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A simple explanation for taxon abundance patterns.

For taxonomic levels higher than species, the abundance distributions of the number of subtaxa per taxon tend to approximate power laws but often show strong deviations from such laws. Previously, these deviations were attributed to finite-time effects in a continuous-time branching process at the generic level. Instead, we describe herein a simple discrete branching process that generates the observed distributions and find that the distribution's deviation from power law form is not caused by disequilibration, but rather that it is time independent and determined by the evolutionary properties of the taxa of interest. Our model predicts-with no free parameters-the rank-frequency distribution of the number of families in fossil marine animal orders obtained from the fossil record. We find that near power law distributions are statistically almost inevitable for taxa higher than species. The branching model also sheds light on species-abundance patterns, as well as on links between evolutionary processes, self-organized criticality, and fractals.

Animals↗

Contribution of antibody heavy chain CDR1 to digoxin binding analyzed by random mutagenesis of phage-displayed Fab 26-10.

We constructed a bacteriophage-displayed library containing randomized mutations at H chain residues 30-35 of the anti-digoxin antibody 26-10 Fab to investigate sequence constraints necessary for high affinity binding in an antibody of known crystal structure. Phage were selected by panning against digoxin and three C-16-substituted analogues. All antigen-positive mutants selected using other analogues also bound digoxin. Among 73 antigen-positive clones, 26 different nucleotide sequences were found. The majority of Fabs had high affinity for digoxin (Ka 3.4 x 10(9) M-1) despite wide sequence diversity. Two mutants displayed affinities 2- and 4-fold higher than the parental antibody. Analysis of the statistical distribution of sequences showed that highest affinity binding occurred with a restricted set of amino acid substitutions at positions H33-35. All clones save two retained the parental Asn-H35, which contacts hapten and hydrogen bonds to other binding site residues in the parental structure. Positions H30-32 display remarkable diversity, with 10-14 different substitutions for each residue, consistent with high affinity binding. Thus complementarity can be retained and even improved despite diversity in the conformation of the N-terminal portion of the H-CDR1 loop.

Amino Acid Sequence↗

Mechanism of inhibition of HIV-1 integrase by G-tetrad-forming oligonucleotides in Vitro.

The G-tetrad-forming oligonucleotides and have been identified as potent inhibitors of human immunodeficiency virus type 1 integrase (HIV-1 IN) activity (Rando, R. F., Ojwang, J., Elbaggari, A., Reyes, G. R., Tinder, R., McGrath, M. S., and Hogan, M. E. (1995) J. Biol. Chem. 270, 1754-1760; Mazumder, A., Neamati, N., Ojwang, J. O., Sunder, S., Rando, R. F., and Pommier, Y. (1996) Biochemistry 35, 13762-13771; Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). To understand the inhibition of HIV-1 IN activity by the G-quartet inhibitors, we have designed the oligonucleotides and, composed of three and four G-quartets with stem lengths of 19 and 24 A, respectively. The fact that increasing the G-quartet stem length from 15 to 24 A kept inhibition of HIV-1 IN activity unchanged suggests that the binding interaction occurs between a GTGT loop domain of the G-quartet inhibitors and a catalytic site of HIV-1 IN, referred to as a face-to-face interaction. Docking the NMR structure of (Jing and Hogan (1998)) into the x-ray structure of the core domain of HIV-1 IN, HIV-1 IN-(51-209) (Maignan, S., Guilloteau, J.-P. , Qing, Z.-L., Clement-Mella, C., and Mikol, V. (1998) J. Mol. Biol. 282, 359-368), was performed using the GRAMM program. The statistical distributions of hydrogen bonding between HIV-1 IN and were obtained from the analyses of 1000 random docking structures. The docking results show a high probability of interaction between the GTGT loop residues of the G-quartet inhibitors and the catalytic site of HIV-1 IN, in agreement with the experimental observation.

Base Composition↗

Histone octamer instability under single molecule experiment conditions.

We have studied the sample concentration-dependent and external stress-dependent stability of native and reconstituted nucleosomal arrays. Whereas upon stretching a single chromatin fiber in a solution of very low chromatin concentration the statistical distribution of DNA length released upon nucleosome unfolding shows only one population centered around approximately 25 nm, in nucleosome stabilizing conditions a second population with average length of approximately 50 nm was observed. Using radioactively labeled histone H3 and H2B, we demonstrate that upon lowering the chromatin concentration to very low values, first the linker histones are released, followed by the H2A-H2B dimer, whereas the H3-H4 tetramer remains stably attached to DNA even at the lowest concentration studied. The nucleosomal arrays reconstituted on a 5 S rDNA tandem repeat exhibited similar behavior. This suggests that the 25-nm disruption length is a consequence of the histone H2A-H2B dimer dissociation from the histone octamer. In nucleosome stabilizing conditions, a full approximately 145 bp is constrained in the nucleosome. Our data demonstrate that the nucleosome stability and histone octamer integrity can be severely degraded in experiments where the sample concentration is low.

Animals↗

Diffuse reflection from a stochastically bounded, semi-infinite medium.

In order to determine the diffuse reflection from a medium bounded by a rough surface, we consider the problem of radiative transfer in a boundary layer characterized by a statistical distribution of heights. For the case that the surface is defined by a multivariate normal probability density, we derive the propagation probability for rays traversing the boundary layer and, from that probability, a corresponding radiative transfer equation. A solution of the Eddington (two stream) type is found explicitly, and examples are given. The results should be applicable to reflection from the regoliths of solar system bodies, as well as from a rough ocean surface.

Astronomical Phenomena↗

Frequency responses of cat rapidly adapting mechanoreceptive fibers.

The frequency responses of 11 rapidly adapting (RA) fibers in cat were studied by representing the average firing rate as a function of sinusoidal stimulus amplitude and stimulus frequency. Specifically, rate-intensity functions at different stimulation frequencies were fitted by four-parameter (a0, a1, a2, a3), piece-wise linear functions using nonlinear regression (n = 59; R2 > 0.877). Rate-intensity functions at intermediate frequencies were found by linear interpolation. The result of this analysis is rate-amplitude-frequency functions plotted as two-dimensional surfaces. The surfaces consist of five regions separated and sufficiently defined by four space curves. At 14 different frequencies, the statistical distribution of each rate-intensity-function parameter could be approximated by a particular lognormal distribution (n = 56; R2 > 0.796). The Kolmogorov-Smirnov test fails to reject this hypothesis for each combination of frequency and parameter (56 tests; p > 0.39). Therefore, at a given frequency, the variation of the parameters can be represented by lognormal distributions with specific means and standard deviations. Responses of six RA fibers, which are different from the data-set used for modeling, were compared with the stochastic model at different frequencies. The parameters of those fibers were tested against the null hypotheses that they were sampled from the particular parameter distributions dictated by the model. The Kolmogorov-Smirnov test fails to reject all the hypotheses at the alpha = 0.05 level (44 tests). At the alpha = 0.10 level, only a few test parameters were found to be departing from the model (a0 and a1 at 5 Hz; a2 at 20 Hz; a2 and a3 at 50 Hz). The remaining test parameters could be accurately described by the model. Having confirmed the validity of the model, the logarithmic means and the logarithmic standard deviations of the lognormally distributed rate-intensity-function parameters were estimated in the frequency range of 4-200 Hz. The rate-amplitude-frequency surfaces sampled from the established stochastic model completely characterize the rate responses of RA fibers to sinusoidal stimuli and are superior to tuning curves which require selecting criterion responses. The current rate-response model is promising for future computational work, especially on population modeling.

Action Potentials↗

Decoupling functional mechanisms of adaptive encoding.

In a natural setting, adaptive mechanisms constantly modulate the encoding properties of sensory neurons in response to changes in the external environment. Recent experiments have revealed that adaptation affects both the spatiotemporal integration properties and baseline membrane potential of sensory neurons. However, the precise functional role of adaptation remains an open question, due in part to contradictory experimental results. Here, we develop a framework to characterize adaptive encoding, including a cascade model with a time-varying receptive field (reflecting spatiotemporal integration properties) and offset (reflecting baseline membrane potential), and a recursive technique for tracking changes in the model parameters during a single stimulus/response trial. Simulated and experimental responses from retinal neurons are used to track adaptive changes in receptive field structure and offset during nonstationary stimulation. Due to the nonlinear nature of spiking neurons, the parameters of the receptive field and offset must be estimated simultaneously, or changes in the offset (or even in the statistical distribution of the stimulus) can mask, confound, or create the illusion of adaptive changes in the receptive field. Our analysis suggests that these confounding effects may be at the root of the inconsistency in the literature and shows that seemingly conflicting experimental results can be reconciled within our framework.

Adaptation, Physiological↗

High energy radiation effects in single histones. I. Preparation of histones and irradiation of histone H2B.

Histone H2B from calf thymus was irradiated with 50 or 100 ns pulses of 16 MeV electrons in N2O-saturated aqueous solution at pH 9 in the presence of NaN3. All tyrosine moieties in the histone were found to be freely accessible to the attack of .N3 radicals (formed by the reaction .OH + N3(-)----OH- + .N3). At sufficiently high concentrations of H2B, tyrosyl radicals were formed with G(TyrO.) = 5.4/100 eV and dityrosine groups with G(dityr) = 1.6/100 eV, indicating that about 60 per cent of tyrosyl radicals formed bisphenolic products. There is no polymer effect with respect to G(dityr) as inferred from comparison with other authors' data obtained with low molecular weight compounds. Kinetic measurements revealed that tyrosyl radicals reacted in two modes, a fast one with a value of tau 1/2 of about several milliseconds and a slow second order process also in the millisecond range. The fast process is assigned to intramolecular reactions of tyrosyl radicals generated in close proximity to each other and the slow process to intermolecular self reactions of isolated tyrosyl radicals distributed statistically in the solution. There is a polymer effect with respect to the rate constant of the slow process: 2k8 = 4.8 X 10(7) dm3 mol-1 s-1 (H2B) and 2k8 = 4 X 10(8) dm3 mol-1 s-1 (Lys-Tyr-Lys, Prütz et al. (1983)). The five histones contained in calf thymus were isolated chromatographically with the aid of two gels, Bio-Gel P-60 (BioRad) and Sephadex G100 (Pharmacia).

Animals↗

Induction of IgG by lipid A in the newborn mouse.

IgG of paternal allotype first becomes detectable in the serum of (BALB/c x C57BL/6)F(1) mice between day 12 and 14 after birth and reaches adult levels at an age of 5 wk. Since in mice there is a transfer of maternal IgG molecules through the placenta and via milk, F(1) heterozygous at the allotype locus were used and the concentrations of IgG with paternal allotype were measured. This was done by a sensitive method capable of detecting IgG concentrations as low as 5 x 10(-4) of normal adult serum levels. It is based on the quantitative inhibition of allotype-specific facilitation of hemolysis. When lipid A or Salmonella bacteria were injected into neonatal mice, a stimulation of IgG synthesis was observed. Thus IgG levels were enhanced 10-30-fold compared to the nontreated mice. No increase in IgG levels was obtained in adult mice after treatment with lipid A. Whether the newborns were injected at birth, on day 2, 4, or 7, IgG was first demonstrable in the treated mice at an age of 6-11 days. The increase in IgG levels was not paralleled by a demonstrable antibody activity against lipid A, SRBC, and LPS. Thus the bulk of newly induced IgG is probably a statistical distribution of different specificities.

Animals↗

A search model and figure of merit for observer data acquired according to the free-response paradigm.

Search is a basic activity that is performed routinely in many different tasks. In the context of medical imaging it involves locating lesions in images under conditions of uncertainty regarding the number and locations of lesions that may be present. A search model is presented that applies to situations, as in the free-response paradigm, where on each image the number of normal regions that could be mistaken for lesions is unknown, and the number of observer generated localizations of suspicious regions (marks) is unpredictable. The search model is based on a two-stage model that has been proposed in the literature, according to which, at the first stage (the preattentive stage) the observer uses mainly peripheral vision to identify likely lesion candidates, and at the second stage the observer decides (i.e., cognitively evaluates) whether or not to report the candidates. The search model regards the unpredictable numbers of lesion and non-lesion localizations as random variables and models them via appropriate statistical distributions. The model has three parameters quantifying the lesion signal-to-noise ratio, the observer's expertise at rejecting non-lesion locations, and the observer's expertise at finding lesions. A figure-of-merit quantifying the observer's search performance is described. The search model bears a close resemblance to the initial detection and candidate analysis (IDCA) model that has been recently proposed for analysing computer aided detection (CAD) algorithms. The ability to analytically model and quantify the search process would enable more powerful assessment and optimization of performance in these activities, which could be highly significant.

Algorithms↗

Status of anthropometry and body composition data in elderly subjects.

Understanding the normal changes in the body and its composition with increasing old age and their health implications are important to the health care and nutritional support of elderly subjects. Distribution statistics for selected body measurements of persons aged 65-80 y are available from the national health surveys. Recumbent anthropometric techniques and B-mode ultrasound may be applicable to measuring those greater than 80 y who have difficulty standing or are chair- or bedfast. The problems of estimating body composition in elderly subjects could be improved by using a four-compartment model. Noninvasive methods, such as anthropometry and bioelectric impedance, could be used to predict body composition in elderly subjects if appropriate equations were available and validated against direct methods. The most pressing need is for the development of suitable reference data for anthropometry and body composition in large representative samples of black, white, Hispanic and Oriental elderly persons in the US.

Aged↗

The interval between successive cases of an infectious disease.

The interval between successive cases of an infectious disease is determined by the time from infection to infectiousness, the duration of infectiousness, the time from infection to disease onset (incubation period), the duration of any extra-human phase of the infectious agent, and the proportion clinically affected among infected individuals. The interval is important in the interpretation of infectious disease surveillance and trend data, in the identification of outbreaks, and in the optimization of quarantine and contact tracing. This paper discusses the properties of these intervals, as measured between transmission events or between clinical onsets of successive infected individuals, noting the determinants of their ranges and frequency distributions, the circumstances under which secondary cases may arise before primaries, and under which the infection transmission interval will be different from the interval between clinical onsets of successive cases. It discusses the derivation of interval distribution statistics from descriptive data given in standard textbooks, with illustrations from published data on outbreaks, households, and epidemiologic tracing. Finally, it discusses the implications of such measures for studies of secondary attack rates, for the persistence of infection in human communities, for outbreak response, and for elimination or eradication programs.

Communicable Diseases↗

Combining evidence using p-values: application to sequence homology searches.

MOTIVATION: To illustrate an intuitive and statistically valid method for combining independent sources of evidence that yields a p-value for the complete evidence, and to apply it to the problem of detecting simultaneous matches to multiple patterns in sequence homology searches. RESULTS: In sequence analysis, two or more (approximately) independent measures of the membership of a sequence (or sequence region) in some class are often available. We would like to estimate the likelihood of the sequence being a member of the class in view of all the available evidence. An example is estimating the significance of the observed match of a macromolecular sequence (DNA or protein) to a set of patterns (motifs) that characterize a biological sequence family. An intuitive way to do this is to express each piece of evidence as a p-value, and then use the product of these p-values as the measure of membership in the family. We derive a formula and algorithm (QFAST) for calculating the statistical distribution of the product of n independent p-values. We demonstrate that sorting sequences by this p-value effectively combines the information present in multiple motifs, leading to highly accurate and sensitive sequence homology searches.

Algorithms↗

Tactile exploration of shape after subcortical ischaemic infarction studied with PET.

We studied the cerebral activations related to restitution of hand function in five patients with first hemiplegic subcortical stroke due to ischaemic infarction in the area of the basal ganglia or thalamus. In two subjects, involvement of the cortico-spinal tract was demonstrated by magnetic evoked potentials. The subjects were requested to discriminate rectangular parallelepipeda of identical mass with their affected hands. Regional cerebral blood flow (rCBF) was measured with PET after intravenous bolus injection of [15O]butanol, at rest and during task execution. Evaluation of the rCBF changes was based on pixel-by-pixel t statistics of spatially standardized and averaged PET images and on a statistical distribution analysis of regions of interest in the individual subjects. For anatomical localization of the significant rCBF changes, a computerized brain atlas (Greitz et al. J Comput Assist Tomogr 1991; 15: 26-38) and a matching procedure that directly aligns individual PET and high resolution magnetic resonance images were used. The rCBF at rest and the task-induced rCBF changes varied from subject to subject, as did the residual neurological deficits at the time of PET scanning. In all subjects there were large activation areas in the motor and the sensory hand area contralateral to the affected hand. Poor performance of the task was correlated with a low rCBF in the contralateral sensorimotor cortex at rest and a bilateral activation of the primary sensorimotor cortex during task performance. The premotor cortex, ipsilateral and anterior cerebellum, contralateral to the affected hand, were also significantly activated. Further activations were observed in the contralateral premotor cortex, supplementary motor area and bilaterally in the posterior cingulate cortex, but were less consistent among the subjects. Our data suggest that recovery from hemiplegic stroke is associated with a marked reorganization of the cerebral activation patterns, including common and subject-specific activation sites. With respect to task-specific information processing a lower discrimination rate of objects compared with controls was associated with diminished activations in parietal lobe.

Adult↗

Handedness and hemispheric language dominance in healthy humans.

In most people the left hemisphere of the brain is dominant for language. Because of the increased incidence of atypical right-hemispheric language in left-handed neurological patients, a systematic association between handedness and dominance has long been suspected. To clarify the relationship between handedness and language dominance in healthy subjects, we measured lateralization directly by functional transcranial Doppler sonography in 326 healthy individuals using a word-generation task. The incidence of right-hemisphere language dominance was found to increase linearly with the degree of left-handedness, from 4% in strong right-handers (handedness = 100) to 15% in ambidextrous individuals and 27% in strong left-handers (handedness = -100). The relationship could be approximated by the formula: f1.gif" BORDER="0">. These results clearly demonstrate that the relationship between handedness and language dominance is not an artefact of cerebral pathology but a natural phenomenon.

Adolescent↗

Definition and estimation of higher-order gene fixation indices.

Fixation indices summarize the associations between genes that arise from the joint effects of inbreeding and selection. In this paper, fixation indices are derived for pairs, triplets and quadruplets of genes at a single multiallelic locus. The fixation indices are obtained by dividing cumulants by constants; the cumulants describe the statistical distribution of alleles and the constants are functions of gene frequency. The use of cumulants instead of moments is necessary only for four-gene indices, when the fourth cumulant is used. A second type of four-gene index is also required, and this index is based upon the covariation of second-order cumulants. At multiallelic loci, a large number of indices is possible. If alleles are selectively neutral, the number of indices is reduced and the relationship between gene identity and gene cumulants is shown.--Two-gene indices can always be estimated from genotypic frequency data at a single polymorphic locus. Three-gene indices are also estimable except when allele frequency equals one-half. Four-gene indices are not estimable unless selection is assumed to have an equal effect upon each allele (such as under selective neutrality) and the locus contains at least three alleles of unequal frequency. For diallelic or selected loci, an alternative four-gene fixation index is proposed. This index incorporates both types of four-gene associations but cannot be related to gene identity.

Alleles↗

Visualization of RecA filaments and DNA by fluorescence microscopy.

We have developed two experimental methods for observing Escherichia coli RecA-DNA filament under a fluorescence microscope. First, RecA-DNA filaments were visualized by immunofluorescence staining with anti-RecA monoclonal antibody. Although the detailed filament structures below submicron scale were unable to be measured accurately due to optical resolution limit, this method has an advantage to analyse a large number of RecA-DNA filaments in a single experiment. Thus, it provides a reliable statistical distribution of the filament morphology. Moreover, not only RecA filament, but also naked DNA region was visualized separately in combination with immunofluorescence staining using anti-DNA monoclonal antibody. Second, by using cysteine derivative RecA protein, RecA-DNA filament was directly labelled by fluorescent reagent, and was able to observe directly under a fluorescence microscope with its enzymatic activity maintained. We showed that the RecA-DNA filament disassembled in the direction from 5' to 3' of ssDNA as dATP hydrolysis proceeded.

DNA↗

A question of blood, race, and politics.

This article explores the political and intellectual context of a controversy arising from a proposal made at the 1959 meetings of the American Society of Blood Banks to divide the blood supply by race. The authors, a group of blood-bankers and surgeons in New York, outlined difficulties in finding compatible blood for transfusion during open-heart surgery, which they attributed to prior sensitization of their patient, a Caucasian, by a previous transfusion from an African American donor. Examining the statistical distribution of blood-group antigens among the various races, they concluded that risk of adverse hemolytic reactions and the cost of testing could be reduced by establishing separate donor pools. The media reported the suggestion, which, given the political climate of the day, rapidly became a public issue involving geneticists, blood-bankers, physical anthropologists, and the African American medical community. Liberals condemned it, whereas eugenically inclined segregationists used the finding to support their views concerning evolutionary distance between the races and the dangers of miscegenation. Here we examine the contribution of comparative racial serology to this affair, the arguments and background of the main players, and the relevance of the debate to discussions about the role of "race" in post-genomic medicine.

Blood Banks↗