidemiologic studies. As with other molecular biomarker fields, however, miRNA research has become beleaguered by pitfalls related to terminology and classification; procedural, assay, and study cohort heterogeneity; and methodological inconsistencies. Together, these issues have led to both false-positive and potentially false-negative miRNA associations. In this review, we summarize the biological rationale for studying miRNAs in human disease with a specific focus on circulating miRNAs, which highlight some of the most challenging topics in the field to date. Examples from lung cancer are used to illustrate the potential utility and some of the pitfalls in contemporary miRNA research. Although the field is in its infancy, several important lessons have been learned relating to cohort development, sample preparation, and statistical analysis that should be considered for future studies. The goal of this primer is to equip epidemiologists and clinical researchers with sound principles of study design and analysis when using miRNAs.
doi:10.1093/aje/kwu135
PMCID: PMC4082346  PMID: 24966218
blood; cancer; circulating biomarkers; lung cancer; microRNA; review
15.  Passive Smoking and Preterm Birth in Urban China 
American Journal of Epidemiology  2014;180(1):94-102.
Studies investigating the relationship between maternal passive smoking and the risk of preterm birth have reached inconsistent conclusions. A birth cohort study that included 10,095 nonsmoking women who delivered a singleton live birth was carried out in Lanzhou, China, between 2010 and 2012. Exposure to passive smoking during pregnancy was associated with an increased risk of very preterm birth (<32 completed weeks of gestation; odds ratio = 1.98, 95% confidence interval: 1.41, 2.76) but not moderate preterm birth (32–36 completed weeks of gestation; odds ratio = 0.98, 95% confidence interval: 0.81, 1.19). Risk of very preterm birth increased with the duration of exposure (P for trend = 0.0014). There was no variability in exposures by trimester. The associations were consistent for both medically indicated and spontaneous preterm births. Overall, our findings support a positive association between passive smoking and the risk of very preterm birth.
doi:10.1093/aje/kwu092
PMCID: PMC4070933  PMID: 24838804
birth cohort; China; passive smoking; preterm birth
16.  Kidney Function and Cognitive Health in Older Adults: The Cardiovascular Health Study 
American Journal of Epidemiology  2014;180(1):68-75.
Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C–based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m2 had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m2. Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m2 had fewer cognitive impairment–free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m2, independent of confounders and mediating cardiovascular events (mean difference = −0.44, 95% confidence interval: −0.62, −0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.
doi:10.1093/aje/kwu102
PMCID: PMC4070934  PMID: 24844846
aging; chronic kidney disease; cognitive function; congestive heart failure; myocardial infarction; prospective study; stroke; successful aging
17.  Do Generous Unemployment Benefit Programs Reduce Suicide Rates? A State Fixed-Effect Analysis Covering 1968–2008 
American Journal of Epidemiology  2014;180(1):45-52.
The recent economic recession has led to increases in suicide, but whether US state unemployment insurance programs ameliorate this association has not been examined. Exploiting US state variations in the generosity of benefit programs between 1968 and 2008, we tested the hypothesis that more generous unemployment benefit programs reduce the impact of economic downturns on suicide. Using state linear fixed-effect models, we found a negative additive interaction between unemployment rates and benefits among the US working-age (20–64 years) population (β = −0.57, 95% confidence interval: −0.86, −0.27; P < 0.001). The finding of a negative additive interaction was robust across multiple model specifications. Our results suggest that the impact of unemployment rates on suicide is offset by the presence of generous state unemployment benefit programs, though estimated effects are small in magnitude.
doi:10.1093/aje/kwu106
PMCID: PMC4070935  PMID: 24939978
recession; social epidemiology; suicide; unemployment; unemployment benefits
18.  Who is More Affected by Ozone Pollution? A Systematic Review and Meta-Analysis 
American Journal of Epidemiology  2014;180(1):15-28.
Ozone is associated with adverse health; however, less is known about vulnerable/sensitive populations, which we refer to as sensitive populations. We systematically reviewed epidemiologic evidence (1988–2013) regarding sensitivity to mortality or hospital admission from short-term ozone exposure. We performed meta-analysis for overall associations by age and sex; assessed publication bias; and qualitatively assessed sensitivity to socioeconomic indicators, race/ethnicity, and air conditioning. The search identified 2,091 unique papers, with 167 meeting inclusion criteria (73 on mortality and 96 on hospitalizations and emergency department visits, including 2 examining both mortality and hospitalizations). The strongest evidence for ozone sensitivity was for age. Per 10-parts per billion increase in daily 8-hour ozone concentration, mortality risk for younger persons, at 0.60% (95% confidence interval (CI): 0.40, 0.80), was statistically lower than that for older persons, at 1.27% (95% CI: 0.76, 1.78). Findings adjusted for publication bias were similar. Limited/suggestive evidence was found for higher associations among women; mortality risks were 0.39% (95% CI: −0.22, 1.00) higher than those for men. We identified strong evidence for higher associations with unemployment or lower occupational status and weak evidence of sensitivity for racial/ethnic minorities and persons with low education, in poverty, or without central air conditioning. Findings show that some populations, especially the elderly, are particularly sensitive to short-term ozone exposure.
doi:10.1093/aje/kwu115
PMCID: PMC4070938  PMID: 24872350
age; air pollution; effect modifiers; hospitalization; mortality; ozone; sex
19.  Pregnancy-Induced Hypertension and Diabetes and the Risk of Cardiovascular Disease, Stroke, and Diabetes Hospitalization in the Year Following Delivery 
American Journal of Epidemiology  2014;180(1):41-44.
Although pregnancy events predict the long-term risk of chronic disease, little is known about their short-term impact because of the rarity of clinical events. We examined hospital discharge diagnoses linked to birth certificate data in the year following delivery for 849,639 births during 1995–2004 in New York City, New York. Adjusted odds ratios characterized the relationship between pregnancy complications and subsequent hospitalization for cardiovascular disease, stroke, and diabetes. Gestational hypertension was related to heart failure (adjusted odds ratio = 2.6, 95% confidence interval: 1.5, 4.5). Preeclampsia was related to all of the outcomes considered except type 1 diabetes, with adjusted odds ratios ranging from 2.0 to 4.1. Gestational diabetes was strongly related to the risk of subsequent diabetes (for type 1 diabetes, adjusted odds ratio = 40.4, 95% confidence interval: 23.8, 68.5; for type 2 diabetes, adjusted odds ratio = 22.6, 95% confidence interval: 16.9, 30.4) but to no other outcomes. The relationship of pregnancy complications to future chronic disease is apparent as early as the year following delivery. Moreover, elucidating short-term clinical outcomes offers the potential for etiological insights into the relationship between pregnancy events and chronic disease over the life course.
doi:10.1093/aje/kwu118
PMCID: PMC4070939  PMID: 24879314
cardiovascular disease; diabetes; gestational diabetes; preeclampsia; pregnancy; stroke
20.  Medication Use in Pregnancy in Relation to the Risk of Isolated Clubfoot in Offspring 
American Journal of Epidemiology  2014;180(1):86-93.
Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007–2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2–4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)2), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21–1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.
doi:10.1093/aje/kwu096
PMCID: PMC4133556  PMID: 24824985
clubfoot; malformation; medications; pregnancy
21.  Cylus et al. Respond to “Unrealized Benefits?” 
American Journal of Epidemiology  2014;180(1):56-57.
doi:10.1093/aje/kwu105
PMCID: PMC4133557  PMID: 24939979
22.  Efficient Estimation of Smooth Distributions From Coarsely Grouped Data 
American Journal of Epidemiology  2015;182(2):138-147.
Ungrouping binned data can be desirable for many reasons: Bins can be too coarse to allow for accurate analysis; comparisons can be hindered when different grouping approaches are used in different histograms; and the last interval is often wide and open-ended and, thus, covers a lot of information in the tail area. Age group–specific disease incidence rates and abridged life tables are examples of binned data. We propose a versatile method for ungrouping histograms that assumes that only the underlying distribution is smooth. Because of this modest assumption, the approach is suitable for most applications. The method is based on the composite link model, with a penalty added to ensure the smoothness of the target distribution. Estimates are obtained by maximizing a penalized likelihood. This maximization is performed efficiently by a version of the iteratively reweighted least-squares algorithm. Optimal values of the smoothing parameter are chosen by minimizing Akaike's Information Criterion. We demonstrate the performance of this method in a simulation study and provide several examples that illustrate the approach. Wide, open-ended intervals can be handled properly. The method can be extended to the estimation of rates when both the event counts and the exposures to risk are grouped.
doi:10.1093/aje/kwv020
PMCID: PMC4493979  PMID: 26081676
grouped data; penalized composite link model; smoothing; ungrouping
23.  African American Race and HIV Virological Suppression: Beyond Disparities in Clinic Attendance 
American Journal of Epidemiology  2014;179(12):1484-1492.
Racial disparities in clinic attendance may contribute to racial disparities in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels among HIV-positive patients in care. Data from 946 African American and 535 Caucasian patients receiving HIV care at the University of North Carolina Center for AIDS Research HIV clinic between January 1, 1999, and August 1, 2012, were used to estimate the association between African American race and HIV virological suppression (i.e., undetectable HIV-1 RNA) when racial disparities in clinic attendance were lessened. Clinic attendance was measured as the proportion of scheduled clinic appointments attended (i.e., visit adherence) or the proportion of six 4-month intervals with at least 1 attended scheduled clinic appointment (i.e., visit constancy). In analyses accounting for patient characteristics, the risk ratio for achieving suppression when comparing African Americans with Caucasians was 0.91 (95% confidence interval: 0.85, 0.98). Lessening disparities in adherence or constancy lowered disparities in virological suppression by up to 44.4% and 11.1%, respectively. Interventions that lessen disparities in adherence may be more effective in eliminating disparities in suppression than interventions that lessen disparities in constancy. Given that gaps in care were limited to be no more than 2 years for both attendance measures, the impact of lessening disparities in adherence may be overstated.
doi:10.1093/aje/kwu069
PMCID: PMC4051874  PMID: 24812158
clinic visits; cohort studies; health status disparities; human immunodeficiency virus; viral load
24.  Human Metabolome Associates With Dietary Intake Habits Among African Americans in the Atherosclerosis Risk in Communities Study 
American Journal of Epidemiology  2014;179(12):1424-1433.
The human metabolome is a measurable outcome of interactions among an individual's inherited genome, microbiome, and dietary intake. We explored the relationship between dietary intake and serum untargeted metabolomic profiles in a subsample of 1,977 African Americans from the Atherosclerosis Risk in Communities (ARIC) Study in 1987–1989. For each metabolite, we conducted linear regression to estimate its relationships with each food group and food category. Potential confounding factors included age, sex, body mass index (weight (kg)/height (m)2), energy intake, kidney function, and food groups. We used a modified Bonferroni correction to determine statistical significance. In total, 48 pairs of diet-metabolite associations were identified, including multiple novel associations. The food group “sugar-rich foods and beverages” was inversely associated with 5 metabolites in the 2-hydroxybutyrate–related subpathway and positively associated with 5 γ-glutamyl dipeptides. The hypothesized mechanism of these associations may be through oxidative stress. “Sugar-rich foods and beverages” were also inversely associated with 7 unsaturated long-chain fatty acids. These findings suggest that the contribution of a sugar-rich dietary pattern to increased cardiovascular disease risk may be partially attributed to oxidative stress and disordered lipid profiles. Metabolomics may reveal novel metabolic biomarkers of dietary intake and provide insight into biochemical pathways underlying nutritional effects on disease development.
doi:10.1093/aje/kwu073
PMCID: PMC4051875  PMID: 24801555
African Americans; dietary habits; metabolomics
25.  Invited Commentary: Parental Smoking as a Risk Factor for Adult Tobacco Use: Can Maternal Smoking During Pregnancy Be Distinguished From the Social Environmental Influence During Childhood? 
American Journal of Epidemiology  2014;179(12):1418-1421.
Parental smoking is known to have prenatal health effects on developing fetuses, and postnatal exposure to secondhand smoke causes adverse health effects during childhood and beyond. Further, there is solid evidence that parental smoking during childhood is a potent risk factor for smoking in offspring. In this issue of the Journal, Rydell et al. (Am J Epidemiol. 2014;179(12):1409–1417) add to a growing body of evidence showing that maternal smoking during pregnancy is statistically associated with the long-term risk of tobacco use in offspring. The data revealed a strong signal between maternal smoking during pregnancy and tobacco use in young adulthood, an association that was largely concentrated in snus use but not cigarette smoking. This new study adds to a growing body of epidemiologic evidence that consistently points toward maternal smoking during pregnancy being associated with an increased risk of offspring tobacco use in later life. There is also evidence from animal models indicating that fetal exposure to maternal nicotine use in utero can have a durable impact on the neural pathways that affect lifetime sensitivity to nicotine. This is an important research topic that continues to yield a consistent signal despite an array of inferential challenges.
doi:10.1093/aje/kwu079
PMCID: PMC4051876  PMID: 24761006
cigarette smoking; parental smoking; pregnancy; risk factors

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