Resolving conflicts between statistical methods by probability combination: Application to empirical Bayes analyses of genomic data

In the typical analysis of a data set, a single method is selected for statistical reporting even when equally applicable methods yield very different results. Examples of equally applicable methods can correspond to those of different ancillary statistics in frequentist inference and of different prior distributions in Bayesian inference. More broadly, choices are made between parametric and nonparametric methods and between frequentist and Bayesian methods. Rather than choosing a single method, it can be safer, in a game-theoretic sense, to combine those that are equally appropriate in light of the available information. Since methods of combining subjectively assessed probability distributions are not objective enough for that purpose, this paper introduces a method of distribution combination that does not require any assignment of distribution weights. It does so by formalizing a hedging strategy in terms of a game between three players: nature, a statistician combining distributions, and a statistician refusing to combine distributions. The optimal move of the first statistician reduces to the solution of a simpler problem of selecting an estimating distribution that minimizes the Kullback-Leibler loss maximized over the plausible distributions to be combined. The resulting combined distribution is a linear combination of the most extreme of the distributions to be combined that are scientifically plausible. The optimal weights are close enough to each other that no extreme distribution dominates the others. The new methodology is illustrated by combining conflicting empirical Bayes methodologies in the context of gene expression data analysis

The quest for the solar g modes

Solar gravity modes (or g modes) -- oscillations of the solar interior for which buoyancy acts as the restoring force -- have the potential to provide unprecedented inference on the structure and dynamics of the solar core, inference that is not possible with the well observed acoustic modes (or p modes). The high amplitude of the g-mode eigenfunctions in the core and the evanesence of the modes in the convection zone make the modes particularly sensitive to the physical and dynamical conditions in the core. Owing to the existence of the convection zone, the g modes have very low amplitudes at photospheric levels, which makes the modes extremely hard to detect. In this paper, we review the current state of play regarding attempts to detect g modes. We review the theory of g modes, including theoretical estimation of the g-mode frequencies, amplitudes and damping rates. Then we go on to discuss the techniques that have been used to try to detect g modes. We review results in the literature, and finish by looking to the future, and the potential advances that can be made -- from both data and data-analysis perspectives -- to give unambiguous detections of individual g modes. The review ends by concluding that, at the time of writing, there is indeed a consensus amongst the authors that there is currently no undisputed detection of solar g modes.Comment: 71 pages, 18 figures, accepted by Astronomy and Astrophysics Revie

Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study

BACKGROUND: Pulmonary dysfunction following cardiac surgery is believed to be caused, at least in part, by a lung vascular injury and/or atelectasis following cardiopulmonary bypass (CPB) perfusion and collapse of non-ventilated lungs. METHODS: To test this hypothesis, we studied the postoperative pulmonary leak index (PLI) for (67)Ga-transferrin and (transpulmonary) extravascular lung water (EVLW) in consecutive patients undergoing on-pump (n = 31) and off-pump (n = 8) cardiac surgery. We also studied transfusion history, radiographs, ventilatory and gas exchange variables. RESULTS: The postoperative PLI and EVLW were elevated above normal in 42 and 29% after on-pump surgery and 63 and 37% after off-pump surgery, respectively (ns). Transfusion of red blood cell (RBC) concentrates, PLI, EVLW, occurrence of atelectasis, ventilatory variables and duration of mechanical ventilation did not differ between groups, whereas patients with atelectasis had higher venous admixture and airway pressures than patients without atelectasis (P = 0.037 and 0.049). The PLI related to number of RBC concentrates infused (P = 0.025). CONCLUSION: The lung vascular injury in about half of patients after cardiac surgery is not caused by CPB perfusion but by trauma necessitating RBC transfusion, so that off-pump surgery may not afford a benefit in this respect. However, atelectasis rather than lung vascular injury is a major determinant of postoperative pulmonary dysfunction, irrespective of CPB perfusion

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

<p>Abstract</p> <p>Background</p> <p>Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.</p> <p>Methods</p> <p>Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ET_A) and type B (ET_B), and angiotensin type 1 (AT₁) and type 2 (AT₂) receptors expression and function were examined using immunohistochemistry, Western blot and <it>in vitro </it>pharmacology.</p> <p>Results</p> <p>ET_Aand, to a lesser extent, ET_Breceptor staining was observed in the healthy vascular smooth muscle cells. The level of ET_Breceptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ET_Breceptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ET_Areceptors. AT₁and, to a lesser extent, AT₂receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT₁receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT₁receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).</p> <p>Conclusion</p> <p>The results demonstrate, for the first time, upregulation of ET_Band AT₁receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.</p

Dietary intake of micronutrients and the risk of developing bladder cancer: results from the Belgian case–control study on bladder cancer risk

OBJECTIVE: We aimed to investigate the effect of dietary intake of micronutrients that are metabolized and excreted via the urinary tract on bladder cancer risk. METHODS: A semi-quantitative 322 item food frequency questionnaire (FFQ) was used to collect dietary data from 200 bladder cancer cases and 386 control subjects participating in the Belgian case-control study on bladder cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, sex, smoking characteristics, occupational exposures, and energy intake. RESULTS: We observed a positive association between calcium intake and bladder cancer (OR: 1.77; 95% CI: 1.00-3.15; p-trend = 0.049) and increased odds, although not statistically significant, for highest tertile of phosphorus intake (OR: 1.82; 95% CI: 0.95-3.49; p-trend = 0.06). We identified possible modification of the effects of both calcium and phosphorus by level of magnesium intake. Increased odds of bladder cancer were also observed for participants with highest intake of phosphorus and lowest intake of vitamin D (OR: 4.25; 95% CI: 1.44-12.55) and among older participants with the highest intakes of calcium (OR: 1.90; 95% CI: 1.08-3.36) and phosphorus (OR: 2.02; 95% CI: 1.05-3.92). CONCLUSION: The positive associations we observed between bladder cancer and intake of calcium and phosphorus require confirmation by other studies. The balances between inter-related micronutrients also warrant further examination

Transgenic Expression of Nonclassically Secreted FGF Suppresses Kidney Repair

FGF1 is a signal peptide-less nonclassically released growth factor that is involved in angiogenesis, tissue repair, inflammation, and carcinogenesis. The effects of nonclassical FGF export in vivo are not sufficiently studied. We produced transgenic mice expressing FGF1 in endothelial cells (EC), which allowed the detection of FGF1 export to the vasculature, and studied the efficiency of postischemic kidney repair in these animals. Although FGF1 transgenic mice had a normal phenotype with unperturbed kidney structure, they showed a severely inhibited kidney repair after unilateral ischemia/reperfusion. This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase. In addition, the postischemic kidneys of transgenic mice were characterized by hyperplasia of interstitial cells, paucity of epithelial tubular structures, increase of the areas occupied by connective tissue, and neutrophil and macrophage infiltration. The continuous treatment of transgenic mice with the cell membrane stabilizer, taurine, inhibited nonclassical FGF1 export and significantly rescued postischemic kidney repair. It was also found that similar to EC, the transgenic expression of FGF1 in monocytes and macrophages suppresses kidney repair. We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs

Cardiac tumours in children

Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic. Primary cardiac tumours are rare in paediatric practice with a prevalence of 0.0017 to 0.28 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 0.14%. The vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. Secondary malignant tumours are 10–20 times more prevalent than primary malignant tumours. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Echocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis. Surgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. The outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival. The prognosis for malignant primary cardiac tumours is generally extremely poor

Adaptations to Climate-Mediated Selective Pressures in Humans

Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans

Patient Safety in the Cardiac Operating Room: Human Factors and Teamwork: A Scientific Study from the American Heart Association

The cardiac surgical operating room (OR) is a complex environment in which highly trained subspecialists interact with each other using sophisticated equipment to care for patients with severe cardiac disease and significant comorbidities. Thousands of patient lives have been saved or significantly improved with the advent of modern cardiac surgery. Indeed, both mortality and morbidity for coronary artery bypass surgery have decreased during the past decade. Nonetheless, the highly skilled and dedicated personnel in cardiac ORs are human and will make errors. Refined techniques, advanced technologies, and enhanced coordination of care have led to significant improvements in cardiac surgery outcomes