Estimation of conditional laws given an extreme component

Let $(X,Y)$ be a bivariate random vector. The estimation of a probability of the form $P(Y\leq y \mid X >t)$ is challenging when $t$ is large, and a fruitful approach consists in studying, if it exists, the limiting conditional distribution of the random vector $(X,Y)$, suitably normalized, given that $X$ is large. There already exists a wide literature on bivariate models for which this limiting distribution exists. In this paper, a statistical analysis of this problem is done. Estimators of the limiting distribution (which is assumed to exist) and the normalizing functions are provided, as well as an estimator of the conditional quantile function when the conditioning event is extreme. Consistency of the estimators is proved and a functional central limit theorem for the estimator of the limiting distribution is obtained. The small sample behavior of the estimator of the conditional quantile function is illustrated through simulations.Comment: 32 pages, 5 figur

Calculating the potential for within-flight transmission of influenza A (H1N1)

Abstract Background Clearly air travel, by transporting infectious individuals from one geographic location to another, significantly affects the rate of spread of influenza A (H1N1). However, the possibility of within-flight transmission of H1N1 has not been evaluated; although it is known that smallpox, measles, tuberculosis, SARS and seasonal influenza can be transmitted during commercial flights. Here we present the first quantitative risk assessment to assess the potential for within-flight transmission of H1N1. Methods We model airborne transmission of infectious viral particles of H1N1 within a Boeing 747 using methodology from the field of quantitative microbial risk assessment. Results The risk of catching H1N1 will essentially be confined to passengers travelling in the same cabin as the source case. Not surprisingly, we find that the longer the flight the greater the number of infections that can be expected. We calculate that H1N1, even during long flights, poses a low to moderate within-flight transmission risk if the source case travels First Class. Specifically, 0-1 infections could occur during a 5 hour flight, 1-3 during an 11 hour flight and 2-5 during a 17 hour flight. However, within-flight transmission could be significant, particularly during long flights, if the source case travels in Economy Class. Specifically, two to five infections could occur during a 5 hour flight, 5-10 during an 11 hour flight and 7-17 during a 17 hour flight. If the aircraft is only partially loaded, under certain conditions more infections could occur in First Class than in Economy Class. During a 17 hour flight, a greater number of infections would occur in First Class than in Economy if the First Class Cabin is fully occupied, but Economy class is less than 30% full. Conclusions Our results provide insights into the potential utility of air travel restrictions on controlling influenza pandemics in the winter of 2009/2010. They show travel by one infectious individual, rather than causing a single outbreak of H1N1, could cause several simultaneous outbreaks. These results imply that, during a pandemic, quarantining passengers who travel in Economy on long-haul flights could potentially be an important control strategy. Notably, our results show that quarantining passengers who travel First Class would be unlikely to be an effective control strategy

What have we learnt from palaeoclimate simulations?

There has been a gradual evolution in the way that palaeoclimate modelling and palaeoenvironmental data are used together to understand how the Earth System works, from an initial and largely descriptive phase through explicit hypothesis testing to diagnosis of underlying mechanisms. Analyses of past climate states are now regarded as integral to the evaluation of climate models, and have become part of the toolkit used to assess the likely realism of future projections. Palaeoclimate assessment has demonstrated that changes in large-scale features of climate that are governed by the energy and water balance show consistent responses to changes in forcing in different climate states, and these consistent responses are reproduced by climate models. However, state-of-the-art models are still largely unable to reproduce observed changes in climate at a regional scale reliably. While palaeoclimate analyses of state-of-the-art climate models suggest an urgent need for model improvement, much work is also needed on extending and improving palaeoclimate reconstructions and quantifying and reducing both numerical and interpretative uncertainties

The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome

Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation

Phylogenetic Analysis of the Neks Reveals Early Diversification of Ciliary-Cell Cycle Kinases

NIMA-related kinases (Neks) have been studied in diverse eukaryotes, including the fungus Aspergillus and the ciliate Tetrahymena. In the former, a single Nek plays an essential role in cell cycle regulation; in the latter, which has more than 30 Neks in its genome, multiple Neks regulate ciliary length. Mammalian genomes encode an intermediate number of Neks, several of which are reported to play roles in cell cycle regulation and/or localize to centrosomes. Previously, we reported that organisms with cilia typically have more Neks than organisms without cilia, but were unable to establish the evolutionary history of the gene family

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Effect of Heterogeneous Mixing and Vaccination on the Dynamics of Anthelmintic Resistance: A Nested Model

Anthelmintic resistance is a major threat to current measures for helminth control in humans and animals. The introduction of anthelmintic vaccines, as a complement to or replacement for drug treatments, has been advocated as a preventive measure. Here, a computer-based simulation, tracking the dynamics of hosts, parasites and parasite-genes, shows that, depending on the degree of host-population mixing, the frequency of totally recessive autosomes associated with anthelmintic resistance can follow either a fast dynamical regime with a low equilibrium point or a slow dynamical regime with a high equilibrium point. For fully dominant autosomes, only one regime is predicted. The effectiveness of anthelminthic vaccines against resistance is shown to be strongly influenced by the underlying dynamics of resistant autosomes. Vaccines targeting adult parasites, by decreasing helminth fecundity or lifespan, are predicted to be more effective than vaccines targeting parasite larvae, by decreasing host susceptibility to infection, in reducing the spread of resistance. These results may inform new strategies to prevent, monitor and control the spread of anthelmintic resistance, including the development of viable anthelmintic vaccines

The relation between socioeconomic and demographic factors and tumour stage in women diagnosed with breast cancer in Denmark, 1983–1999

The authors investigated the association between socioeconomic position and stage of breast cancer at the time of diagnosis in a nationwide Danish study. All 28 765 women with a primary invasive breast cancer diagnosed between 1983 and 1999 were identified in a nationwide clinical database and information on socioeconomic variables was obtained from Statistics Denmark. The risk of being diagnosed with a high-risk breast cancer, that is size >20 mm, lymph-node positive, ductal histology/high histologic grade and hormone receptor negative, was analysed by multivariate logistic regression. The adjusted odds ratio (OR) for high-risk breast cancer was reduced with longer education with a 12% reduced risk (95% confidence interval (CI), 0.80,0.96) in women with higher education and increased with reduced disposable income (low income group: OR, 1.22; 95% CI, 1.10,1.34). There was an urban–rural gradient, with higher risk among rural women (OR 1.10; 95 % CI, 1.02, 1.18) and lower risk among women in the capital suburbs (OR, 0.85; 95% CI, 0.78, 0.93) and capital area (OR, 0.93; 95% CI, 0.84–1.02). These factors were significant only for postmenopausal women, although similar patterns were observed among the premenopausal women, suggesting a subgroup of aggressive premenopausal breast cancers less influenced by socioeconomic factors

Cost-efficiency assessment of Advanced Life Support (ALS) courses based on the comparison of advanced simulators with conventional manikins

<p>Abstract</p> <p>Background</p> <p>Simulation is an essential tool in modern medical education. The object of this study was to assess, in cost-effective measures, the introduction of new generation simulators in an adult life support (ALS) education program.</p> <p>Methods</p> <p>Two hundred fifty primary care physicians and nurses were admitted to ten ALS courses (25 students per course). Students were distributed at random in two groups (125 each). Group A candidates were trained and tested with standard ALS manikins and Group B ones with new generation emergency and life support integrated simulator systems.</p> <p>Results</p> <p>In group A, 98 (78%) candidates passed the course, compared with 110 (88%) in group B (p < 0.01). The total cost of conventional courses was €7689 per course and the cost of the advanced simulator courses was €29034 per course (p < 0.001). Cost per passed student was €392 in group A and €1320 in group B (p < 0.001).</p> <p>Conclusion</p> <p>Although ALS advanced simulator systems may slightly increase the rate of students who pass the course, the cost-effectiveness of ALS courses with standard manikins is clearly superior.</p