Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Ranking the accelerated weathering of plastic polymers.

The timespans over which different plastics degrade in the environment are poorly understood. This study aimed to rank the degradation speed of five widespread plastic polymers-low density polyethylene (LDPE), polypropylene (PP), polystyrene (PS), polylactic acid (PLA) and polyethylene terephthalate (PET)-in terms of their physicochemical properties. Five of the six samples were plastic films with identical dimensions, which allowed the influence of morphology to be excluded, with a polyethylene carrier bag (PEB) tested for comparison. An accelerated weathering chamber was used to photochemically degrade samples over 41 days, with degradation monitored via mass loss and changes to carbonyl index, crystallinity and contact angle. The mass loss ranking was PP ≫ LDPE > PEB > PS > PLA > PET. Estimates of the time needed for complete degradation ranged from 0.27 years for PP to 1179 years for PET. Therefore, mass loss in PP proceeded more rapidly than the other polymers, which was unexpected based on previous literature and is plausibly explained by the presence of an unlisted additive which accelerated degradation. Increases in carbonyl index proceeded more rapidly in PP and LDPE than the other polymers tested. However, changes in contact angle and crystallinity did not correspond to the mass loss ranking. Therefore, monitoring the carbonyl index during accelerated weathering trials can indicate which polymers will fragment more quickly. However, alternative approaches are needed to simulate conditions where photooxidation reactions are negligible, such as the ocean floor.

Effects of the maternal and fetal proteome on birth weight: a Mendelian randomization analysis.

Fetal growth is an indicator of fetal survival, regulated by maternal and fetal factors, but little is known about the underlying molecular mechanisms. We used Mendelian randomization to explore the effects of maternal and fetal genetically-instrumented plasma proteins on birth weight using genome-wide association summary data (n=406,063 with maternal and/or fetal genotype), with independent replication (n=74,932 mothers and n=62,108 offspring), and colocalisation. Higher genetically-predicted maternal levels of PCSK1 increased birthweight (mean-difference: 9g (95% CI: 5g, 13g) per 1 standard deviation protein level). Higher maternal levels of LGALS4 decreased birthweight (-54g (-29g, -80g)), as did VCAM1, RAD51D and GP1BA. In the offspring, higher genetically-predicted fetal levels of LGALS4 (46g (23g, 70g)) increased birthweight, alongside FCGR2B. Higher offspring levels of PCSK1 decreased birth weight (-9g (-16g, 4g), alongside LEPR. Results support maternal and fetal protein effects on birth weight, implicating roles for glucose metabolism, energy homeostasis, endothelial function and adipocyte differentiation.

Disinfection By-Products Formation from Chlor(am)ination of Algal Organic Matter of Chlorella sorokiniana.

Eutrophication in water reservoirs releases algal organic matter (AOM), which is an important precursor of disinfection by-products (DBPs) formed during water treatment. Chlorella sorokiniana is a microalgae which flourishes under conditions of high light intensity and temperature, thus its prevalence in algal blooms is expected to increase with climate change. However, Chlorella sorokiniana AOM has not been previously investigated as a DBP precursor. In this context, this study evaluated the effect of AOM concentration, humic acid (HA), and pH on DBP formation from chlor(am)ination of AOM Chlorella sorokiniana. DBP yields determined by linear regression for trichloromethane (TCM) and chloral hydrate (CH) were 57.9 and 46.0 µg·mg DOC-1 in chlorination, while the TCM, CH, dichloroacetonitrile (DCAN), 1,1,1-trichloropropanone (1,1,1-TCP), and chloropicrin (CPN) concentrations were 33.6, 29.8, 16.7, 2.1, and 1.2 µg·mg DOC-1 in chloramination. Chloramination reduced the formation of TCM and CH but increased CPN, DCAN, and 1,1,1-TCP yields. AOM Chlorella sorokiniana showed a higher DBP formation than 9 of 11 algae species previously investigated in the literature. At basic pH, the concentration of TCM increased while the concentration of other DBP classes decreased. Bromide was effectively incorporated into the AOM structure and high values of bromine incorporation factor were found for THM (1.81-1.89) and HAN (1.32) at 1.5 mg Br·L-1. Empirical models predicted successfully the formation of THM and HAN (R2 > 0.86). The bromide concentration had more impact in the model on the DBP formation than AOM and HA. These results provide the first insights into the DBP formation from AOM chlor(am)ination of Chlorella sorokiniana.

The impact of riverine particles on the vertical velocities of large microplastics.

Microplastics interact with other suspended particles in aquatic systems, which may impact their environmental fate. Little is known about aggregation between suspended sediment and larger microplastics (1-5 mm), and how this impacts the vertical velocities of microplastics, although it was hypothesised these are size limited. Consumer items made of five common polymers: polypropylene (PP), high density polyethylene (HDPE), polyethylene terephthalate (PET), polyvinyl chloride (PVC) and polystyrene (PS), were fragmented by cryomilling and their vertical velocities (rising/settling) measured experimentally before and after 24-hours of aggregation with riverine particles. Microplastic size (microscopy), zeta potential and density (density gradient column) were measured, with aggregation quantified using microscopy. PP had an experimental density of 1052 kg·m-3, and sank in river water, although it is often stated as being buoyant based on literature density values. Aggregation occurred with all five polymers: 39 %-72 % of microplastics were observed to have sediment and/or organic particles adhered, depending on the polymer type. PVC had the least negative zeta potential, -8.0 ± 3.0, and showed a much higher number of adhered sediment particles than all other polymers: on average 4.55 particles, compared with <1.72 particles for other polymers. For four polymers, aggregation did not significantly change vertical velocities. However, PP particles showed a significantly slower settling velocity after aggregation: a decrease of 6.3 % based on mean averages, from 9.7 × 10-3 to 9.1 × 10-3 m·s-1. Theoretical calculations showed the amount of adsorbed sediment or biofilm required to induce a microplastic density change of ∼50 kg·m-3 was much higher than observed experimentally. Overall, this study indicates that the vertical velocities of larger microplastics are less influenced by interactions with natural particles than smaller microplastics.

Birth weight and cardiometabolic risk factors: a discordant twin study in the UK Biobank.

One of the longstanding debates in life-course epidemiology is whether an adverse intrauterine environment, often proxied by birth weight, causally increases the future risk of cardiometabolic disease. The use of a discordant twin study design, which controls for the influence of shared genetic and environmental confounding factors, may be useful to investigate whether this relationship is causal. We conducted a discordant twin study of 120 monozygotic (MZ) and 148 dizygotic (DZ) twin pairs from the UK Biobank to explore the potential causal relationships between birth weight and a broad spectrum of later-life cardiometabolic risk factors. We used a linear mixed model to investigate the association between birth weight and later-life cardiometabolic risk factors for twins, allowing for both within-pair differences and between-pair differences in birth weight. Of primary interest is the within-pair association between differences in birth weight and cardiometabolic risk factors, which could reflect an intrauterine effect on later-life risk factors. We found no strong evidence of association in MZ twins between the within-pair differences in birth weight and most cardiometabolic risk factors in later life, except for nominal associations with C-reactive protein and insulin-like growth factor 1. However, these associations were not replicated in DZ twin pairs. Our study provided no strong evidence for intrauterine effects on later-life cardiometabolic risk factors, which is consistent with previous large-scale studies of singletons testing the potential causal relationship. It does not support the hypothesis that adverse intrauterine environments increase the risk of cardiometabolic disease in later life.

Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk.

BACKGROUND: Observational epidemiological studies suggest a link between several factors related to ovulation and reproductive function and endometrial cancer (EC) risk; however, it is not clear whether these relationships are causal, and whether the risk factors act independently of each other. The aim of this study was to investigate putative causal relationships between the number of live births, age at last live birth, and years ovulating and EC risk.  METHODS: We conducted a series of observational analyses to investigate various risk factors and EC risk in the UK Biobank (UKBB). Additionally, multivariate analysis was performed to elucidate the relationship between the number of live births, age at last live birth, and years ovulating and other related factors such as age at natural menopause, age at menarche, and body mass index (BMI). Secondly, we used Mendelian randomization (MR) to assess if these observed relationships were causal. Genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from previous studies of woman's number of live births, age at menopause and menarche, and BMI. We conducted a genome-wide association analysis using the UKBB to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth. RESULTS: We found evidence for a causal effect of the number of live births (inverse variance weighted (IVW) odds ratio (OR): 0.537, p = 0.006), the number of years ovulating (IVW OR: 1.051, p = 0.014), in addition to the known risk factors BMI, age at menarche, and age at menopause on EC risk in the univariate MR analyses. Due to the close relationships between these factors, we followed up with multivariable MR (MVMR) analysis. Results from the MVMR analysis showed that number of live births had a causal effect on EC risk (OR: 0.783, p = 0.036) independent of BMI, age at menarche and age at menopause. CONCLUSIONS: MVMR analysis showed that the number of live births causally reduced the risk of EC.

Surface properties and rising velocities of pristine and weathered plastic pellets.

This study compared the surface properties and rising velocities of pristine and weathered plastic production pellets, to evaluate impacts of environmental conditions. Rising velocities were measured for 140 weathered pellets collected from a Spanish beach and compared with pristine low-density polyethylene, high-density polyethylene and polypropylene pellets. A subset of 49 weathered pellets were analysed by Fourier-transform infrared spectroscopy (FTIR), with all found to be polyethylene. Experimental rising velocities for the weathered pellets varied widely, from (2.36 ± 0.01) cm s-1 to (10.56 ± 0.26) cm s-1, with a mean value of (5.79 ± 0.06) cm s-1. Theoretical rising velocities were consistently higher than experimental velocities for all pellet types: on average 136% of experimental values for weathered pellets. This discrepancy was more distinct for less spherical pellets, which were often more weathered. Flatter pellets often oscillated as they rose, which explains at least some of this finding. Atomic force microscopy (AFM) analysis revealed that the roughness of the pristine and weathered pellets was (59 ± 11) nm, and (74 ± 26) nm respectively. X-ray photoelectron spectroscopy (XPS) analysis showed that the proportion of surface oxidised carbon species were 2.3% and 4.0% of the total carbon signal for a pristine and a weathered pellet, respectively; consistent with photochemical reactions changing the surface chemistry of weathered pellets. As determined by density column, weathered pellets had slightly lower experimental densities than pristine pellets. Overall, this study illustrates why it is important that modelling studies on the environmental fate and/or movements of microplastics validate or correct predictions using experimental data.

Identification, Occurrence, and Cytotoxicity of Haloanilines: A New Class of Aromatic Nitrogenous Disinfection Byproducts in Chloraminated and Chlorinated Drinking Water.

Identifying disinfection byproducts (DBPs) with high health risk is an unresolved challenge. In this study, six members of a new class of aromatic nitrogenous DBPs─2-chloroaniline, 2-bromoaniline, 2,4-dichloroaniline, 2-chloro-4-bromoaniline, 4-chloro-3-nitroaniline, and 2-chloro-4-nitroaniline─are reported as DBPs in drinking water for the first time. Haloanilines completely degraded within 1 h in the presence of chlorine (1 mg/L), while about 20% remained in the presence of chloramine (1 mg/L) after 120 h. Haloanilines showed high stability in the absence of disinfectants, with <30% degradation at pH 5-9 over 120 h. Eight haloanilines were determined in chloraminated finished water and tap water at total concentrations of up to 443 ng/L. The most abundant was 2-bromoaniline, with a median concentration of 104 ng/L. The cytotoxicity of eight haloanilines and regulated trichloromethane and dichloroacetic acid (DCAA) was evaluated using Hep G2 cell assay. The EC50 values of eight haloanilines were 1-2 orders of magnitude lower than those of the regulated DBPs. The lowest toxic concentration of 2-chloro-4-nitroaniline was 1 µM, 500 times lower than that of DCAA. The formation and control of haloanilines in drinking water warrant further investigation.

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.

BACKGROUND: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. METHODS: We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). RESULTS: MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. CONCLUSIONS: Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Predicting the global environmental distribution of plastic polymers.

This study represents the first quantitative global prediction of the mass distribution of six widespread polymers, plus plastic fibers and rubber across four environmental compartments and 11 sub-compartments. The approach used probabilistic material flow analysis for 2015, with model input values and transfer coefficients between compartments taken from literature. We estimated that 3.2 ± 1.8 Mt/year of polyethylene, 1.3 ± 0.8 Mt/year of polypropylene, 0.5 ± 0.3 Mt/year of polystyrene, 0.3 ± 0.15 Mt/year of polyvinyl chloride, 1.6 ± 0.9 Mt/year of polyethylene terephthalate and 2.4 ± 1.2 Mt/year of plastic fibers enter the environment. Combining all plastic, including rubber, 4.9 ± 1.3, 4.8 ± 1.9 and 1.8 ± 1.2 Mt/year accumulated in the soil, ocean, and freshwater, respectively. Urban soils and ocean shorelines were predicted as hotspots for plastic accumulation, accounting for 33% and 25% of total plastic, respectively. The floor of freshwater systems and the ocean were predicted as hotspots for high density plastic such as polyethylene terephthalate, polyvinyl chloride and plastic fibers. Furthermore, 59% of environmental rubber was predicted to accumulate in soil. The findings of this study provide baseline data for quantifying plastic transport and accumulation, which can inform future ecotoxicity studies and risk assessments, as well as targeting efforts to mitigate plastic pollution.

Investigating a Potential Causal Relationship Between Maternal Blood Pressure During Pregnancy and Future Offspring Cardiometabolic Health.

Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population sample also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.

The link between attention deficit hyperactivity disorder (ADHD) symptoms and obesity-related traits: genetic and prenatal explanations.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with obesity, however, the potential causality between the traits remains unclear. We examined both genetic and prenatal evidence for causality using Mendelian Randomisation (MR) and polygenic risk scores (PRS). We conducted bi-directional MR on ADHD liability and six obesity-related traits using summary statistics from the largest available meta-analyses of genome-wide association studies. We also examined the shared genetic aetiology between ADHD symptoms (inattention and hyperactivity) and body mass index (BMI) by PRS association analysis using longitudinal data from Northern Finland Birth Cohort 1986 (NFBC1986, n = 2984). Lastly, we examined the impact of the prenatal environment by association analysis of maternal pre-pregnancy BMI and offspring ADHD symptoms, adjusted for PRS of both traits, in NFBC1986 dataset. Through MR analyses, we found evidence for bidirectional causality between ADHD liability and obesity-related traits. PRS association analyses showed evidence for genetic overlap between ADHD symptoms and BMI. We found no evidence for a difference between inattention and hyperactivity symptoms, suggesting that neither symptom subtype is driving the association. We found evidence for association between maternal pre-pregnancy BMI and offspring ADHD symptoms after adjusting for both BMI and ADHD PRS (association p-value = 0.027 for inattention, p = 0.008 for hyperactivity). These results are consistent with the hypothesis that the co-occurrence between ADHD and obesity has both genetic and prenatal environmental origins.

Ozonation Treatment Increases Chlorophenylacetonitrile Formation in Downstream Chlorination or Chloramination.

Chlorophenylacetonitriles (CPANs) are an emerging group of aromatic nitrogenous disinfection byproducts (DBPs). However, their dominant precursors and formation pathways remain unclear, which hinders the further development of effective control strategies. For the first time, CPAN precursors were screened by conducting formation potential (FP) tests on real water samples from six drinking water treatment plants (DWTPs). The average overall removal of CPAN precursors across all six DWTPs was only 10%. Moreover, ozonation increased CPAN precursors by 140% on average. Fluorescence spectroscopy showed a dramatic reduction in aromatic proteins, tyrosine-like proteins, and tryptophan-like proteins following ozonation. Low-apparent-molecular-weight (AMW) (<1 kDa) substances were correlated with the CPAN FP in these samples. We therefore hypothesized that protein fragments with low AMW, such as amino acids, are important CPAN precursors during downstream chlor(am)ination. Two aromatic free amino acids, tyrosine and tryptophan, were selected to investigate the formation of CPANs during chlor(am)ination. Both amino acids were found to act as CPAN precursors for the first time. CPAN formation pathways from these model precursors were proposed based on the frontier molecular orbital theory and intermediate products identified using high-resolution mass spectrometry. This study provides a powerful theoretical foundation for controlling CPAN formation in drinking water.

Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts.

BACKGROUND: The study aimed to explore the association between early life and life-course exposure to social disadvantage and later life body mass index (BMI) accounting for genetic predisposition and maternal BMI. METHODS: We studied participants of Helsinki Birth Cohort Study born in 1934-1944 (HBCS1934-1944, n = 1277) and Northern Finland Birth Cohorts born in 1966 and 1986 (NFBC1966, n = 5807, NFBC1986, n = 6717). Factor analysis produced scores of social disadvantage based on social and economic elements in early life and adulthood/over the life course, and was categorized as high, intermediate and low. BMI was measured at 62 years in HBCS1934-1944, at 46 years in NFBC1966 and at 16 years in NFBC1986. Multivariable linear regression analysis was used to explore associations between social disadvantages and BMI after adjustments for polygenic risk score for BMI (PRS BMI), maternal BMI and sex. RESULTS: The association between exposure to high early social disadvantage and increased later life BMI persisted after adjustments (ß = 0.79, 95% CI, 0.33, 1.25, p < 0.001) in NFBC1966. In NFBC1986 this association was attenuated by PRS BMI (p = 0.181), and in HBCS1934-1944 there was no association between high early social disadvantage and increased later life BMI (ß 0.22, 95% CI -0.91,1.35, p = 0.700). In HBCS1934-1944 and NFBC1966, participants who had reduced their exposure to social disadvantage during the life-course had lower later life BMI than those who had increased their exposure (ß - 1.34, [- 2.37,-0.31], p = 0.011; ß - 0.46, [- 0.89,-0.03], p = 0.038, respectively). CONCLUSIONS: High social disadvantage in early life appears to be associated with higher BMI in later life. Reducing exposure to social disadvantage during the life-course may be a potential pathway for obesity reduction.

Predictive Accuracy of a Polygenic Risk Score-Enhanced Prediction Model vs a Clinical Risk Score for Coronary Artery Disease.

Importance: The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain. Objective: To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations. Design, Setting, and Participants: Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency-matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD. Exposures: Polygenic risk score for CAD, pooled cohort equations, and both combined. Main Outcomes and Measures: CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed. Results: In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and -0.4% (95% CI, -0.5% to -0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]). Conclusions and Relevance: The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.

The formation of disinfection by-products from the chlorination and chloramination of amides.

This study examined the potential of six aliphatic and aromatic amides, commonly found in natural waters or used as chemical aids in water treatment, to act as organic precursors for nine haloacetamides (HAcAms), five haloacetonitriles (HANs), regulated trihalomethanes (THMs) and haloacetic acids (HAAs) upon chlorination and chloramination. The impact of key experimental conditions, representative of drinking water, including pH (7 & 8), retention time (4 & 24 h) and bromide levels (0 & 100 µg/L), on the generation of the target DBPs was investigated. The highest aggregate DBP yields upon chlor(am)ination were reported for the aromatic and hydrophobic hydroxybenzamide; 2.7% ± 0.1% M/M (chlorination) and 1.7% M/M (chloramination). Increased reactivity was observed in aliphatic and hydrophilic compounds, acrylamide (2.5 ± 0.2% M/M) and acetamide (1.3 ± 0.2% M/M), in chlorination and chloramination, respectively. The addition of bromide increased average DBP yields by 50-70%. Relative to chlorination, the application of chloramines reduced DBP formation by 66.5% (without Br-) and by 46.4% (with Br-). However, bromine incorporation in HAAs and HAcAms was enhanced following chloramination, of concern due to the higher toxicological potency of brominated compounds.

Exploring the role of genetic confounding in the association between maternal and offspring body mass index: evidence from three birth cohorts.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding. METHODS: We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (n ≤11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged individual participant data from all cohorts, enabling calculation of pooled estimates. RESULTS: Phenotypic covariance (equivalent here to Pearson's correlation coefficient) between maternal BMI and offspring phenotype was 0.15 [95% confidence interval (CI): 0.13, 0.17] for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW [-0.04 (95% CI: -0.09, 0.01)], but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results. CONCLUSIONS: Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI-offspring BMI association.

Interference from haloacetamides during the determination of haloacetic acids using gas chromatography.

Haloacetic acids (HAAs) are the second largest class of disinfection by-products (DBPs) by weight in water and are more cytotoxic and genotoxic to mammalian cells than trihalomethanes, the first largest class of DBPs. Gas chromatography (GC) is the most widely used technique for determining HAAs. Due to their polar nature, derivatization prior to GC analysis is required. Typically, derivatization is undertaken with acidic methanol, which converts HAAs to the corresponding methyl ester (haloacetic acid methyl esters, abbreviated as HAAMEs), and HAAs are quantified by measuring HAAMEs. In this study, the interference from two other groups of DBPs, the haloacetonitriles (HANs) and haloacetamides (HAMs), on the determination of HAAs was investigated. HANs and HAMs at a range of concentrations (0, 20, 40, 60, 80, and 100 µg/L) were subjected to the same derivatization and analytical procedures as HAAs. The stability of HANs and HAMs under strongly acidic conditions was assessed and the operative mechanism of interference was investigated. The results showed that HAMs significantly interfered with the determination of the corresponding HAAs and the transformation rates of HAMs (representing the extent of HAMs transforming to corresponding HAAMEs) ranged from 6.5 to 45.7%, while the impact of HANs can be neglected. The stability of HANs and HAMs under strongly acidic conditions indicated that hydrolysis was not the cause of the interference. Instead, it was proposed that HAMs react with methyl alcohol, to generate the same corresponding HAAMEs that was generated when HAAs reacted with methyl alcohol. A method for revising HAA concentrations in the presence of HAMs is suggested.

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.