Bayesian Variable Selection for Probit Mixed Models Applied to Gene Selection

In computational biology, gene expression datasets are characterized by very few individual samples compared to a large number of measurements per sample. Thus, it is appealing to merge these datasets in order to increase the number of observations and diversify the data, allowing a more reliable selection of genes relevant to the biological problem. Besides, the increased size of a merged dataset facilitates its re-splitting into training and validation sets. This necessitates the introduction of the dataset as a random effect. In this context, extending a work of Lee et al. (2003), a method is proposed to select relevant variables among tens of thousands in a probit mixed regression model, considered as part of a larger hierarchical Bayesian model. Latent variables are used to identify subsets of selected variables and the grouping (or blocking) technique of Liu (1994) is combined with a Metropolis-within-Gibbs algorithm (Robert and Casella 2004). The method is applied to a merged dataset made of three individual gene expression datasets, in which tens of thousands of measurements are available for each of several hundred human breast cancer samples. Even for this large dataset comprised of around 20000 predictors, the method is shown to be efficient and feasible. As an illustration, it is used to select the most important genes that characterize the estrogen receptor status of patients with breast cancer

Parallel Tempering with Equi-Energy Moves

The Equi-Energy Sampler (EES) introduced by Kou et al [2006] is based on a population of chains which are updated by local moves and global moves, also called equi-energy jumps. The state space is partitioned into energy rings, and the current state of a chain can jump to a past state of an adjacent chain that has energy level close to its level. This algorithm has been developed to facilitate global moves between different chains, resulting in a good exploration of the state space by the target chain. This method seems to be more efficient than the classical Parallel Tempering (PT) algorithm. However it is difficult to use in combination with a Gibbs sampler and it necessitates increased storage. In this paper we propose an adaptation of this EES that combines PT with the principle of swapping between chains with same levels of energy. This adaptation, that we shall call Parallel Tempering with Equi-Energy Moves (PTEEM), keeps the original idea of the EES method while ensuring good theoretical properties, and practical implementation even if combined with a Gibbs sampler. Performances of the PTEEM algorithm are compared with those of the EES and of the standard PT algorithms in the context of mixture models, and in a problem of identification of gene regulatory binding motifs

Likelihood-Free Parallel Tempering

Approximate Bayesian Computational (ABC) methods (or likelihood-free methods) have appeared in the past fifteen years as useful methods to perform Bayesian analyses when the likelihood is analytically or computationally intractable. Several ABC methods have been proposed: Monte Carlo Markov Chains (MCMC) methods have been developped by Marjoramet al. (2003) and by Bortotet al. (2007) for instance, and sequential methods have been proposed among others by Sissonet al. (2007), Beaumont et al. (2009) and Del Moral et al. (2009). Until now, while ABC-MCMC methods remain the reference, sequential ABC methods have appeared to outperforms them (see for example McKinley et al. (2009) or Sisson et al. (2007)). In this paper a new algorithm combining population-based MCMC methods with ABC requirements is proposed, using an analogy with the Parallel Tempering algorithm (Geyer, 1991). Performances are compared with existing ABC algorithms on simulations and on a real example

Social and environmental malaria risk factors in urban areas of Ouagadougou, Burkina Faso

<p>Abstract</p> <p>Background</p> <p>Despite low endemicity, malaria remains a major health problem in urban areas where a high proportion of fevers are presumptively treated using anti-malarial drugs. Low acquired malaria immunity, behaviour of city-dwellers, access to health care and preventive interventions, and heterogenic suitability of urban ecosystems for malaria transmission contribute to the complexity of the malaria epidemiology in urban areas.</p> <p>Methods</p> <p>The study was designed to identify the determinants of malaria transmission estimated by the prevalence of anti-circumsporozoite (CSP) antibodies, the prevalence and density of <it>Plasmodium falciparum </it>infection, and the prevalence of malarial disease in areas of Ouagadougou, Burkina-Faso. Thick blood smears, dried blood spots and clinical status have been collected from 3,354 randomly chosen children aged 6 months to 12 years using two cross-sectional surveys (during the dry and rainy seasons) in eight areas from four ecological strata defined according to building density and land tenure (regular versus irregular). Demographic characteristics, socio-economic information, and sanitary and environmental data concerning the children or their households were simultaneously collected. Dependent variables were analysed using mixed multivariable models with random effects, taking into account the clustering of participants within compounds and areas.</p> <p>Results</p> <p>Overall prevalences of CSP-antibodies and <it>P. falciparum </it>infections were 7.7% and 16.6% during the dry season, and 12.4% and 26.1% during the rainy season, respectively, with significant differences according to ecological strata. Malaria risk was significantly higher among children who i) lived in households with lower economic or education levels, iii) near the hydrographic network, iv) in sparsely built-up areas, v) in irregularly built areas, vi) who did not use a bed net, vii) were sampled during the rainy season or ii) had traveled outside of Ouagadougou.</p> <p>Conclusion</p> <p>Malaria control should be focused in areas which are irregularly or sparsely built-up or near the hydrographic network. Furthermore, urban children would benefit from preventive interventions (e.g. anti-vectorial devices or chemoprophylaxis) aimed at reducing malaria risk during and after travel in rural areas.</p

Plasmodium falciparum Na+/H+ Exchanger 1 Transporter Is Involved in Reduced Susceptibility to Quinine ▿

Polymorphisms in the Plasmodium falciparum crt (Pfcrt), Pfmdr1, and Pfmrp genes were not significantly associated with quinine (QN) 50% inhibitory concentrations (IC50s) in 23 strains of Plasmodium falciparum. An increased number of DNNND repeats in Pfnhe-1 microsatellite ms4760 was associated with an increased IC50 of QN (P = 0.0007). Strains with only one DNNND repeat were more susceptible to QN (mean IC50 of 154 nM). Strains with two DNNND repeats had intermediate susceptibility to QN (mean IC50 of 548 nM). Strains with three DNNND repeats had reduced susceptibility to QN (mean IC50 of 764 nM). Increased numbers of NHNDNHNNDDD repeats were associated with a decreased IC50 of QN (P = 0.0020). Strains with profile 7 for Pfnhe-1 ms4760 (ms4760-7) were significantly associated with reduced QN susceptibility (mean IC50 of 764 nM). The determination of DNNND and NHNDNHNNDDD repeats in Pfnhe-1 ms4760 could be a good marker of QN resistance and provide an attractive surveillance method to monitor temporal trends in P. falciparum susceptibility to QN. The validity of the markers should be further supported by analyzing more isolates

Dihydroethanoanthracene derivatives reverse in vitro quinoline resistance in Plasmodium falciparum malaria.

International audienceThe capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains. These synthetic compounds were more effective in combination with CQ than verapamil, ketotifen, chlorpromazine, reserpine or nicardipine, which reversed less than 50% of the CQ resistant strains. DEAs significantly reversed 67 to 100% of MDAQ resistant parasites. These compounds were more effective in combination with MDAQ than ketotifen (60% of reversal), chlorpromazine (45%), verapamil (33%), reserpine (30%) or nicardipine (9%). The reversal activity of MQ resistance was less pronounced, regardless of the molecule tested, and was homogeneous with a rate ranging from 42% for ketotifen to 58% for reserpine, nicardipine, verapamil and cyproheptadine. The four DEAs significantly reversed 50 to 55% of the parasites resistant to MQ. Fifty-six to 78 % of the QN resistant parasites were reversed by the synthetic DEAs. There were few differences in the rate of reversal activity on QN resistant strains between the ten compounds, with rates ranging between 56 to 78% for the ten chemosensitizers. The use of DEAs in combination with quinoline seems to be thus a promising strategy for limiting the development of drug resistant strains and for treating patients in drug resistant areas

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline▿

The distribution and range of 50% inhibitory concentrations (IC50s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC50 geometric mean ranged from 6.2 μM to 11.1 μM according to the geographical origin, with a mean of 9.3 μM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC50 mean of 4.9 μM (±2.1 μM [standard deviation]); component B, with an IC50 mean of 7.7 μM (±1.2 μM); and component C, with an IC50 mean of 17.9 μM (±1.4 μM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 μM