Bayesian network data imputation with application to survival tree analysis

Retrospective clinical datasets are often characterized by a relatively small sample size and many missing data. In this case, a common way for handling the missingness consists in discarding from the analysis patients with missing covariates, further reducing the sample size. Alternatively, if the mechanism that generated the missing allows, incomplete data can be imputed on the basis of the observed data, avoiding the reduction of the sample size and allowing methods to deal with complete data later on. Moreover, methodologies for data imputation might depend on the particular purpose and might achieve better results by considering specific characteristics of the domain. The problem of missing data treatment is studied in the context of survival tree analysis for the estimation of a prognostic patient stratification. Survival tree methods usually address this problem by using surrogate splits, that is, splitting rules that use other variables yielding similar results to the original ones. Instead, our methodology consists in modeling the dependencies among the clinical variables with a Bayesian network, which is then used to perform data imputation, thus allowing the survival tree to be applied on the completed dataset. The Bayesian network is directly learned from the incomplete data using a structural expectation–maximization (EM) procedure in which the maximization step is performed with an exact anytime method, so that the only source of approximation is due to the EM formulation itself. On both simulated and real data, our proposed methodology usually outperformed several existing methods for data imputation and the imputation so obtained improved the stratification estimated by the survival tree (especially with respect to using surrogate splits).

Effects of baited crab pots on cultivated mussel (Mytilus edulis) survival rates

The shore crab, Carcinus maenas, is recognized as a voracious predator of blue mussels, Mytilus edulis, having the potential to greatly reduce stocks in the benthic cultivation industry. As a consequence, baited crab pots are often deployed on and around cultivated benthic mussel beds to trap and remove crabs, in an attempt to reduce predatory pressure. Little is known about how C. maenas behaves around crab pots, but for many other crustacean fisheries, the trapping efficiency of pots is often low. Crabs may be attracted towards but not enter pots, instead feeding on cultivated mussels outside pots on the surrounding substratum. We tested whether the rate of loss of mussels attached to plates differed in areas next to baited pots compared with unbaited pots and to areas without any pots, at two sea loughs (60 km apart) in Northern Ireland. In Strangford Lough, more mussels were lost from plates next to baited pots than the other treatments. In Carlingford Lough, however, we found no difference in the number of mussels lost from plates in any treatment. This difference could be attributed to the different assemblages of mobile benthic predators at the two loughs. The presence of the starfish Asterias rubens, which was absent from experimental sites in Carlingford Lough, was thought to be responsible for increased predation rates near baited pots in Strangford. It is, therefore, important to consider local predator communities when deploying crab pots as a predator mitigation technique to ensure predation rates are in fact reduced and not enhanced. This study is of relevance not only to attempts to limit predation on commercial stocks of benthic cultivated mussels but also in situations where baited traps are deployed close to species vulnerable to mobile benthic predators.

Lack of genetic structure and evidence for long-distance dispersal in ash (Fraxinus excelsior) populations under threat from an emergent fungal pathogen: implications for restorative planting

Genetic analysis on populations of European ash (Fraxinus excelsior) throughout Ireland was carried out to determine the levels and patterns of genetic diversity in naturally seeded trees in ash woodlands and hedgerows, with the aim of informing conservation and replanting strategies in the face of potential loss of trees as a result of ash dieback. Samples from 33 sites across Northern Ireland and three sites in the Republic of Ireland were genotyped for eight nuclear and ten chloroplast microsatellites. Levels of diversity were high (mean A R = 10.53; mean H O = 0.709; mean H E = 0.765) and were similar to those in Great Britain and continental Europe, whilst levels of population genetic differentiation based on nuclear microsatellites were extremely low (Φ ST = 0.0131). Levels of inbreeding (mean F IS = 0.067) were significantly lower than those reported for populations from Great Britain. Fine-scale analysis of seed dispersal indicated potential for dispersal over hundreds of metres. Our results suggest that ash woodlands across Ireland could be treated as a single management unit, and thus native material from anywhere in Ireland could be used as a source for replanting. In addition, high potential for dispersal has implications for recolonization processes post-ash dieback (Chalara fraxinea) infection, and could aid in our assessment of the capacity of ash to shift its range in response to global climate change.

The fungal microbiota of de-novo paediatric inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients. 

Burden of fungal disease in Ireland

Our objective was to estimate the burden of fungal disease on the island of Ireland, as part of a coordinated project estimating the global burden. Published epidemiology data describing fungal infection in Ireland were identified. Population and underlying disease data were collected for 2010 and a structured set of assumptions were applied to estimate burden of fungal disease based on immunosuppression, chronic disease, and other demographic information indicating predisposition to fungal infection. From Ireland’s population of 6.4 million, we estimate 117 000 patients develop significant fungal disease each year. By far the most common fungal disease is recurrent Candida vaginitis, with an estimated 95 000 episodes annually (3000 per 100 000 women). Other fungal diseases which may be less well recognized are severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis, with estimated episodes per year of 11 700 and 9000, respectively (182 and 140 per 100 000 population, respectively). The model also estimates 450 episodes of invasive aspergillosis, 200 of chronic pulmonary aspergillosis, 600 of oesophageal candidiasis and 450 of candidaemia per year (7, 3, 9 and 6 episodes per 100 000 population, respectively). This is, we believe, the first attempt to estimate the burden of fungal disease in our population and provides a basis for estimating its impact on human health and resource use.

Fungal stress biology: A preface to the Fungal Stress Responses special edition

There is currently an urgent need to increase global food security, reverse the trends of increasing cancer rates, protect environmental health, and mitigate climate change. Toward these ends, it is imperative to improve soil health and crop productivity, reduce food spoilage, reduce pesticide usage by increasing the use of biological control, optimize bioremediation of polluted sites, and generate energy from sustainable sources such as biofuels. This review focuses on fungi that can help provide solutions to such problems. We discuss key aspects of fungal stress biology in the context of the papers published in this Special Issue of Current Genetics. This area of biology has relevance to pure and applied research on fungal (and indeed other) systems, including biological control of insect pests, roles of saprotrophic fungi in agriculture and forestry, mycotoxin contamination of the food-supply chain, optimization of microbial fermentations including those used for bioethanol production, plant pathology, the limits of life on Earth, and astrobiology.

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify breast cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39–2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72–1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

The International Symposium on Fungal Stress - ISFUS

Fungi play central roles in many biological processes, influencing soil fertility, decomposition, cycling of minerals, and organic matter, plant health, and nutrition. They produce a wide spectrum of molecules, which are exploited in a range of industrial processes to manufacture foods, food preservatives, flavoring agents, and other useful biological products. Fungi can also be used as biological control agents of microbial pathogens, nematodes or insect pests, and affect plant growth, stress tolerance, and nutrient acquisition. Successful exploitation of fungi requires better understanding of the mechanisms that fungi use to cope with stress as well as the way in which they mediate stress tolerance in other organisms. It is against this backdrop that a scientific meeting on fungal stress was held in São José dos Campos, Brazil, in October 2014. The meeting, hosted by Drauzio E. N. Rangel and Alene E. Alder-Rangel, and supported by the São Paulo Research Foundation (FAPESP), brought together more than 30 young, mid-career, and highly accomplished scientists from ten different countries. Here we summarize the highlights of the meeting.

Time and Cell Type Dependency of Survival Responses in Co-cultured Tumor and Fibroblast Cells after Exposure to Modulated Radiation Fields

Advanced radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) achieve high levels of conformity to the target volume through the sequential delivery of highly spatially and temporally modulated radiation fields, which have been shown to impact radiobiological response. This study aimed to characterize the time and cell type dependency of survival responses to modulated fields using single cell type (SCT) and mixed cell type (MCT) co-culture models of transformed fibroblast (AG0-1522b) cells, and prostate (DU-145) and lung (H460) cancer cells. In SCT cultures, in-field responses showed no significant time dependency while out-of-field responses occurred early, and plateaued 6 h after irradiation in both DU-145 and H460 cells. Under modulated beam configurations MCT co-cultures showed cell-specific, differential out-of-field responses depending on the irradiated in-field and responding out-of-field cell type. The observed differential out-of-field responses may be due to the genetic background of the cells, in particular p53 status, which has been shown to mediate radiation-induced bystander effects (RIBEs). These data provide further insight into the radiobiological parameters that influence out-of-field responses, which have potential implications for advanced radiotherapy modalities and may provide opportunities for biophysical optimization in radiotherapy treatment planning.

Intracellular survival of Burkholderia cepacia complex in phagocytic cells

Burkholderia cepacia complex (Bcc) species are a group of Gram-negative opportunistic pathogens that infect the airways of cystic fibrosis patients, and occasionally they infect other immunocompromised patients. Bcc bacteria display high-level multidrug resistance, and chronically persist in the infected host while eliciting robust inflammatory responses. Studies using macrophages, neutrophils and dendritic cells, combined with advances to genetically manipulate these bacteria have increased our understanding of the molecular mechanisms of virulence in these pathogens and the molecular details of cell-host responses triggering inflammation. This article discusses our current view of the intracellular survival of B. cenocepacia within macrophages.

Statin use after colorectal cancer diagnosis and survival: a population-based cohort study

PURPOSE: To investigate whether statins used after colorectal cancer diagnosis reduce the risk of colorectal cancer-specific mortality in a cohort of patients with colorectal cancer.

PATIENTS AND METHODS: A cohort of 7,657 patients with newly diagnosed stage I to III colorectal cancer were identified from 1998 to 2009 from the National Cancer Data Repository (comprising English cancer registry data). This cohort was linked to the United Kingdom Clinical Practice Research Datalink, which provided prescription records, and to mortality data from the Office of National Statistics (up to 2012) to identify 1,647 colorectal cancer-specific deaths. Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% CIs by postdiagnostic statin use and to adjust these HRs for potential confounders.

RESULTS: Overall, statin use after a diagnosis of colorectal cancer was associated with reduced colorectal cancer-specific mortality (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84). A dose-response association was apparent; for example, a more marked reduction was apparent in colorectal cancer patients using statins for more than 1 year (adjusted HR, 0.64; 95% CI, 0.53 to 0.79). A reduction in all-cause mortality was also apparent in statin users after colorectal cancer diagnosis (fully adjusted HR, 0.75; 95% CI, 0.66 to 0.84).

CONCLUSION: In this large population-based cohort, statin use after diagnosis of colorectal cancer was associated with longer rates of survival.

Explaining variation in cancer survival between 11 jurisdictions in the International Cancer Benchmarking Partnership: a primary care vignette survey

OBJECTIVES: The International Cancer Benchmarking Partnership (ICBP) is a collaboration between 6 countries and 12 jurisdictions with similar primary care-led health services. This study investigates primary care physician (PCP) behaviour and systems that may contribute to the timeliness of investigating for cancer and subsequently, international survival differences.

DESIGN: A validated survey administered to PCPs via the internet set out in two parts: direct questions on primary care structure and practice relating to cancer diagnosis, and clinical vignettes, assessing management of scenarios relating to the diagnosis of lung, colorectal or ovarian cancer.

PARTICIPANTS: 2795 PCPs in 11 jurisdictions: New South Wales and Victoria (Australia), British Columbia, Manitoba, Ontario (Canada), England, Northern Ireland, Wales (UK), Denmark, Norway and Sweden.

PRIMARY AND SECONDARY OUTCOME MEASURES: Analysis compared the cumulative proportion of PCPs in each jurisdiction opting to investigate or refer at each phase for each vignette with 1-year survival, and conditional 5-year survival rates for the relevant cancer and jurisdiction. Logistic regression was used to explore whether PCP characteristics or system differences in each jurisdiction affected the readiness to investigate.

RESULTS: 4 of 5 vignettes showed a statistically significant correlation (p<0.05 or better) between readiness to investigate or refer to secondary care at the first phase of each vignette and cancer survival rates for that jurisdiction. No consistent associations were found between readiness to investigate and selected PCP demographics, practice or health system variables.

CONCLUSIONS: We demonstrate a correlation between the readiness of PCPs to investigate symptoms indicative of cancer and cancer survival rates, one of the first possible explanations for the variation in cancer survival between ICBP countries. No specific health system features consistently explained these findings. Some jurisdictions may consider lowering thresholds for PCPs to investigate for cancer-either directly, or by specialist referral, to improve outcomes.

Ericoid mycorrhiza:A partnership that exploits harsh edaphic conditions

Plants that form ericoid mycorrhizal associations are widespread in harsh habitats. Ericoid mycorrhizal fungal endophytes are a genetically diverse group, and they appear to be able to alleviate certain environmental stresses and so facilitate the establishment and survival of Ericaceae. Some of the fungal taxa that form ericoid mycorrhizas, or at least closely related strains, also form associations with other plant hosts (trees and leafy liverworts). The functional significance of these associations and putative mycelial links between Ericaceae and other plant taxa, however, remain unclear. Evidence from environments that are contaminated by toxic metals indicates that ericoid mycorrhizal fungal endophytes, and in some instances their plant hosts, can evolve resistance to these metals. The apparent ability of these endophytes to develop resistance enables ericoid mycorrhizal plants to colonize polluted soil. This seems to be a major factor in the success of ericoid mycorrhizal taxa in a range of harsh environments.