Predictive response-relevant clustering of expression data provides insights into disease processes

This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of ;response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the ;meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes-including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets

Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA

Inclusive photoproduction of D*+- mesons has been measured for photon-proton centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of 37 pb^-1. Total and differential cross sections as functions of the D* transverse momentum and pseudorapidity are presented in restricted kinematical regions and the data are compared with next-to-leading order (NLO) perturbative QCD calculations using the "massive charm" and "massless charm" schemes. The measured cross sections are generally above the NLO calculations, in particular in the forward (proton) direction. The large data sample also allows the study of dijet production associated with charm. A significant resolved as well as a direct photon component contribute to the cross section. Leading order QCD Monte Carlo calculations indicate that the resolved contribution arises from a significant charm component in the photon. A massive charm NLO parton level calculation yields lower cross sections compared to the measured results in a kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure

Measurement of Jet Shapes in Photoproduction at HERA

The shape of jets produced in quasi-real photon-proton collisions at centre-of-mass energies in the range $134-277$ GeV has been measured using the hadronic energy flow. The measurement was done with the ZEUS detector at HERA. Jets are identified using a cone algorithm in the $\eta - \phi$ plane with a cone radius of one unit. Measured jet shapes both in inclusive jet and dijet production with transverse energies $E^{jet}_T>14$ GeV are presented. The jet shape broadens as the jet pseudorapidity ($\eta^{jet}$) increases and narrows as $E^{jet}_T$ increases. In dijet photoproduction, the jet shapes have been measured separately for samples dominated by resolved and by direct processes. Leading-logarithm parton-shower Monte Carlo calculations of resolved and direct processes describe well the measured jet shapes except for the inclusive production of jets with high $\eta^{jet}$ and low $E^{jet}_T$. The observed broadening of the jet shape as $\eta^{jet}$ increases is consistent with the predicted increase in the fraction of final state gluon jets.Comment: 29 pages including 9 figure

Randomized Controlled Trial of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

Background:The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01E and RTS,S/AS02D in infants and young children 5&ndash;17 months of age in Ghana.Methodology:A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule), of 19 months duration was conducted in two (2) centres in Ghana between August 2006 and May 2008. Subjects were allocated randomly (1:1:1:1:1:1) to one of six study groups at each study site, each defining which vaccine should be given and by which schedule (0,1-, 0,1,2- or 0,1,7-months). For the 0,1,2-month schedule participants received RTS,S/AS01E or rabies vaccine at one center and RTS,S/AS01E or RTS,S/AS02D at the other. For the other schedules at both study sites, they received RTS,S/AS01E or RTS,S/AS02D. The primary outcome measure was the occurrence of serious adverse events until 10 months post dose 1.Results:The number of serious adverse events reported across groups was balanced. One child had a simple febrile convulsion, which evolved favourably without sequelae, considered to be related to RTS,S/AS01E vaccination. Low grade reactions occurred slightly more frequently in recipients of RTS,S/AS than rabies vaccines; grade 3 reactions were infrequent. Less local reactogenicity occurred with RTS,S/AS01E than RTS,S/AS02D. Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies. Recipients of RTS,S/AS01E compared to RTS,S/AS02D had higher peak anti-circumsporozoite antibody responses for all 3 schedules. Three dose schedules were more immunogenic than 2 dose schedules. Area under the curve analyses for anti-circumsporozoite antibodies were comparable between the 0,1,2- and 0,1,7-month RTS,S/AS01E schedules.Conclusions:Both candidate malaria vaccines were well tolerated. Anti-circumsporozoite responses were greater with RTS,S/AS01E than RTS,S/AS02D and when 3 rather than 2 doses were given. This study supports the selection of RTS,S/AS01E and a 3 dose schedule for further development in children and infants

MicroRNA Profiling of BRCA1/2 Mutation-Carrying and Non-Mutation-Carrying High-Grade Serous Carcinomas of Ovary

BACKGROUND:MicroRNAs (miRNA) are 20 approximately 25 nucleotide non-coding RNAs that inhibit the translation of targeted mRNA, and they have been implicated in the development of human malignancies. High grade serous ovarian carcinomas, the most common and lethal subtype of ovarian cancer, can occur sporadically or in the setting of BRCA1/2 syndromes. Little is known regarding the miRNA expression profiles of high grade serous carcinoma in relation to BRCA1/2 status, and compared to normal tubal epithelium, the putative tissue of origin for high grade serous carcinomas. METHODOLOGY/PRINCIPAL FINDINGS:Global miRNA expression profiling was performed on a series of 33 high grade serous carcinomas, characterized with respect to BRCA1/2 status (mutation, epigenetic silencing with loss of expression or normal), and with clinical follow-up, together with 2 low grade serous carcinomas, 2 serous borderline tumors, and 3 normal fallopian tube samples, using miRNA microarrays (328 human miRNA). Unsupervised hierarchical clustering based on miRNA expression profiles showed no clear separation between the groups of carcinomas with different BRCA1/2 status. There were relatively few miRNAs that were differentially expressed between the genotypic subgroups. Comparison of 33 high grade serous carcinomas to 3 normal fallopian tube samples identified several dysregulated miRNAs (false discovery rate <5%), including miR-422b and miR-34c. Quantitative RT-PCR analysis performed on selected miRNAs confirmed the pattern of differential expression shown by microarray analysis. Prognostically, lower level miR-422b and miR-34c in high grade serous carcinomas were both associated with decreased disease-specific survival by Kaplan-Meier analysis (p<0.05). CONCLUSIONS/SIGNIFICANCE:High grade serous ovarian carcinomas with and without BRCA1/2 abnormalities demonstrate very similar miRNA expression profiles. High grade serous carcinomas as a group exhibit significant miRNA dysregulation in comparison to tubal epithelium and the levels of miR-34c and miR-422b appear to be prognostically important

Measurement of the Diffractive Cross Section in Deep Inelastic Scattering using ZEUS 1994 Data

The DIS diffractive cross section, $d\sigma^{diff}_{\gamma^* p \to XN}/dM_X$, has been measured in the mass range $M_X < 15$ GeV for $\gamma^*p$ c.m. energies $60 < W < 200$ GeV and photon virtualities $Q^2 = 7$ to 140 GeV$^2$. For fixed $Q^2$ and $M_X$, the diffractive cross section rises rapidly with $W$, $d\sigma^{diff}_{\gamma^*p \to XN}(M_X,W,Q^2)/dM_X \propto W^{a^{diff}}$ with $a^{diff} = 0.507 \pm 0.034 (stat)^{+0.155}_{-0.046}(syst)$ corresponding to a $t$-averaged pomeron trajectory of \bar{\alphapom} = 1.127 \pm 0.009 (stat)^{+0.039}_{-0.012} (syst) which is larger than \bar{\alphapom} observed in hadron-hadron scattering. The $W$ dependence of the diffractive cross section is found to be the same as that of the total cross section for scattering of virtual photons on protons. The data are consistent with the assumption that the diffractive structure function $F^{D(3)}_2$ factorizes according to \xpom F^{D(3)}_2 (\xpom,\beta,Q^2) = (x_0/ \xpom)^n F^{D(2)}_2(\beta,Q^2). They are also consistent with QCD based models which incorporate factorization breaking. The rise of \xpom F^{D(3)}_2 with decreasing \xpom and the weak dependence of $F^{D(2)}_2$ on $Q^2$ suggest a substantial contribution from partonic interactions

Comparison of ZEUS data with standard model predictions for e+p→e+Xe^+ p \rightarrow e^+ X scattering at high xx and Q2Q^2

Using the ZEUS detector at HERA, we have studied the reaction e(+)p --> e(+)X for Q(2) > 5000 GeV2 with a 20.1 pb(-1) data sample collected during the years 1993 to 1996. For Q(2) below 15000 GeV2, the data are in good agreement with Standard Model expectations. For Q(2) > 35000 GeV2. two events are observed while 0.145 +/- 0.013 events are expected, A statistical analysis of a large ensemble of simulated Standard Model experiments indicates that with probability 6.0%, an excess at least as unlikely as that observed would occur above some Q(2) cut. For x > 0.55 and y > 0.75, four events are observed where 0.91 +/- 0.08 events are expected, A statistical analysis of the two-dimensional distribution of the events in x and y yields a probability of 0.72% for the region x > 0.55 and y > 0.25 and a probability of 7.8% for the entire Q(2) > 5000 GeV2 data sample. The observed excess above Standard Model expectations is particularly interesting because it occurs in a previously unexplored kinematic region

Measurement of the F2 structure function in deep inelastic e+^{+}p scattering using 1994 data from the ZEUS detector at HERA

We present measurements of the structure function \Ft\ in e^+p scattering at HERA in the range 3.5\;\Gevsq < \qsd < 5000\;\Gevsq. A new reconstruction method has allowed a significant improvement in the resolution of the kinematic variables and an extension of the kinematic region covered by the experiment. At \qsd < 35 \;\Gevsq the range in x now spans 6.3\cdot 10^{-5} < x < 0.08 providing overlap with measurements from fixed target experiments. At values of Q^2 above 1000 GeV^2 the x range extends to 0.5. Systematic errors below 5\perc\ have been achieved for most of the kinematic urray, W

Exclusive Electroproduction of ρ0\rho^0 and J/ψJ/\psi Mesons at HERA

Exclusive production of $\rho^0$ and $J/\psi$ mesons in e^+ p collisions has been studied with the ZEUS detector in the kinematic range $0.25 < Q^2 < 50 GeV^2, 20 < W < 167 GeV$ for the $\rho^0$ data and $2 < Q^2 < 40 GeV^2, 50 < W < 150 GeV$ for the $J/\psi$ data. Cross sections for exclusive $\rho^0$ and $J/\psi$ production have been measured as a function of $Q^2, W$ and $t$. The spin-density matrix elements $r^{04}_{00}, r^1_{1-1}$ and $Re r^{5}_{10}$ have been determined for exclusive $\rho^0$ production as well as $r^{04}_{00}$ and $r^{04}_{1-1}$ for exclusive $J/\psi$ production. The results are discussed in the context of theoretical models invoking soft and hard phenomena.Comment: 57 pages including 21 figures, minor modifications to Figs. 19-21, these figures supercede those of Eur. Phys. J. C6 (1999) 603-62