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PubMed1999

Two stage model for carcinogenesis: number and size distributions of premalignant clones in longitudinal studies.

The two stage clonal expansion model of carcinogenesis provides a convenient biologically based framework for the description of toxicologic and epidemiologic data on carcinogenesis. Under this model, a cancer cell is generated following the occurrence of two critical mutations in a single stem cell. Initiated cells that have sustained the first mutation undergo a stochastic birth-death process resulting in clonal expansion of the initiated cell population. In this article, we consider the analysis of longitudinal data on the number and size of premalignant clones, formed by clonal expansion of initiated cells. In particular, the joint distribution of the number of premalignant clones observed at different points in time in the same subject is derived. The application of these results in the statistical analysis of longitudinal data on the number and size of premalignant clones observed in initiation-promotion experiments is indicated.

Animals↗
PubMed1998

Impact of spatial distribution of permethrin-impregnated bed nets on child mortality in rural northern Ghana.

Effects of the distribution in space of permethrin (insecticide)-impregnated bed nets (IIBNS) on child mortality were studied in a randomized controlled trial of IIBNs in a an area highly endemic for Plasmodium falciparum malaria in rural northern Ghana. Eight hundred sixty-two deaths occurred among children 6-59 months of age during 16,841 child-years-at-risk. Mortality increased with the distance from health facilities but not with proximity to identifiable anopheline breeding sites (reservoirs). The efficacy of IIBNs was independent of these distances. Mortality in users of IIBNs was independent of the proximity of nonusers, and mortality rates of nonusers and users living close to each other were similar. Poisson regression estimated a 6.7% increase in mortality among nonusers with each 100-m shift away from the nearest compound with IIBNS, indicating that the insecticide protects nearby nonusers. High coverage of IIBNs achieves maximum impact, but users of IIBNs offer some protection to less fortunate neighbors if coverage is incomplete.

Animals↗
PubMedDate not supplied

Spatial distribution of neurons in tissue culture wells: implications for sampling methods to estimate population size.

Many laboratory procedures require the counting of cells in culture. While many cultured cells may be counted by automated methods, neuronal cultures often require manual cell counting methods that are prohibitively time-consuming. This paper examines methods of sampling from tissue culture wells for estimating total cell counts. Performance of sampling and estimation schemes will depend in part on how the cells distribute themselves within a well. Spatial statistical analysis techniques are applied to the known total number and distribution of neurons in two wells counted in a grid scheme to demonstrate some important features of the neuron distributional patterns. Based on these two wells and simulated realizations from other point processes, a new sampling and estimation technique using open wedge-shaped sampling regions radiating from the centre of the well is proposed. This method is shown to result in more accurate estimates of the total number of neurons in the well than standard methods.

Animals↗
PubMed1999

Modelling of location- and time-dependent deformation of chondrocytes during cartilage loading.

Experimental evidence suggests that the biosynthetic activity of chondrocytes is regulated primarily by the mechanical environment. In order to study the mechanisms underlying remodeling, adaptation, and degeneration of articular cartilage in a joint subjected to changing loads, it is important to know the time-dependent fluid pressure and stress-strain state in chondrocytes. The purpose of the present study was to develop a theoretical model to simulate the mechanical behaviour of articular cartilage and to describe the time-dependent stress-strain state and fluid pressure distribution in chondrocytes during cartilage deformation. It was assumed that the volume occupied by the chondrocytes is small and that cartilage can be treated as a macroscopically homogenized material with effective material properties which depend on the material properties of the cells and matrix and the volumetric fraction of the cells. Model predictions on the time-dependent distribution of fluid pressure and stress and on the time-dependent cell deformation during confined and unconfined compression tests agree with previous theoretical predictions and experimental observations. The proposed model supplies the tools to study the mechanisms of degeneration, adaptation and remodelling of cartilage associated with cell loading and deformation.

Adaptation, Physiological↗
PubMed2003

Modelling the epidemic of variant Creutzfeldt-Jakob disease in the UK based on age characteristics: updated, detailed analysis.

Incubation period of the new variant Creutzfeldt-Jakob disease (vCJD) from infection to clinical onset and the eventual impact of the disease remain major concerns. Based on i) epidemiological conceptualization of human exposure to BSE contaminated material, ii) exponentially decreasing susceptibility after 15 years of age, and iii) typical incubation period (IP) distributions for time from infection to onset, we have previously estimated mean incubation period and projected number of vCJD cases. In this paper, we investigate the robustness of these estimates with respect to i-iii using the UK's 113 vCJD cases with clinical onset before December 2000. Mean incubation period was estimated at 16.4 years (95% CI 11.4-24.8), 15.9 years (95% CI 11.4-22.0), 14.1 years (95% CI 10.4-24.2) with the log-normal, Gamma and Weibull distributions respectively. Corresponding predictions for the total size of the epidemic ranged from 183 to 304. Maximal susceptibility to infection between 1.3 and 15.9 years and decreasing by 15% per year of age thereafter yielded the best fit. The shape of the IP distribution did not affect the predictions. In summary, within a set of reasonable assumptions, mean incubation period for vCJD ranged from 15 to 20 years, and the eventual impact of vCJD was a few hundred patients.

Age Factors↗
PubMed2003

Intussusception-associated hospitalization among Venezuelan infants during 1998 through 2001: anticipating rotavirus vaccines.

BACKGROUND: The first licensed rotavirus vaccine was withdrawn from use in the United States because of a low risk of intussusception. Consequently tests of new rotavirus vaccines will require some baseline knowledge of the rates and treatment of intussusception in countries where these vaccines will be tested. Therefore the objective of this study was to assess hospitalization rates and describe the epidemiologic and clinical characteristics of intussusception in Carabobo, Venezuela. METHODS: This study reviewed hospital data and clinical records of pediatric patients with intussusception admitted to eight hospitals in Carabobo between January 1, 1998 and December 31, 2001. RESULTS: For the 4-year period the average annual hospitalization rate for intussusception among infants (<1 year old) in Carabobo was 35 per 100 000 infants per year (range, 22 to 44), and intussusception was more common among boys (58 per 100 000 infants per year) than girls (29 per 100 000 infants per year) (P = 0.006). One of 67 cases occurred in the first 3 months of life (0 to 2), 55% (37) patients were 3 to 5 months old, 31% (21) were 6 to 11 months old and 12% (8) were > or =12 months old. Surgical reduction was required in 88% (52 of 59) of infants but only 1 required bowel resection. The monthly distribution of intussusception-associated hospitalizations showed no consistent seasonal pattern with the seasonality observed for patients hospitalized with rotavirus disease. CONCLUSIONS: This study provides some data about the incidence of intussusception and its epidemiology in a developing country where current or future field trials with rotavirus vaccine will be conducted.

Confidence Intervals↗
PubMed2000

Modeling repeated count data subject to informative dropout.

In certain diseases, outcome is the number of morbid events over the course of follow-up. In epilepsy, e.g., daily seizure counts are often used to reflect disease severity. Follow-up of patients in clinical trials of such diseases is often subject to censoring due to patients dying or dropping out. If the sicker patients tend to be censored in such trials, estimates of the treatment effect that do not incorporate the censoring process may be misleading. We extend the shared random effects approach of Wu and Carroll (1988, Biometrics 44, 175-188) to the setting of repeated counts of events. Three strategies are developed. The first is a likelihood-based approach for jointly modeling the count and censoring processes. A shared random effect is incorporated to introduce dependence between the two processes. The second is a likelihood-based approach that conditions on the dropout times in adjusting for informative dropout. The third is a generalized estimating equations (GEE) approach, which also conditions on the dropout times but makes fewer assumptions about the distribution of the count process. Estimation procedures for each of the approaches are discussed, and the approaches are applied to data from an epilepsy clinical trial. A simulation study is also conducted to compare the various approaches. Through analyses and simulations, we demonstrate the flexibility of the likelihood-based conditional model for analyzing data from the epilepsy trial.

Anticonvulsants↗
PubMed2005

Exact two-sample inference with missing data.

When comparing follow-up measurements from two independent populations, missing records may arise due to censoring by events whose occurrence is associated with baseline covariates. In these situations, inferences based only on the completely followed observations may be biased if the follow-up measurements and the covariates are correlated. This article describes exact inference for a class of modified U-statistics under covariate-dependent dropouts. The method involves weighing each permutation according to the retention probabilities, and thus requires estimation of the missing data mechanism. The proposed procedure is nonparametric in that no distributional assumption is necessary for the outcome variables and the missingness patterns. Monte Carlo approximation by the Gibbs sampler is proposed, and is shown to be fast and accurate via simulation. The method is illustrated in two small data sets for which asymptotic inferential procedures may not be appropriate.

Biometry↗
PubMedDate not supplied

Using severity rather than randomization for assignment in clinical trials: Monte Carlo tests and practical illustrations of the Robbins-Zhang method.

In randomized clinical trials, patients are not differentially assigned to treatments by severity because available methods of data analysis are sensitive to regression to the mean and yield biased estimates of treatment effect. However, a method proposed by Robbins and Zhang provides consistent estimates of treatment effect in clinical trials, even when the more severely ill are assigned to the active treatment and the less severely ill are assigned to a placebo. This method was assessed by Monte Carlo trials. All combinations of two models of drug effect, five true score distributions, four magnitudes of error variance, and four sample sizes were assessed. The method works sufficiently well that its use should be considered. Further, the method gives correct results even when the regression discontinuity method fails. The method was also compared with a standard analysis of variance of difference scores using real psychiatric data from two ordinary randomized trials; similar results were obtained by both methods.

Bias↗
PubMed1997

Estimation of variance in Cox's regression model with shared gamma frailties.

The Cox regression model with a shared frailty factor allows for unobserved heterogeneity or for statistical dependence between the observed survival times. Estimation in this model when the frailties are assumed to follow a gamma distribution is reviewed, and we address the problem of obtaining variance estimates for regression coefficients, frailty parameter, and cumulative baseline hazards using the observed nonparametric information matrix. A number of examples are given comparing this approach with fully parametric inference in models with piecewise constant baseline hazards.

Adult↗
PubMed2006

Accident proneness, does it exist? A review and meta-analysis.

Accident related health problems have been suggested to cluster within persons. This phenomenon became known as accident proneness and has been a subject of many discussions. This study provides an overview of accident proneness. Therefore, 79 articles with empirical data on accident rates were identified from databases Embase, Medline, and Psychinfo. First, definitions of accidents varied highly, but most studies focused on accidents resulting in injuries requiring medical attention. Second, operationalisations of accident proneness varied highly. Studies categorised individuals into groups with ascending accident rates or made non-accident, accident, and repetitive accident groups. Third, studies examined accidents in specific contexts (traffic, work, and sports) or populations (children, students, and patients). Therefore, we concluded that no overall prevalence rate of accident proneness could be given due to the large variety in operationalisations. However, a meta-analysis of the distribution of accidents in the general population showed that the observed number of individuals with repeated accidents was higher than the number expected by chance. In conclusion, accident proneness exists, but its study is severely hampered by the variation in operationalisations of the concept. In an effort to reach professional consensus on the concept, we end this paper with recommendations for further research.

Accidents↗
PubMed2006

Indirect measurement of the lag time distribution of single cells of Listeria innocua in food.

The distribution of log counts at a given time during the exponential growth phase of Listeria innocua measured in food samples inoculated with one cell each was applied to estimate the distribution of the single-cell lag times. Three replicate experiments in broth showed that the distribution of the log counts is a linear mapping of the distribution of the detection times measured by optical density. The detection time distribution reflects the lag time distribution but is shifted in time. The log count distribution was applied to estimate the distributions of the lag times in a liquid dairy product and in liver paté after different heat treatments. Two batches of ca. 100 samples of the dairy product were inoculated and heated at 55 degrees C for 45 min or at 62 degrees C for 2 min, and an unheated batch was incubated at 4 degrees C. The final concentration of surviving bacteria was ca. 1 cell per sample. The unheated cells showed the shortest lag times with the smallest variance. The mean and the variance of the lag times of the surviving cells at 62 degrees C were greater than those of the cells treated at 55 degrees C. Three batches of paté samples were heated at 55 degrees C for 25 min, 62 degrees C for 81 s, or 65 degrees C for 20 s. A control batch was inoculated but not heated. All paté samples were incubated at 15 degrees C. The distribution of the lag times of the cells heated at 55 degrees C was not significantly different from that of the unheated cells. However, at the higher temperatures, 62 degrees C and 65 degrees C, the lag duration was longer and its variance greater.

Animals↗
PubMed1999

Mortality in farmed mink: systematic collection versus arbitrary submissions for diagnostic investigation.

The distribution of diagnoses of mortality in mink submitted to the Danish Veterinary Laboratory (DVL) for diagnostic investigation in the calendar year 1997 was compared with the diagnoses of mortality in all dead mink collected at 4 selected farms (project farms) during the same period. A total of 1,015 submitted mink and 1,149 mink from the 4 project farms were subjected to post mortem investigation. The average size (breeding stock) of the project farms was larger than Danish farms on average. However, the distribution of colour types of the mink was comparable. The seasonal distribution of the material from project farms and that of the submissions were approximately the same. Differences in the distribution of diagnoses as well as recovered microorganisms were found, however, mainly related to the proportion of gastro-intestinal disorders and E. coli respectively. These proportions were negatively correlated. Overall the results showed that extrapolating diagnostic results of laboratory submissions to the population of farmed mink may be problematic, and more reliable methods for disease surveillance must be considered.

Animals↗
PubMed2004

Influence of spectral diffusion on single-molecule photon statistics.

We investigate the distribution of the number of photons emitted by a single molecule undergoing a spectral diffusion process and interacting with a continuous wave field. Using a generating function formalism an exact analytical formula for Mandel's Q parameter is obtained. The solution, which is valid for weak and strong excitation fields, exhibits transitions between (i) quantum sub-Poissonian and classical super-Poissonian behaviors, and (ii) fast to slow modulation limits.

Algorithms↗
PubMed2001

Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe.

OBJECTIVE: The aetiopathogenesis of the primary systemic vasculitides (PSV) is unknown but includes both environmental and genetic factors. The development of classification criteria/definitions for PSV allows comparison of the epidemiology between different regions. METHODS: The same methods and the American College of Rheumatology (1990) criteria or Chapel Hill definitions were used to compare the epidemiology of Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa in Norwich (east England population 413 500) and Lugo (northwest Spain population 204 100). Patients with PSV were identified between 1 January 1988 and 31 December 1998. RESULTS: Overall, the incidence of PSV in adults was almost equal in Norwich (18.9/million) and Spain (18.3/million). The incidence of Wegener's granulomatosis in Norwich (10.6/million) was greater than in Spain (4.9/million). There was a marked age-specific increase in incidence in Norwich with a peak age 65-74 years (52.9/million), but a virtually equal age distribution between ages 45 and 74 in Lugo (34.1/million). There was no significant increase with time in either population, or evidence of cyclical changes in incidence. CONCLUSION: These data support the suggestion that environmental factors may be important in the pathogenesis of PSV.

Adolescent↗
PubMed2003

Protective efficacy of the RTS,S/AS02 Plasmodium falciparum malaria vaccine is not strain specific.

RTS,S/AS02 is a recombinant protein malaria vaccine that contains a large portion of the C-terminal of the circumsporozoite protein (CSP) sequence of the NF54 isolate of Plasmodium falciparum fused to the hepatitis B virus surface antigen. It has been shown to induce significant protection to challenge infection with a homologous parasite strain in American volunteers. In a recently completed trial in semi-immune Gambian adults, vaccine efficacy against natural infection was 34% (95% confidence interval = 8-53%, P = 0.014) during the malaria season following vaccination. Breakthrough P. falciparum parasites sampled from vaccinated subjects and from controls were genotyped at two polymorphic regions of the csp gene encoding T cell epitopes (csp-th2r and csp-th3r) to determine if the vaccine conferred a strain-specific effect. The overall distribution of csp allelic variants was similar in infections occurring in vaccine and control groups. Also, the mean number of genotypes per infection in the RTS,S/AS02 group was not reduced compared with the controls.

Adolescent↗
PubMed2003

Maximum likelihood and Bayesian methods for estimating the distribution of selective effects among classes of mutations using DNA polymorphism data.

Maximum likelihood and Bayesian approaches are presented for analyzing hierarchical statistical models of natural selection operating on DNA polymorphism within a panmictic population. For analyzing Bayesian models, we present Markov chain Monte-Carlo (MCMC) methods for sampling from the joint posterior distribution of parameters. For frequentist analysis, an Expectation-Maximization (EM) algorithm is presented for finding the maximum likelihood estimate of the genome wide mean and variance in selection intensity among classes of mutations. The framework presented here provides an ideal setting for modeling mutations dispersed through the genome and, in particular, for the analysis of how natural selection operates on different classes of single nucleotide polymorphisms (SNPs).

Bayes Theorem↗
PubMed2001

Spatial pattern of prion protein deposits in patients with sporadic Creutzfeldt-Jakob disease.

The spatial pattern of the prion protein (PrP) deposits was studied in the cerebral cortex and cerebellum in 10 patients with sporadic Creutzfeldt-Jakob disease (CJD). In all patients the PrP deposits were aggregated into clusters and, in 90% of cortical areas and in 50% of cerebellar sections, the clusters exhibited a regular periodicity parallel to the tissue boundary; a spatial pattern also exhibited by beta-amyloid (Abeta) deposits in Alzheimer's disease (AD). In the cerebral cortex, the incidence of regular clustering of the PrP deposits was similar in the upper and lower cortical laminae. The sizes of the PrP clusters in the upper and lower cortex were uncorrelated. No significant differences in mean cluster size of the PrP deposits were observed between brain regions. The size, location and distribution of the PrP deposit clusters suggest that PrP deposition occurs in relation to specific anatomical pathways and supports the hypothesis that prion pathology spreads through the brain via such pathways. In addition, the data suggest that there are similarities in the pathogenesis of extracellular protein deposits in prion disease and in AD.

Aged↗