[Show abstract][Hide abstract] ABSTRACT: In spite of its major impact on life-long health, the process of microbial succession in the gut of infants remains poorly understood. Here, we analyze the patterns of taxonomic and functional change in the gut microbiota during the first year of life for a birth cohort of 13 infants. We detect that individual instances of gut colonization vary in the temporal dynamics of microbiota richness, diversity, and composition at both functional and taxonomic levels. Nevertheless, trends discernible in a majority of infants indicate that gut colonization occurs in two distinct phases of succession, separated by the introduction of solid foods to the diet. This change in resource availability causes a sharp decrease in the taxonomic richness of the microbiota due to the loss of rare taxa (p = 2.06e-9), although the number of core genera shared by all infants increases substantially. Moreover, although the gut microbial succession is not strictly deterministic, we detect an overarching directionality of change through time towards the taxonomic and functional composition of the maternal microbiota. Succession is however not complete by the one year mark, as significant differences remain between one-year-olds and their mothers in terms of taxonomic (p = 0.009) and functional (p = 0.004) microbiota composition, and in taxonomic richness (p = 2.76e-37) and diversity (p = 0.016). Our results also indicate that the taxonomic composition of the microbiota shapes its functional capacities. Therefore, the observed inter-individual variability in taxonomic composition during succession is not fully compensated by functional equivalence among bacterial genera and may have important physiological consequences. Finally, network analyses suggest that positive interactions among core genera during community assembly contribute to ensure their permanence within the gut, and highlight an expansion of complexity in the interactions network as the core of taxa shared by all infants grows following the introduction of solid foods.
[Show abstract][Hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a largely unknown aetiology and a wide range of symptoms. Most cross-sectional studies carried out so far suggest subtle alterations in the structure of the intestinal microbiota that are barely reproduced, partly because of the high inter-subject variation in the community composition and disorder-specific features. We performed a longitudinal study to explore the within-subject variation of the faecal microbiota in two IBS patients classified into the diarrhoea subtype and the healthy spouse of one of them. Faecal communities were monitored over six to eight weeks and analysed through metagenomic and metatranscriptomic approaches. We found a higher temporal instability in the fraction of active microbiota related to the IBS condition and fluctuating symptoms. Strong and quick shifts in the distribution of the active microbiota and changes in the global pattern of gene expression were detected in association with acute diarrhoea, whereas microbial composition and encoded functions were more stable. The specific alterations in the microbiota were barely reproduced within and between patients. Further research is needed to assess whether these changes are a consequence of the abnormal gut function in acute diarrhoeic episodes and the potential usefulness of tackling them. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Cardiovascular disease (CVD) mortality has more than halved in England since the 1980s, but there are few data on small-area trends. We estimated CVD mortality by ward in 5-year intervals between 1982 and 2006, and examined trends in relation to starting mortality, region and community deprivation. METHODS: We analysed CVD death rates using a Bayesian spatial technique for all 7932 English electoral wards in consecutive 5-year intervals between 1982 and 2006, separately for men and women aged 30-64 years and ≥65 years. RESULTS: Age-standardized CVD mortality declined in the majority of wards, but increased in 186 wards for women aged ≥65 years. The decline was larger where starting mortality had been higher. When grouped by deprivation quintile, absolute inequality between most- and least-deprived wards narrowed over time in those aged 30-64 years, but increased in older adults; relative inequalities worsened in all four age-sex groups. Wards with high CVD mortality in 2002-06 fell into two groups: those in and around large metropolitan cities in northern England that started with high mortality in 1982-86 and could not 'catch up', despite impressive declines, and those that started with average or low mortality in the 1980s but 'fell behind' because of small mortality reductions. CONCLUSIONS: Improving population health and reducing health inequalities should be treated as related policy and measurement goals. Ongoing analysis of mortality by small area is essential to monitor local effects on health and health inequalities of the public health and healthcare systems.
International Journal of Epidemiology 11/2012; · 6.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gut microbiota presents a symbiotic relationship with the human host playing a beneficial role in human health. Since its establishment, the bacterial community is subjected to the influence of many different factors that shape its composition within each individual. However, an important convergence is observed at functional level in the gut microbiota. A metatranscriptomic study of healthy individuals showed homogeneity in the composition of the active microbiota that increased further at functional level.
[Show abstract][Hide abstract] ABSTRACT: The establishment of a balanced intestinal microbiota is essential for numerous aspects of human health, yet the microbial colonization of the gastrointestinal tract of infants is both complex and highly variable among individuals. In addition, the gastrointestinal tract microbiota is often exposed to antibiotics, and may be an important reservoir of resistant strains and of transferable resistance genes from early infancy. We are investigating by means of diverse metagenomic approaches several areas of microbiota development in infants, including the deployment of functional capabilities at the community level, the presence of antibiotic resistances and the population dynamics of the most abundant genera.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: An important question in genetic studies is to determine those genetic variants, in particular CNVs, that arespecific to different groups of individuals. This could help in elucidating differences in disease predispositionand response to pharmaceutical treatments. We propose a Bayesian model designed to analyze thousands of copynumber variants (CNVs) where only few of them are expected to be associated with a specific phenotype. RESULTS: The model is illustrated by analyzing three major human groups belonging to HapMap data. We also show howthe model can be used to determine specific CNVs related to response to treatment in patients diagnosed withovarian cancer. The model is also extended to address the problem of how to adjust for confounding covariates(e.g., population stratification). Through a simulation study, we show that the proposed model outperforms otherapproaches that are typically used to analyze this data when analyzing common copy-number polymorphisms(CNPs) or complex CNVs. We have developed an R package, called bayesGen, that implements the model andestimating algorithms. CONCLUSIONS: Our proposed model is useful to discover specific genetic variants when different subgroups of individuals areanalyzed. The model can address studies with or without control group. By integrating all data in a unique modelwe can obtain a list of genes that are associated with a given phenotype as well as a different list of genes that areshared among the different subtypes of cases.
[Show abstract][Hide abstract] ABSTRACT: When analyzing the geographical variations of disease risk, one common problem is data sparseness. In such a setting, we investigate the possibility of using Bayesian shared spatial component models to strengthen inference and correct for any spatially structured sources of bias, when distinct data sources on one or more related diseases are available. Specifically, we apply our models to analyze the spatial variation of risk of two forms of scrapie infection affecting sheep in Wales (UK) using three surveillance sources on each disease. We first model each disease separately from the combined data sources and then extend our approach to jointly analyze diseases and data sources. We assess the predictive performances of several nested joint models through pseudo cross-validatory predictive model checks.
[Show abstract][Hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder in western countries. Previous studies on IBS, mostly based on faecal samples, suggest alterations in the intestinal microbiota. However, no consensus has been reached regarding the association between specific bacteria and IBS. We explore the alterations of intestinal bacterial communities in IBS using massive sequencing of amplified 16S rRNA genes. Mucosal biopsies of the ascending and descending colon and faeces from 16 IBS patients and 9 healthy controls were analysed. Strong inter-individual variation was observed in the composition of the bacterial communities in both patients and controls. These communities showed less diversity in IBS cases. There were larger differences in the microbiota composition between biopsies and faeces than between patients and controls. We found a few over-represented and under-represented taxa in IBS cases with respect to controls. The detected alterations varied by site, with no changes being consistent across sample types.
[Show abstract][Hide abstract] ABSTRACT: In the last decade, an extensive effort has been made to characterize the human intestinal microbiota by means of SSU rRNA gene sequence and metagenomic analysis. Relatively few studies have followed intestinal bacterial communities over time to assess their stability in the absence of perturbation. In this study, we have monitored the faecal bacteria of three healthy subjects during 15 consecutive days. The global community structure was analysed through SSU rRNA gene sequencing. In agreement with previous studies, we found that the between-subject variation in community structure was larger than within. The composition was fairly stable throughout, although daily fluctuations were detected for all genera and phylotypes at 97% of sequence identity. While the core shared between subjects was very small, each subject harboured a stable high-abundance core composed of a small number of bacterial groups (9% of the phylotypes accounted for between 74% and 93% of the sequences). This may suggest that studies aimed at linking the microbiota composition with disease risk should be limited to the numerically most dominant phylotypes, as the rest appears transient. Networks of potential interactions between co-occurring genera were also subject-specific, even for the same bacterial genus, which might be reflecting host-specific selective pressures and historic events.
[Show abstract][Hide abstract] ABSTRACT: Predictors of sustained virological response (SVR) to antiviral therapy post-liver transplantation (LT) for chronic hepatitis C are needed. In non-transplanted patients, viral kinetics can predict SVR.
To determine the early viral kinetics in LT recipients with different immunosuppression (tacrolimus - Tac- vs. cyclosporine - CsA-) during treatment with peg-IFN+RBV.
Prospective pilot study in HCV-1b infected patients: (LT CsA n=8; Tac n=8; non-LT n=4), treated with IFN α-2a vs. α-2b (180 μg or 1.5 μg/kg, respectively) once weekly plus weight-based RBV. Median CsA or Tac baseline trough levels were 141 and 7.70 ng/mL, respectively. HCV-RNA was quantified before treatment and after 3, 6, 12h; days 1-6; and weeks 4, 12, 24, 48 and 78 (follow-up).
Different kinetics were observed: early viral load declines with shoulder phase (n=12), delayed monophasic without first phase (n=5, all CsA), and biphasic (n=1) or flat (n=1), without influence of IL28B rs12979860 donor/recipient alleles. In LT, median declines (log(10)UI/mL) at week 4 were -3.62 and -1.49 for Tac vs. CsA; and -2.10 vs.-1.50 for IFN α-2a vs. α-2b (NS), with a trend for faster declines in Tac patients. Generalized additive models suggested a cut-off for predicting response in LT patients of 30 days for Tac, but beyond day 40 for CsA.
In LT, the viral kinetics during peg-IFN+RBV treatment is delayed. HCV-RNA at 48 h. may not be predictive of response, and CsA-immunosupressed patients with delayed monophasic declines may potentially achieve ETVR and SVR despite unfavourable or absent early viral load declines.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 03/2012; 53(3):231-8. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The establishment of a balanced intestinal microbiota is essential for numerous aspects of human health, yet the microbial colonization of the gastrointestinal tract of infants is both complex and highly variable among individuals. In addition, the gastrointestinal tract micro-biota is often exposed to antibiotics, and may be an important reservoir of resistant strains and of transferable resistance genes from early infancy. We are investigating by means of diverse metagenomic approaches several areas of microbiota development in infants, including the deployment of functional capabilities at the community level, the presence of antibiotic resistances and the population dynamics of the most abundant genera.
Clinical Microbiology and Infection 01/2012; 18:21-26. · 4.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The authors analyse the spatio-temporal variations of the incidence of bladder cancer between 1973 and 2004 in Utah at the census tract level (496 areas) to highlight areas of high and low relative risks that remained so throughout the 32 year period. Using these identified areas, a novel strategy is used to carry out a geographical case-control study of association between the risk of bladder cancer and presence of Toxic Release Inventory sites, where areas with stable high RRs are 'case areas' and all remaining areas with stable non increased risks are 'control areas'.
The time trend of bladder cancer risk fluctuated over the study period: A steady decrease was observed, followed by an abrupt increase from 1992 to 2004. Using a Bayesian space-time model, 93 census tracts were classified as having an excess relative risk and 81 a lower relative risk, sustained over the 32 years. We showed that these high relative risk areas for bladder cancer were associated with the presence of Toxic Release Inventory sites, after adjusting for the proportion of Latter-Day Saint Church members as an area level proxy for smoking habits.
Our study has demonstrated that the modeling of data in time and space has additional benefits over a purely spatial analysis. In addition to highlighting the areas with high and low relative risks, this model also allows the simultaneous study of persistency of spatial patterns over time and detection of 'unusual' time trends that may warrant further investigation.
International Journal of Health Geographics 02/2011; 10:16. · 2.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gut microbiota is the most complex bacterial community in the human body and its study may give important clues to the etiology of different intestinal diseases. Most studies carried out so far have used fecal samples, assuming that these samples have a similar distribution to the communities present throughout the colon. The present study was designed to test this assumption by comparing samples from the rectal mucosa and feces of nine healthy volunteers by sequencing libraries of 16S rRNA genes. At the family taxonomic level, where rarefaction curves indicate that the observed number of taxa is close to the expected one, we observe under different statistical analyses that fecal and mucosal samples cluster separately. The same is found at the level of species considering phylogenetic information. Consequently, it cannot be stated that both samples from a given individual are of similar composition. We believe that the evidence in support of this statement is strong and that it would not change by increasing the number of individuals and/or performing massive sequencing. We do not expect clinicians to stop using feces for research, but we think it is important to caution them on their potential lack of representativeness with respect to the bacterial biofilm on the rectal mucosa.
[Show abstract][Hide abstract] ABSTRACT: The human gut is the natural habitat for a large and dynamic bacterial community that has a great relevance for health. Metagenomics is increasing our knowledge of gene content as well as of functional and genetic variability in this microbiome. However, little is known about the active bacteria and their function(s) in the gastrointestinal tract. We performed a metatranscriptomic study on ten healthy volunteers to elucidate the active members of the gut microbiome and their functionality under conditions of health. First, the microbial cDNAs obtained from each sample were sequenced using 454 technology. The analysis of 16S transcripts showed the phylogenetic structure of the active microbial community. Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Prevotellaceae, and Rickenellaceae were the predominant families detected in the active microbiota. The characterization of mRNAs revealed a uniform functional pattern in healthy individuals. The main functional roles of the gut microbiota were carbohydrate metabolism, energy production and synthesis of cellular components. In contrast, housekeeping activities such as amino acid and lipid metabolism were underrepresented in the metatranscriptome. Our results provide new insights into the functionality of the complex gut microbiota in healthy individuals. In this RNA-based survey, we also detected small RNAs, which are important regulatory elements in prokaryotic physiology and pathogenicity.
PLoS ONE 01/2011; 6(3):e17447. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe the application of Bayesian hierarchical models (BHM) to the analysis of risk of sheep scrapie using data from multiple surveillance sources. More specifically, we analysed data from the test results of three surveillance sources on classical and atypical scrapie in Wales for the period 2002-2006. For each form of scrapie, a BHM was fitted to assess the occurrence of spatial patterns of risk shared by the multiple surveillance sources and the association between covariates and disease. We defined a shared-component model whereby the two types of data sources: exhaustive lists (e.g. reports of clinical cases) and sample-based data sources (e.g. abattoir survey) shared a common spatial pattern of risks at parish level. This shared component was adjusted by a risk-gradient parameter that moderated the individual contribution of the datasets. For both forms of scrapie, the risk-gradient was not significantly different indicating that the sensitivity of the two types of dataset was similar for the two diseases. The spatial patterns of the combinations of data sources appeared similar within disease. However, our results suggest that classical and atypical scrapie differ in their spatial patterns and disease determinants. The joint approach permitted inference from all the available evidence and resulted in robust and less biased estimates of risk, particularly for atypical scrapie where the number of observations was very limited.
Preventive Veterinary Medicine 10/2010; 98(1):29-38. · 2.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The initiation of environmental public health tracking systems in the United States and the United Kingdom provided an opportunity to advance techniques and tools available for spatial epidemiological analysis integrating both health and environmental data.
The Rapid Inquiry Facility (RIF) allows users to calculate adjusted and unadjusted standardized rates and risks. The RIF is embedded in ArcGIS so that further geographical information system (GIS) spatial functionality can be exploited or results can be exported to statistical packages for further tailored analyses where required. The RIF also links directly to several statistical packages and displays the results in the GIS.
The value of the RIF is illustrated here with two case studies: risk of leukemia in areas surrounding oil refineries in the State of Utah (USA) and an analysis of the geographical variation of risk of esophageal cancer in relation to zinc cadmium sulfide exposure in Norwich (United Kingdom).
The risk analysis study in Utah did not suggest any evidence of increased relative risk of leukemia, multiple myeloma, or Hodgkin's lymphoma in the populations around the five oil-refining facilities but did reveal an excess risk of non-Hodgkin's lymphoma that might warrant further investigation. The disease-mapping study in Norwich did not reveal any areas with higher relative risks of esophageal cancer common to both males and females, suggesting that a common geographically determined exposure was unlikely to be influencing cancer risk in the area.
The RIF offers a tool that allows epidemiologists to quickly carry out ecological environmental epidemiological analysis such as risk assessment or disease mapping.
Environmental Health Perspectives 05/2010; 118(9):1306-12. · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increasing availability of gene sequences of prokaryotic species in samples extracted from all kind of locations allows addressing the study of the influence of environmental patterns in prokaryotic biodiversity. We present a comprehensive study to address the potential existence of environmental preferences of prokaryotic taxa and the commonness of the specialist and generalist strategies. We also assessed the most significant environmental factors shaping the environmental distribution of taxa.
We used 16S rDNA sequences from 3,502 sampling experiments in natural and artificial sources. These sequences were taxonomically assigned, and the corresponding samples were also classified into a hierarchical classification of environments. We used several statistical methods to analyze the environmental distribution of taxa. Our results indicate that environmental specificity is not very common at the higher taxonomic levels (phylum to family), but emerges at lower taxonomic levels (genus and species). The most selective environmental characteristics are those of animal tissues and thermal locations. Salinity is another very important factor for constraining prokaryotic diversity. On the other hand, soil and freshwater habitats are the less restrictive environments, harboring the largest number of prokaryotic taxa. All information on taxa, samples and environments is provided at the envDB online database, http://metagenomics.uv.es/envDB.
This is, as far as we know, the most comprehensive assessment of the distribution and diversity of prokaryotic taxa and their associations with different environments. Our data indicate that we are still far from characterizing prokaryotic diversity in any environment, except, perhaps, for human tissues such as the oral cavity and the vagina.
[Show abstract][Hide abstract] ABSTRACT: To investigate the risk of congenital anomalies in relation to an index of geographic density of landfill sites across 5x5 km grid squares in England.
2 km zones were constructed in a geographical information system around 8804 landfill sites, including 607 that handled special (hazardous) wastes, and intersected with postcode coordinates of over 10 million births (136,821 with congenital anomalies), 1983-98. A landfill exposure index was calculated to represent the geographic density of landfill sites within 2 km of births for each 5x5 km grid square, calculated separately for landfill sites handling special, and non-special or unknown, waste. For each group of landfills, the index was classified into four categories of intensity, and risks for the second, third and top categories were compared to the bottom category, comprising areas with no such landfill sites within 2 km (index of zero). We used hierarchical logistic regression modelling in a Bayesian framework, with adjustment for potential confounding.
For special waste sites, adjusted odds ratios were significant for the third category of the landfill exposure index for all anomalies combined and cardiovascular defects (OR 1.08 (95% credible interval 1.02 to 1.13) and 1.16 (1.00 to 1.33), respectively) and for hypospadias and epispadias for the third and top categories (OR 1.11 (1.02 to 1.21) and 1.12 (1.02 to 1.22), respectively). After adjustment, there were no excess risks in relation to sites handling non-special or unknown waste types.
There was a weak spatial association between risk of certain congenital anomalies and geographic density of special (hazardous) waste sites at the level of 5x5 km grid squares. Exposure pathways and mechanisms to help interpret these findings are not well-established.
Occupational and environmental medicine 01/2009; 66(2):81-9. · 3.64 Impact Factor