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PubMed1998

[Evaluation of a linear TEOAE protocol in hearing screening of neonates: feasibility study].

The audiological screening of newborns based on recording TEOAEs--the expression of anatomical-functional integrity of the cochlea--has unanimously gained importance. The prevalence of severe of genetic or congenital hearing loss in the healthy infant population and in the population at risk for audiological disorders, as well as the consequent psycholinguist and socialization problems such children have to deal with, have led the authors to set up a preliminary protocol for the audiological screening of neonates. The purpose of this protocol is to improve the feasibility of applying such a program. To this purpose, the preliminary protocol called for the recording of the TEOAE in both non linear (NL) and linear (L) modes. Examination was performed in 347 newborns (30% of all the children born during 1997) the second day of life and during spontaneous sleep. The ILO 92 was used for the screening. The results obtained with the two methods were statistically compared using the 9 parameters considered response indicators. Using the linear method of a function-window and improving the signal-to-noise ratio, the study showed a significant difference in the quality of the TEOAE using the linear method as compared with the non linear method, although this did not modify response reliability. This lead to the definition, through free distribution statistical analysis, of broader than normal criteria by which to evaluate the responses evoked with the L method. All this is aimed at increasing system specificity and reducing the number of false positives which feeds family anxiety.

Acoustic Stimulation↗

PubMed1986

[Statistical patterns of the anomalous staining of 5-bromodeoxyuridine-substituted chromosomes].

Five large chromosome segments showing sometimes an abnormal staining were found in the genome of Chinese hamster (clone 237). Three types of abnormal staining were recorded. After one round of replication in the presence of BrdUrd these segments showed a hetero-staining, whereas after two rounds of replication the same segments showed iso-dark or iso-light staining. Pulse labeling with 3H-thymidine showed that all these segments were the late-replicating ones. The labeling proceeded according to all-or-none principle; in a given cell all five segments showed either presence or absence of the label. On the contrary, the abnormal staining was statistically distributed among these segments. These results are in disagreement with the current view that the abnormal staining is associated with asymmetrical distribution of thymine among two strands of DNA duplex. The above regularities are considered as an argument for the two-stranded model of chromosome.

Animals↗

PubMed1997

NMR analysis of main-chain conformational preferences in an unfolded fibronectin-binding protein.

A 130-residue fragment of the Staphylococcus aureus fibronectin-binding protein has been found to exist in a highly unfolded conformation at neutral pH. Measurement of experimental NMR 3JHNalpha coupling constants provides evidence for individual residues having distinct main-chain conformational preferences that are dependent both on the amino acid concerned and on neighbouring residues in the sequence. Analysis shows that these variations in the populations of individual residues can be explained in detail in terms of statistical distributions of conformational states derived from the protein data base. In particular, when the preceding residue has a beta-branched or aromatic side-chain, a significant increase occurs in the population of the less sterically restricted b region of phi,psi space. The results indicate that the local structure of the fibronectin binding protein in solution, under conditions where it displays full activity, approximates very closely to a statistical random coil structure. This may be an important feature in the biological role of this and other polypeptides involved in protein-protein interactions.

Adhesins, Bacterial↗

PubMed1984

Estimation of cumulative exposures to ethylene oxide associated with hospital sterilizer operation.

The statistical distribution of exposures to ethylene oxide was estimated for a task involving transfer of materials from a hospital sterilizer. The exposure data are consistent with either a normal or log-normal distribution. It is shown how the single-task distribution and the number of task repetitions can be used to determine the minimum differences in task repetitions necessary to distinguish for epidemiological purposes between worker groups on the basis of cumulative exposure.

Environmental Exposure↗

PubMed1998

Evaluation of bioequivalence of highly variable drugs using clinical trial simulations. II: Comparison of single and multiple-dose trials using AUC and Cmax.

PURPOSE: Evaluating of the effects of high intrasubject variability in clearance (CL) and volume of distribution (V), on 90% confidence intervals (CIs) for AUC (Area Under the concentration Curve) in single and multiple-dose bioequivalence studies. The main methodology was Monte Carlo simulation, and we also used deterministic simulation, and examination of clinical trials. The results are compared with those previously observed for Cmax (maximum concentration.) METHODS: The time course of drug concentration in plasma was simulated using a one-compartment model with log-normal statistical distributions of intersubject and intrasubject variabilities in the pharmacokinetic parameters. Both immediate-release and prolonged-release products were simulated using several levels of intrasubject variability in single-dose and multiple-dose studies. Simulations of 2000 clinical bioequivalence trials per condition (138 conditions) with 30 subjects in each crossover trial were carried out. Simulated data were compared with data from actual bioequivalence trials. RESULTS: The current simulations for AUC show similar probabilities of failure for single-dose and multiple-dose bioequivalence studies, even with differences in the rate of absorption or fraction absorbed. AUC values from prolonged-release scenario studies are more sensitive to changes in the first order absorption rate constant ka, and to variability in CL and V than AUC from studies of immediate-release studies. CONCLUSIONS: We showed that multiple-dose designs for highly variable drugs do not always reduce intrasubject variability in either AUC or Cmax, although the behavior of AUC differs from Cmax. Single dose AUC to the last quantifiable concentration was more reliable than either single dose AUC extrapolated to infinity, or multiple dose AUC during a steady-state interval. Multiple-dose designs may not be the best solution for assessing bioequivalence of highly variable drugs.

Area Under Curve↗

PubMed1994

A statistical analysis of side-chain conformations in proteins: comparison with ECEPP predictions.

A comparison of the statistical distributions of side-chain conformations of 17 amino acids (Gly, Ala, and Pro excluded), observed in 63 nonhomologous globular proteins (covering 10,832 residues), is made with similar distributions calculated from the low-energy conformational states for the same amino acids (blocked with acetyl and N-methylamide groups at the N- and C-termini, respectively) obtained by Vásquez et al. [(1983), Macromolecules 16, 1043-1049] using the ECEPP/2 force field. Those residues (i) with linear side chains (Arg, Lys, Met, Cys, Ser), or those that are unbranched through the gamma-carbon atom (Glu, Gln) show good agreement, whereas (ii) those with side chains that are branched at C beta or C gamma show poor agreement with ECEPP calculations. A possible explanation for this is shown to be the greater tendency for side-chain atoms in class (ii) to interact with the backbone and/or adjacent side chains. Accordingly, ECEPP/3 calculations, carried out after elongating the backbone chain of the model peptide unit (by adding three Ala residues on each side of the central residue, and then blocking the termini as before), result in distributions that are often closer to the observed side-chain distributions. The implications of these results for the relative importance of short-range versus long-range interactions in determining protein structure are discussed.

Amino Acids↗

PubMed1987

The galactose-specific receptor system in rat liver during development.

The number and distribution of galactose-specific binding sites were investigated in rat liver cells during perinatal development. Ligand binding to hepatocytes, macrophages and endothelial cells was followed with in vitro and in situ experiments by electron microscopy, using lactosylated bovine serum albumin adsorbed onto 5 nm colloidal gold particles as ligand. Binding capacity, starting at a late stage of fetal development, is very low both on the hepatocyte and on the macrophage surface, which show single particles statistically distributed. By contrast, bound particles are absent from fetal endothelial cells, which also lack the typical coated regions. In vivo, experiments at 37 degrees C show that endocytosis occurs to some extent in prenatal life. These results indicate that the expression of galactose-specific receptors' activity on the different liver cell types follows different developmental patterns, which are independently modulated.

Animals↗

PubMed1989

Marked regional heterogeneity in blood flow within a single skeletal muscle at rest and during exercise hyperaemia in the rabbit.

In 1985 both Pendergast et al. and Piiper et al. described a major regional heterogeneity in blood flow within single skeletal muscles both at rest and during exercise. Based on the microsphere method they described large variations in blood flow between muscle samples as large as 1 g each. The aims of the present study were: (1) To test this notion of regional heterogeneity in microsphere deposition within single skeletal muscles both at rest and during exercise. (2) To compare the distribution of microspheres with other blood flow tracers. (3) To test whether or not any heterogeneity was due to vasomotion in small arteries or arterioles. Microspheres were infused into anaesthetized rabbits over either 10, 30 or 120 s, or 10 min. Exercise was mimicked by tetanic contractions obtained by electrical stimulation of the motor nerves. Three hindleg muscles were divided into samples of 0.25 g each. Regional heterogeneity was expressed as the coefficient of variation corrected for statistical distribution of microspheres (CVc). The CVc at rest was about 0.34. The CVc was unaffected by the various infusion periods and did not change during exercise. Simultaneous infusions of microspheres and 86Rb+ or antipyrine gave high correlations between the two blood flow tracers, with all r values exceeding 0.83 (n = 18). We conclude that the microsphere method provides reliable estimates for regional blood flow within single skeletal muscles. The distribution of blood flow was markedly heterogeneous both at rest and during exercise. The heterogeneity in blood flow was apparently not a result of vasomotion.

Animals↗

PubMed1981

Development of statistical analysis for single dose bronchodilators.

When measurements developed for the diagnosis of patients are used to detect treatment effects in clinical trials with chronic disease, problems in definition of response and in the statistical distributions of those measurements within patients have to be resolved before the results of clinical studies can be analyzed. An example of this process is shown in the development of the analysis of single-dose bronchodilator trials.

Bronchodilator Agents↗

PubMedDate not supplied

Fluorescence microscopic observation of catalysis by single or few LDH-1 enzyme molecules.

Lactate dehydrogenase (LDH-1) catalyzes the reaction of lactate and nonfluorescent NAD+ to pyruvate, NADH (fluorescence at lambda em = 455 nm, lambda em = 365 nm) and H+. The injection of highly diluted LDH-1 solution into a drop of substrate solution results in the formation of a bubble of enzyme inside the drop of substrate. At the contact surface between the enzyme solution and the substrate, discrete and statistically distributed zones of increasing fluorescence intensity and different size can be observed after enzyme injection. These zones can be interpreted as clouds of NADH around a single or a few enzyme molecules. The kinetics of the NADH formation in every fluorescent zone, and the size of the zone, can be described by a zero order production combined with a diffusion controlled loss of the reaction's product NADH from the reaction zone. From the dilution of the enzyme solution and from statistical analysis one can conclude that only few enzyme molecules in the center of the fluorescent reaction zones catalyze the NADH formation.

Catalysis↗

PubMed1998

Method to assist in the scheduling of add-on surgical cases--upper prediction bounds for surgical case durations based on the log-normal distribution.

BACKGROUND: A problem that operating room (OR) managers face in running an OR suite on the day of surgery is to identify "holes" in the OR schedule in which to assign "add-on" cases. This process necessitates knowing the typical and maximum amounts of time that the case is likely to require. The OR manager may know previous case durations for the particular surgeon performing a particular scheduled procedure. The "upper prediction bound" specifies with a certain probability that the duration of the surgeon's next case will be less than or equal to the bound. METHODS: Prediction bounds were calculated by using methods that (1) do not assume that case durations follow a specific statistical distribution or (2) assume that case durations follow a log-normal distribution. These bounds were tested using durations of 48,847 cases based on 15,574 combinations of scheduled surgeon and procedure. RESULTS: Despite having 3 yr of data, 80 or 90% prediction bounds would not be able to be calculated using the distribution-free method for 35 or 49% of future cases versus 22 or 22% for the log-normal method, respectively. Prediction bounds based on the log-normal distribution overestimated the desired value less often than did the distribution-free method. The chance that the duration of the next case would be less than or equal to its 90% bound based on the log-normal distribution was within 2% of the expected rate. CONCLUSIONS: Prediction bounds classified by scheduled surgeon and procedure can be accurately calculated using a method that assumes that case durations follow a log-normal distribution.

Algorithms↗

PubMed1995

Pol gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy.

The nucleotide sequences of two pol gene regions (codons 41 to 108 and 181 to 219 of reverse transcriptase) of 60 human immunodeficiency virus type 1 genomes obtained directly from primary lymphocytes from infected individuals are reported. In addition, the mutant spectra of several quasispecies have been sampled by repetitive sequencing of molecular clones representing the same pol genomic regions. Average mutation frequencies ranged from 1.6 x 10(-2) to 3.4 x 10(-2) substitutions per nucleotide for independent samples (relative to their consensus nucleotide sequence) and from 3.6 x 10(-3) to 1.1 x 10(-2) substitutions per nucleotide for individual quasispecies distributions. Several mutations leading to amino acid substitutions related to loss of sensitivity to reverse transcriptase inhibitors have been identified in samples from patients not subjected to antiretroviral therapy. Mutation frequencies in the codons previously identified as involved in resistance to reverse transcriptase inhibitors were very similar to the average mutation frequencies in the pol region analyzed. Thus, the finding of mutations related to drug resistance (even in the absence of positive selection by the corresponding drugs) is the expected consequence of the statistical distribution of mutations along the pol gene. The presence of such critical amino acid replacements in human immunodeficiency virus type 1 populations underscores the importance of viral quasispecies as reservoirs of phenotypic virus variants and has a number of implications for AIDS control.

Amino Acid Sequence↗

PubMed1996

Probabilistic assessment of health risks of methylmercury from burning coal.

This paper describes a probabilistic assessment of neurological risks incurred from consuming fish containing methylmercury (MeHg), focusing on the incremental effects of Hg deposited from local coal combustion. A Monte Carlo model is used to simulate a "worst case" scenario in which a population of 5000 fish eaters in the upper midwestern United States derive the freshwater fish portion of their diet from local waters near a hypothetical large coal-fired power plant. This population is characterized by distributions of body mass, half-life of MeHg, and the ratios of blood to body burden and hair to blood MeHg. Each person's diet consists of varying amounts of tuna fish, freshwater sportfish, and marine fish and shellfish, the MeHg contents of which are characterized by national distribution statistics, as are the consumption rates for marine fish. The consumption rates for freshwater fish are specific to the region. The fish portion size is linked to body mass by a variable correlation. Each meal is assumed to be an independent sample; thus, as metabolic equilibrium is approached, each person's body burden of MeHg tends to approach the value corresponding to the mean MeHg intake for the population. Predictions of MeHg levels in hair by this model compared well with an observed distribution of 1437 women. Two neurological endpoints were examined: adult paresthesia, as related to MeHg body burden, and congenital neurological effects, as associated with average concentrations of MeHg in maternal hair during pregnancy. Two exposure scenarios are considered: a "baseline" in which the source of the mercury in fish is from background atmospheric deposition, and an "impact" scenario, in which local Hg deposition and concentrations in fish are roughly doubled to represent additional deposition from the hypothetical nearby power plant. For both scenarios, the 99th percentile of MeHg body burden was more than an order of magnitude below the lowest level at which increased transient adult paresthesia was experienced in an acute MeHg poisoning incident in Iraq. We thus conclude that neurological risks to adults from MeHg resulting from atmospheric Hg deposition are trivial. Based on three epidemiological studies of congenital neurological risks, we find that fetal effects appear to be more critical and that there is a smaller margin of safety for pregnant consumers of freshwater sportfish. However, the margin of safety is still considerable and may have been diminished by uncertainties in the relationships between maternal hair Hg and the actual fetal exposures.

Adult↗

PubMed1999

Selective assembly of cyclodextrins on poly(ethylene oxide)-poly(propylene oxide) block copolymers.

This paper presents a computational study on the formation of a molecular necklace formed by specific threading of cyclodextrins (CDs) on block copolymers. Structural as well as energetic principles for the selective complexation of alpha- and beta-cyclodextrin with poly(ethylene oxide)-poly(propylene oxide) block copolymers (PEO-PPO) are elucidated considering a diblock copolymer of equimolecular composition (PEO)4-(PPO)4 as guest. A non-statistical distribution of CDs, i.e. alpha-CDs primarily located on the PEO chain and beta-CDs on PPO blocks of the polymer, is based on a variety of structural features and energetic preferences considering both potential as well as solvation energies. This selectivity becomes already obvious considering 1:1 complexes between PEO and PPO monomers and the two CDs, but is increasingly evident when calculating higher order ensembles. Besides the host-guest interaction, docking between CDs themselves is an important, also non-statistical, prerequisite for the self-assembly of highly ordered tubes. The formation of intermolecular hydrogen bonds between adjacent CDs in a tubular aggregate gives an important contribution to the overall stability of the molecular necklace. The net effect, based on the preferential interaction between host and guest as well as between the host molecules themselves, results in the formation of a stable, highly ordered macromolecular, multicomponent aggregate.

Cyclodextrins↗

PubMed1981

Analysis of the spatial organization of the cell: a statistical method for revealing the non-random location of an organelle.

A method is proposed for testing the randomness of the location of an organelle within a given area of a cell section. The approach chosen is to analyse the distance between this organelle and a specific point considered as a point of reference. The method consists of converting this distance into the ratio of one given area to another and comparing the statistical distribution of the converted values to the uniform distribution. This method has the advantage of being valid in the absence of any restrictive assumptions concerning the heterogeneity in size and/or shape of the collection of sections sampled. Detailed examples are given to illustrate the practical use of the method, and its possible extensions are discussed.

Cell Nucleolus↗

PubMed1997

Advances in statistical methods to map quantitative trait loci in outbred populations.

Statistical methods to map quantitative trait loci (QTL) in outbred populations are reviewed, extensions and applications to human and plant genetic data are indicated, and areas for further research are identified. Simple and computationally inexpensive methods include (multiple) linear regression of phenotype on marker genotypes and regression of squared phenotypic differences among relative pairs on estimated proportions of identity-by-descent at a locus. These methods are less suited for genetic parameter estimation in outbred populations but allow the determination of test statistic distributions via simulation or data permutation; however, further inferences including confidence intervals of QTL location require the use of Monte Carlo or bootstrap sampling techniques. A method which is intermediate in computational requirements is residual maximum likelihood (REML) with a covariance matrix of random QTL effects conditional on information from multiple linked markers. Testing for the number of QTLs on a chromosome is difficult in a classical framework. The computationally most demanding methods are maximum likelihood and Bayesian analysis, which take account of the distribution of multilocus marker-QTL genotypes on a pedigree and permit investigators to fit different models of variation at the QTL. The Bayesian analysis includes the number of QTLs on a chromosome as an unknown.

Bayes Theorem↗

PubMed1995

The mutational demography of protein C deficiency.

The geographical distribution and prevalence of 256 single base-pair substitutions (105 of them being different) within the coding region of the human protein C (PROC) gene were correlated with their initial likelihoods of generation. A significant positive correlation was observed between these "mutational likelihoods" and the geographical dispersal of the PROC gene lesions within and between 16 different countries. This relationship could be attributed to the fact that, with few exceptions, high dispersal was only exhibited by CG-->TG and CG-->CA transitions, i.e. those substitutions that are known to arise de novo at the highest frequency. The statistical distribution of mutational likelihoods was as predicted on the basis of the PROC cDNA sequence alone, allowing however for the redundancy of the genetic code. These findings suggest (1) that genetic drift and lesion-specific selection have been of relatively minor importance in determining the mutational spectrum observed in the PROC gene and (2) that most multiple reports of particular substitutions in different geographical locations appear to reflect recurrent mutation rather than identity-by-descent.

Blood Coagulation Disorders↗

PubMed2000

Learning overcomplete representations.

In an overcomplete basis, the number of basis vectors is greater than the dimensionality of the input, and the representation of an input is not a unique combination of basis vectors. Overcomplete representations have been advocated because they have greater robustness in the presence of noise, can be sparser, and can have greater flexibility in matching structure in the data. Overcomplete codes have also been proposed as a model of some of the response properties of neurons in primary visual cortex. Previous work has focused on finding the best representation of a signal using a fixed overcomplete basis (or dictionary). We present an algorithm for learning an overcomplete basis by viewing it as probabilistic model of the observed data. We show that overcomplete bases can yield a better approximation of the underlying statistical distribution of the data and can thus lead to greater coding efficiency. This can be viewed as a generalization of the technique of independent component analysis and provides a method for Bayesian reconstruction of signals in the presence of noise and for blind source separation when there are more sources than mixtures.

Algorithms↗