26,036 research outputs found
Design of Experiments for Screening
The aim of this paper is to review methods of designing screening
experiments, ranging from designs originally developed for physical experiments
to those especially tailored to experiments on numerical models. The strengths
and weaknesses of the various designs for screening variables in numerical
models are discussed. First, classes of factorial designs for experiments to
estimate main effects and interactions through a linear statistical model are
described, specifically regular and nonregular fractional factorial designs,
supersaturated designs and systematic fractional replicate designs. Generic
issues of aliasing, bias and cancellation of factorial effects are discussed.
Second, group screening experiments are considered including factorial group
screening and sequential bifurcation. Third, random sampling plans are
discussed including Latin hypercube sampling and sampling plans to estimate
elementary effects. Fourth, a variety of modelling methods commonly employed
with screening designs are briefly described. Finally, a novel study
demonstrates six screening methods on two frequently-used exemplars, and their
performances are compared
Searching for New Leads to Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents
The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N,N′-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N,N′-diphenethylsulfamide.Fil: Palestro, Pablo Hernán. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Enrique, Nicolás Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Goicoechea, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; ArgentinaFil: Villalba, Maria Luisa. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sabatier, Laureano Leonel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martín, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Milesi, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Bruno Blanch, Luis Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin
A Bayesian measurement error model for two-channel cell-based RNAi data with replicates
RNA interference (RNAi) is an endogenous cellular process in which small
double-stranded RNAs lead to the destruction of mRNAs with complementary
nucleoside sequence. With the production of RNAi libraries, large-scale RNAi
screening in human cells can be conducted to identify unknown genes involved in
a biological pathway. One challenge researchers face is how to deal with the
multiple testing issue and the related false positive rate (FDR) and false
negative rate (FNR). This paper proposes a Bayesian hierarchical measurement
error model for the analysis of data from a two-channel RNAi high-throughput
experiment with replicates, in which both the activity of a particular
biological pathway and cell viability are monitored and the goal is to identify
short hair-pin RNAs (shRNAs) that affect the pathway activity without affecting
cell activity. Simulation studies demonstrate the flexibility and robustness of
the Bayesian method and the benefits of having replicates in the experiment.
This method is illustrated through analyzing the data from a RNAi
high-throughput screening that searches for cellular factors affecting HCV
replication without affecting cell viability; comparisons of the results from
this HCV study and some of those reported in the literature are included.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS496 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Significance Analysis for Pairwise Variable Selection in Classification
The goal of this article is to select important variables that can
distinguish one class of data from another. A marginal variable selection
method ranks the marginal effects for classification of individual variables,
and is a useful and efficient approach for variable selection. Our focus here
is to consider the bivariate effect, in addition to the marginal effect. In
particular, we are interested in those pairs of variables that can lead to
accurate classification predictions when they are viewed jointly. To accomplish
this, we propose a permutation test called Significance test of Joint Effect
(SigJEff). In the absence of joint effect in the data, SigJEff is similar or
equivalent to many marginal methods. However, when joint effects exist, our
method can significantly boost the performance of variable selection. Such
joint effects can help to provide additional, and sometimes dominating,
advantage for classification. We illustrate and validate our approach using
both simulated example and a real glioblastoma multiforme data set, which
provide promising results.Comment: 28 pages, 7 figure
False discovery rate regression: an application to neural synchrony detection in primary visual cortex
Many approaches for multiple testing begin with the assumption that all tests
in a given study should be combined into a global false-discovery-rate
analysis. But this may be inappropriate for many of today's large-scale
screening problems, where auxiliary information about each test is often
available, and where a combined analysis can lead to poorly calibrated error
rates within different subsets of the experiment. To address this issue, we
introduce an approach called false-discovery-rate regression that directly uses
this auxiliary information to inform the outcome of each test. The method can
be motivated by a two-groups model in which covariates are allowed to influence
the local false discovery rate, or equivalently, the posterior probability that
a given observation is a signal. This poses many subtle issues at the interface
between inference and computation, and we investigate several variations of the
overall approach. Simulation evidence suggests that: (1) when covariate effects
are present, FDR regression improves power for a fixed false-discovery rate;
and (2) when covariate effects are absent, the method is robust, in the sense
that it does not lead to inflated error rates. We apply the method to neural
recordings from primary visual cortex. The goal is to detect pairs of neurons
that exhibit fine-time-scale interactions, in the sense that they fire together
more often than expected due to chance. Our method detects roughly 50% more
synchronous pairs versus a standard FDR-controlling analysis. The companion R
package FDRreg implements all methods described in the paper
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