An important feature of microbiome count data is the presence of a large number of zeros. A common strategy to handle these excess zeros is to add a small number called pseudo-count (e.g., 1). Other ...strategies include using various probability models to model the excess zero counts. Although adding a pseudo-count is simple and widely used, as demonstrated in this paper, it is not ideal. On the other hand, methods that model excess zeros using a probability model often make an implicit assumption that all zeros can be explained by a common probability models. As described in this article, this is not always recommended as there are potentially three types/sources of zeros in a microbiome data. The purpose of this paper is to develop a simple methodology to identify and accomodate three different types of zeros and to test hypotheses regarding the relative abundance of taxa in two or more experimental groups. Another major contribution of this paper is to perform constrained (directional or ordered) inference when there are more than two ordered experimental groups (e.g., subjects ordered by diet or age groups or environmental exposure groups). As far as we know this is the first paper that addresses such problems in the analysis of microbiome data.
Using extensive simulation studies, we demonstrate that the proposed methodology not only controls the false discovery rate at a desired level of significance while competing well in terms of power with DESeq2, a popular procedure derived from RNASeq literature. As expected, the method using pseudo-counts tends to be very conservative and the classical t-test that ignores the underlying simplex structure in the data has an inflated FDR.
•We aimed to estimate global trends of antimicrobial resistance of E. coli and K. pneumoniae invasive isolates.•By 2030, over half of E. coli and K. pneumoniae invasive isolates could become ...resistant to third generation cephalosporins.•Carbapenem resistance is increasing rapidly among K. pneumoniae invasive isolates.
To project future antimicrobial resistance (AMR) in Escherichia coli and Klebsiella pneumoniae.
Mixed linear models were constructed from a sample of countries with AMR data in the ResistanceMap database. Inverse probability weighting methods were used to account for countries without AMR data.
The estimated prevalence of AMR in 2015 was 64.5% (95% confidence interval (CI) 42–87%) for third-generation cephalosporin-resistant (3GCR) Escherichia coli, 5.8% (95% CI 1.8–9.7%) for carbapenem-resistant (CR) E. coli, 66.9% (95% CI 47.1–86.8%) for 3GCR Klebsiella pneumoniae, and 23.4% (95% CI 7.4–39.4%) for CR K. pneumoniae. The projected AMR prevalence in 2030 was 77% (95% CI 55–99.1%) for 3GCR E. coli, 11.8% (95% CI 3.7–19.9%) for CR E. coli, 58.2% (95% CI 50.2–66.1%) for 3GCR K. pneumoniae, and 52.8% (95% CI 16.3–89.3%) for CR K. pneumoniae.
The models suggest that third-generation cephalosporins and carbapenems could be ineffective against a sizeable proportion of infections by E. coli and K. pneumoniae in most parts of the world by 2030, supporting both the need to enhance stewardship efforts and to prioritize research and development of new antibiotics for resistant Enterobacteriaceae.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Early disruption of the microbial community may influence life-long health. Environmental toxicants can contaminate breast milk and the developing infant gut microbiome is directly exposed. We ...investigated whether environmental toxicants in breastmilk affect the composition and function of the infant gut microbiome at 1 month. We measured environmental toxicants in breastmilk, fecal short-chain fatty acids (SCFAs), and gut microbial composition from 16S rRNA gene amplicon sequencing using samples from 267 mother-child pairs in the Norwegian Microbiota Cohort (NoMIC). We tested 28 chemical exposures: polychlorinated biphenyls (PCBs), polybrominated flame retardants (PBDEs), per- and polyfluoroalkyl substances (PFASs), and organochlorine pesticides. We assessed chemical exposure and alpha diversity/SCFAs using elastic net regression modeling and generalized linear models, adjusting for confounders, and variation in beta diversity (UniFrac), taxa abundance (ANCOM), and predicted metagenomes (PiCRUSt) in low, medium, and high exposed groups.
PBDE-28 and the surfactant perfluorooctanesulfonic acid (PFOS) were associated with less microbiome diversity. Some sub-OTUs of Lactobacillus, an important genus in early life, were lower in abundance in samples from infants with relative "high" (> 80th percentile) vs. "low" (< 20th percentile) toxicant exposure in this cohort. Moreover, breast milk toxicants were associated with microbiome functionality, explaining up to 34% of variance in acetic and propionic SCFAs, essential signaling molecules. Per one standard deviation of exposure, PBDE-28 was associated with less propionic acid (- 24% 95% CI - 35% to - 14% relative to the mean), and PCB-209 with less acetic acid (- 15% 95% CI - 29% to - 0.4%). Conversely, PFOA and dioxin-like PCB-167 were associated with 61% (95% CI 35% to 87%) and 22% (95% CI 8% to 35%) more propionic and acetic acid, respectively.
Environmental toxicant exposure may influence infant gut microbial function during a critical developmental window. Future studies are needed to replicate these novel findings and investigate whether this has any impact on child health.
Preterm birth is the main reason for neonatal deaths worldwide. We investigate whether maternal gut microbiota may play a previously overlooked role.
The Norwegian Microbiota Study (NoMIC) is a case ...control study on preterm birth (<259 days of gestation, calculated primarily based on the last menstrual period), including two consecutively born term infants per infant born prematurely. Eligible mothers were fluent in Norwegian and recruited from the maternity ward at a county hospital in Eastern Norway in the period 2002-2005. Fecal samples were collected at day 4 postpartum, and analyzed using 16S ribosomal RNA gene sequencing. We used samples from 121 mothers giving birth vaginally. Measures of alpha diversity (Shannon, Phylogenetic Diversity and Observed Operational Taxonomic Units) and microbiome composition were combined with information from the Medical Birth Registry, pregnancy journals, and questionnaires.
The association between maternal gut diversity and preterm delivery was examined using logistic regression. One IQR increase in Shannon diversity was significantly associated with 38% lower odds of spontaneous preterm birth, (95% confident interval (CI): 1%, 61%), and the association was stronger when adjusting for maternal age, marital status, ethnicity, parity, BMI, education, antibiotic use, pets in the household, income and smoking (48% lower odds, 95% CI: 4.2%, 72%). Mothers delivering prematurely also had lower abundance of OTUs belonging to Bifidobacterium and Streptococcus, and of the Clostridiales order.
Analysis of maternal gut microbiota using next-generation sequencing shows that low gut diversity, with a distinct microbial composition, is associated with spontaneous preterm delivery.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pollutants in ambient air have been linked with type-2 diabetes mellitus (T2DM) in low as well as high pollution scenarios. Mechanisms of action include disruption of endothelial function, imbalance ...in the autonomic nervous system and direct translocation. Although reductions in exposure to ambient air pollution (AP) could translate to meaningful clinical and public health benefits, policy changes targeting AP are usually at the population level, multisectoral, and time consuming. The human gut microbiome (GM) is an ecosystem within individuals which has been linked with health in both beneficial and detrimental ways. During the last decade, mechanistic and epidemiological research on GM suggests altered microbial diversity and differential composition influencing T2DM through inflammation, metabolites, and microbial functions. This offers a scope to design individual level interventions to target AP related T2DM through GM. In this paper, we presented a combination approach of evidence synthesis by literature review and application of causal inference framework to investigate the role of GM in the association of AP and T2DM, to help design epidemiological studies and direct data analysis. We formulated Directed Acyclic Graphs with methodological considerations for mediatory, interacting, or effect modification role of GM in the association of AP and T2DM. Additionally, we considered the emerging links between gut and oral microbiome, the different T2DM disease patterns in South Asia, and unique co-exposures in these settings (for example, indoor air pollution).
•Comprehensive multi-city study across the largest cities in India.•Strong evidence of heatwaves impact on daily mortality.•Longer and more intense heatwaves are linked to an increased mortality ...risk.•Higher heatwave-related deaths with shorter and less extreme heatwaves.•Policymakers should consider both heatwave definitions and their associated burden.
Heatwaves are expected to increase with climate change, posing a significant threat to population health. In India, with the world’s largest population, heatwaves occur annually but have not been comprehensively studied. Accordingly, we evaluated the association between heatwaves and all-cause mortality and quantifying the attributable mortality fraction in India.
We obtained all-cause mortality counts for ten cities in India (2008–2019) and estimated daily mean temperatures from satellite data. Our main extreme heatwave was defined as two-consecutive days with an intensity above the 97th annual percentile. We estimated city-specific heatwave associations through generalised additive Poisson regression models, and meta-analysed the associations. We reported effects as the percentage change in daily mortality, with 95% confidence intervals (CI), comparing heatwave vs non-heatwave days. We further evaluated heatwaves using different percentiles (95th, 97th, 99th) for one, two, three and five-consecutive days. We also evaluated the influence of heatwave duration, intensity and timing in the summer season on heatwave mortality, and estimated the number of heatwave-related deaths.
Among ∼ 3.6 million deaths, we observed that temperatures above 97th percentile for 2-consecutive days was associated with a 14.7 % (95 %CI, 10.3; 19.3) increase in daily mortality. Alternative heatwave definitions with higher percentiles and longer duration resulted in stronger relative risks. Furthermore, we observed stronger associations between heatwaves and mortality with higher heatwave intensity. We estimated that around 1116 deaths annually (95 %CI, 861; 1361) were attributed to heatwaves. Shorter and less intense definitions of heatwaves resulted in a higher estimated burden of heatwave-related deaths.
We found strong evidence of heatwave impacts on daily mortality. Longer and more intense heatwaves were linked to an increased mortality risk, however, resulted in a lower burden of heatwave-related deaths. Both definitions and the burden associated with each heatwave definition should be incorporated into planning and decision-making processes for policymakers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Maternal diet can influence the developing immune system of the offspring. We hypothesized that maternal fibre and gluten intake during pregnancy were associated with the risk of celiac disease in ...the child. In the Norwegian Mother, Father and Child Cohort Study (MoBa, n = 85,898) higher maternal fibre intake (median 29.5 g/day) was associated with a lower risk of celiac disease in the offspring (adjusted relative risk 0.90, 95% CI 0.83 to 0.98 per 10 g/d increase). Gluten intake during pregnancy (median 13.0 g/d) was associated with a higher risk of childhood CD (adjusted relative risk = 1.21, 95% CI 1.02 to 1.43 per 10 g/d increase). These results were largely unaffected by adjustment for the child's gluten intake at 18 months. In an independent study of 149 mother/child dyads, maternal fibre intake did not predict concentrations of total or sub-types of short-chain fatty acids in repeated infant stool samples, or fecal microbiome diversity in the mother or child. Our results suggest that high fibre and low gluten intake during pregnancy could be protective factors for celiac disease, although the mechanism is unknown.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although most Indians live in rural settings, data on cardiovascular disease risk factors in these groups are limited. We describe the association between socioeconomic position and cardiovascular ...disease risk factors in a large rural population in north India.
We performed representative, community-based sampling from 2013 to 2014 of Solan district in Himachal Pradesh. We used education, occupation, household income, and household assets as indicators of socioeconomic position. We used tobacco use, alcohol use, low physical activity, obesity, hypertension, and diabetes as risk factors for cardiovascular disease. We performed hierarchical multivariable logistic regression, adjusting for age, sex and clustering of the health sub-centers, to evaluate the cross-sectional association of socioeconomic position indicators and cardiovascular disease risk factors.
Among 38,457 participants, mean (SD) age was 42.7 (15.9) years, and 57% were women. The odds of tobacco use was lowest in participants with graduate school and above education (adjusted OR 0.11, 95% CI 0.09, 0.13), household income >15,000 INR (adjusted OR 0.35, 95% CI 0.29, 0.43), and highest quartile of assets (adjusted OR 0.28, 95% CI 0.24, 0.34) compared with other groups but not occupation (skilled worker adjusted OR 0.93, 95% CI 0.74, 1.16). Alcohol use was lower among individuals in the higher quartile of income (adjusted OR 0.75, 95% CI 0.64, 0.88) and assets (adjusted OR 0.70, 95% CI 0.59, 0.82). The odds of obesity was highest in participants with graduate school and above education (adjusted OR 2.33, 95% CI 1.85, 2.94), household income > 15,000 Indian rupees (adjusted OR 1.89, 95% CI 1.63, 2.19), and highest quartile of household assets (adjusted OR 2.87, 95% CI 2.39, 3.45). The odds of prevalent hypertension and diabetes were also generally higher among individuals with higher socioeconomic position.
Individuals with lower socioeconomic position in Himachal Pradesh were more likely to have abnormal behavioral risk factors, and individuals with higher socioeconomic position were more likely to have abnormal clinical risk factors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vitamins B12 and B6 and folate are known to have implications for pregnancy outcomes. We aimed to describe B6, B12, and folate status in pregnancy and investigate their associations with low birth ...weight and preterm delivery in mothers recruited from public hospitals in urban Bengaluru. Pregnant women between 18 and 45 years were included in the MAASTHI prospective cohort study. Each participant's age, socioeconomic status, and anthropometry were recorded during baseline and followed up after delivery. Blood samples were collected between the 24th and 32nd weeks of gestation and stored at -80° for analysis. B6, B12, folate, homocysteine, and methylmalonic acid (MMA) levels were analyzed in the stored samples. We found low plasma vitamin B12, folate, and B6 levels in 48.5%, 42.0%, and 10.4% of the women (
= 230), respectively. Elevated MMA and homocysteine were observed among 73.6% and 6.1% of the women, respectively. We found B6 levels were significantly associated with birth weight (β(SE) -0.002(0.0),
= 0.001) after adjusting for age, parity, adiposity, gestational diabetes, and socioeconomic status of the mother. Those with impaired folate deficiency were twice at risk (AOR 1.95 (1.29, 3.07),
= 0.002) of low birth weight. Vitamin B6 levels and impaired folate status were associated with low birth weight in the MAASTHI birth cohort.
IntroductionExposure to fine particulate matter has been associated with several cardiovascular and cardiometabolic diseases. However, such evidence mostly originates from low-pollution settings or ...cross-sectional studies, thus necessitating evidence from regions with high air pollution levels, such as India, where the burden of non-communicable diseases is high.Research design and methodsWe studied the associations between ambient PM2.5 levels and fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) and incident type 2 diabetes mellitus (T2DM) among 12 064 participants in an adult cohort from urban Chennai and Delhi, India. A meta-analytic approach was used to combine estimates, obtained from mixed-effects models and proportional hazards models, from the two cities.ResultsWe observed that 10 μg/m3 differences in monthly average exposure to PM2.5 was associated with a 0.40 mg/dL increase in FPG (95% CI 0.22 to 0.58) and 0.021 unit increase in HbA1c (95% CI 0.009 to 0.032). Further, 10 μg/m3 differences in annual average PM2.5 was associated with 1.22 (95% CI 1.09 to 1.36) times increased risk of incident T2DM, with non-linear exposure response.ConclusionsWe observed evidence of temporal association between PM2.5 exposure, and higher FPG and incident T2DM in two urban environments in India, thus highlighting the potential for population-based mitigation policies to reduce the growing burden of diabetes.
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