Random forest Gini importance favours SNPs with large minor allele frequency: impact, sources and recommendations

The use of random forests is increasingly common in genetic association studies. The variable importance measure (VIM) that is automatically calculated as a by-product of the algorithm is often used to rank polymorphisms with respect to their ability to predict the investigated phenotype. Here, we investigate a characteristic of this methodology that may be considered as an important pitfall, namely that common variants are systematically favoured by the widely used Gini VIM. As a consequence, researchers may overlook rare variants that contribute to the missing heritability. The goal of the present article is 3-fold: (i) to assess this effect quantitatively using simulation studies for different types of random forests (classical random forests and conditional inference forests, that employ unbiased variable selection criteria) as well as for different importance measures (Gini and permutation based); (ii) to explore the trees and to compare the behaviour of random forests and the standard logistic regression model in order to understand the statistical mechanisms behind the preference for common variants; and (iii) to summarize these results and previously investigated properties of random forest VIMs in the context of genetic association studies and to make practical recommendations regarding the choice of the random forest and variable importance type. All our analyses can be reproduced using R code available from the companion website: http://www.ibe.med.uni-muenchen.de/organisation/mitarbeiter/020_professuren/boulesteix/ginibias/.     

Inhibition of ATP-sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture

The purpose of this study was to determine if potassium channel activity is required for the proliferation of MCF-7 human mammary carcinoma cells. We examined the sensitivities of proliferation and progress through the cell cycle to each of nine potassium channel antagonists. Five of the potassium channel antagonists produced a concentration-dependent inhibition of cell proliferation with no evidence of cytotoxicity following a 3-day or 5-day exposure to drug. The IC₅₀ values for these five drugs, quinidine (25 μM), glibenclamide (50 μM), linogliride (770 μM), 4-aminopyridine (1.6 mM), and tetraethylammmonium (5.8 mM) were estimated from their respective concentration-response curves. Four other potassium channel blockers were tested at supra-maximal channel blocking concentrations, including charybdotoxin (200 nM), iberiotoxin (100 nM), margatoxin (10 nM), and apamin (500 nM), and they had no effect on MCF-7 cell proliferation, viability, or cell cycle distribution. Of the five drugs that inhibited proliferation, only quinidine, glibenclamide, and linogliride also affected the cell cycle distribution. Cell populations exposed to each of these drugs for 3 days showed a statistically significant accumulation in GO/G1 phase and a significant proportional reduction in S phase and G2/M phase cells. The inhibition of cell proliferation correlated significantly with the extent of cell accumulation in GO/G1 phase, and the threshold concentrations for inhibition of growth and GO/G1 arrest were similar. The GO/G1 arrest produced by quinidine and glibenclamide was reversed by removing the drug, and cells released from arrest entered S phase synchronously with a lag period of ～24 hours. Based on the differential sensitivity of cell proliferation and cell cycle progression to the nine potassium channel antagonists, we conclude that inhibition of ATP-sensitive potassium channels in these human mammary carcinoma cells reversibly arrests the cells in the GO/G1 phase of the cell cycle, resulting in an inhibition of cell proliferation. © 1995 Wiley-Liss, Inc.     

Flora des Etna

Ohne Zusammenfassung     

Evaluation of the mood-stabilizing agent valproic acid as a preventative for toxoplasmosis in mice and activity against tissue cysts in mice

Toxoplasma gondii is a common intracellular protozoan infection of humans worldwide. Severe disease can occur in immunocompromised individuals and the in the fetuses of nonimmune pregnant women. Chronic infection is associated with vision and hearing problems, and functional mental alterations, including schizophrenia. The mood-stabilizing agent valproic acid has been shown to inhibit the development of T. gondii in vitro at dosages that are normally achieved in the serum and cerebral spinal fluid of human patients and to have positive effects on the behavior of rats chronically infected with T. gondii. The present study was done to examine the in vivo activity of valproic acid against acute toxoplasmosis in mice. Two studies were done with valproic acid given in the drinking water at concentrations of 1.5 mg/ml (Experiment 1) or 3.0 mg/ml (Experiment 2). In a third experiment (Experiment 3), valproic acid was injected intraperitoneally (i.p.) at doses of 200 or 300 mg/kg every 12 hr. Valproic acid was not effective in preventing acute toxoplasmosis. All mice treated with valproic acid died or were killed and did not (P > 0.05) live significantly longer than the controls. Tachyzoites were demonstrated in the tissues of infected valproic-acid-treated mice. A fourth study was done to determine if valproic acid has activity against T. gondii tissue cysts in chronically infected mice. Mice were chronically infected with the ME-49 strain of T. gondii for 8 wk and then treated orally with valproic acid at approximately 6.6 mg/ml (800 mg/kg/day) in the drinking water for 10 wk (amount was varied due to increasing mouse weights). No significant differences (P > 0.05) were present in tissue cyst numbers in valproic-acid-treated T. gondii chronically infected mice and in mice chronically infected with T. gondii but not given valproic acid. Our results indicate that valproic acid, although effective in vitro against T. gondii tachyzoites, is not effective as a preventative in mice inoculated with T. gondii tachyzoites. Additionally, no activity against tissue cysts was observed in chronically T. gondii-infected valproic-acid-treated mice.     

Preservation of fresh edible cactus stems (<i>Opuntia ficus indica</i> Mill.) by modified atmosphere packaging

Cactus stems, the cladodes of Opuntia spp. cacti, are consumed in Mexico and other countries due to their fresh and herbaceous flavor, and because of their widely known nutraceutical benefits. In order to extend the postharvest life of this vegetable, the effect of a modified atmosphere packaging (MAP) was studied in cactus stems of the cultivar Atlixco stored at 4 ± 1 °C for 20 days under three types of atmospheres: (1) air (passive atmosphere), (2) 5 kPa O₂ + 4 kPa CO₂, and (3) N₂. During storage, the titratable acidity decreased and the color of cladodes became darker and less green; however, the 5 kPa O₂ + 4 kPa CO₂ atmosphere was able to preserve both quality characteristics. All modified atmospheres reduced weight loss (from 8 to <2%) and the symptoms of chilling injury, and this physiological disorder appeared earlier in controls than in MAP-stored cladodes. The levels of fermentation metabolites were low in all three evaluated atmospheres. Because of this, only cladodes stored under the N₂ atmosphere were selected for furthersensory analysis of the MAP effect on odor perception as evaluated by a trained panel. Results indicated that there was no detrimental effect (atypical odors) of MAP on this sensory characteristic. We conclude that cultivar Atlixco is suitable for preservation using MAP technology.     

Visualization of elusive structures using intracardiac echocardiography: Insights from electrophysiology

Echocardiography has the ability to noninvasively explore hemodynamic variables during pharmacologic or exercise stress test in patients with heart failure. In this review, we detail some important potential applications of stress echocardiography in patients with heart failure. In patients with coronary artery disease and chronic LV dysfunction, dobutamine stress echocardiography is able to distinguish between viable and fibrotic tissue to make adequate clinical decisions. Exercise testing, in combination with echocardiographic monitoring, is a method of obtaining accurate information in the assessment of functional capacity and prognosis. Functional mitral regurgitation is a common finding in patients with dilated and ischaemic cardiomyopathy and stress echocardiography in the form of exercise or pharmacologic protocols can be useful to evaluate the behaviour of mitral regurgitation. It is clinical useful to search the presence of contractile reserve in non ischemic dilated cardiomyopathy such as to screen or monitor the presence of latent myocardial dysfunction in patients who had exposure to cardiotoxic agents. Moreover, in patients with suspected diastolic heart failure and normal systolic function, exercise echocardiography could be able to demonstrate the existence of such dysfunction and determine that it is sufficient to limit exercise tolerance. Finally, in the aortic stenosis dobutamine echocardiography can distinguish severe from non-severe stenosis in patients with low transvalvular gradients and depressed left ventricular function.     

Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus

We have characterized the hemagglutinin-esterase (HE) of puffinosis virus (PV), a coronavirus closely related to mouse hepatitis virus (MHV). Analysis of the cloned gene revealed approximately 85% sequence identity to HE proteins of MHV and approximately 60% identity to the corresponding esterase of bovine coronavirus. The HE protein exhibited acetylesterase activity with synthetic substrates p-nitrophenyl acetate, alpha-naphthyl acetate, and 4-methylumbelliferyl acetate. In contrast to other viral esterases, no activity was detectable with natural substrates containing 9-O-acetylated sialic acids. Furthermore, PV esterase was unable to remove influenza C virus receptors from human erythrocytes, indicating a substrate specificity different from HEs of influenza C virus and bovine coronavirus. Solid-phase binding assays revealed that purified PV was unable to bind to sialic acid-containing glycoconjugates like bovine submaxillary mucin, mouse alpha1 macroglobulin or bovine brain extract. Because of the close relationship to MHV, possible implications on the substrate specificity of MHV esterases are suggested.