Assessment Method for a Power Analysis to Identify Differentially Expressed Pathways

Gene expression data can provide a very rich source of information for elucidating the biological function on the pathway level if the experimental design considers the needs of the statistical analysis methods. The purpose of this paper is to provide a comparative analysis of statistical methods for detecting the differentially expression of pathways (DEP). In contrast to many other studies conducted so far, we use three novel simulation types, producing a more realistic correlation structure than previous simulation methods. This includes also the generation of surrogate data from two large-scale microarray experiments from prostate cancer and ALL. As a result from our comprehensive analysis of 41,004 parameter configurations, we find that each method should only be applied if certain conditions of the data from a pathway are met. Further, we provide method-specific estimates for the optimal sample size for microarray experiments aiming to identify DEP in order to avoid an underpowered design. Our study highlights the sensitivity of the studied methods on the parameters of the system. © 2012 Tripahti and Emmert-Streib.

Harnessing the complexity of gene expression data from cancer: from single gene to structural pathway methods

High-dimensional gene expression data provide a rich source of information because they capture the expression level of genes in dynamic states that reflect the biological functioning of a cell. For this reason, such data are suitable to reveal systems related properties inside a cell, e.g., in order to elucidate molecular mechanisms of complex diseases like breast or prostate cancer. However, this is not only strongly dependent on the sample size and the correlation structure of a data set, but also on the statistical hypotheses tested. Many different approaches have been developed over the years to analyze gene expression data to (I) identify changes in single genes, (II) identify changes in gene sets or pathways, and (III) identify changes in the correlation structure in pathways. In this paper, we review statistical methods for all three types of approaches, including subtypes, in the context of cancer data and provide links to software implementations and tools and address also the general problem of multiple hypotheses testing. Further, we provide recommendations for the selection of such analysis methods.

Gene Sets Net Correlations Analysis (GSNCA): a multivariate differential coexpression test for gene sets

Motivation: To date, Gene Set Analysis (GSA) approaches primarily focus on identifying differentially expressed gene sets (pathways). Methods for identifying differentially coexpressed pathways also exist but are mostly based on aggregated pairwise correlations, or other pairwise measures of coexpression. Instead, we propose Gene Sets Net Correlations Analysis (GSNCA), a multivariate differential coexpression test that accounts for the complete correlation structure between genes.

Results: In GSNCA, weight factors are assigned to genes in proportion to the genes' cross-correlations (intergene correlations). The problem of finding the weight vectors is formulated as an eigenvector problem with a unique solution. GSNCA tests the null hypothesis that for a gene set there is no difference in the weight vectors of the genes between two conditions. In simulation studies and the analyses of experimental data, we demonstrate that GSNCA, indeed, captures changes in the structure of genes' cross-correlations rather than differences in the averaged pairwise correlations. Thus, GSNCA infers differences in coexpression networks, however, bypassing method-dependent steps of network inference. As an additional result from GSNCA, we define hub genes as genes with the largest weights and show that these genes correspond frequently to major and specific pathway regulators, as well as to genes that are most affected by the biological difference between two conditions. In summary, GSNCA is a new approach for the analysis of differentially coexpressed pathways that also evaluates the importance of the genes in the pathways, thus providing unique information that may result in the generation of novel biological hypotheses.

Parametric study of non-relativistic electrostatic shocks and the structure of their transition layer

Nonrelativistic electrostatic unmagnetized shocks are frequently observed in laboratory plasmas and they are likely to exist in astrophysical plasmas. Their maximum speed, expressed in units of the ion acoustic speed far upstream of the shock, depends only on the electron-to-ion temperature ratio if binary collisions are absent. The formation and evolution of such shocks is examined here for a wide range of shock speeds with particle-in-cell simulations. The initial temperatures of the electrons and the 400 times heavier ions are equal. Shocks form on electron time scales at Mach numbers between 1.7 and 2.2. Shocks with Mach numbers up to 2.5 form after tens of inverse ion plasma frequencies. The density of the shock-reflected ion beam increases and the number of ions crossing the shock thus decreases with an increasing Mach number, causing a slower expansion of the downstream region in its rest frame. The interval occupied by this ion beam is on a positive potential relative to the far upstream. This potential pre-heats the electrons ahead of the shock even in the absence of beam instabilities and decouples the electron temperature in the foreshock ahead of the shock from the one in the far upstream plasma. The effective Mach number of the shock is reduced by this electron heating. This effect can potentially stabilize nonrelativistic electrostatic shocks moving as fast as supernova remnant shocks. 

On the structure and dynamics of ionic liquids

The structure and dynamics of the ionic liquid 1-ethyl-3-methylimidazolium nitrate is studied by molecular dynamics simulations. We find long-range spatial correlations between the ions and a three-dimensional local structure that reflects the asymmetry of the cations. The main contribution to the configurational energy comes from the electrostatic interactions which leads to charge-ordering effects. Radial screening and threedimensional distribution of charge are also analyzed. The motion of a single ion is studied via velocity and reorientational correlation functions. It is found that ions "rattle" in a long-lived cage, while the orientational structure relaxes on a time scale longer than 200 ps. As in a supercooled liquid, the mean square displacements reveal a subdiffusive dynamics. In addition, the presence of dynamic heterogeneities can be detected by analyzing the non-Gaussian behavior of the van Hove correlation function and the spatial arrangement of the most mobile ions. The short-time collective dynamics is also studied through the electric current time correlation function.

Structure and dynamics of a confined ionic liquid. topics of relevance to dye-sensitized solar cells

The behavior of a model ionic liquid (IL) confined between two flat parallel walls was studied at various interwall distances using computer simulations. The results focus both on structural and dynamical properties. Mass and charge density along the confinement axis reveal a structure of layers parallel to the walls that leads to an oscillatory profile in the electrostatic potential. Orientational correlation functions indicate that cations at the interface orient tilted with respect to the surface and that any other orientational order is lost thereafter. The diffusion coefficients of the ions exhibit a maximum as a function of the confinement distance, a behavior that results from a combination of the structure of the liquid as a whole and a faster molecular motion in the vicinity of the walls. We discuss the relevance of the present results and elaborate on topics that need further attention regarding the effects of ILs in the functioning of IL-based dye-sensitized solar cells.

Thermodynamics, structure, and dynamics in room temperature ionic liquids: The case of 1-butyl-3-methyl imidazolium hexafluorophosphate ([bmim][PF6])

A detailed investigation of the phase diagram of 1-butyl-3-methyl imidazolium hexafluorophosphate ([bmim][PF6]) is presented on the basis of a wide set of experimental data accessing thermodynamic, structural, and dynamical properties of this important room temperature ionic liquid (RTIL). The combination of quasi adiabatic, continuous calorimetry, wide angle neutron and X-ray diffraction, and quasi elastic neutron scattering allows the exploration of many novel features of this material. Thermodynamic and microscopic structural information is derived on both glassy and crystalline states and compared with results that recently appeared in the literature allowing direct information to be obtained on the existence of two crystalline phases that were not previously characterized and confirming the view that RTILs show a substantial degree of order (even in their amorphous states), which resembles the crystalline order. We highlight a strong connection between structure and dynamics, showing the existence of three temperature ranges in the glassy state across which both the spatial correlation and the dynamics change. The complex crystalline polymorphism in [bmim][PF6] also is investigated; we compare our findings with the corresponding findings for similar RTILs. These results provide a strong experimental basis for the exploration of the features of the phase diagram of RTILs and for the further study of longer alkyl chain salts.

Liquid structure of the ionic liquid 1,3-dimethylimidazolium bis{(trifluoromethyl)sulfonyl}amide

Neutron diffraction has been used to determine the liquid structure of 1,3-dimethylimidazolium bis{( trifluoromethyl) sulfonyl} amide ([dmim][NTf2]). Significantly smaller charge ordering is found in this liquid compared with analogous chloride and hexafluorophosphate salts due to the diffuse charge density and size of the [NTf2](-) anion. This is manifested in a much larger cation-cation and cation-anion separation and an overlap of the cation-cation and cation-anion shells. Comparison of the liquid structure with the crystal structure reported by Holbrey et al. ( Dalton Trans. 2004, 2267) indicates little correlation, for example, the [NTf2](-) anion adopts a trans orientation predominantly in the liquid whereas a cis orientation is found in the solid phase.

Anomalous helicon wave absorption and parametric excitation of electrostatic fluctuations in a helicon-produced plasma

The nonlinear nature of the rf absorption in a helicon-produced plasma was recently evidenced by the observation that the helicon wave damping as well as the level of short-scale electrostatic fluctuations excited in the helicon plasma increases with rf power. Correlation methods using electrostatic probes as well as microwave back-scattering at the upper-hybrid resonance allow identifying the fluctuations as ion-sound and Trivelpiece– Gould waves satisfying the frequency and wavenumber matching conditions for the parametric decay instability of the helicon pump wave. Furthermore, the growth rates and thresholds deduced from their temporal growth are in good agreement with theoretical predictions for the parametric decay instability that takes into account realistic damping rates for the decay waves as well as a non-vanishing parallel wavenumber of the helicon pump. The close relationship between the rf absorption and the excitation of the fluctuations was investigated in more detail by performing time- and space-resolved measurements of the helicon wave field and the electrostatic fluctuations.

Development of a QSPR correlation for the parachor of 1,3-dialkyl imidazolium based ionic liquids

Ionic liquids have received significant interest from both academia and industry for a wide range of applications which often requires knowledge of their thermophysical properties. Quantitative structure-property relationship correlations and group contribution methods for thermophysical properties of ionic liquids are a basic necessity for the development of computer aided molecular design approaches for these liquids and subsequently offer the potential for designing an ionic liquid having a desirable set of thermophysical properties. However, the limited availability of experimental thermophysical data and their quality have prevented the development of such tools. Based on previously reported experimental surface tension data, a correlation of the parachors with the molar volume of the ionic liquids has been developed. The predicted parachor values have been shown to be in good agreement with the experimental data. A maximum deviation of

Thermodynamic properties and atomistic structure of the dry amorphous silica surface from a reactive force field model

A force field model of the Keating type supplemented by rules to break, form, and interchange bonds is applied to investigate thermodynamic and structural properties of the amorphous SiO2 surface. A simulated quench from the liquid phase has been carried out for a silica sample made of 3888 silicon and 7776 oxygen atoms arranged on a slab similar to 40 angstrom thick, periodically repeated along two directions. The quench results into an amorphous sample, exposing two parallel square surfaces of similar to 42 nm(2) area each. Thermal averages computed during the quench allow us to determine the surface thermodynamic properties as a function of temperature. The surface tension turns out to be gamma=310 +/- 20 erg/cm(2) at room temperature and gamma=270 +/- 30 at T=2000 K, in fair agreement with available experimental estimates. The entropy contribution Ts-s to the surface tension is relatively low at all temperatures, representing at most similar to 20% of the surface energy. Almost without exceptions, Si atoms are fourfold coordinated and oxygen atoms are twofold coordinated. Twofold and threefold rings appear only at low concentration and are preferentially found in proximity of the surface. Above the glass temperature T-g=1660 +/- 50 K, the mobility of surface atoms is, as expected, slightly higher than that of bulk atoms. The computation of the height-height correlation function shows that the silica surface is rough in the equilibrium and undercooled liquid phase, becoming smooth below the glass temperature T-g.

Significant correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy

Prior family and adoption studies have suggested a genetic relationship between schizophrenia and schizotypy. However, this has never been verified using linkage methods. We therefore attempted to test for a correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy. The Irish study of high-density schizophrenia families comprises 270 families with at least two members with schizophrenia or poor-outcome schizoaffective disorder (n = 637). Non-psychotic relatives were assessed using the structured interview for schizotypy (n = 746). A 10-cM multipoint, non-parametric, autosomal genomewide scan of schizophrenia was performed in Merlin. A scan of a quantitative trait comprising ratings of DSM-III-R criteria for schizotypal personality disorder in non-psychotic relatives was also performed. Schizotypy logarithm of the odds (LOD) scores were regressed onto schizophrenia LOD scores at all loci, with adjustment for spatial autocorrelation. To assess empirical significance, this was also carried out using 1000 null scans of schizotypy. The number of jointly linked loci in the real data was compared to distribution of jointly linked loci in the null scans. No markers were suggestively linked to schizotypy based on strict Lander Kruglyak criteria. Schizotypy LODs predicted schizophrenia LODs above chance expectation genome wide (empirical P = 0.04). Two and four loci yielded nonparametric LOD (NPLs) > 1.0 and > 0.75, respectively, for both schizophrenia and schizotypy (genome-wide empirical P = 0.04 and 0.02, respectively). These results suggest that at least a subset of schizophrenia susceptibility genes also affects schizotypy in non-psychotic relatives. Power may therefore be increased in molecular genetic studies of schizophrenia if they incorporate measures of schizotypy in non-psychotic relatives.

Structure observed in measured electron energy distribution functions in capacitively coupled radio frequency hydrogen plasmas

Electron energy probability functions measured with a passively compensated Langmuir probe in asymmetric capacitively coupled hydrogen and deuterium plasmas exhibit structure. The otherwise relatively continuous distribution appears to have an abrupt peak in electron density near 5 eV. This structure occurs at a higher energy in deuterium than hydrogen and there is a correlation between floating potential and the voltage at which the structure is observed in the second derivative of the I(V) characteristic. While the cause of the structure has yet to be clarified, spectroscopic observations and computer-based hydrogen models indicate that the high energy tail of the distribution is strongly modulated during the radio frequency cycle. The effect of this modulation on plasma properties and probe measurements has yet to be explored. (C) 1999 American Institute of Physics. [S0003-6951(99)00819-0].

Structure, stereochemistry and synthesis of enantiopure cyclohexenone cis-diol bacterial metabolites derived from phenols

Biotransformation of 3-substituted and 2,5-disubstituted phenols, using whole cells of P. putida UV4, yielded cyclohexenone cis-diols as single enantiomers; their structures and absolute configurations have been determined by NMR and ECD spectroscopy, X-ray crystallography, and stereochemical correlation involving a four step chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites. An active site model has been proposed, to account for the formation of enantiopure cyclohexenone cis-diols with opposite absolute configurations.