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Entropy-based gene ranking without selection bias for the predictive classification of microarray data.

BACKGROUND: We describe the E-RFE method for gene ranking, which is useful for the identification of markers in the predictive classification of array data. The method supports a practical modeling scheme designed to avoid the construction of classification rules based on the selection of too small gene subsets (an effect known as the selection bias, in which the estimated predictive errors are too optimistic due to testing on samples already considered in the feature selection process). RESULTS: With E-RFE, we speed up the recursive feature elimination (RFE) with SVM classifiers by eliminating chunks of uninteresting genes using an entropy measure of the SVM weights distribution. An optimal subset of genes is selected according to a two-strata model evaluation procedure: modeling is replicated by an external stratified-partition resampling scheme, and, within each run, an internal K-fold cross-validation is used for E-RFE ranking. Also, the optimal number of genes can be estimated according to the saturation of Zipf's law profiles. CONCLUSIONS: Without a decrease of classification accuracy, E-RFE allows a speed-up factor of 100 with respect to standard RFE, while improving on alternative parametric RFE reduction strategies. Thus, a process for gene selection and error estimation is made practical, ensuring control of the selection bias, and providing additional diagnostic indicators of gene importance.

Adenocarcinoma↗

Haplotypic analysis of the TNF locus by association efficiency and entropy.

BACKGROUND: To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods. RESULTS: We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p < 10-5 by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNF are poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity. CONCLUSIONS: The TNF locus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF SNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.

Adult↗

Promoter features related to tissue specificity as measured by Shannon entropy.

BACKGROUND: The regulatory mechanisms underlying tissue specificity are a crucial part of the development and maintenance of multicellular organisms. A genome-wide analysis of promoters in the context of gene-expression patterns in tissue surveys provides a means of identifying the general principles for these mechanisms. RESULTS: We introduce a definition of tissue specificity based on Shannon entropy to rank human genes according to their overall tissue specificity and by their specificity to particular tissues. We apply our definition to microarray-based and expressed sequence tag (EST)-based expression data for human genes and use similar data for mouse genes to validate our results. We show that most genes show statistically significant tissue-dependent variations in expression level. We find that the most tissue-specific genes typically have a TATA box, no CpG island, and often code for extracellular proteins. As expected, CpG islands are found in most of the least tissue-specific genes, which often code for proteins located in the nucleus or mitochondrion. The class of genes with no CpG island or TATA box are the most common mid-specificity genes and commonly code for proteins located in a membrane. Sp1 was found to be a weak indicator of less-specific expression. YY1 binding sites, either as initiators or as downstream sites, were strongly associated with the least-specific genes. CONCLUSIONS: We have begun to understand the components of promoters that distinguish tissue-specific from ubiquitous genes, to identify associations that can predict the broad class of gene expression from sequence data alone.

Animals↗

Translational clinical trials: an entropy-based approach to sample size.

Translational clinical trials are small studies of therapies emerging from the laboratory. These trials are essential for generating early evidence regarding the effects of treatment on specific targets in the disease pathway and for guiding the next studies to be done. The statistical properties of such studies have been neglected, in part, because they do not fit the well-known clinical trials developmental paradigm. This paper discusses the translational trial setting, and presents an information (entropy) based approach to understanding the properties and use of these trials. The combination of biological knowledge with a designed experiment (albeit a small one) is a powerful device for resolving much of the considerable uncertainty surrounding an emerging therapeutic concept. An approach to motivating the sample size for translational trials is presented.

Animals↗

A comparison of bispectral index and entropy, or how to misinterpret both.

Consciousness monitoring has become increasingly popular in general anesthesia cases, and a new technology has recently been introduced with potential advantages over the other available products. In this case report, we discuss a patient who was monitored simultaneously with Bispectral Index and Entropy and evaluate the differences between the two. More importantly, we emphasize the importance of vigilance when using new technologies and discuss the potential impact of lack of vigilance on patient outcome.

Aged↗

Entropy and information content of laboratory test results.

This article introduces the use of information theoretic concepts such as entropy, S, for the evaluation of laboratory tests results, and it offers a new measure of information, 1 - S, which tells us just how far toward certainty a laboratory test result can predict a binary outcome. The derived method is applied to the serum markers troponin I and prostate-specific antigen and to histologic grading of HER-2/neu staining, to cytologic diagnosis of cervical specimens, and to the measurement of tumor thickness in malignant melanoma. Not only do the graphic results provide insight for these tests, they also validate prior conclusions. Thus, this information theoretic approach shows promise for evaluating and understanding laboratory test results.

Cervix Uteri↗

Episodic secretion of parathyroid hormone in postmenopausal women: assessment by deconvolution analysis and approximate entropy.

In health young subjects, parathyroid hormone (PTH) is secreted presumptively in a dual fashion, with low amplitude pulses apparently superimposed on tonic secretion. In contrast, PTH secretion has not been as well characterized in postmenopausal women, and relationships among bone density, estrogen status, and PTH release have not been explored. It is possible that a pulsatile pattern of PTH secretion is important for bone remodeling, since exogenous PTH administered in a pulsatile manner stimulates bone formation. To assess the importance of pulsatile PTH secretion as a determinant of bone mass, we measured PTH in blood sampled every 2 minutes for 6 h in four groups of older women: (1) high bone density receiving estrogen (n = 6), (2) high bone density not receiving estrogen (n = 5), (3) low bone density receiving estrogen (n = 6), and (4) low bone density not receiving estrogen (n = 8). The plasma PTH release profiles were subjected to deconvolution analysis, which resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In postmenopausal subjects, PTH was secreted in a fashion similar to that observed in young adults, with significant tonic secretion and PTH pulse occurrences averaging every 18-19 minutes. Pulsatile PTH secretion accounted for approximately 25% of the total secreted PTH. There were no differences in the amplitude or frequency of pulsatile PTH secretory parameters or in ApEn values among the four groups or compared with young controls. We conclude that in postmenopausal women, PTH secretory patterns and temporal organization are similar to those in healthy young subjects and are not altered in states of low bone density or estrogen deficiency. This suggests that abnormalities in orderly pulsatile PTH secretion are unlikely to play a major role in established postmenopausal osteoporosis.

Adult↗

A seqlet-based maximum entropy Markov approach for protein secondary structure prediction.

A novel method for predicting the secondary structures of proteins from amino acid sequence has been presented. The protein secondary structure seqlets that are analogous to the words in natural language have been extracted. These seqlets will capture the relationship between amino acid sequence and the secondary structures of proteins and further form the protein secondary structure dictionary. To be elaborate, the dictionary is organism-specific. Protein secondary structure prediction is formulated as an integrated word segmentation and part of speech tagging problem. The word-lattice is used to represent the results of the word segmentation and the maximum entropy model is used to calculate the probability of a seqlet tagged as a certain secondary structure type. The method is markovian in the seqlets, permitting efficient exact calculation of the posterior probability distribution over all possible word segmentations and their tags by viterbi algorithm. The optimal segmentations and their tags are computed as the results of protein secondary structure prediction. The method is applied to predict the secondary structures of proteins of four organisms respectively and compared with the PHD method. The results show that the performance of this method is higher than that of PHD by about 3.9% Q3 accuracy and 4.6% SOV accuracy. Combining with the local similarity protein sequences that are obtained by BLAST can give better prediction. The method is also tested on the 50 CASP5 target proteins with Q3 accuracy 78.9% and SOV accuracy 77.1%. A web server for protein secondary structure prediction has been constructed which is available at http://www.insun.hit.edu.cn:81/demos/biology/index.html.

Algorithms↗

Multiresolution spot detection by means of entropy thresholding.

Many imaging applications deal with the detection of small targets or spots embedded within an inhomogeneous background. We present a method that accomplishes a multiresolution detection on the wavelet-transformed image. The targets are separated from the background by the exploitation of Renyi's information, which is evaluated at the different decomposition levels of the wavelet transform. The scale-dependent candidate detections are successively combined by means of majority voting for final detection. Connections with results provided in different fields such as multifractal analysis, generalized information measures in scale-space, and cross-entropy analysis in fine-to-coarse transformations are discussed. Detection performance is investigated through an example from medical image analysis.

Diagnostic Imaging↗

Contrast statistics for foveated visual systems: fixation selection by minimizing contrast entropy.

The human visual system combines a wide field of view with a high-resolution fovea and uses eye, head, and body movements to direct the fovea to potentially relevant locations in the visual scene. This strategy is sensible for a visual system with limited neural resources. However, for this strategy to be effective, the visual system needs sophisticated central mechanisms that efficiently exploit the varying spatial resolution of the retina. To gain insight into some of the design requirements of these central mechanisms, we have analyzed the effects of variable spatial resolution on local contrast in 300 calibrated natural images. Specifically, for each retinal eccentricity (which produces a certain effective level of blur), and for each value of local contrast observed at that eccentricity, we measured the probability distribution of the local contrast in the unblurred image. These conditional probability distributions can be regarded as posterior probability distributions for the "true" unblurred contrast, given an observed contrast at a given eccentricity. We find that these conditional probability distributions are adequately described by a few simple formulas. To explore how these statistics might be exploited by central perceptual mechanisms, we consider the task of selecting successive fixation points, where the goal on each fixation is to maximize total contrast information gained about the image (i.e., minimize total contrast uncertainty). We derive an entropy minimization algorithm and find that it performs optimally at reducing total contrast uncertainty and that it also works well at reducing the mean squared error between the original image and the image reconstructed from the multiple fixations. Our results show that measurements of local contrast alone could efficiently drive the scan paths of the eye when the goal is to gain as much information about the spatial structure of a scene as possible.

Algorithms↗

On the use of band-target entropy minimization to simplify the interpretation of two-dimensional correlation spectroscopy.

Two-dimensional (2D) correlation spectroscopy has been extensively applied to analyze various vibrational spectroscopic data, especially infrared and Raman. However, when it is applied to real-world experimental data, which often contains various imperfections (such as noise interference, baseline fluctuations, and band-shifting) and highly overlapping bands, many artifacts and misleading features in synchronous and asynchronous maps will emerge, and this will lead to difficulties with interpretation. Therefore, an approach that counters many artifacts and therefore leads to simplified interpretation of 2D correlation analysis is certainly useful. In the present contribution, band-target entropy minimization (BTEM) is employed as a spectral pretreatment to handle many of the artifact problems before the application of 2D correlation analysis. BTEM is employed to elucidate the pure component spectra of mixtures and their corresponding concentration profiles. Two alternate forms of analysis result. In the first, the normally vxv problem is converted to an equivalent nvxnv problem, where n represents the number of species present. In the second, the pure component spectra are transformed into simple distributions, and an equivalent and less computationally intensive nv'xnv' problem results (v'<v). In both cases, the separation of spectral contributions greatly simplifies interpretation of the 2D plots. This new approach is successfully applied to a solvent evaporation study where in situ Fourier transform infrared (FT-IR) spectroscopy is used as the analytical tool.

Acetophenones↗

Application of band-target entropy minimization to infrared emission spectroscopy and the reconstruction of pure component emissivities from thin films and liquid samples.

Thermal emission spectral data sets were collected for a thin solid film (parafilm) and a thin liquid film (isopropanol) on the interval of 298-348 K. The measurements were performed using a conventional Fourier transform infrared (FT-IR) spectrometer with external optical bench and in-house-designed emission cell. Both DTGS and MCT detectors were used. The data sets were analyzed with band-target entropy minimization (BTEM), which is a pure component spectral reconstruction program. Pure component emissivities of the parafilm, isopropanol, and thermal background were all recovered without any a priori information. Furthermore, the emissivities were obtained with increased signal-to-noise ratios, and the signals due to absorbance of thermal radiation by gas-phase moisture and CO2 were significantly reduced. As expected, the MCT results displayed better signal-to-noise ratios than the DTGS results, but the latter results were still rather impressive given the low temperatures used in this study. Comparison is made with spectral reconstruction using the orthogonal projection approach-alternating least squares (OPA-ALS) technique. This contribution introduces the primary equation for emission spectral reconstruction using BTEM and discusses some of the unusual characteristics of thermal emission and their impact on the analysis.

Algorithms↗

On side-chain conformational entropy of proteins.

The role of side-chain entropy (SCE) in protein folding has long been speculated about but is still not fully understood. Utilizing a newly developed Monte Carlo method, we conducted a systematic investigation of how the SCE relates to the size of the protein and how it differs among a protein's X-ray, NMR, and decoy structures. We estimated the SCE for a set of 675 nonhomologous proteins, and observed that there is a significant SCE for both exposed and buried residues for all these proteins-the contribution of buried residues approaches approximately 40% of the overall SCE. Furthermore, the SCE can be quite different for structures with similar compactness or even similar conformations. As a striking example, we found that proteins' X-ray structures appear to pack more "cleverly" than their NMR or decoy counterparts in the sense of retaining higher SCE while achieving comparable compactness, which suggests that the SCE plays an important role in favouring native protein structures. By including a SCE term in a simple free energy function, we can significantly improve the discrimination of native protein structures from decoys.

Algorithms↗

Approximate entropy of human respiratory movement during eye-closed waking and different sleep stages.

STUDY OBJECTIVE: The breath-to-breath variability of respiratory parameters changes with sleep stage. This study investigates any alteration in the approximate entropy (ApEn) of respiratory movement as a gauge of complexity in respiration, by stage of consciousness, in the light of putative brain interactions. PARTICIPANTS: Eight healthy men, who were between the ages of 23 and 29 years, were investigated. MEASUREMENTS AND RESULTS: The signals of chest wall movement and EEG were recorded from 10:30 PM to 6:00 AM. After analog-to-digital conversion, the ApEn of respiratory movement (3 min) and EEG (20 s) were computed. Surrogate data were tested for nonlinearity in the original time series. The most impressive reduction in the ApEn of respiratory movement was associated with stage IV sleep, when the ApEn of the EEG was also statistically significantly decreased. A statistically significant linear relation is found between the ApEn of both variables. Surrogate data indicated that respiratory movement had nonlinear properties during all stages of consciousness that were investigated. CONCLUSION: Respiratory movement and EEG signals are more regular during stage IV sleep than during other stages of consciousness. The change in complexity described by the ApEn of respiration depends in part on the ApEn of the EEG, suggesting the involvement of nonlinear dynamic processes in the coordination between brain and lungs.

Adult↗

Molecular dynamics simulations of duplex stretching reveal the importance of entropy in determining the biomechanical properties of DNA.

Advances in nanomanipulation techniques have made it possible to measure the response of an individual biomolecule to a force applied in the laboratory. Experiments that stretch a single molecule of duplex DNA have been difficult to interpret theoretically, particularly as the major changes in molecular structure caused by the force cannot be measured. In principle, computer simulation can calculate these conformational changes in atomic level detail, but to date such studies have failed to reproduce the experimental data due to the computational expense of the calculations. Here we show that a combination of molecular modeling and statistical physics can be used successfully to understand the stretching behavior of DNA. Our simulations provide new information about the dynamics of DNA denaturation under force in atomic level detail and also show the importance of entropy in determining biomechanical properties in general.

Biomechanical Phenomena↗

Entropy and barrier-controlled fluctuations determine conformational viscoelasticity of single biomolecules.

Biological macromolecules have complex and nontrivial energy landscapes, endowing them with a unique conformational adaptability and diversity in function. Hence, understanding the processes of elasticity and dissipation at the nanoscale is important to molecular biology and emerging fields such as nanotechnology. Here we analyze single molecule fluctuations in an atomic force microscope, using a generic model of biopolymer viscoelasticity that includes local "internal" conformational dissipation. Comparing two biopolymers, dextran and cellulose (polysaccharides with and without local bistable transitions), demonstrates that signatures of simple conformational change are minima in both the elastic and internal friction constants around a characteristic force. A novel analysis of dynamics on a bistable energy landscape provides a simple explanation: an elasticity driven by the entropy, and friction by a barrier-controlled hopping time of populations between states, which is surprisingly distinct to the well-known relaxation time. This nonequilibrium microscopic analysis thus provides a means of quantifying new dynamical features of the energy landscape of the glucopyranose ring, revealing an unexpected underlying roughness and information on the shape of the barrier of the chair-boat transition in dextran. The results presented herein provide a basis toward probing the viscoelasticity of macromolecular conformational transitions on more complex energy landscapes, such as during protein folding.

Biopolymers↗

Approximate Entropy as a measure of complexity in sap flow temporal dynamics of two tropical tree species under water deficit.

Approximate Entropy (ApEn), a model-independent statistics to quantify serial irregularities, was used to evaluate changes in sap flow temporal dynamics of two tropical species of trees subjected to water deficit. Water deficit induced a decrease in sap flow of G. ulmifolia, whereas C. legalis held stable their sap flow levels. Slight increases in time series complexity were observed in both species under drought condition. This study showed that ApEn could be used as a helpful tool to assess slight changes in temporal dynamics of physiological data, and to uncover some patterns of plant physiological responses to environmental stimuli.

Biological Transport↗

Characterization of surface EMG signals using improved approximate entropy.

An improved approximate entropy (ApEn) is presented and applied to characterize surface electromyography (sEMG) signals. In most previous experiments using nonlinear dynamic analysis, this certain processing was often confronted with the problem of insufficient data points and noisy circumstances, which led to unsatisfactory results. Compared with fractal dimension as well as the standard ApEn, the improved ApEn can extract information underlying sEMG signals more efficiently and accurately. The method introduced here can also be applied to other medium-sized and noisy physiological signals.

Algorithms↗