Bayesian model search and multilevel inference for SNP association studies

Technological advances in genotyping have given rise to hypothesis-based association studies of increasing scope. As a result, the scientific hypotheses addressed by these studies have become more complex and more difficult to address using existing analytic methodologies. Obstacles to analysis include inference in the face of multiple comparisons, complications arising from correlations among the SNPs (single nucleotide polymorphisms), choice of their genetic parametrization and missing data. In this paper we present an efficient Bayesian model search strategy that searches over the space of genetic markers and their genetic parametrization. The resulting method for Multilevel Inference of SNP Associations, MISA, allows computation of multilevel posterior probabilities and Bayes factors at the global, gene and SNP level, with the prior distribution on SNP inclusion in the model providing an intrinsic multiplicity correction. We use simulated data sets to characterize MISA's statistical power, and show that MISA has higher power to detect association than standard procedures. Using data from the North Carolina Ovarian Cancer Study (NCOCS), MISA identifies variants that were not identified by standard methods and have been externally ``validated'' in independent studies. We examine sensitivity of the NCOCS results to prior choice and method for imputing missing data. MISA is available in an R package on CRAN.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS322 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Management of patients presenting with diarrhoea to a regional emergency department in KwaZulu-Natal: Call for clearer, more relevant guidance

Background. HIV is prevalent throughout South Africa, and diarrhoea is a common presentation to the emergency department (ED) among both HIV-infected and -uninfected individuals. Method. We audited the management of diarrhoea against standard guidelines in the ED of a regional hospital in KwaZulu-Natal. Patients presenting with diarrhoea as their chief complaint were eligible and data were collected prospectively. Results. A total of 72 patients were included: 58 (81%) of patients were HIV-positive with an average CD4+ count of 180 cells/ μl. A total of 34 stool samples were sent for standard microscopy and culture (M&C), among which 26 were positive (76%). Forty-three patients (60%) received antibiotics, 15 of whom had positive stool M&C. In all cases, the final diagnosis was listed as acute gastroenteritis without further specification, and antibiotic use according to guidelines appeared inconsistent. Conclusion. Based on this audit, we suggest that current guidelines are not clear concerning management of acute diarrhoea in HIVinfected individuals, and that the lack of clear management strategies is likely to affect patient safety and increase antibiotic resistance

Long-term carbon and nitrogen dynamics at SPRUCE revealed through stable isotopes in peat profiles

Peatlands encode information about past vegetation dynamics, climate, and microbial processes. Here, we used δ15N and δ13C patterns from 16 peat profiles to deduce how the biogeochemistry of the Marcell S1 forested bog in northern Minnesota responded to environmental and vegetation change over the past  ∼ 10000 years. In multiple regression analyses, δ15N and δ13C correlated strongly with depth, plot location, C∕N, %N, and each other. Correlations with %N, %C, C∕N, and the other isotope accounted for 80% of variance for δ15N and 38% of variance for δ13C, reflecting N and C losses. In contrast, correlations with depth and topography (hummock or hollow) reflected peatland successional history and climate. Higher δ15N in plots closer to uplands may reflect upland-derived DON inputs and accompanying shifts in N dynamics in the lagg drainage area surrounding the bog. The Suess effect (declining δ13CO2 since the Industrial Revolution) lowered δ13C in recent surficial samples. High δ15N from −35 to −55cm probably indicated the depth of ectomycorrhizal activity after tree colonization of the peatland over the last 400 years, as confirmed by the occasional presence of wood down to −35cm depth. High δ13C at  ∼ 4000 years BP (−65 to −105cm) could reflect a transition at that time to slower rates of peat accumulation, when 13C discrimination during peat decomposition may increase in importance. Low δ13C and high δ15N at −213 and −225cm ( ∼ 8500 years BP) corresponded to a warm period during a sedge-dominated rich fen stage. The above processes appear to be the primary drivers of the observed isotopic patterns, whereas there was no clear evidence for methane dynamics influencing δ13C patterns

Depth-resolved particle associated microbial respiration in the northeast Atlantic

Atmospheric levels of carbon dioxide are tightly linked to the depth at which sinking particulate organic carbon (POC) is remineralised in the ocean. Rapid attenuation of downward POC flux typically occurs in the upper mesopelagic (top few hundred metres of the water column), with much slower loss rates deeper in the ocean. Currently, we lack understanding of the processes that drive POC attenuation, resulting in large uncertainties in the mesopelagic carbon budget. Attempts to balance the POC supply to the mesopelagic with respiration by zooplankton and microbes rarely succeed. Where a balance has been found, depth-resolved estimates reveal large compensating imbalances in the upper and lower mesopelagic. In particular, it has been suggested that respiration by free-living microbes and zooplankton in the upper mesopelagic are too low to explain the observed flux attenuation of POC within this layer. We test the hypothesis that particle-associated microbes contribute significantly to community respiration in the mesopelagic, measuring particle-associated microbial respiration of POC in the northeast Atlantic through shipboard measurements on individual marine snow aggregates collected at depth (36–500 m). We find very low rates of both absolute and carbon-specific particle-associated microbial respiration (< 3 % d−1), suggesting that this term cannot solve imbalances in the upper mesopelagic POC budget. The relative importance of particle-associated microbial respiration increases with depth, accounting for up to 33 % of POC loss in the mid-mesopelagic (128–500 m). We suggest that POC attenuation in the upper mesopelagic (36–128 m) is driven by the transformation of large, fast-sinking particles to smaller, slow-sinking and suspended particles via processes such as zooplankton fragmentation and solubilisation, and that this shift to non-sinking POC may help to explain imbalances in the mesopelagic carbon budget

Exploring positive pathways to care for members of the UK Armed Forces receiving treatment for PTSD: a qualitative study

Objective: To examine the factors which facilitate UK military personnel with post-traumatic stress disorder (PTSD) to engage in help-seeking behaviours. Methods: The study recruited active service personnel who were attending mental health services, employed a qualitative design, used semi-structured interview schedules to collect data, and explored these data using interpretative phenomenological analysis (IPA). Results: Five themes emerged about how participants were able to access help; having to reach a crisis point before accepting the need for help, overcoming feelings of shame, the importance of having an internal locus of control, finding a psychological explanation for their symptoms and having strong social support. Conclusions: This study reported that for military personnel who accessed mental health services, there were a number of factors that supported them to do so. In particular, factors that combated internal stigma, such as being supported to develop an internal locus of control, appeared to be critical in supporting military personnel to engage in help-seeking behaviour