Quantifying exploration in reward-based motor learning.

Exploration in reward-based motor learning is observable in experimental data as increased variability. In order to quantify exploration, we compare three methods for estimating other sources of variability: sensorimotor noise. We use a task in which participants could receive stochastic binary reward feedback following a target-directed weight shift. Participants first performed six baseline blocks without feedback, and next twenty blocks alternating with and without feedback. Variability was assessed based on trial-to-trial changes in movement endpoint. We estimated sensorimotor noise by the median squared trial-to-trial change in movement endpoint for trials in which no exploration is expected. We identified three types of such trials: trials in baseline blocks, trials in the blocks without feedback, and rewarded trials in the blocks with feedback. We estimated exploration by the median squared trial-to-trial change following non-rewarded trials minus sensorimotor noise. As expected, variability was larger following non-rewarded trials than following rewarded trials. This indicates that our reward-based weight-shifting task successfully induced exploration. Most importantly, our three estimates of sensorimotor noise differed: the estimate based on rewarded trials was significantly lower than the estimates based on the two types of trials without feedback. Consequently, the estimates of exploration also differed. We conclude that the quantification of exploration depends critically on the type of trials used to estimate sensorimotor noise. We recommend the use of variability following rewarded trials.

The quantitative measure and statistical distribution of fame.

Fame and celebrity play an ever-increasing role in our culture. However, despite the cultural and economic importance of fame and its gradations, there exists no consensus method for quantifying the fame of an individual, or of comparing that of two individuals. We argue that, even if fame is difficult to measure with precision, one may develop useful metrics for fame that correlate well with intuition and that remain reasonably stable over time. Using datasets of recently deceased individuals who were highly renowned, we have evaluated several internet-based methods for quantifying fame. We find that some widely-used internet-derived metrics, such as search engine results, correlate poorly with human subject judgments of fame. However other metrics exist that agree well with human judgments and appear to offer workable, easily accessible measures of fame. Using such a metric we perform a preliminary investigation of the statistical distribution of fame, which has some of the power law character seen in other natural and social phenomena such as landslides and market crashes. In order to demonstrate how such findings can generate quantitative insight into celebrity culture, we assess some folk ideas regarding the frequency distribution and apparent clustering of celebrity deaths.

Elevated congenital anomaly rates and incorporated cesium-137 in the Polissia region of Ukraine.

BACKGROUND: Investigations soon after the 1986 Chornobyl (Chernobyl in Russian) accident of exposed populations residing elsewhere in Europe led government and international agencies to conclude that exposures to cesium-137 (Cs-137) were not teratogenic. Our observations of elevated population rates of neural tube defects (NTDs) and microcephaly and microphthalmia (M/M) in the Rivne Province in Ukraine, which were among the highest in Europe, prompted this follow-up investigation inclusive of whole-body counts (WBCs) of Cs-137 among ambulatory patients and pregnant women residing in Polissia, the most polluted region in Rivne. METHODS: Yearly (2000-2012) population rates of NTDs and M/M and WBC patterns of ambulatory patients (2001-2010) and pregnant women (2011-2013) in Polissia and non-Polissia regions of Rivne were analyzed. RESULTS: The NTD and M/M population rates in Rivne remain elevated and are statistically significantly higher in Polissia than in non-Polissia. The WBCs among residents in Polissia are statistically significantly higher than among those from non-Polissia. CONCLUSION: NTD and M/M rates are highest in the Polissia region of Rivne and are among the highest in Europe. In Polissia, the WBCs of Cs-137 are above officially set permissible upper limits. The results are based on aggregate data of NTDs and M/Ms and average WBC values. Further investigations of causality of the high rates of NTDs and M/Ms are needed and urgent strengthening policies and implementations to reduce exposures to teratogens, in particular radioactive nuclides and alcohol, and consumption of folic acid supplements are indicated.

Characterisation of non-constant background in counting measurements.

A 'moving-target' method for characterising background in a counting measurement in which the instantaneous background count rate is a function of time, rather than being fixed, is proposed. This model treats the average Poisson mean in observation period P as coming from a gamma distribution with parameters αP and ßP. This model is applied to a large dataset of replicate observations, consisting of 242 (234)U method blank measurements collected over a 2-y period. Point estimates of the model parameters are determined by comparing the mean and variance of the observed data and by maximising the likelihood function. Posterior distributions of the parameters are obtained by Markov Chain Monte Carlo. Assuming time-invariant fluctuations of the background count rate, the variation of the instantaneous count rate is described by a correlation function, which can be interpreted as describing how rapidly the background changes with time, or how likely the background is to change between measurements. An 'exponential-correlation' model of background time dependence is proposed, with parameters α, ß and correlation time τ. Once determined, these parameters fully describe the distribution of background, just as NB and TB in the fixed-target model.

An alternative approach to confidence interval estimation for the win ratio statistic.

Pocock et al. (2012, European Heart Journal 33, 176-182) proposed a win ratio approach to analyzing composite endpoints comprised of outcomes with different clinical priorities. In this article, we establish a statistical framework for this approach. We derive the null hypothesis and propose a closed-form variance estimator for the win ratio statistic in all pairwise matching situation. Our simulation study shows that the proposed variance estimator performs well regardless of the magnitude of treatment effect size and the type of the joint distribution of the outcomes.

Forecasting of the selected features of Poaceae (R. Br.) Barnh., Artemisia L. and Ambrosia L. pollen season in Szczecin, north-western Poland, using Gumbel's distribution.

INTRODUCTION AND OBJECTIVES: The allergenic pollen content of the atmosphere varies according to climate, biogeography and vegetation. Minimisation of the pollen allergy symptoms is related to the possibility of avoidance of large doses of the allergen. Measurements performed in Szczecin over a period of 13 years (2000-2012 inclusive) permitted prediction of theoretical maximum concentrations of pollen grains and their probability for the pollen season of Poaceae, Artemisia and Ambrosia. Moreover, the probabilities were determined of a given date as the beginning of the pollen season, the date of the maximum pollen count, Seasonal Pollen Index value and the number of days with pollen count above threshold values. MATERIALS AND METHODS: Aerobiological monitoring was conducted using a Hirst volumetric trap (Lanzoni VPPS). Linear trend with determination coefficient (R(2)) was calculated. Model for long-term forecasting was performed by the method based on Gumbel's distribution. RESULTS: A statistically significant negative correlation was determined between the duration of pollen season of Poaceae and Artemisia and the Seasonal Pollen Index value. Seasonal, total pollen counts of Artemisia and Ambrosia showed a strong and statistically significant decreasing tendency. On the basis of Gumbel's distribution, a model was proposed for Szczecin, allowing prediction of the probabilities of the maximum pollen count values that can appear once in e.g. 5, 10 or 100 years. CONCLUSIONS: Short pollen seasons are characterised by a higher intensity of pollination than long ones. Prediction of the maximum pollen count values, dates of the pollen season beginning, and the number of days with pollen count above the threshold, on the basis of Gumbel's distribution, is expected to lead to improvement in the prophylaxis and therapy of persons allergic to pollen.

Protein-protein interaction site predictions with three-dimensional probability distributions of interacting atoms on protein surfaces.

Protein-protein interactions are key to many biological processes. Computational methodologies devised to predict protein-protein interaction (PPI) sites on protein surfaces are important tools in providing insights into the biological functions of proteins and in developing therapeutics targeting the protein-protein interaction sites. One of the general features of PPI sites is that the core regions from the two interacting protein surfaces are complementary to each other, similar to the interior of proteins in packing density and in the physicochemical nature of the amino acid composition. In this work, we simulated the physicochemical complementarities by constructing three-dimensional probability density maps of non-covalent interacting atoms on the protein surfaces. The interacting probabilities were derived from the interior of known structures. Machine learning algorithms were applied to learn the characteristic patterns of the probability density maps specific to the PPI sites. The trained predictors for PPI sites were cross-validated with the training cases (consisting of 432 proteins) and were tested on an independent dataset (consisting of 142 proteins). The residue-based Matthews correlation coefficient for the independent test set was 0.423; the accuracy, precision, sensitivity, specificity were 0.753, 0.519, 0.677, and 0.779 respectively. The benchmark results indicate that the optimized machine learning models are among the best predictors in identifying PPI sites on protein surfaces. In particular, the PPI site prediction accuracy increases with increasing size of the PPI site and with increasing hydrophobicity in amino acid composition of the PPI interface; the core interface regions are more likely to be recognized with high prediction confidence. The results indicate that the physicochemical complementarity patterns on protein surfaces are important determinants in PPIs, and a substantial portion of the PPI sites can be predicted correctly with the physicochemical complementarity features based on the non-covalent interaction data derived from protein interiors.

[Investigation on the relationship between the solar term of onset and syndrome types in 430 patients with acute myocardial infarction by circular statistical analysis].

OBJECTIVE: To study the relationship between the solar term of onset of acute myocardial infarction (AMI) and its syndrome types in traditional Chinese medicine (TCM). METHODS: The clinical data about 430 patients with AMI hospitalized in Foshan Hospital of TCM from February 4th 2003 (Beginning of Spring) to February 3rd 2008 (Beginning of Spring) were collected, and the solar term of onset as angle coordinate was regarded, then the peak phase of the onset solar term in each syndrome type of AMI was calculated by circular statistical analysis. RESULTS: Among 430 patients with AMI, 134 patients were considered to have qi stagnancy and blood stasis syndrome, 188 patients showed the syndrome of turbid sputum obstruction, 29 of them showed deficiency of yin-blood, and 79 showed deficiency of yang qi. The clinical manifestation of AMI was mainly asthenia syndrome (qi stagnancy and blood stasis+turbid sputum obstruction, 74.9%). According to the circular statistical analysis, the peak of the solar terms of AMI onset occurred at the Beginning of Spring in all cases (r=0.127 4, P<0.01), and standard deviation (s)=116.300 6 degree angle, showed it mainly occurred in winter and spring. As the peak of the onset of qi stagnancy and blood stasis occurred at Winter Solstice and Lesser Cold (r=0.200 5, P<0.01), its peak occurred in winter; the turbid sputum obstruction syndrome occurred at Spring Equinox (r=0.147 0, P<0.05), mainly in spring, yet the symptoms of above two peaks were generally mild. Besides, there was no significant difference in onset of the solar term in regard to onset of deficiency of yin-blood and deficiency of yang qi (both P>0.05). CONCLUSION: There is a close relationship between periodicity of the solar terms and onset of AMI. The main treatment for AMI is to expel turbid sputum, activate blood to resolve stasis and promote blood circulation to relieve pain; also the method of activating blood to resolve stasis is frequently contemplated in winter, and the method of expelling turbid sputum is the main strategy in spring.

Confidence intervals for random effects meta-analysis and robustness to publication bias.

The DerSimonian-Laird confidence interval for the average treatment effect in meta-analysis is widely used in practice when there is heterogeneity between studies. However, it is well known that its coverage probability (the probability that the interval actually includes the true value) can be substantially below the target level of 95 per cent. It can also be very sensitive to publication bias. In this paper, we propose a new confidence interval that has better coverage than the DerSimonian-Laird method, and that is less sensitive to publication bias. The key idea is to note that fixed effects estimates are less sensitive to such biases than random effects estimates, since they put relatively more weight on the larger studies and relatively less weight on the smaller studies. Whereas the DerSimonian-Laird interval is centred on a random effects estimate, we centre our confidence interval on a fixed effects estimate, but allow for heterogeneity by including an assessment of the extra uncertainty induced by the random effects setting. Properties of the resulting confidence interval are studied by simulation and compared with other random effects confidence intervals that have been proposed in the literature. An example is briefly discussed.

Statistical distribution of amino acid sequences: a proof of Darwinian evolution.

MOTIVATION: The article presents results of the listing of the quantity of amino acids, dipeptides and tripeptides for all proteins available in the UNIPROT-TREMBL database and the listing for selected species and enzymes. UNIPROT-TREMBL contains protein sequences associated with computationally generated annotations and large-scale functional characterization. Due to the distinct metabolic pathways of amino acid syntheses and their physicochemical properties, the quantities of subpeptides in proteins vary. We have proved that the distribution of amino acids, dipeptides and tripeptides is statistical which confirms that the evolutionary biodiversity development model is subject to the theory of independent events. It seems interesting that certain short peptide combinations occur relatively rarely or even not at all. First, it confirms the Darwinian theory of evolution and second, it opens up opportunities for designing pharmaceuticals among rarely represented short peptide combinations. Furthermore, an innovative approach to the mass analysis of bioinformatic data is presented. CONTACT: eitner@amu.edu.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ordinal regression models for continuous scales.

Ordinal regression analysis is a convenient tool for analyzing ordinal response variables in the presence of covariates. In this paper we extend this methodology to the case of continuous self-rating scales such as the Visual Analog Scale (VAS) used in pain assessment, or the Linear Analog Self-Assessment (LASA) scales in quality of life studies. These scales measure subjects' perception of an intangible quantity, and cannot be handled as ratio variables because of their inherent nonlinearity. We express the likelihood in terms of a function connecting the scale with an underlying continuous latent variable and approximate this function either parametrically or non-parametrically. Then a general semi-parametric regression framework for continuous scales is developed. Two data sets have been analyzed to compare our method to the standard discrete ordinal regression model, and the parametric to the non-parametric versions of the model. The first data set uses VAS data from a study on the efficacy of low-level laser therapy in the treatment of chronic neck pain; the second comes from a study on chemotherapy treatments in advanced breast cancer and looks at the impact of different drugs on patients' quality of life. The continuous formulation of the ordinal regression model has the advantage of no loss of precision due to categorization of the scores and no arbitrary choice of the number and boundaries of categories. The semi-parametric form of the model makes it a flexible method for analysis of continuous ordinal scales.

Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord-blood-derived neutrophils.

Fish oil supplementation has been shown to reduce neutrophil production of inflammatory LTB4 (leukotriene B4) in adults. The present study is the first to examine the effects on neonatal neutrophil function following supplementation in pregnancy. Pregnant women with allergic disease (n=98) were randomized to receive either fish oil [3.7 g of n-3 long-chain PUFAs (polyunsaturated fatty acids)/day] or a placebo supplement for the final 20 weeks of pregnancy. Leukotriene production by neonatal neutrophils was measured after stimulation with the calcium ionophore A23187. This was examined in relation to supplementation, cell membrane fatty acid levels and mononuclear cytokine production. Neutrophil LTB4 production was significantly reduced in neonates whose mothers had received fish oil in pregnancy. This was most evident for isomer 2 of LTB4 (P=0.031), although this was also observed for total LTB4 (P=0.051) and isomer 1 (P=0.088). There was also a trend for lower production of other PUFA metabolites, namely 5-HETE (5-hydroxyeicosatetraenoic acid; P=0.054) in the fish oil group. Accordingly, LTB4 levels were inversely related to membrane n-3 PUFA levels. Less inflammatory products (LTB5) were only produced at very low levels, although there was a trend for higher levels of this metabolite in the fish oil group. Consistent with this, LTB5 levels were positively correlated with n-3 PUFA membrane levels, particularly EPA (eicosapentanoic acid) and negatively correlated with n-6 PUFAs. Neonates with lower neutrophil LTB4 production also had lower production of pro-inflammatory IL (interleukin)-6 responses (r=0.35, P=0.005) and regulatory IL-10 responses (r=0.37, P=0.003) by LPS (lipopolysaccharide)-stimulated neonatal mononuclear cells. In conclusion, maternal dietary changes can modify neonatal neutrophil function. This has implications for the early immune programming, which can be influenced by the inflammatory milieu of local tissues during initial antigen encounter. It also provides evidence of another pathway through which long-chain PUFAs status can influence early immune development.

Model-based segmentation of medical imagery by matching distributions.

The segmentation of deformable objects from three-dimensional (3-D) images is an important and challenging problem, especially in the context of medical imagery. We present a new segmentation algorithm based on matching probability distributions of photometric variables that incorporates learned shape and appearance models for the objects of interest. The main innovation over similar approaches is that there is no need to compute a pixelwise correspondence between the model and the image. This allows for a fast, principled algorithm. We present promising results on difficult imagery for 3-D computed tomography images of the male pelvis for the purpose of image-guided radiotherapy of the prostate.

Does socio-demographic status influence the effect of pollens and molds on hospitalization for asthma? Results from a time-series study in 10 Canadian cities.

PURPOSE: Social status influences asthma morbidity but the mechanisms are not well understood. To determine if sociodemographics influence the susceptibility to ambient aeroallergens, we determined the association between daily hospitalizations for asthma and daily concentrations of ambient pollens and molds in 10 large Canadian cities. METHODS: Daily time-series analyses were performed and results were adjusted for day of the week, temperature, barometric pressure, relative humidity, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide. Results were then stratified by age, gender, and neighborhood family education and income. RESULTS: There appeared to be age and gender interactions in the relation between aeroallergens and asthma. An increase in basidiomycetes equivalent to its mean value, about 300/m3, increased asthma admissions for younger males (under 13 years of age) by 9.3% (95% CI, 4.8%, 13.8%) vs. 4.2% (95% CI, - 0.1%, 8.5%) for older males. The reverse was true among females with increased effect in the older age group: 2.3% (95% CI, 1.2%, 5.8%) in those under 13 years vs. 7.1% (95% CI, 4.1%, 10.1%) for older females. Associations were seen between aeroallergens and asthma hospitalization in the lowest but not the highest education group. CONCLUSIONS: Our results suggest that younger males and those within less educated families may be more vulnerable to aeroallergens as reflected by hospitalization for asthma.

Fisher information matrix of the Dirichlet-multinomial distribution.

In this paper we derive explicit expressions for the elements of the exact Fisher information matrix of the Dirichlet-multinomial distribution. We show that exact calculation is based on the beta-binomial probability function rather than that of the Dirichlet-multinomial and this makes the exact calculation quite easy. The exact results are expected to be useful for the calculation of standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters for data that arise in practice in toxicology and other similar fields. Standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters, based on the exact and the asymptotic Fisher information matrix based on the Dirichlet distribution, are obtained for a set of data from Haseman and Soares (1976), a dataset from Mosimann (1962) and a more recent dataset from Chen, Kodell, Howe and Gaylor (1991). There is substantial difference between the standard errors of the estimates based on the exact Fisher information matrix and those based on the asymptotic Fisher information matrix.

Multidelayed random walks: theory and application to the neolithic transition in Europe.

We present a model in which particles (or individuals of a biological population) disperse with a rest time between consecutive motions (or migrations) which may take several possible values from a discrete set. Particles (or individuals) may also react (or reproduce). We derive a new equation for the effective rest time T of the random walk. Application to the neolithic transition in Europe makes it possible to derive more realistic theoretical values for its wavefront speed than those following from the single-delayed framework presented previously [J. Fort and V. Méndez, Phys. Rev. Lett. 82, 867 (1999)]. The new results are consistent with the archaeological observations of this important historical process.

Functional inference from non-random distributions of conserved predicted transcription factor binding sites.

MOTIVATION: Our understanding of how genes are regulated in a concerted fashion is still limited. Especially, complex phenomena like cell cycle regulation in multicellular organisms are poorly understood. Therefore, we investigated conserved predicted transcription factor binding sites (TFBSs) in man-mouse upstream regions of genes that can be associated to a particular cell cycle phase in HeLa cells. TFBSs were predicted from selected binding site motifs (represented by position weight matrices, PWMs) based on a statistical approach. A regulatory role for a transcription factor is more probable if its predicted TFBSs are enriched in upstream regions of genes, that are associated with a subset of cell cycle phases. We tested for this association by computing exact P-values for the observed phase distributions under the null distribution defined by the relative amount of conserved upstream sequence of genes per cell cycle phase. We considered non-exonic and 5'-untranslated region (5'-UTR) binding sites separately and corrected for multiple testing by taking the false discovery rate into account. RESULTS: We identified 22 non-exonic and 11 5'-UTR significant PWM phase distributions although expecting one false discovery. Many of the corresponding transcription factors (e.g. members of the thyroid hormone/retinoid receptor subfamily) have already been associated with cell cycle regulation, proliferation and development. It appears that our method is a suitable tool for detecting putative cell cycle regulators in the realm of known human transcription factors. AVAILABILITY: Further details and supplementary data can be obtained from http://corg.molgen.mpg.de/cellcycle

Boltzmann-type distribution of side-chain conformation in proteins.

We analyze packing imperfections in globular proteins as reflected in deviations of torsion angles from the equilibrium values for the isolated side chains. The distribution of conformations of methionine and lysine residues in a database of high-resolution structures is compared with energies of model compounds calculated with high-level quantum-mechanics. The distribution of the C-C and C-S torsion angles (chi(3)) correlates well with the Boltzmann factor of the torsion energy, exp(-betaE) of the model compounds C(2)H(5)-C(2)H(5) and C(2)H(5)-S-CH(3). An exponential relation was again found between the relative occurrence of g+, g- and t conformations for C(alpha)-C(beta) bonds in long side chains and the energy differences of rotamers of alpha-amino n-butyric acid, when dependence on backbone conformation was taken into account. The distribution of all 27 rotamers of methionine was correlated with the energy differences between the model's rotamers, corrected for clashes with nearby residues, the correlation being good for a set with backbone in the beta-conformation, but less clear for backbone alpha-conformation. In all correlations, the value of the coefficient beta corresponds to a temperature of circa 300 K. These results can be interpreted with a model that considers the structure of a folded protein as resulting from packing imperfectly complementary parts, with a requirement of an overall low energy. Compromises are required to optimize the fit of nonbonded contacts with surrounding groups, and side chains assume conformations away from the energy minimum. An exponential distribution is a most probable distribution, and this can be established easily under conditions other than thermal equilibrium.

Natural variation for seed oil composition in Arabidopsis thaliana.

The biochemical pathways involved in the biosynthesis and accumulation of storage lipids in seeds have been extensively studied. However, the regulatory mechanisms of those pathways, their environmental interactions and the ecological implications of variation are poorly understood. We have initiated a new approach: the analysis of natural variation in Arabidopsis thaliana. Three hundred and sixty accessions were surveyed for content of oil, very long chain fatty acids (VLCFAs) and polyunsaturated fatty acids (PUFAs) in their seeds. The results revealed extensive natural variation. A core set of accessions, the seeds of which reproducibly contain extreme amounts of oil, VLCFAs and PUFAs have been identified. Reproducible oil content ranged from 34.6 to 46.0% of seed dry weight. VLCFA content ranged from 13.0 to 21.2% of total fatty acids. PUFA content, ranged from 53.3 to 66.1% of total fatty acids. Interactions were also identified for PUFA and VLCFA content of seeds with vernalisation of plants. Mapping of the regions of the genome involved in controlling the traits was conducted in an F(2) population and indicated that natural variation at the loci FAE1 and FAD3 might be involved in the regulation of VLCFA and PUFA content, respectively. A set of accessions, which capture a broad range of the natural variation for these traits available in A. thaliana, has been selected to form a core set which can be used to further dissect the genetics of the regulation of seed lipid traits and to identify the genes involved.

Processivity of the single-headed kinesin KIF1A through biased binding to tubulin.

Conventional isoforms of the motor protein kinesin behave functionally not as 'single molecules' but as 'two molecules' paired. This dimeric structure poses a barrier to solving its mechanism. To overcome this problem, we used an unconventional kinesin KIF1A (refs 5, 6) as a model molecule. KIF1A moves processively as an independent monomer, and can also work synergistically as a functional dimer. Here we show, by measuring its movement with an optical trapping system, that a single ATP hydrolysis triggers a single stepping movement of a single KIF1A monomer. The step size is distributed stochastically around multiples of 8 nm with a gaussian-like envelope and a standard deviation of 15 nm. On average, the step is directional to the microtubule's plus-end against a load force of up to 0.15 pN. As the source for this directional movement, we show that KIF1A moves to the microtubule's plus-end by approximately 3 nm on average on binding to the microtubule, presumably by preferential binding to tubulin on the plus-end side. We propose a simple physical formulation to explain the movement of KIF1A.