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Geographical and ecological analyses of childhood Wilms' tumours and soft-tissue sarcomas in North West England.

The aim of this paper was to study the geographical distribution of Wilms' tumours (WT) and soft-tissue sarcomas (STS) for 0-14 year olds included in a population-based registry from North West England during 1976-2000. Standardised morbidity ratios (SMRs) were calculated. Relationships between incidence rates and small area (ward) population density, ethnic composition, deprivation index and urban-rural status were examined using Poisson regression. There was a non-linear relationship between WT incidence and population density (P=0.008), with a higher incidence associated with wards with low deprivation scores (P=0.02); and which included a greater proportion of whites (P=0.01). For STS, a higher incidence was associated with wards with low deprivation scores (P=0.04); and which were 'more rural/less urban' (P=0.03). These results are consistent with a role for localised environmental exposures, in combination with lifestyle factors, in the aetiology of WT. For STS, there is some evidence for the involvement of environmental and/or lifestyle factors.

Adolescent↗

GB virus C infection in children with perinatal human immunodeficiency virus infection.

BACKGROUND: GB virus C (GBV-C) infection occurs in 20-40% of human immunodeficiency virus (HIV)-infected adults, and coinfection is associated with improved HIV disease outcome. METHODS: To determine the prevalence of GBV-C infection in children who were perinatally infected with HIV, we conducted a cross-sectional prevalence survey in a cohort of perinatally infected HIV-positive children selected from a large, multicenter observational protocol. A blood specimen was obtained and tested for GBV-C viremia with the use of a qualitative GBV-C RNA assay and screened for past GBV-C infection with enzyme-linked immunosorbent assay to detect antibodies to the GBV-C envelope protein E2 (E2 Ab). RESULTS: The 354 children who participated in the substudy were relatively healthy, with a median CD4 of 784 cells/mm and median HIV-1 viral load of 1055 copies/mL. The prevalence of GBV-C viremia was 20 of 353 or 5.7% (95% confidence interval, 3.5-8.6%), and the prevalence of E2 Ab was 12 of 354 or 3.4% (95% confidence interval, 1.8-5.8%). GBV-C viremic patients were older than patients without past GBV-C infection (median age, 12.8 years versus 10.7 years). Median CD4 lymphocyte counts were highest in subjects without GBV-C infection and lowest in those with E2 Ab. CONCLUSIONS: GBV-C prevalence rates are lower in children with perinatal HIV infection than those reported for HIV-infected adults. With the exception of evidence that GBV-C viremic children had lower rates of Centers for Disease Control and Prevention HIV disease category C disease before GBV-C testing, we did not find evidence of improved HIV disease outcome in coinfected patients, but the number of HIV/GBV-C-coinfected children was small.

AIDS-Related Opportunistic Infections↗

The polymerase chain reaction and branching processes.

We construct a mathematical model for the polymerase chain reaction and its mutations using the theory of branching processes. Under this model we study the number of mutations in a randomly chosen sequence after n PCR cycles. A method for estimating the mutation is proposed and the variance of this estimator is studied. We also study the distribution of the Hamming distance between two randomly chosen sequences and a method for estimating the mutation rate based on pairwise differences is proposed.

Base Sequence↗

Does gestational age in combination with birthweight provide better statistical adjustment of neonatal mortality rates than birthweight alone?

Between-area comparisons of neonatal mortality rates should be adjusted for differences in the underlying mortality risk. The traditional approach to this problem is to adjust neonatal mortality rates statistically for between-area differences in the birthweight distributions. However, in other types of perinatal research, birthweight is usually considered in combination with gestational age. For between-area comparisons of neonatal mortality rates, some researchers have argued that ad-justment by gestational age in addition to birthweight might not be necessary. This present study used graphical methods based on a non-parametric version of Poisson regression to underline the importance of examining neonatal mortality rates by both gestational age and birthweight. Six years of data from a whole-population database (Queensland Perinatal Data Collection) were used. The analysis also illustrates the value of non-parametric modelling in perinatal epidemiology.

Birth Weight↗

On fluctuation analysis: a new, simple and efficient method for computing the expected number of mutants.

Fluctuation analysis, which is often used to demonstrate random mutagenesis in cell lines (and to estimate mutation rates), is based on the properties of a probability distribution known as the Luria-Delbrück distribution (and its generalizations). The two main new results reported in this paper are (i) a simple, completely general, and computationally efficient procedure for calculating probability distributions arising from fluctuation analysis and (ii) the formula for this procedure when cells in a colony have only grown for a finite number of generations after initial seeding. It is also shown that the procedure reduces to one that was developed earlier when an infinite number of generations is assumed. The derivation of the generating function of the distribution is also clarified. The results obtained should also be useful to experimentalists when only a relatively short time elapses between seeding and harvesting cultures for fluctuation analysis.

Cell Line↗

Population dynamics, demographic stochasticity, and the evolution of cooperation.

A basic evolutionary problem posed by the Iterated Prisoner's Dilemma game is to understand when the paradigmatic cooperative strategy Tit-for-Tat can invade a population of pure defectors. Deterministically, this is impossible. We consider the role of demographic stochasticity by embedding the Iterated Prisoner's Dilemma into a population dynamic framework. Tit-for-Tat can invade a population of defectors when their dynamics exhibit short episodes of high population densities with subsequent crashes and long low density periods with strong genetic drift. Such dynamics tend to have reddened power spectra and temporal distributions of population size that are asymmetric and skewed toward low densities. The results indicate that ecological dynamics are important for evolutionary shifts between adaptive peaks.

Biological Evolution↗

Look-back investigation after human immunodeficiency virus seroconversion in a pediatric dentist.

Routine military screening identified human immunodeficiency virus (HIV) infection in an asymptomatic dentist who had three prior negative antibody tests. A look-back investigation evaluated the provider and the practice and provided notification, counseling, and HIV testing for patients. Test results were linked to dental procedures categorized by levels of invasiveness. Of 1631 patients tested, all were negative for antibody to HIV. Analysis of 12,164 procedures on 876 patients determined 20.5% of patients had procedures from the highest stratum of invasiveness; 42% had only low-risk exposure. Stratification of the degree of invasive exposure and clinical evaluation of disease stage in the infected health care worker are important in look-back investigations. The early stage of disease in the provider, the adherence to infection control precautions, and the low percentage of invasive procedures may have contributed to the lack of transmission. These results are consistent with current assessment that risk of transmission of HIV during invasive medical procedures is low.

Adult↗

Uncertainty in most probable number calculations for microbiological assays.

Microbiological assays commonly use incubations of multiple tubes in a dilution series, and microorganism concentration is read as a most probable number (MPN) in standard tables for the observed pattern of positive tubes. Published MPN tables differ, sometimes substantially, because of use of approximate MPN calculation procedures, different rounding conventions in the results, and different methods of calculating confidence or credible intervals. We conclude that the first 2 issues can now be resolved by using recently developed exact MPN calculation methods and by reporting rounding conventions in standard tables. The third issue is not amenable to complete resolution, especially if credible interval (as opposed to confidence interval) limits are desired--as we think they most often are. In that case, Bayesian statistics are called for and the analyst must provide a distribution of concentration that was presumed to be true before the assay was performed. This is mathematically combined with the assay data, resulting in a posterior concentration distribution. These distributions may then be used to quantify the uncertainty in the MPN estimate, and the best approach is to use the highest posterior density regions of these distributions. If based on diffuse prior information (positing that, prior to an assay being performed, all positive concentrations are equally likely), then established procedures might be used to calculate the limits and publish them in standard tables. In the event that this prior assumption is held to be not satisfactory, we show results for an empirical Bayes procedure, with a Poisson prior distribution, giving credible interval widths much narrower than in the other cases examined.

Bayes Theorem↗

Effects of variance in mini amplitude on stimulus-evoked release: a comparison of two models.

The strength of synaptic connections between two neurons is characterized by the number of release sites (N) on the presynaptic cell, the probability (p) of transmitter release at those sites in response to a stimulus, and the average size (A) of the postsynaptic response from each site. Quantal analysis can determine N, p, and A, but the large variance in the amplitudes of minis at central synapses is predicted to obscure quantal peaks and render quantal analysis unusable. Recently it has been suggested that the variance in mini amplitude is generated by differences between release sites, rather than by quantum-to-quantum fluctuations at identical sites, and that this form of variance in mini amplitude reduces the amount of variance expected in quantal peaks. Using simulations, we examine the possibility of resolving quantal peaks assuming either form of variance in mini amplitude. We find that individual quantal peaks are resolvable in neither case, provided that the uniquantal distribution is similar to the mini distribution. Because this lack of resolution compromises the utility of quantal analysis, we develop a general description that can solve N and p, given the statistical parameters of the mini distribution and the evoked distribution. We find that this description is relatively insensitive to the source of variance in mini amplitude.

Analysis of Variance↗

Monte Carlo simulation of bifurcation in the intracellular viral kinetics.

Intracellular viral kinetics are of special interest because the virion population inside an infected cell is well known to tend to grow exponentially and the corresponding kinetics may be unstable. To clarify the special features of such kinetics, we present Monte Carlo simulations taking into account the key steps of virion formation and competition of the host and viral mRNA for the host translation apparatus. Asymptotically, the model employed predicts either a stable steady state or 'ignition' with the unlimited viral growth. Under steady-state conditions, the mean square fluctuations of the viral genome and virion numbers are found to be appreciably larger than those expected on the basis of the Poissonian distribution. In the case of unstable kinetics, the simulations show the type of deviations from the corresponding mean-field results.

Algorithms↗

Values of "S," , and <(z1)2> for dosimetry using alpha-particle emitters.

In a recent paper [J. Nucl. Med. 38, 1923-1929 (1997)], the authors presented a dosimetry system which combines the computational ease of the MIRD schema with additional information provided by microdosimetry for use with alpha-particle emitters. In addition to the absorbed dose (average specific energy) to the targets (cell nuclei), this system gives the spread (standard deviation) in values of this specific energy received by individual targets. It also gives the fraction of targets receiving zero (or any number of) hits. In this paper, input quantities are presented for alpha-particle energies and cell and nuclear sizes appropriate for the radionuclides being investigated. The quantities include S values for the usual determination of the absorbed dose along with the microdosimetric quantities, and <(z1)2>, the average and average square, respectively, of the single-hit specific energy. Using analytical procedures described previously [Med. Phys. 19, 1385-1393 (1992)], the single-hit distributions of specific energy are determined for the given alpha-particle energies, source locations, and target sizes. From these distributions, the values for the input quantities are calculated. Sources considered are (1) those located inside and on the surface of the target cell and an unbounded source in the medium external to the cell; (2) those distributed uniformly on either side of a plane boundary or on the surface of the plane with a spherical target at various distances from the plane; and (3) those located either inside or on the surface of a spherical boundary centered externally to the target. Examples show how the input quantities are used to provide the spread in specific-energy values and the probability of any number of hits for nuclei of cells exposed to these sources. Thus a complete micro-dosimetric analysis involving the calculation of multi-hit specific energy distributions is not necessary to provide this information. Such information may be useful in interpreting the biological response due to alpha-particle emitters.

Alpha Particles↗

What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?

Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole.

Brain↗

The distribution of inhaled particles in aerosol measurements of pulmonary airspace size.

When the deposition of aerosol boluses is used to estimate mean pulmonary airspace size, an implicit assumption is made that the inhaled particles are distributed uniformly among normal and diseased lung regions. This assumption was examined in a series of dogs in which emphysema was experimentally induced by exposure to papain. After the experimental disease had developed for several weeks, boluses of fluorescent particles were inhaled, using a breathing pattern similar to that used for aerosol measurements of airspace size. The lungs were then excised and 18-20 tissue blocks were obtained from each lung. A section from each tissue block was analyzed to determine the mean liner intercept (Lm), which was considered as an index of lung injury. In the same sections, the density of particles was determined by counting particles in a number of microscopic fields and dividing the particle count by the number of fields sampled. Correlation analysis generally revealed a negative correlation of particle density with Lm, indicating fewer particles being delivered to diseased regions. One lung, however, showed a positive correlation between particle density and Lm. Correction for the fractional deposition of aerosol in the lung regions weakened but did not reverse the relationship between particle density and Lm. A model calculation of the effect of the observed nonuniform distribution of aerosol on the determination of airspace size found a negligible effect of uneven ventilation on mean airspace size determination in this experimental preparation.

Administration, Inhalation↗

A model of the magnetic fields created by single motor unit compound action potentials in skeletal muscle.

We have developed a computationally simple model for calculating the magnetic-field strength at a point due to a single motor unit compound action potential (SMUCAP). The motor unit is defined only in terms of its anatomical features, and the SMUCAP is approximated using the tripole model. The distributed current density J is calculated within the volume defined by the motor unit. The law of Biot and Savart can then be cast in a form necessitating that J be integrated only over the region containing current sources or conductivity boundaries. The magnetic-field strength is defined as the summation of the contributions to the field made by every muscle fiber in the motor unit. Applying this model to SMUCAP measurements obtained using a high-resolution SUper Conducting Quantum Interference Device (SQUID) magnetometer may yield information regarding the distribution of action currents (AC's) and the anatomical properties of single motor units within a muscle bundle.

Action Potentials↗

Models for association in bivariate survival data.

This paper reviews dependence models for bivariate survival data, classifying them into the four groups: the shock model, the Freund model, the Clayton model, and the mixture model. The paper then concentrates on the mixture model, discussing the testing problem for the equality of marginal distributions under the Weibull type baseline hazard assumption. The new test proposed recently by Fujii is introduced, and its characteristic is studied with respect to the test proposed by Nayak and the sign test by simulation study.

Humans↗

Congenital malformations and childhood cancer.

BACKGROUND: We investigated the epidemiology of congenital malformations and childhood cancer. PROCEDURE: By employing the cases of the Registry of Childhood Malignancies in Hokkaido Prefecture, Japan, from 1969 to 1996, the numbers of malignancies in cases (diagnosis at 0-14 years of age) with Down syndrome (DS), mental retardation (MR) excluding DS, luxatio coxae congenita (LCC), congenital heart disease (CHD) excluding DS, undescended testicle (UT), and cleft palate-lip (CPL) were calculated. Using the percentages of malignancies in the 2,349 cases without malformation, expected numbers of malignancies in the cases with the malformations were calculated. The observed numbers were statistically compared to expected ones. RESULTS: In the DS cases, leukemia developed with a significantly high frequency, but no UT cases developed leukemia. No brain tumor was preceded by DS. This could not be explained only by early death from coexisting diseases such as CHD, insofar as the CHD cases without DS developed brain tumors more frequently than expected. The ratio of acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) was different among the malformations. The MR cases developed ANLL more frequently than expected, whereas the CPL cases developed ALL more frequently. The distribution of the age at diagnosis for Wilms' tumor was different according to the underlying malformation. CONCLUSIONS: Malformations might have some factors that inhibit or delay as well as promote the development of certain malignancies.

Adolescent↗

Mortality and causes of death of 513 Danish patients with systemic lupus erythematosus.

A multicentre cohort of 513 clinic attenders with systemic lupus erythematosus (SLE) was retrospectively identified, representing 4185 patient-years of follow-up. Expected numbers of death were calculated by means of age- and sex-specific mortality rates of the general Danish population. The observed number of deaths was 122. The survival rates were 97%, 91%, 76%, 64% and 53% after 1, 5, 10, 15, and 20 years respectively. The overall mortality rate was 2.9% per year (95% CI 2.4-3.5), and the standardized mortality rate (SMR) was 4.6 (95% CI 3.8-5.5). The causes of death included active SLE (n = 19), end stage organ failure due to SLE (n = 16), infections (n = 25), malignancy (n = 9), cardiovascular disease (n = 32), and other causes (n = 21). SLE was directly related to one third of the excess mortality. In conclusion, SLE patients in the present cohort had a 4.6-fold increased mortality compared with the general population and half of the deaths were caused by SLE manifestations or infections, especially in young patients during the early period of the disease.

Adolescent↗

Adjusting SIDS rates by seasonality in births in Minnesota.

This paper is concerned with the formation of sudden infant death syndrome (SIDS) rates over time. Because of differential numbers of births throughout the year, a new SIDS rate is developed that takes into account the changing number of infants at risk and in particular the changing age distribution throughout the year. Differences between this newly adjusted rate and the commonly used unadjusted rates will be presented. Data from Minnesota linked birth--death records from 1990--1998 will be used for analysis.

Birth Certificates↗