Accurate Noise Projection for Reduced Stochastic Epidemic Models

We consider a stochastic Susceptible-Exposed-Infected-Recovered (SEIR) epidemiological model. Through the use of a normal form coordinate transform, we are able to analytically derive the stochastic center manifold along with the associated, reduced set of stochastic evolution equations. The transformation correctly projects both the dynamics and the noise onto the center manifold. Therefore, the solution of this reduced stochastic dynamical system yields excellent agreement, both in amplitude and phase, with the solution of the original stochastic system for a temporal scale that is orders of magnitude longer than the typical relaxation time. This new method allows for improved time series prediction of the number of infectious cases when modeling the spread of disease in a population. Numerical solutions of the fluctuations of the SEIR model are considered in the infinite population limit using a Langevin equation approach, as well as in a finite population simulated as a Markov process.Comment: 38 pages, 10 figures, new title, Final revision to appear in Chao

Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis

Abstract Background The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not. Methods and Results We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes. Conclusions In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.http://deepblue.lib.umich.edu/bitstream/2027.42/112500/1/12920_2010_Article_214.pd

Time-Resolved Transposon Insertion Sequencing Reveals Genome-Wide Fitness Dynamics during Infection

ABSTRACT Transposon insertion sequencing (TIS) is a powerful high-throughput genetic technique that is transforming functional genomics in prokaryotes, because it enables genome-wide mapping of the determinants of fitness. However, current approaches for analyzing TIS data assume that selective pressures are constant over time and thus do not yield information regarding changes in the genetic requirements for growth in dynamic environments (e.g., during infection). Here, we describe structured analysis of TIS data collected as a time series, termed pattern analysis of conditional essentiality (PACE). From a temporal series of TIS data, PACE derives a quantitative assessment of each mutant’s fitness over the course of an experiment and identifies mutants with related fitness profiles. In so doing, PACE circumvents major limitations of existing methodologies, specifically the need for artificial effect size thresholds and enumeration of bacterial population expansion. We used PACE to analyze TIS samples of Edwardsiella piscicida (a fish pathogen) collected over a 2-week infection period from a natural host (the flatfish turbot). PACE uncovered more genes that affect E. piscicida’s fitness in vivo than were detected using a cutoff at a terminal sampling point, and it identified subpopulations of mutants with distinct fitness profiles, one of which informed the design of new live vaccine candidates. Overall, PACE enables efficient mining of time series TIS data and enhances the power and sensitivity of TIS-based analyses

Orientia tsutsugamushi Stimulates an Original Gene Expression Program in Monocytes: Relationship with Gene Expression in Patients with Scrub Typhus

Orientia tsutsugamushi is the causal agent of scrub typhus, a public health problem in the Asia-Pacific region and a life-threatening disease. O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells. We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors. In addition, O. tsutsugamushi altered the expression of more than 4,500 genes, as demonstrated by microarray analysis. The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated. O. tsutsugamushi also induced the expression of apoptosis-related genes and promoted cell death in a small percentage of monocytes. Live organisms were indispensable to the type I interferon response and apoptosis and enhanced the expression of M1-associated cytokines. These data were related to the transcriptional changes detected in mononuclear cells isolated from patients with scrub typhus. Here, the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients, similar to what was observed in O. tsutsugamushi-stimulated monocytes in vitro. This is the first report demonstrating that monocytes are clearly polarized in vitro and ex vivo following exposure to O. tsutsugamushi. These results would improve our understanding of the pathogenesis of scrub typhus, during which interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical. This study may give us a clue of new tools for the diagnosis of patients with scrub typhus

Strong microsite control of seedling recruitment in tundra

The inclusion of environmental variation in studies of recruitment is a prerequisite for realistic predictions of the responses of vegetation to a changing environment. We investigated how seedling recruitment is affected by seed availability and microsite quality along a steep environmental gradient in dry tundra. A survey of natural seed rain and seedling density in vegetation was combined with observations of the establishment of 14 species after sowing into intact or disturbed vegetation. Although seed rain density was closely correlated with natural seedling establishment, the experimental seed addition showed that the microsite environment was even more important. For all species, seedling emergence peaked at the productive end of the gradient, irrespective of the adult niches realized. Disturbance promoted recruitment at all positions along the environmental gradient, not just at high productivity. Early seedling emergence constituted the main temporal bottleneck in recruitment for all species. Surprisingly, winter mortality was highest at what appeared to be the most benign end of the gradient. The results highlight that seedling recruitment patterns are largely determined by the earliest stages in seedling emergence, which again are closely linked to microsite quality. A fuller understanding of microsite effects on recruitment with implications for plant community assembly and vegetation change is provided

Family social environment in childhood and self-rated health in young adulthood

<p>Abstract</p> <p>Background</p> <p>Family social support, as a form of social capital, contributes to social health disparities at different age of life. In a life-course epidemiological perspective, the aims of our study were to examine the association between self-reported family social environment during childhood and self-reported health in young adulthood and to assess the role of family functioning during childhood as a potential mediating factor in explaining the association between family breakup in childhood and self-reported health in young adulthood.</p> <p>Methods</p> <p>We analyzed data from the first wave of the Health, Inequalities and Social Ruptures Survey (SIRS), a longitudinal health and socio-epidemiological survey of a random sample of 3000 households initiated in the Paris metropolitan area in 2005. Sample-weighted logistic regression analyses were performed to determine the association between the quality of family social environment in childhood and self-rated health (overall health, physical health and psychological well-being) in young adults (n = 1006). We used structural equation model to explore the mediating role of the quality of family functioning in childhood in the association between family breakup in childhood and self-rated health in young adulthood.</p> <p>Results</p> <p>The multivariate results support an association between a negative family social environment in childhood and poor self-perceived health in adulthood. The association found between parental separation or divorce in childhood and poor self-perceived health in adulthood was mediated by parent-child relationships and by having witnessed interparental violence during childhood.</p> <p>Conclusion</p> <p>These results argue for interventions that enhance family cohesion, particularly after family disruptions during childhood, to promote health in young adulthood.</p

The devil is in the details: trends in avoidable hospitalization rates by geography in British Columbia, 1990–2000

BACKGROUND: Researchers and policy makers have focussed on the development of indicators to help monitor the success of regionalization, primary care reform and other health sector restructuring initiatives. Certain indicators are useful in examining issues of equity in service provision, especially among older populations, regardless of where they live. AHRs are used as an indicator of primary care system efficiency and thus reveal information about access to general practitioners. The purpose of this paper is to examine trends in avoidable hospitalization rates (AHRs) during a period of time characterized by several waves of health sector restructuring and regionalization in British Columbia. AHRs are examined in relation to non-avoidable and total hospitalization rates as well as by urban and rural geography across the province. METHODS: Analyses draw on linked administrative health data from the province of British Columbia for 1990 through 2000 for the population aged 50 and over. Joinpoint regression analyses and t-tests are used to detect and describe trends in the data. RESULTS: Generally speaking, non-avoidable hospitalizations constitute the vast majority of hospitalizations in a given year (i.e. around 95%) with AHRs constituting the remaining 5% of hospitalizations. Comparing rural areas and urban areas reveals that standardized rates of avoidable, non-avoidable and total hospitalizations are consistently higher in rural areas. Joinpoint regression results show significantly decreasing trends overall; lines are parallel in the case of avoidable hospitalizations, and lines are diverging for non-avoidable and total hospitalizations, with the gap between rural and urban areas being wider at the end of the time interval than at the beginning. CONCLUSION: These data suggest that access to effective primary care in rural communities remains problematic in BC given that rural areas did not make any gains in AHRs relative to urban areas under recent health sector restructuring initiatives. It remains important to continue to monitor the discrepancy between them as a reflection of inequity in service provision. In addition, it is important to consider alternative explanations for the observed trends paying particular attention to the needs of rural and urban populations and the factors influencing local service provision

The astrobiology primer: An outline of general knowledge - Version 1, 2006

Peer reviewe

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group