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Multicomponent internal recalibration of an LC-FTICR-MS analysis employing a partially characterized complex peptide mixture: systematic and random errors.

In high-throughput proteomics, a promising current approach is the use of liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS) of tryptic peptides from complex mixtures of proteins. To apply this method, it is necessary to account for any systematic measurement error, and it is useful to have an estimate of the random error expected in the measured masses. Here, we analyze by LC-FTICR-MS a complex mixture of peptides derived from a sample previously characterized by LC-QTOF-MS. Application of a Bayesian probability model of the data and partial knowledge of the composition of the sample suffice to estimate both the systematic and random errors in measured masses.

Amino Acid Sequence↗

HIV testing and retesting for men and women in Switzerland.

This study was conducted to describe voluntary HIV testing in the general population in Switzerland and to estimate yearly HIV test incidence. In 1994, a representative telephone survey of individuals aged 17 to 45 years obtained self-reported information on HIV testing. In addition to describing cumulative HIV test incidence, yearly HIV test incidence over time was estimated by a Bayesian hurdle model allowing for the plausible scenario of test consumption differing between first test and subsequent retests. Overall, 33% of the Swiss population (age 17 to 45 years) has been tested at some time for HIV on a voluntary basis (30% men, 36% women). For the time period 1990-1994, the result showed for 35-year-old individuals with supposedly low risk behavior, that 1) annual test incidence (first test or retest) showed a greater increase for men (4.2 to 5.9%) than for women (5.0 to 6.0%); 2) annual first test incidence increased moderately and differed for men and women (2.9 to 3.4% for men, 4.6 to 5.2% for women), and 3) annual retest incidence was twice as high for men (17.6%) as for women (8.6%). In conclusion, a substantial part of the Swiss population has been tested at some stage for HIV on a voluntary basis, and differences exist for testing and retesting between men and women.

Adolescent↗

On Bayesian inference for proportional hazards models using noninformative priors.

In this article, we investigate the properties of the posterior distribution under the uniform improper prior for two commonly used proportional hazards models; the Weibull regression model and the extreme value regression model. We allow the observations to be right censored. We obtain sufficient conditions for the existence of the posterior moment generating function of the regression coefficients. A dataset involving a lung cancer clinical trial and a simulation are presented to illustrate our results.

Bayes Theorem↗

Predicting patterns of mammography use: a geographic perspective on national needs for intervention research.

OBJECTIVE: To introduce a methodology for planning preventive health service research that takes into account geographic context. DATA SOURCES: National Health Interview Survey (NHIS) self-reports of mammography within the past two years, 1987, and 1993-94. Area Resource File (ARF), 1990. Database of mammography intervention research studies conducted from 1984 to 1994. DESIGN: Bayesian hierarchical modeling describes mammography as a function of county-level socioeconomic data and explicitly estimates the geographic variation unexplained by the county-level data. This model produces county use estimates (both NHIS-sampled and unsampled), which are aggregated for entire states. The locations of intervention research studies are examined in light of the statewide mammography utilization estimates. DATA EXTRACTION: Individual level NHIS data were merged with county-level data from the ARF. PRINCIPAL FINDINGS: State maps reveal the estimated distribution of mammography utilization and intervention research. Eighteen states with low mammography use reported no intervention research activity. County-level occupation and education were important predictors for younger women in 1993-94. In 1987, they were not predictive for any demographic group. CONCLUSIONS: Opportunities exist to improve the planning of future intervention research by considering geographic context. Modeling results suggest that the choice of predictors be tailored to both the population and the time period under study when planning interventions.

Black or African American↗

Pneumococcal population structure influences the effects of air pollution on invasive disease risk in South Africa.

Streptococcus pneumoniae is highly diverse, comprising over 100 serotypes and hundreds of genomic lineages amid widespread vaccination. While it can cause invasive pneumococcal disease (IPD) which exhibits pronounced seasonal spikes, the interplay between pneumococcal diversity and environmental drivers remains unexplored. Here we analysed 59,017 IPD cases over 19 years from South Africa, incorporating 4,350 genome-sequenced isolates, using Bayesian spatiotemporal models to link environmental exposure and pneumococcal diversity. Cumulatively, across an 8-week period, moderate relative humidity (33-49%) and cold minimum temperatures (4-10 °C) increased IPD risk by 5% and 4%, respectively. Conversely, warm maximum temperatures (27-38 °C) were associated with up to a 10% increased risk within a week of exposure. There was a positive association between air pollution (PM2.5) and IPD, although it varied by age, disease presentation, and most notably serotype and lineage. Specifically, the lag time between PM2.5 exposure and disease onset varied by serotype, with only serotypes 4, 8 and 23F conferring an immediate IPD risk. High prevalence of GPSC21 lineage (serotype 19F) also modified the pollution response, shifting the lag structure to produce immediate risk of disease following high PM2.5 exposure. Our results demonstrate that pneumococcal population structure shapes air quality risk which in turn can shape the fitness landscape of microbial populations. Integration of these data may inform public health policy.

Journal Article↗

Limited contributions of bacteria and fungi to coral nutrition revealed by amino acid δ13C analysis.

Corals often form reef ecosystems that support diverse marine life, but they are sensitive to environmental fluctuations that can affect their nutrient acquisition. While coral-associated microbes (e.g., Symbiodiniaceae, bacteria and fungi) may supplement nutrients to coral hosts via metabolite translocation and nutrient recycling, the extent to which these microbial partners contribute to coral autotrophy or heterotrophy remains unclear. Here, we seasonally measure the carbon isotopes of amino acids (δ13CAA) in reef-building coral Pocillopora damicornis and its nutrient sources (e.g., Symbiodiniaceae and particulate organic matter). Regional Bayesian mixing models show that P. damicornis increased autotrophy (from 67.1 to 80.5%), but decreased particulate feeding (from 32.9 to 19.5%) from the cool season to the warm season. Stable essential δ13CAA values (valine, leucine and isoleucine) suggest limited seasonal changes in microbial contributions. Linear discriminant analysis, which combines current and published data from basal organisms (e.g., bacteria and fungi) to coral consumers, also reveals limited bacterial and fungal contributions to coral nutrition. Thus, we advocate that coral nutrition is primarily determined by Symbiodiniaceae translocation and particulate feeding. As these nutritional pathways are highly subject to environmental fluctuations, corals lacking trophic flexibility may suffer more from malnutrition and even population decline under global environmental change.

Anthozoa↗

Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors.

The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.

Acute Disease↗

Admixture analysis of South Asian cattle.

We present population genetic analysis of microsatellite variation in seven Bos indicus cattle breeds from a variety of locations in South Asia. This is the first such study focusing within this area, which is one of the postulated centres of origin of domestic cattle. An estimate of the influence of Bos taurus ancestry was carried out using three approaches: by the systematic selection of population-associated alleles for B. taurus and examination of their frequency; by examining the truncation of genetic distances from European populations; and by a model-based Bayesian admixture analysis. These analyses revealed a B. taurus influence in the Indian subcontinent; part of a gradation which stretches from Europe through the Near East towards Indian and which may be of ancient origin.

Alleles↗

Modelling exposure to disinfection by-products in drinking water for an epidemiological study of adverse birth outcomes.

We are conducting an epidemiological study on the association between disinfection by-product concentrations in drinking water and adverse birth outcomes in the UK, using trihalomethane (THM) concentrations over defined water zones as an exposure index. Here we construct statistical models using sparse routinely collected THMs measurements to obtain quarterly estimates of mean THM concentrations for each water zone. We modelled the THM measurements using a Bayesian hierarchical mixture model, taking into account heterogeneity in THM concentrations between water originating from different source types, quarterly variation in THM concentrations and uncertainty in the true value of undetected and rounded measurements. Quarterly estimates of mean THM concentrations plus estimates of the water source type (ground, lowland surface or upland surface) were obtained for each water zone. THM concentration estimates were typically highest from July to September (third quarter), and varied considerably between water sources. Our exposure estimates were categorized into 'low', 'medium' and 'high' THM classes. Our modelled quarterly exposure estimates were compared to a simple alternative: annual means of the raw data for each water zone. In all, 15-25% of exposure estimates were classified differently. The modelled THM estimates led to slightly stronger and more precise estimates of association with risk of still birth and low birth weight than did the raw annual means. We conclude that our modelling approach enabled us to provide robust quarterly estimates of ecological exposure to THMs in a situation where the raw data were too sparse to base exposure assessment on empirical summaries alone.

Adult↗

Eye movements reveal the on-line computation of lexical probabilities during reading.

Skilled readers are able to derive meaning from a stream of visual input with remarkable efficiency. In this article, we present the first evidence that statistical information latent in the linguistic environment can contribute to an account of reading behavior. In two eye-tracking studies, we demonstrate that the transitional probabilities between words have a measurable influence on fixation durations, and using a simple Bayesian statistical model, we show that lexical probabilities derived by combining transitional probability with the prior probability of a word's occurrence provide the most parsimonious account of the eye movement data. We suggest that the brain is able to draw upon statistical information in order to rapidly estimate the lexical probabilities of upcoming words: a computationally inexpensive mechanism that may underlie proficient reading.

Bayes Theorem↗

Historical and contemporary multilocus population structure of Ascochyta rabiei (teleomorph: Didymella rabiei) in the Pacific Northwest of the United States.

The historical and contemporary population genetic structure of the chickpea Ascochyta blight pathogen, Ascochyta rabiei (teleomorph: Didymella rabiei), was determined in the US Pacific Northwest (PNW) using 17 putative AFLP loci, four genetically characterized, sequence-tagged microsatellite loci (STMS) and the mating type locus (MAT). A single multilocus genotype of A. rabiei (MAT1-1) was detected in 1983, which represented the first recorded appearance of Ascochyta blight of chickpea in the PNW. During the following year many additional alleles, including the other mating type allele (MAT1-2), were detected. By 1987, all alleles currently found in the PNW had been introduced. Highly significant genetic differentiation was detected among contemporary subpopulations from different hosts and geographical locations indicating restricted gene flow and/or genetic drift occurring within and among subpopulations and possible selection by host cultivar. Two distinct populations were inferred with high posterior probability which correlated to host of origin and date of sample using Bayesian model-based population structure analyses of multilocus genotypes. Allele frequencies, genotype distributions and population assignment probabilities were significantly different between the historical and contemporary samples of isolates and between isolates sampled from a resistance screening nursery and those sampled from commercial chickpea fields. A random mating model could not be rejected in any subpopulation, indicating the importance of the sexual stage of the fungus both as a source of primary inoculum for Ascochyta blight epidemics and potentially adaptive genotypic diversity.

Ascomycota↗

Evidence of genetic distinction and long-term population decline in wolves (Canis lupus) in the Italian Apennines.

Historical information suggests the occurrence of an extensive human-caused contraction in the distribution range of wolves (Canis lupus) during the last few centuries in Europe. Wolves disappeared from the Alps in the 1920s, and thereafter continued to decline in peninsular Italy until the 1970s, when approximately 100 individuals survived, isolated in the central Apennines. In this study we performed a coalescent analysis of multilocus DNA markers to infer patterns and timing of historical population changes in wolves surviving in the Apennines. This population showed a unique mitochondrial DNA control-region haplotype, the absence of private alleles and lower heterozygosity at microsatellite loci, as compared to other wolf populations. Multivariate, clustering and Bayesian assignment procedures consistently assigned all the wolf genotypes sampled in Italy to a single group, supporting their genetic distinction. Bottleneck tests showed evidences of population decline in the Italian wolves, but not in other populations. Results of a Bayesian coalescent model indicate that wolves in Italy underwent a 100- to 1000-fold population contraction over the past 2000-10,000 years. The population decline was stronger and longer in peninsular Italy than elsewhere in Europe, suggesting that wolves have apparently been genetically isolated for thousands of generations south of the Alps. Ice caps covering the Alps at the Last Glacial Maximum (c. 18,000 years before present), and the wide expansion of the Po River, which cut the alluvial plains throughout the Holocene, might have provided effective geographical barriers to wolf dispersal. More recently, the admixture of Alpine and Apennine wolf populations could have been prevented by deforestation, which was already widespread in the fifteenth century in northern Italy. This study suggests that, despite the high potential rates of dispersal and gene flow, local wolf populations may not have mixed for long periods of time.

Animals↗

Evolutionary changes of metabolic networks and their biosynthetic capacities.

The metabolic networks of different species show a large variety in their structural design. In this work, the evolution of functional properties of metabolism in relation with metabolic network structure is investigated. The metabolism of ancestral species is inferred from the metabolism of contemporary species using a Bayesian network model for metabolism evolution. Subsequently, these networks are analysed with the recently developed method of network expansion. This method allows for a structural analysis of metabolic networks as well as a quantification of network functions in terms of their synthesising capacities when they are provided with certain external resources. The evolutionary dynamics of one particular network function: the metabolic expansion of glucose is investigated.

Adaptation, Physiological↗

A spatio-temporal analysis of BSE cases born before and after the reinforced feed ban in France.

A spatio-temporal analysis was carried out to see how the risk distribution of bovine spongiform encephalopathy (BSE) in France changed depending on the period of birth. The data concerned the 539 BSE cases born in France after the ban (BAB) of meat and bone meal (MBM) in 1990 and detected between July 1, 2001 and December 31, 2003, when the surveillance of BSE was comprehensive. Seventy-two of these cases were born after the reinforced (second) ban (BASB) in 1996, which involved the removal of BSE-risk materials and cadavers from the processing of MBM. The Ederer-Myers-Mantel (EMM) time and space cluster test was applied, after classifying the cases by trimester and region of birth, BAB or BASB status, and dairy or beef status. Then disease mapping was performed for four successive birth periods, three for the BAB cases (January 1991 through June 1994, July 1994 through June 1995, July 1995 through June 1996), and one for the BASB (July 1996 through October 1998). It was elaborated with the Bayesian graphical modelling methods and based on a Poisson distribution with spatial smoothing. The parameters were estimated by a Markov Chain Monte Carlo (MCMC) simulation method. The main finding was that the areas with the highest risk of BSE changed largely from one birth period to another; from the west, it reached the east of France for birth cohort 1994-1995 and the southwest for birth cohort 1995-1996. The EMM test identified a peak risk in this region both for dairy and beef cattle in the fall 1995. The spatial distribution of the risk for the BASB cases matched the spatial pattern of risk for the preceding BAB birth cohort quite well; this was in favour of a common origin of the infection of the BAB and BASB cases, despite the complementary control measures.

Animal Feed↗

Predicting the clinical status of human breast cancer by using gene expression profiles.

Prognostic and predictive factors are indispensable tools in the treatment of patients with neoplastic disease. For the most part, such factors rely on a few specific cell surface, histological, or gross pathologic features. Gene expression assays have the potential to supplement what were previously a few distinct features with many thousands of features. We have developed Bayesian regression models that provide predictive capability based on gene expression data derived from DNA microarray analysis of a series of primary breast cancer samples. These patterns have the capacity to discriminate breast tumors on the basis of estrogen receptor status and also on the categorized lymph node status. Importantly, we assess the utility and validity of such models in predicting the status of tumors in crossvalidation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications on the basis of the selection of gene subsets for each validation analysis. This latter point is of critical importance in the ability to apply these methodologies to clinical assessment of tumor phenotype.

Bacillus anthracis↗

Nanomolar affinity small molecule correctors of defective Delta F508-CFTR chloride channel gating.

Deletion of Phe-508 (Delta F508) is the most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) causing cystic fibrosis. Delta F508-CFTR has defects in both channel gating and endoplasmic reticulum-to-plasma membrane processing. We identified six novel classes of high affinity potentiators of defective Delta F508-CFTR Cl- channel gating by screening 100,000 diverse small molecules. Compounds were added 15 min prior to assay of iodide uptake in epithelial cells co-expressing Delta F508-CFTR and a high sensitivity halide indicator (YFP-H148Q/I152L) in which Delta F508-CFTR was targeted to the plasma membrane by culture at 27 degrees C for 24 h. Thirty-two compounds with submicromolar activating potency were identified; most had tetrahydrobenzothiophene, benzofuran, pyramidinetrione, dihydropyridine, and anthraquinone core structures (360-480 daltons). Further screening of >1000 structural analogs revealed tetrahydrobenzothiophenes that activated DeltaF508-CFTR Cl- conductance reversibly with Kd < 100 nm. Single-cell voltage clamp analysis showed characteristic CFTR currents after Delta F508-CFTR activation. Activation required low concentrations of a cAMP agonist, thus mimicking the normal physiological response. A Bayesian computational model was developed using tetrahydrobenzothiophene structure-activity data, yielding insight into the physical character and structural features of active and inactive potentiators and successfully predicting the activity of structural analogs. Efficient potentiation of defective Delta F508-CFTR gating was also demonstrated in human bronchial epithelial cells from a Delta F508 cystic fibrosis subject after 27 degrees C temperature rescue. In conjunction with correctors of defective Delta F508-CFTR processing, small molecule potentiators of defective Delta F508-CFTR gating may be useful for therapy of cystic fibrosis caused by the Delta F508 mutation.

Animals↗

Regional patterns of birthweights in Papua New Guinea in relation to diet, environment and socio-economic factors.

Regional differences in mean birthweight in rural Papua New Guinea (PNG) and the importance of differences in family diet and maternal education and socio-economic status on such patterns were explored using birthweight data collected by the 1982/83 PNG National Nutrition Survey. A total of 6137 birthweight measurements from 85 PNG districts were available, representing 22% of all children included in the survey. The nature of possible selection biases are assessed and their implications discussed. Hierarchical Bayesian spatial models based on conditional autoregressive (CAR) priors were used to model spatial patterns in birthweights and their relation to different sets of covariates. Birthweights were found to exhibit striking geographical differences. Children from the central PNG highlands and from affluent lowland areas had the highest birthweights, while they were lowest in the (largely lowland) Sepik, Western, Madang and Milne Bay Provinces and in remote highland fringe areas. Maternal education, socio-economic status and diet were all important predictors, but only differences in family diet were correlated with the observed spatial patterns. The results of the present study highlight the importance of nutrition and socio-economic status in explaining differences in birthweights in PNG. Besides improving maternal health, interventions for improving birthweights in PNG should therefore aim at strengthening the economic base of rural populations and promote the cultivation and consumption of high quality foods.

Birth Weight↗

Spatial patterns of child growth in Papua New Guinea and their relation to environment, diet, socio-economic status and subsistence activities.

Anthropometric data from the 1982/83 Papua New Guinea (PNG) National Nutrition Survey were analysed to identify geographical patterns of child growth and investigate their relation to a wide range of environmental, dietary and socio-economic variables. Standardized growth scores for length-for-age (LAZ), weight-for-age (WAZ) and weight-for-length (WLZ) were calculated based on an internal PNG growth reference. Hierarchical Bayesian spatial models based on conditional autoregressive (CAR) priors were subsequently used to model spatial patterns in scores and their relation to different sets of covariates. The geographical differences were bigger for linear growth than for increases in weight. Growth was most reduced in parts of Milne Bay Province, Madang Province, the Torricelli/Prinz Alexander Ranges, and in the area occupied by Angan people. Socio-economic status was the most important factor determining variation in growth within populations. Differences in diet and, to a lesser extent, the physical environment were the main determining factor of differences among populations. Covariate adjustment accounted for more spatially structured variation in LAZ and WAZ than in WLZ. All variables indicating higher socio-economic status were correlated with better growth, as was a high consumption of imported and local high quality foods such as cereals, legumes, tinned fish/meat or fresh fish. This indicates that nutritional interventions in PNG should aim at promoting the consumption of such high energy and high protein foods as well as strengthening the general economic base of rural populations.

Analysis of Variance↗