IMPORTANCE: The oral microbiome likely plays key roles in human health. Yet, population-representative characterizations are lacking. OBJECTIVE: To characterize the composition, diversity, and correlates of the oral microbiome in US adults. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study analyzed data from the population-representative National Health and Nutrition Examination Survey (NHANES) from 2009 to 2012. Microbiome data were made publicly available in 2024. NHANES participants were aged 18 to 69 years and provided oral rinse samples in 1 of 2 consecutive NHANES cycles (2009-2010 and 2011-2012). EXPOSURES: Demographic, socioeconomic, behavioral, anthropometric, metabolic, and clinical characteristics. MAIN OUTCOMES AND MEASURES: Oral microbiome measures, characterized through 16S ribosomal RNA gene sequencing, included α diversity (observed amplicon sequence variants [ASVs], Faith phylogenetic diversity, Shannon-Weiner Index, and Simpson Index); β diversity (unweighted UniFrac, weighted UniFrac, and Bray-Curtis dissimilarity); and prevalence and relative abundance at phylum level through genus level. Analyses accounted for the NHANES complex sample design. RESULTS: This study included 8237 US adults aged 18 to 69 years, representing 202 314 000 individuals (102 813 000 men [50.8%]; mean [SD] age, 42.3 [14.4] years; 9.3% self-reported as Mexican American, 12.1% as non-Hispanic Black, 64.7% as non-Hispanic White, 5.9% as other Hispanic, and 8.1% as other non-Hispanic individuals). The oral microbiome encompassed 37 bacterial phyla, 99 classes, 212 orders, 446 families, and 1219 genera. Five phyla (Firmicutes, Actinobacteria, Bacteroidetes, Proteobacteria, and Fusobacteria) and 6 genera (Veillonella, Streptococcus, Prevotella 7, Rothia, Actinomyces, and Gemella) were present in nearly all US adults (weighted prevalence, >99%). These genera were the most abundant, accounting for 65.7% of total abundance. Observed ASVs showed a quadratic pattern with age (peak at 30 years), were similar by sex, significantly lower among non-Hispanic White individuals, and increased with greater body mass index (BMI), alcohol use, and periodontal disease severity. All covariates together accounted for a modest proportion of oral microbiome variability as measured by β diversity: R2 = 8.7% (95% CI, 8.4%-9.1%) for unweighted UniFrac, R2 = 7.2% (95% CI, 6.6%-7.7%) for weighted UniFrac, and R2 = 6.3% (95% CI, 3.1%-6.7%) for Bray-Curtis matrices. By contrast, relative abundance of a few genera explained a high percentage of variability in β diversity for weighted UniFrac: Aggregatibacter (R2 = 22.4%; 95% CI, 22.1%-22.8%), Lactococcus (R2 = 21.6%; 95% CI, 20.9%-22.3%), and Haemophilus (R2 = 18.4%; 95% CI, 18.1%-18.8%). Prevalence and relative abundance of numerous genera were associated with age, race and ethnicity, smoking, BMI categories, alcohol use, and periodontal disease severity. CONCLUSIONS AND RELEVANCE: This cross-sectional study of the oral microbiome in US adults showed that a few genera were universally present and a different set of genera explained a high percentage of oral microbiome diversity across the population. This comprehensive characterization provides a contemporary reference standard for future studies.

BACKGROUND: Chronic respiratory diseases (CRDs) are the third leading cause of death worldwide. Data of the associations between specific volatile organic compounds (VOCs), a major component of air pollution and tobacco smoke, and subsequent CRD mortality in the general population are scarce. METHODS: In a case-cohort analysis within the population-based Golestan cohort study (n = 50045, aged 40-75 years, 58% women, enrollment: 2004-2008, northeastern Iran), we included all participants who died from CRD during follow-up through 2018 (n = 242) as cases and stratified them into 16 strata defined by age, sex, residence, and tobacco smoking. Subcohort participants (n = 610) were randomly selected from all eligible cohort participants in each stratum, and sampling fractions were calculated. Baseline urine samples were used to measure 20 VOCs using ultra high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. After excluding participants with previous history of CRDs, we used stratified Cox regression models weighted by the inverse sampling fractions (i.e. inverse probability weighting) adjusted for potential confounders, including urinary cotinine and pack-years of smoking, to calculate hazard ratios (HR) for the associations between biomarker tertiles and CRD mortality. RESULTS: Data from 545 non-case, sub-cohort participants and 149 cases (69.1% chronic obstructive pulmonary disease, 13.4% asthma, 17.5% other CRDs) were assessed in this study. During a follow-up of 10.5 years, associations [2nd and 3rd vs. 1st tertiles, HR (95% confidence interval), p for trend] were observed between metabolites of acrolein [1.56 (0.64,3.79), 3.53 (1.53,8.16), 0.002] and styrene/ethylbenzene [1.17 (0.53,2.60), 3.24 (1.37,7.66), 0.005] and CRD mortality, which persisted after excluding the first four years of follow-up. CONCLUSION: Our findings support prior research suggesting respiratory toxicity of VOCs. Further investigation and monitoring of these compounds, especially acrolein and styrene/ethylbenzene, as CRD risk factors, are recommended.

Background: Volatile organic compounds (VOCs) are major components of air pollution and tobacco smoke, two known risk factors for cardiovascular diseases. VOCs are ubiquitous in the environment and originate from a wide range of sources, including the burning of biomass, fossil fuels, and consumer products. Direct evidence for associations between specific VOCs and ischemic heart disease (IHD) mortality in the general population is scarce. Methods: In a case-cohort study (stratified by age groups, sex, residence, and tobacco smoking), nested within the population-based Golestan cohort study (n = 50,045, 40–75 years, 58% women, enrollment: 2004–2008) in northeastern Iran, we measured urinary concentrations of 20 smoking-related VOC biomarkers using ultra high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. We calculated hazard ratio (HR) and 95% confidence interval (CI) for their associations with IHD mortality during follow-up to 2018, using Cox regression models adjusted for age, ethnicity, education, marital status, body mass index, physical activity, wealth, and urinary cotinine. Results: There were 575 non-cases from random subcohort and 601 participants who died from IHD, mean (standard deviation) age, 58.2 (9.3) years, with a median of 8.4 years follow-up. Significant associations [3rd vs. 1st tertile, HR (95% CI), P for trend] were observed between biomarkers of acrylamide [1.68(1.05,2.69), 0.025], acrylonitrile [2.06(1.14,3.72), 0.058], acrolein [1.98(1.30,3.01), 0.003 and 2.44(1.43,4.18), 0.002], styrene/ethylbenzene [1.83(1.19,2.84), 0.007 and 1.44(1.01,2.07), 0.046], dimethylformamide/methylisocyanate [2.15(1.33,3.50), 0.001], and 1,3butadiene [2.35(1.52,3.63),<0.001] and IHD mortality. These associations were independent of tobacco smoking, and they were only present in the non-smoking subgroup. Conclusion: Our findings provide direct evidence for associations between exposure to several VOCs with widespread household and commercial use and IHD mortality many years after these exposures. These results highlight the importance of VOC exposure in the general population as a risk factor for cardiovascular diseases and underline the importance of bio-monitoring non-tobacco VOC exposure. © 2024

BACKGROUND: The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths. OBJECTIVE: Our purpose was to characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation. METHODS: We conducted a case-control study of lung cancer nested in a cohort of 12,315 workers in eight nonmetal mines (376 lung cancer deaths, 718 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 y). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. To evaluate time windows of exposure, we evaluated the joint OR patterns for cumulative REC within each of four preselected exposure time windows,  < 5, 5-9, 10-19, and  ≥ 20 y prior to death/reference date, and we evaluated the interaction of cumulative exposure across time windows under additive and multiplicative forms for the joint association. RESULTS: ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of  ∼ 950 to < 1,700 μg/m3-y [OR = 3.23; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed (OR = 1.85; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows (phomogeneity < 0.001), with ORs increasing for exposures accrued primarily 10-19 y prior to death (ptrend < 0.001). Results provided little support for a waning of risk among workers whose exposures ceased for  ≥ 20 y. CONCLUSION: DEMS II findings provide insight into the exposure-response relationship between diesel exhaust and lung cancer mortality. The pronounced effect of exposures occurring in the window 10-19 y prior to death, the sustained risk 20 or more years after exposure ceases, and the plateau/decline in risk among the most heavily exposed provide direction for future research on the mechanism of diesel-induced carcinogenesis in addition to having important implications for the assessment of risk from diesel exhaust by regulatory agencies. https://doi.org/10.1289/EHP11980.

This cohort study uses National Health and Nutrition Examination Survey data to estimate the number of deaths that could be prevented through increased physical activity among US adults.

Importance: It is unclear whether the number of steps per day and the intensity of stepping are associated with lower mortality. Objective: Describe the dose-response relationship between step count and intensity and mortality. Design, Setting, and Participants: Representative sample of US adults aged at least 40 years in the National Health and Nutrition Examination Survey who wore an accelerometer for up to 7 days ( from 2003-2006). Mortality was ascertained through December 2015. Exposures: Accelerometer-measured number of steps per day and 3 step intensity measures (extended bout cadence, peak 30-minute cadence, and peak 1-minute cadence [steps/min]). Accelerometer data were based on measurements obtained during a 7-day period at baseline. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular disease (CVD) and cancer mortality. Hazard ratios (HRs), mortality rates, and 95% CIs were estimated using cubic splines and quartile classifications adjusting for age; sex; race/ethnicity; education; diet; smoking status; body mass index; self-reported health; mobility limitations; and diagnoses of diabetes, stroke, heart disease, heart failure, cancer, chronic bronchitis, and emphysema. Results: A total of 4840 participants (mean age, 56.8 years; 2435 [54%] women; 1732 [36%] individuals with obesity) wore accelerometers for a mean of 5.7 days for a mean of 14.4 hours per day. The mean number of steps per day was 9124. There were 1165 deaths over a mean 10.1 years of follow-up, including 406 CVD and 283 cancer deaths. The unadjusted incidence density for all-cause mortality was 76.7 per 1000 person-years (419 deaths) for the 655 individuals who took less than 4000 steps per day; 21.4 per 1000 person-years (488 deaths) for the 1727 individuals who took 4000 to 7999 steps per day; 6.9 per 1000 person-years (176 deaths) for the 1539 individuals who took 8000 to 11999 steps per day; and 4.8 per 1000 person-years (82 deaths) for the 919 individuals who took at least 12000 steps per day. Compared with taking 4000 steps per day, taking 8000 steps per day was associated with significantly lower all-cause mortality (HR, 0.49 [95% CI, 0.44-0.55]), as was taking 12000 steps per day (HR, 0.35 [95% CI, 0.28-0.45]). Unadjusted incidence density for all-cause mortality by peak 30 cadence was 32.9 per 1000 person-years (406 deaths) for the 1080 individuals who took 18.5 to 56.0 steps per minute; 12.6 per 1000 person-years (207 deaths) for the 1153 individuals who took 56.1 to 69.2 steps per minute; 6.8 per 1000 person-years (124 deaths) for the 1074 individuals who took 69.3 to 82.8 steps per minute; and 5.3 per 1000 person-years (108 deaths) for the 1037 individuals who took 82.9 to 149.5 steps per minute. Greater step intensity was not significantly associated with lower mortality after adjustment for total steps per day (eg, highest vs lowest quartile of peak 30 cadence: HR, 0.90 [95% CI, 0.65-1.27]; P value for trend = .34). Conclusions and Relevance: Based on a representative sample of US adults, a greater number of daily steps was significantly associated with lower all-cause mortality. There was no significant association between step intensity and mortality after adjusting for total steps per day.

In August 2017 the National Center for Health Statistics (NCHS), part of the U.S. Federal Statistical System, published new standards for determining the reliability of proportions estimated using their data. These standards require an individual to take the Korn-Graubard confidence interval (CI), along with CI widths, sample size, and degrees of freedom, to assess reliability of a proportion and determine if it can be presented. The assessment itself involves determining if several conditions are met. This manuscript presents kg_nchs, a postestimation command that is used following svy: proportion. It allows Stata users to (a) calculate the Korn-Graubard CI and associated statistics used in applying the NCHS presentation standards for proportions, and (b) display a series of three dichotomous flags that show if the standards are met. The empirical examples provided show how kg_nchs can be used to easily apply the standards and prevent Stata users from needing to perform manual calculations. While developed for NCHS survey data, this command can also be used with data that stems from any survey with a complex sample design.

Residents of agricultural areas experience pesticide exposures from sources other than direct agricultural work. We developed a quantitative, active ingredient-specific algorithm for cumulative (adult, married lifetime) non-occupational pesticide exposure intensity for spouses of farmers who applied pesticides in the Agricultural Health Study (AHS). The algorithm addressed three exposure pathways: take-home, agricultural drift, and residential pesticide use. Pathway-specific equations combined (i) weights derived from previous meta-analyses of published pesticide exposure data and (ii) information from the questionnaire on frequency and duration of pesticide use by applicators, home proximity to treated fields, residential pesticide usage (e.g., termite treatments), and spouse's off-farm employment (proxy for time at home). The residential use equation also incorporated a published probability matrix that documented the likelihood active ingredients were used in home pest treatment products. We illustrate use of these equations by calculating exposure intensities for the insecticide chlorpyrifos and herbicide atrazine for 19,959 spouses. Non-zero estimates for >/=1 pathway were found for 78% and 77% of spouses for chlorpyrifos and atrazine, respectively. Variability in exposed spouses' intensity estimates was observed for both pesticides, with 75th to 25th percentile ratios ranging from 7.1 to 7.3 for take-home, 6.5 to 8.5 for drift, 2.4 to 2.8 for residential use, and 3.8 to 7.0 for the summed pathways. Take-home and drift estimates were highly correlated (>/=0.98), but were not correlated with residential use (0.010.02). This algorithm represents an important advancement in quantifying non-occupational pesticide relative exposure differences and will facilitate improved etiologic analyses in the AHS spouses. The algorithm could be adapted to studies with similar information.

INTRODUCTION: We examined the prevalence of cancer screening reported in 2015 among US adults, adjusted for important sociodemographic and access-to-care variables. By using data from the National Health Interview Survey (NHIS) for 2000 through 2015, we examined trends in prevalence of cancer screening that adhered to US Preventive Services Task Force screening recommendations in order to monitor screening progress among traditionally underserved population subgroups. METHODS: We analyzed NHIS data from surveys from 2000 through 2015 to estimate prevalence and trends in use of recommended screening tests for breast, cervical, colorectal, and prostate cancers. We used logistic regression and report predictive margins for population subgroups adjusted for various socioeconomic and demographic variables. RESULTS: Colorectal cancer screening was the only test that increased during the study period. We found disparities in prevalence of test use among subgroups for all tests examined. Factors that reduced the use of screening tests included no contact with a doctor in the past year, no usual source of health care, and no insurance coverage. CONCLUSION: Understanding use of cancer screening tests among different population subgroups is vital for planning public health interventions with potential to increase screening uptake and reduce disparities in cancer morbidity and mortality. Overarching goals of Healthy People 2020 are to "achieve health equity, eliminate disparities, and improve the health of all groups." Adjusted findings for 2015, compared with previous years, show persistent screening disparities, particularly among the uninsured, and progress for colorectal cancer screening only.

Misclassification of body mass index (BMI) categories arising from self-reported weight and height can bias hazard ratios in studies of BMI and mortality. We examined the effects on hazard ratios of such misclassification using national US survey data for 1976 through 2010 that had both measured and self-reported weight and height along with mortality follow-up for 48,763 adults and a subset of 17,405 healthy never-smokers. BMI was categorized as <22.5 (low), 22.5-24.9 (referent), 25.0-29.9 (overweight), 30.0-34.9 (class I obesity), and >/=35.0 (class II-III obesity). Misreporting at higher BMI categories tended to bias hazard ratios upwards for those categories, but that effect was augmented, counterbalanced, or even reversed by misreporting in other BMI categories, in particular those that affected the reference category. For example, among healthy male never-smokers, misclassifications affecting the overweight and the reference categories changed the hazard ratio for overweight from 0.85 with measured data to 1.24 with self-reported data. Both the magnitude and direction of bias varied according to the underlying hazard ratios in measured data, showing that findings on bias from one study should not be extrapolated to a study with different underlying hazard ratios. Because of misclassification effects, self-reported weight and height cannot reliably indicate the lowest-risk BMI category.

Marijuana has been reported to have several effects on the male reproductive system. Marijuana has previously been linked to reduced adult testosterone, however, a study in Denmark reported increased testosterone concentrations among marijuana users. This study was performed to estimate the effect of marijuana use on testosterone in U.S. males. Data on serum testosterone, marijuana use, and covariates for 1577 men from the 2011-2012 U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. Information on marijuana use was collected by a self-administered computer-assisted questionnaire. Serum testosterone was determined using isotope dilution liquid chromatography tandem mass spectrometry. The effects of marijuana use on serum testosterone concentrations were examined by frequency, duration, and recency of use. Adjusted means and 95% confidence intervals (CI) of serum testosterone across levels of marijuana use were estimated using multiple linear regression weighted by the survey weights. The majority (66.2%) of the weighted study population reported ever using marijuana with 26.6% reporting current marijuana use. There was no difference in serum testosterone between ever users (adjusted mean = 3.69 ng/mL, 95% CI: 3.46, 3.93) and never users (adjusted mean = 3.70 ng/mL, 95% CI: 3.45, 3.98) upon multivariable analysis. However, serum testosterone was inversely associated with time since last regular use of marijuana (p-value for trend = 0.02). When restricted to men aged 18-29 years, this relationship strengthened (p-value for trend <0.01), and serum testosterone was also inversely associated with time since last use (p-value for trend <0.01), indicating that recency of use, and not duration or frequency, had the strongest relationship with testosterone levels. Serum testosterone concentrations were higher in men with more recent marijuana use. Studies are needed to determine the extent to which circulating testosterone concentrations mediate the relationship of marijuana use with male reproductive outcomes.

OBJECTIVES: Trichloroethylene, a chlorinated solvent widely used for metal degreasing, is classified by the International Agency for Research on Cancer as a kidney carcinogen. Other chlorinated solvents are suspected carcinogens, most notably the cleaning solvent perchloroethylene, although it is unclear whether they are associated with kidney cancer. We investigated kidney cancer associations with occupational exposure to 6 chlorinated solvents (trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride) within a case-control study using detailed exposure assessment methods. METHODS: Cases (n=1217) and controls (n=1235) provided information on their occupational histories and, for selected occupations, on tasks involving potential exposure to chlorinated solvents through job-specific interview modules. Using this information, an industrial hygienist assessed potential exposure to each solvent. We computed ORs and 95% CIs for different exposure metrics, with unexposed participants as the referent group. RESULTS: 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride were not associated with kidney cancer. Among jobs with high exposure intensity, high cumulative hours exposed to perchloroethylene was associated with increased risk, both overall (third tertile vs unexposed: OR 3.1, 95% CI 1.3 to 7.4) and after excluding participants with ≥50% exposure probability for trichloroethylene (OR 3.0, 95% CI 0.99 to 9.0). A non-significant association with high cumulative hours exposed to trichloroethylene was observed (OR 1.7, 95% CI 0.8 to 3.8). CONCLUSIONS: In this study, high exposure to perchloroethylene was associated with kidney cancer, independent of trichloroethylene. Additional studies are needed to further investigate this finding.

The Physical Activity Monitor component was introduced into the 2003-2004 National Health and Nutrition Examination Survey (NHANES) to collect objective information on physical activity including both movement intensity counts and ambulatory steps. Because of an error in the accelerometer device initialization process, the steps data were missing for all participants in several primary sampling units, typically a single county or group of contiguous counties, who had intensity count data from their accelerometers. To avoid potential bias and loss in efficiency in estimation and inference involving the steps data, we considered methods to accurately impute the missing values for steps collected in the 2003-2004 NHANES. The objective was to come up with an efficient imputation method that minimized model-based assumptions. We adopted a multiple imputation approach based on additive regression, bootstrapping and predictive mean matching methods. This method fits alternative conditional expectation (ace) models, which use an automated procedure to estimate optimal transformations for both the predictor and response variables. This paper describes the approaches used in this imputation and evaluates the methods by comparing the distributions of the original and the imputed data. A simulation study using the observed data is also conducted as part of the model diagnostics. Finally, some real data analyses are performed to compare the before and after imputation results.

BACKGROUND: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. OBJECTIVE: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. METHODS: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). RESULTS: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥20%, respectively (88 statistics, 5 studies). CONCLUSION: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available.

PURPOSE: Obesity is a highly prevalent condition in the United States and elsewhere and is associated with increased mortality and morbidity. Here, we discuss some issues involved in quantifying the health burden of obesity using population attributable fraction (PAF) estimates and provide examples. METHODS: We searched PubMed for articles reporting attributable fraction estimates for obesity. We reviewed eligible articles to identify methodological concerns and tabulated illustrative examples of PAF estimates for obesity relative to cancer, diabetes, cardiovascular disease, and all-cause mortality. RESULTS: There is considerable variability among studies regarding the methods used for PAF calculation and the selection of appropriate counterfactuals. The reported estimates ranged from 5% to 15% for all-cause mortality, -0.2% to 8% for all-cancer incidence, 7% to 44% for cardiovascular disease incidence, and 3% to 83% for diabetes incidence. CONCLUSIONS: To evaluate a given estimate, it is important to consider whether the exposure and outcome were defined similarly for the PAF and for the relative risks, whether the relative risks were suitable for the population at hand, and whether PAF was calculated using correct methods. Strong causal assumptions are not necessarily warranted. In general, PAFs for obesity may be best considered as indicators of association.

We thank Dr. Stevens for her observations (1). We agree with Stevens that standardized body mass index (BMI; weight (kg)/height (m)2) cutpoints can aid comparisons among studies examining different populations. The standard BMI cutpoints of 18.5, 25, and 30, indicating underweight (<18.5), normal weight (18.5–<25), overweight (25–<30), and obesity (≥30), were developed by the National Heart, Lung, and Blood Institute (2) and the World Health Organization (WHO) (3) and were reiterated in the 2013 obesity guidelines (4). Since their inception, these standards have been widely used in studies of BMI and risk of death and appear to be well accepted. In a previous systematic search (5), we found well over 100 published studies of weight and mortality as of 2012 that had reported results using those standard categories, including approximately half of the studies published since 2000. Turner et al. (6) used those BMI standards as their example of an approach to categorization that used well-recognized, published boundaries. In our article (7), we did not suggest that a new or augmented set of standards was needed. Rather, we emphasized that use of the current standard BMI groupings in analysis would avoid issues arising from ad hoc and post hoc selection of BMI categories. Finer BMI categories are not clearly necessary and can create problems of interpretation.

The World Health Organization (Geneva, Switzerland) and the National Heart, Lung, and Blood Institute (Bethesda, Maryland) have developed standard categories of body mass index (BMI) (calculated as weight (kg)/height (m)(2)) of less than 18.5 (underweight), 18.5-24.9 (normal weight), 25.0-29.9 (overweight), and 30.0 or more (obesity). Nevertheless, studies of BMI and the risk of death sometimes use nonstandard BMI categories that vary across studies. In a meta-analysis of 8 large studies that used nonstandard BMI categories and were published between 1999 and 2014 and included 5.8 million participants, hazard ratios tended to be small throughout the range of overweight and normal weight. Risks were similar between subjects of high-normal weight (BMI of approximately 23.0-24.9) and those of low overweight (BMI of approximately 25.0-27.4). In an example using national survey data, minor variations in the reference category affected hazard ratios. For example, choosing high-normal weight (BMI of 23.0-24.9) instead of standard normal weight (BMI of 18.5-24.9) as the reference category produced higher nonsignificant hazard ratios (1.05 vs. 0.97 for men and 1.06 vs. 1.02 for women) for the standard overweight category (BMI of 25.0-29.9). Use of the standard BMI groupings avoids problems of ad hoc and post hoc category selection and facilitates between-study comparisons. The ways in which BMI data are categorized and reported may shape inferences about the degree of risk for various BMI categories.

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the United States (U.S.) population. Stored serum samples from National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999-2004 were available for 12 482 persons age ≥50 years (2331 'black', 2475 Hispanics, 7051 'white', and 625 'others') on which agarose-gel electrophoresis, serum protein immunofixation, serum free light-chain assay, and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the U.S., respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in prevalence of MGUS between the North/Midwest versus the South/West regions of the U.S. was found, which has etiologic implications.

IMPORTANCE: Estimates of the relative mortality risks associated with normal weight, overweight, and obesity may help to inform decision making in the clinical setting. OBJECTIVE: To perform a systematic review of reported hazard ratios (HRs) of all-cause mortality for overweight and obesity relative to normal weight in the general population. DATA SOURCES: PubMed and EMBASE electronic databases were searched through September 30, 2012, without language restrictions. STUDY SELECTION: Articles that reported HRs for all-cause mortality using standard body mass index (BMI) categories from prospective studies of general populations of adults were selected by consensus among multiple reviewers. Studies were excluded that used nonstandard categories or that were limited to adolescents or to those with specific medical conditions or to those undergoing specific procedures. PubMed searches yielded 7034 articles, of which 141 (2.0%) were eligible. An EMBASE search yielded 2 additional articles. After eliminating overlap, 97 studies were retained for analysis, providing a combined sample size of more than 2.88 million individuals and more than 270,000 deaths. DATA EXTRACTION: Data were extracted by 1 reviewer and then reviewed by 3 independent reviewers. We selected the most complex model available for the full sample and used a variety of sensitivity analyses to address issues of possible overadjustment (adjusted for factors in causal pathway) or underadjustment (not adjusted for at least age, sex, and smoking). RESULTS: Random-effects summary all-cause mortality HRs for overweight (BMI of 25-<30), obesity (BMI of ≥30), grade 1 obesity (BMI of 30-<35), and grades 2 and 3 obesity (BMI of ≥35) were calculated relative to normal weight (BMI of 18.5-<25). The summary HRs were 0.94 (95% CI, 0.91-0.96) for overweight, 1.18 (95% CI, 1.12-1.25) for obesity (all grades combined), 0.95 (95% CI, 0.88-1.01) for grade 1 obesity, and 1.29 (95% CI, 1.18-1.41) for grades 2 and 3 obesity. These findings persisted when limited to studies with measured weight and height that were considered to be adequately adjusted. The HRs tended to be higher when weight and height were self-reported rather than measured. CONCLUSIONS AND RELEVANCE: Relative to normal weight, both obesity (all grades) and grades 2 and 3 obesity were associated with significantly higher all-cause mortality. Grade 1 obesity overall was not associated with higher mortality, and overweight was associated with significantly lower all-cause mortality. The use of predefined standard BMI groupings can facilitate between-study comparisons.

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 1988-1991 and 1999-2004. We also examined sex hormone-binding globulin (SHBG), estradiol, and androstanediol glucuronide (3alpha-diol-G) over the same period. Non-Hispanic white, non-Hispanic black, and Mexican-American men from 1988-1991 and 1999-2004 NHANES surveys who were ≥20 years old and had serum from morning blood draws were included in this analysis (1988-1991: N = 1,413; 1999-2004: N = 902). Testosterone, estradiol and SHBG were measured by competitive electrochemiluminescence immunoassays and 3alpha-diol-G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use and smoking. Differences in adjusted mean concentrations (Delta) and two-sided p-values were calculated; p < 0.05 was statistically significant. Overall, 3alpha-diol-G and estradiol declined between 1988-1991 and 1999-2004, but there was little change in testosterone, free testosterone, or SHBG (Delta: 3alpha-diol-G = -1.83 ng/mL, p < 0.01; estradiol = -6.07 pg/mL, p < 0.01; testosterone = -0.03 ng/mL, p = 0.75; free testosterone = -0.001 ng/mL, p = 0.67; SHBG = -1.17 nmol/L, p = 0.19). Stratification by age and race revealed that SHBG and 3alpha-diol-G declined among whites 20-44 years old (Delta: SHBG = -5.14 nmol/L, p < 0.01; 3alpha-diol-G = -2.89 ng/mL, p < 0.01) and free testosterone increased among blacks 20-44 years old (Delta: 0.014 ng/mL, p = 0.03). Estradiol declined among all ages of whites and Mexican-Americans. In conclusion, there was no evidence for testosterone decline between 1988-1991 and 1999-2004 in the US general population. Subgroup analyses suggest that SHBG and 3alpha-diol-G declined in young white men, estradiol declined in white and Mexican-American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men.

INTRODUCTION: Sexual transmission of human herpesvirus 8 (HHV8) has been implicated among homosexual men, but the evidence for sexual transmission among heterosexual individuals is controversial. We investigated the role of sexual transmission of HHV8 in a nationally representative sample in Uganda, where HHV8 infection is endemic and transmitted mostly during childhood. MATERIALS AND METHODS: The study population was a subset of participants (n = 2681) from a population-based HIV/AIDS serobehavioral survey of adults aged 15-59 years conducted in 2004/2005. High risk for sexual transmission was assessed by questionnaire and serological testing for HIV and herpes simplex virus 2. Anti-HHV8 antibodies were measured using two enzyme immunoassays targeting synthetic peptides from the K8.1 and orf65 viral genes. The current study was restricted to 2288 sexually active adults. ORs and 95% CIs for HHV8 seropositivity were estimated by fitting logistic regression models with a random intercept using MPLUS and SAS software. RESULTS: The weighted prevalence of HHV8 seropositivity was 56.2%, based on 1302 seropositive individuals, and it increased significantly with age (P(trend)<0.0001). In analyses adjusting for age, sex, geography, education, and HIV status, HHV8 seropositivity was positively associated with reporting two versus one marital union (OR:1.52, 95% CI: 1.17-1.97) and each unit increase in the number of children born (OR: 1.04, 95% CI: 1.00-1.08), and was inversely associated with ever having used a condom (OR: 0.64, 95% CI: 0.45-0.89). HHV8 seropositivity was not associated with HIV (P = 0.660) or with herpes simplex virus 2 (P = 0.732) seropositivity. Other sexual variables, including lifetime number of sexual partners or having had at least one sexually transmitted disease, and socioeconomic variables were unrelated to HHV8 seropositivity. CONCLUSION: Our findings are compatible with the conclusion that sexual transmission of HHV8 in Uganda, if it occurs, is weak.

BACKGROUND: Previous analyses from the National Health and Nutrition Examination Survey (NHANES III) have found that elevated blood lead levels may be associated with cardiovascular mortality, cancer mortality, and all-cause mortality. The 5-aminolevulinic acid dehydratase (ALAD) G177C genetic polymorphism (rs 1800435) affects lead toxicokinetics and may alter the adverse effects of lead exposure. We examined whether the ALAD G177C single nucleotide polymorphism (SNP) affects the relationship between lead and mortality. METHODS: We analyzed a subset of 3349 genotyped NHANES III participants at least 40 years of age. Using Cox proportional hazards regression, we estimated the relative risk of all-cause, cardiovascular disease, and cancer mortality by ALAD genotype, and by blood lead levels (<5 mug/dL vs. ≥5 mug/dL). We also tested whether the ALAD genotype modified the relationship between blood lead level and mortality. RESULTS: The adjusted overall relative risk for participants with the variant ALAD genotype was decreased for all-cause mortality (hazards ratio = 0.68; [95% confidence interval = 0.50-0.93]) compared with persons having the common GG genotype. There was some suggestion that higher lead levels were associated with cancer mortality (1.48 [0.92-2.38]). We observed no convincing interaction effect between ALAD genotype and blood lead level on mortality risk. CONCLUSION: The ALAD genotype may be associated with decreased mortality from all causes and from cancer. This association does not seem to be affected by lead exposure.

In studies of weight and mortality, the construct of reverse causation has come to be used to imply that the exposure-outcome relation is biased by weight loss due to preexisting illness. Observed weight-mortality associations are sometimes thought to result from this bias. Evidence for the occurrence of such bias is weak and inconsistent, suggesting that either the analytical methods used have been inadequate or else illness-related weight loss is not an important source of bias. Deleting participants has been the most frequent approach to control possible bias. As implemented, this can lead to deletion of almost 90% of all deaths in a sample and to deletion of more overweight and obese participants than participants with normal or below normal weight. Because it has not been demonstrated that the procedures used to adjust for reverse causation increase validity or have large or systematic effects on relative risks, it is premature to consider reverse causation as an important cause of bias. Further research would be useful to elucidate the potential effects and importance of reverse causation or illness-related weight loss as a source of bias in the observed associations between weight and mortality in cohort studies.

Vitamin D has been hypothesized to protect against cancer. We followed 16,819 participants in NHANES III (Third National Health and Nutritional Examination Survey) from 1988 to 2006, expanding on an earlier NHANES III study (1988-2000). Using Cox proportional hazards regression models, we examined risk related to baseline serum 25-hydroxyvitamin D [25(OH)D] for total cancer mortality, in both sexes, and by racial/ethnic groups, as well as for site-specific cancers. Because serum was collected in the south in cooler months and in the north in warmer months, we examined associations by collection season ("summer/higher latitude" and "winter/lower latitude"). We identified 884 cancer deaths during 225,212 person-years. Overall cancer mortality risks were unrelated to baseline 25(OH)D status in both season/latitude groups, and in non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. In men, risks were elevated at higher levels {e.g., for ≥100 nmol/L, relative risk (RR) = 1.85 [95% confidence interval (CI), 1.02-3.35] compared with <37.5 nmol/L}. Although risks were unrelated to 25(OH)D in all women combined, risks significantly decreased with increasing 25(OH)D in the summer/higher latitude group [for ≥100 nmol/L, RR = 0.52 (95% CI, 0.25-1.15) compared with <37.5 nmol/L; P(trend) = 0.03, based on continuous values]. We also observed a suggestion of an inverse association with colorectal cancer mortality (P(trend) = 0.09) and a positive association with lung cancer mortality among males (P(trend) = 0.03). Our results do not support the hypothesis that 25(OH)D is associated with reduced cancer mortality. Although cancer mortality in females was inversely associated with 25(OH)D in the summer/higher latitude group, cancer mortality at some sites was increased among men with higher 25(OH)D. These findings argue for caution before increasing 25(OH)D levels to prevent cancer.

BACKGROUND: Body mass index (BMI)-for-age has been recommended as a screening test for excess adiposity in children and adolescents. OBJECTIVE: We quantified the performance of standard categories of BMI-for-age relative to the population prevalence of high adiposity in children and adolescents overall and by race-ethnic group in a nationally representative US population sample by using definitions of high adiposity that are consistent with expert committee recommendations. DESIGN: Percentage body fat in 8821 children and adolescents aged 8-19 y was measured by using dual-energy X-ray absorptiometry in 1999-2004 as part of a health examination survey. RESULTS: With the use of several different cutoffs for percentage fat to define high adiposity, most children with high BMI-for-age (> or = 95th percentile of the growth charts) had high adiposity, and few children with normal BMI-for-age (<85th percentile) had high adiposity. The prevalence of high adiposity in intermediate BMI categories varied from 45% to 15% depending on the cutoff. The prevalence of a high BMI was significantly higher in non-Hispanic black girls than in non-Hispanic white girls, but the prevalence of high adiposity was not significantly different. CONCLUSIONS: Current BMI cutoffs can identify a high prevalence of high adiposity in children with high BMI-for-age and a low prevalence of high adiposity in children with normal BMI-for-age. By these adiposity measures, less than one-half of children with intermediate BMIs-for-age (85th to <95th percentile) have high adiposity. Differences in high BMI ranges between race-ethnic groups do not necessarily indicate differences in high adiposity.

BACKGROUND: Estimates of obesity-associated deaths in the United States for 1991 were published by Allison et al and subsequently for 2000 by Mokdad et al. Flegal et al then published lower estimates of obesity-associated deaths for 2000. All 3 studies incorporated data from the first National Health and Nutrition Examination Survey (NHANES I). OBJECTIVE: The objective was to clarify the effects of methodologic differences between the 3 studies in estimates of obesity-associated deaths in the US population by using NHANES I hazard ratios. DESIGN: The earlier reports used imputed smoking data for much of the NHANES I sample rather than the available reported data and applied a method of calculating attributable fractions that did not adjust for the effects of age, sex, and smoking on mortality in the target US population and did not account for effect modification by age. The effects of these and other methodologic factors were examined. RESULTS: The NHANES I hazard ratios in the earlier reports were too low, probably because of the imputed smoking data. The low hazard ratios obscured the magnitude and direction of the bias arising from the incompletely adjusted attributable fraction method. When corrected hazard ratios were used, the incompletely adjusted attributable fraction method overestimated obesity-associated mortality in the target population by >100,000 deaths. CONCLUSION: Methodologic sources of bias in the reports by Allison et al and Mokdad et al include the assessment of smoking status in NHANES I and the method of calculating attributable fractions.

BACKGROUND: The etiologies of the male urogenital anomalies cryptorchidism and hypospadias are poorly understood. It has been suggested, however, that in utero hormone levels may be related to risk. Endocrine-disrupting chemicals, including polychlorinated biphenyl (PCB) compounds, may alter hormone levels and thereby affect the fetus. OBJECTIVES: To examine whether in utero PCB exposure is related to cryptorchidism and hypospadias, we examined PCB levels among pregnant women enrolled in the Collaborative Perinatal Project (CPP). METHODS: The CPP enrolled pregnant women at 12 U.S. medical centers between 1959 and 1965. For the present research, we analyzed third-trimester serum samples from the mothers of 230 sons with cryptorchidism, 201 sons with hypospadias, and 593 sons with neither condition. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression and examined the associations of each anomaly with individual PCB congener levels, sum of PCBs, and several functional groupings of PCBs. RESULTS: In general, the ORs for cryptorchidism or hypospadias showed no notable associations with individual PCB congener levels or functional groupings of PCBs. However, the ORs and 95% CIs for the sum of PCBs associated with hypospadias were as follows: 0-1.9 microg/L, reference group; 2-2.9 microg/L, OR = 1.57, 95% CI, 1.05-2.34; 3-3.9 microg/L, OR = 1.45, 95% CI, 0.90-2.34; and > or = 4.0 microg/L, OR = 1.69, 95% CI, 1.06-2.68; p-value for trend = 0.08. CONCLUSIONS: Given the large number of associations examined, these findings do not strongly support the hypothesis that PCBs are associated with cryptorchidism or hypospadias. Because population serum PCB levels at the time of sample collection were considerably higher than levels at present, it is unlikely that current PCB exposure is related to the development of either anomaly.