Improved two-step testing of genome-wide gene–environment interactions

Two-step tests for gene–environment ($G\times E$) interactions exploit marginal single-nucleotide polymorphism (SNP) effects to improve the power of a genome-wide interaction scan. They combine a screening step based on marginal effects used to “bin” SNPs for weighted hypothesis testing in the second step to deliver greater power over single-step tests while preserving the genome-wide Type I error. However, the presence of many SNPs with detectable marginal effects on the trait of interest can reduce power by “displacing” true interactions with weaker marginal effects and by adding to the number of tests that need to be corrected for multiple testing. We introduce a new significance-based allocation into bins for Step-2 $G\times E$ testing that overcomes the displacement issue and propose a computationally efficient approach to account for multiple testing within bins. Simulation results demonstrate that these simple improvements can provide substantially greater power than current methods under several scenarios. An application to a multistudy collaboration for understanding colorectal cancer reveals a G × Sex interaction located near the SMAD7 gene.     

Associations of Pre- and Postnatal Air Pollution Exposures with Child Blood Pressure and Modification by Maternal Nutrition: A Prospective Study in the CANDLE Cohort

Background: Limited data suggest air pollution exposures may contribute to pediatric high blood pressure (HBP), a known predictor of adult cardiovascular diseases.Methods: We investigated this association in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study, a sociodemographically diverse pregnancy cohort in the southern United States with participants enrolled from 2006 to 2011. We included 822 mother–child dyads with available address histories and a valid child blood pressure measurement at 4–6 y. Systolic (SBP) and diastolic blood pressures (DBP) were converted to age-, sex-, and height-specific percentiles for normal-weight U.S. children. HBP was classified based on SBP or DBP ≥90th percentile. Nitrogen dioxide (NO2) and particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) estimates in both pre- and postnatal windows were obtained from annual national models and spatiotemporal models, respectively. We fit multivariate Linear and Poisson regressions and explored multiplicative joint effects with maternal nutrition, child sex, and maternal race using interaction terms.Results: Mean PM2.5 and NO2 in the prenatal period were 10.8 [standard deviation (SD): 0.9] μg/m3 and 10.0 (SD: 2.4) ppb, respectively, and 9.9 (SD: 0.6) μg/m3 and 8.8 (SD: 1.9) ppb from birth to the 4-y-old birthday. On average, SBP percentile increased by 14.6 (95% CI: 4.6, 24.6), and DBP percentile increased by 8.7 (95% CI: 1.4, 15.9) with each 2-μg/m3 increase in second-trimester PM2.5. PM2.5 averaged over the prenatal period was only significantly associated with higher DBP percentiles [β= 11.6 (95% CI: 2.9, 20.2)]. Positive associations of second-trimester PM2.5 with SBP and DBP percentiles were stronger in children with maternal folate concentrations in the lowest quartile (pinteraction= 0.05 and 0.07, respectively) and associations with DBP percentiles were stronger in female children (pinteraction= 0.05). We did not detect significant association of NO2, road proximity, and postnatal PM2.5 with any outcomes.Conclusions: The findings suggest that higher prenatal PM2.5 exposure, particularly in the second trimester, is associated with elevated early childhood blood pressure. This adverse association could be modified by pregnancy folate concentrations. https://doi.org/10.1289/EHP7486     

Air Pollution and Polyclonal Elevation of Serum Free Light Chains: An Assessment of Adaptive Immune Responses in the Prospective Heinz Nixdorf Recall Study

Background: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce.Objectives: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells.Methods: We used repeated data from three examinations (t0: 2000–2003; t1: 2006–2008; and t2: 2011–2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45–75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5μm (PM10 and PM2.5 respectively), nitrogen dioxide (NO2), and particle number concentrations (accumulation mode; PNAM) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season.Results: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO2 (14.1μg/m³). Across the different pollutants, NO2 showed strongest associations with FLC, followed by PM10 and PNAM. Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO2 and PNAM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO2 and PNAM.Discussion: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PNAM, and NO2 showed strongest associations. https://doi.org/10.1289/EHP7164     

Some Heavy Metals Accumulation in Tissues in <Emphasis Type="Italic">Capoeta umbla</Emphasis> (Heckel, 1843) from Uzuncayir Dam Lake (Tunceli,Turkey)

Concentrations of metals were determined in the gills, liver, kidney, heart and muscle in Capoeta umbla caught from six stations from the Munzur River system. Metal concentrations in the tissues tended to vary significantly among stations (p < 0.05). Liver (Cu, 10.10 ± 0.23–23.03 ± 9.37 ppm; Zn, 14.67 ± 3.01–21.82 ± 2.39 ppm; Cd, 18.04 ± 4.56–52.69 ± 10.65 ppb and Fe, 28.87 ± 6.78–115.11 ± 34.87 ppm) and kidney (Cu, 1.80 ± 0.25–3.70 ± 0.62 ppm; Zn, 20.81 ± 0.37–29.36 ± 0.70 ppm; Cd, 132.06 ± 5.29–639.51 ± 20.14 ppb and Fe, 24.40 ± 1.98–59.39 ± 1.97 ppm) tissues showed higher metal concentrations than other tissues. It seems that metal contamination in the river is too high for the health of fish and the people who eat them. The geographical locations of catch, season, nature of diet, and the size of fish used for analyses might lead to different metal concentration in the same fish species.     

Effects of Nitrite and Toxic <Emphasis Type="Italic">Microcystis Aeruginosa</Emphasis> PCC7806 on the Growth of Freshwater Rotifer <Emphasis Type="Italic">Brachionus Calyciflorus</Emphasis>

Over the last two centuries, anthropogenic activities have increased the nitrogen amount in aquatic ecosystems, which has resulted in increased occurrences of blooms of cyanobacteria. This study investigated the effects of nitrite and the cyanobacterium Microcystis aeruginosa on population growth in the rotifer Brachionus calyciflorus. The rotifer was treated for 12 days with nitrite alone (medium containing 0, 3, 6, 10 mg NO₂ ⁻ –N L⁻¹), M. aeruginosa alone (medium containing 0 mg NO₂ ⁻–N L⁻¹ + 5.0 × 10⁵ cell ml⁻¹ M. aeruginosa precultured at 0, 3, 6, 10 mg NO₂ ⁻–N L⁻¹), and nitrite in combination with M. aeruginosa (medium containing 3, 10 mg NO₂ ⁻–N L⁻¹ + 5.0 × 10⁵ cell ml⁻¹ M. aeruginosa precultured at corresponding nitrite concentrations). We observed that a nitrite concentration of 10 mg NO₂ ⁻–N L⁻¹ markedly inhibited the growth of B. calyciflorus; however, rotifer growth declined slightly in the presence of M. aeruginosa precultured at 6 mg NO₂ ⁻–N L⁻¹. Furthermore, reduced population growth of B. calyciflorus was observed when it was treated with both nitrite and M. aeruginosa compared to nitrite alone or M. aeruginosa alone. These results suggested that a high tolerance of B. calyciflorus to nitrite levels may be attributed to the absence of specific respiratory structures and pigments; and that the increased toxicity of nitrite in combination with M. aeruginosa may have been due to increased production of microcystin. It is also possible that nitrite and microcystin could act in a synergistic way in causing toxicity.     

The Ventura planning model: A proposal for mental health reform

The Ventura Planning Model is a proposal for public mental health reform. It addresses the decline in mental health funding. It offers a rationale for increased support—and funding—for public mental health services. The Planning Model grew out of the experience of implementing and operating the Ventura Children’s Demonstration Project. The model has five characteristics, or planning steps: 1) multi-problem target population; 2) systems goals; 3) interagency coalitions; 4) services and standards; and 5) systems monitoring and evaluation. The Ventura Children’s Demonstration Project implemented these planning steps, with an infusion of 1.54 million in funds from the state legislature. The project offset at least 66 percent of its cost by reducing other public agency costs and improved a variety of client-oriented outcomes. The success of the project in offsetting its costs has led the legislature to provide additional funds for three more California counties to implement the model for children and youth, and1.54 million in funds from the state legislature. The project offset at least 66 percent of its cost by reducing other public agency costs and improved a variety of client-oriented outcomes. The success of the project in offsetting its costs has led the legislature to provide additional funds for three more California counties to implement the model for children and youth, and 4 million a year for four years for Ventura County to test the model for adults and seniors. Emphasizing cost offsets in addition to client-oriented outcomes provides a practical rationale for proposing increases in public mental health funds. This rationale also implies substantial changes in the operations of many public mental health agencies.     

Effects of Environmental Factors on the Uptake Rates of Dissolved Nitrogen by a Salt-water Green Alga (<Emphasis Type="Italic">Oocystis borgei</Emphasis> Snow)

Uptake rates for dissolved nitrogen (DN) by a marine alga (Oocystis borgei) were examined in a ¹⁵N tracer experiment. Maximal uptake rates for all forms of DN were observed at temperatures between 25 and 30°C and at algal concentrations between 3.22 × 10⁸ and 4.78 × 10⁸ cell L⁻¹. Light intensity required to achieve the maximal uptake rate was 45 μmol m⁻² s⁻¹ for dissolved inorganic nitrogen (DIN = NO₃ ⁻, NO₂ ⁻, NH₄ ⁺) and methionine, and 126 μmol m⁻² s⁻¹ for urea. Salinity required to achieve the maximal uptake rate was 12.85 ppt for DIN, 19.89 ppt for urea and 26.2 ppt for methionine.     

Long-Term Exposure to Fine Particle Elemental Components and Natural and Cause-Specific Mortality—a Pooled Analysis of Eight European Cohorts within the ELAPSE Project

Background: Inconsistent associations between long-term exposure to particles with an aerodynamic diameter ≤2.5 μm [fine particulate matter (PM2.5)] components and mortality have been reported, partly related to challenges in exposure assessment.Objectives: We investigated the associations between long-term exposure to PM2.5 elemental components and mortality in a large pooled European cohort; to compare health effects of PM2.5 components estimated with two exposure modeling approaches, namely, supervised linear regression (SLR) and random forest (RF) algorithms.Methods: We pooled data from eight European cohorts with 323,782 participants, average age 49 y at baseline (1985–2005). Residential exposure to 2010 annual average concentration of eight PM2.5 components [copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn)] was estimated with Europe-wide SLR and RF models at a 100×100 m scale. We applied Cox proportional hazards models to investigate the associations between components and natural and cause-specific mortality. In addition, two-pollutant analyses were conducted by adjusting each component for PM2.5 mass and nitrogen dioxide (NO2) separately.Results: We observed 46,640 natural-cause deaths with 6,317,235 person-years and an average follow-up of 19.5 y. All SLR-modeled components were statistically significantly associated with natural-cause mortality in single-pollutant models with hazard ratios (HRs) from 1.05 to 1.27. Similar HRs were observed for RF-modeled Cu, Fe, K, S, V, and Zn with wider confidence intervals (CIs). HRs for SLR-modeled Ni, S, Si, V, and Zn remained above unity and (almost) significant after adjustment for both PM2.5 and NO2. HRs only remained (almost) significant for RF-modeled K and V in two-pollutant models. The HRs for V were 1.03 (95% CI: 1.02, 1.05) and 1.06 (95% CI: 1.02, 1.10) for SLR- and RF-modeled exposures, respectively, per 2 ng/m3, adjusting for PM2.5 mass. Associations with cause-specific mortality were less consistent in two-pollutant models.Conclusion: Long-term exposure to V in PM2.5 was most consistently associated with increased mortality. Associations for the other components were weaker for exposure modeled with RF than SLR in two-pollutant models. https://doi.org/10.1289/EHP8368     

Indian vaccine innovation: the case of Shantha Biotechnics

Background  

Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than 1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million.     

Temporal Variation of Metals in Water,Sediment and Tissues of the European Chup (<Emphasis Type="Italic">Squalius cephalus</Emphasis> L.)

The aim of this study was to analyze seasonal variation of levels of Chromium (Cr), Manganese (Mn), Nickel (Ni), Copper (Cu), Zinc (Zn), Cadmium (Cd) and Lead (Pb) in water, sediment and tissues of Squalius cephalus (L., 1758) taken from five different stations chosen at Yamula Dam Lake (Kayseri, Turkey). Concentrations of metals were generally sorted as water<tissue<sediment. The highest concentration of metals in water was observed in the samples taken in the summer (Mn, 1.04 ± 0.15 mg L⁻¹; Ni, 0.42 ± 0.12 mg L⁻¹; Cu, 1.25 ± 0.88 mg L⁻¹; Zn, 3.61 ± 1.53 mg L⁻¹; Pb, 0.58 ± 0.09 mg L⁻¹). While the highest Zn (24.85 ± 21.82 μg g⁻¹) and Pb (10.89 ± 4.2 μg g⁻¹) concentrations in sediment were observed in the winter samples, the highest Mn concentration (167.2 ± 99.37 μg g⁻¹) was observed in the summer. Cd pollution was determined in sediment according to international criteria. The highest metal concentration in tissues was generally observed in the liver and the other tissues; following liver were gills and muscles. In liver tissues, while the highest accumulation of Zn (110.34 ± 13.1) and Mn (22.5 ± 14.85 μg g⁻¹), which are essential for the body, were observed in the winter, Pb (22.58 ± 7.83 μg g⁻¹) and Cd (11.77 ± 7.83 μg g⁻¹), which are toxic, were found to be higher in the summer. Also, concentrations of Mn, Cd and Pb in muscle tissues were found to be above the limits permitted.     

Mouse Lung Structure and Function after Long-Term Exposure to an Atmospheric Carbon Dioxide Level Predicted by Climate Change Modeling

Background: Climate change models predict that atmospheric carbon dioxide [CO2] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO2 (as compared with ∼410 ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied.Objectives: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890 ppm CO2 from preconception to adulthood using a mouse model.Methods: We exposed mice to CO2 (∼890 ppm) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure.Results: CO2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO2 for a similar amount of time (∼8wk), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO2.Discussion: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO2 can impact respiratory function in the mouse. https://doi.org/10.1289/EHP7305     

Physiological responses to high radiant heat exposure

The physiological responses to four levels of radiant heat (R) in combination with two work loads and three ambient humidity levels were studied on seven clothed young men. The globe temperature (t_g) ranged from 40 to 74°C; metabolic work load (M) was either 20 or 50% of maximal aerobic capacity (V?₀₂ max); ambient vapor pressure was either 13 or 23 mm Hg; and dry-bulb temperature (t_db) was 38 or 49°C. The criteria for heat strain were the changes in rectal temperature (T_re), mean skin temperature (T_sk), heart rate (HR), and sweating (Sw). Stress was defined by the calculated heat load requiring dissipation (M + R + C = E_req), the ambient evaporative capacity (E_max), and the skin wettedness (w), defined as the ratio of E_req/E_max. The progressive increase in R resulted in a concomitant rise of T_re and HR reflecting the physiological strain. Similarly the increase in either M or in the humidity resulted in higher T_re and HR. The changes in R or E_max were best defined by the w, thus w and the physiological responses were highly correlated. For practical application a multiple regression of the increments of HR(ΔHR) on t_db above neutral (25°C) and on t_g above t_db was derived as follows:

$\text{△HR}{}_{\mathrm{<mtext>bpm</mtext>}}\text{= 0.96(t}{}_{\mathrm{<mtext>db</mtext>}}\text{? 25°}\text{C}\text{) + 0.81(t}{}_{\mathrm{g}}\text{? t}{}_{\mathrm{db}}\text{) ? 1}$

It was concluded that the calculated skin wettedness is most suitable in the evaluation of heat stress.     

Longitudinal Study of Depressive Symptoms and Social Support in Adolescent Mothers

Previous studies have suggested that adolescent mothers with higher social support have lower depressive symptoms. This is a longitudinal study of adolescent mothers to examine the association of social support and depressive symptoms over one year postpartum. This was a prospective study of adolescent mothers (N at baseline = 120, N at 1 year = 89; age < 19 years) enrolled in a teen tot program. Participants completed the Center for Epidemiological Studies Depression Scale for children (CES-DC) and the Duke-UNC Functional Social Support Questionnaire at baseline, 12 weeks, and 1 year. A score of ≥ 16 on the CES-DC was suggestive of major depression. The mean CES-DC scores of the adolescent mothers were ≥16 points at all three time points (baseline: mean = 18.7 ± 10.3; 53% ≥ 16; 12 weeks: mean = 18.4 ± 11.4, 57% ≥ 16; one year: mean = 20.0 ± 11.4; 57% ≥ 16). Social support had a significant, inverse association with depressive symptoms for all participants from baseline to 12 weeks with a stronger association for those with more depressive symptoms (score ≥ 16) at baseline (beta = −0.030 ± 0.007; P < 0.001) than for those with fewer depressive symptoms (score < 16) at baseline (beta = −0.013 ± 0.006; P = 0.021). From 12 weeks to one year, increased social support was only significantly associated with decreased depressive symptoms for those with a higher baseline level of depressive symptoms (beta = − 0.039 ± 0.009; P < 0.001). Depressive symptoms were prevalent among adolescent mothers. For more depressed adolescent mothers, higher levels of social support were associated with less depressive symptoms over the 1 year follow-up. Effective long-term interventions are needed to lessen depression and enhance social support.