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PubMed2000

Comparison of different approaches to incidence prediction based on simple interpolation techniques.

The paper compares three different methods for performing disease incidence prediction based on simple interpolation techniques. The first method assumes that the age-period specific numbers of observed cases follow a Poisson distribution and the other two methods assume a normal distribution for the incidence rates. The main emphasis of the paper is on assessing the reliability of the three methods. For this purpose, ex post predictions produced by each method are checked for different cancer sites using data from the Cancer Control Region of Turku in Finland. In addition, the behaviour of the estimators of predicted expected values and prediction intervals, crucial for investigation of the reliability of prediction, are assessed using a simulation study. The prediction method making use of the Poisson assumption appeared to be the most reliable of the three approaches. The simulation study found that the estimator of the length of the prediction interval produced by this method has the smallest coverage error and is the most precise.

Adult↗

PubMed1995

Population characteristics of cyclodextrin complex stabilities in aqueous solution.

Binding constants (K11) of 1:1 complexes of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin with many substrates (guests) were collected from published sources and subjected to statistical analysis. All systems refer to 25 +/- 5 degrees C and aqueous solution. The frequency distributions of log K11 are satisfactorily described by normal distributions with the following parameters (n = number of complexes, mu = population mean, sigma = population standard deviation): alpha-cyclodextrin, n = 663, mu = 2.11, sigma = 0.90; beta-cyclodextrin, n = 721, mu = 2.69, sigma = 0.89; gamma-cyclodextrin, n = 166, mu = 2.55, sigma = 0.93. Stabilities of pairs of cyclodextrin complexes with a common substrate are not precisely correlated, but they do not appear to be wholly independent quantities. The stabilities of alpha-cyclodextrin complexes are consistent with a recent interpretation of solvent effects on alpha-cyclodextrin complex stabilities.

Cyclodextrins↗

PubMed2003

On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles.

DNA microarrays provide for unprecedented large-scale views of gene expression and, as a result, have emerged as a fundamental measurement tool in the study of diverse biological systems. Statistical questions abound, but many traditional data analytic approaches do not apply, in large part because thousands of individual genes are measured with relatively little replication. Empirical Bayes methods provide a natural approach to microarray data analysis because they can significantly reduce the dimensionality of an inference problem while compensating for relatively few replicates by using information across the array. We propose a general empirical Bayes modelling approach which allows for replicate expression profiles in multiple conditions. The hierarchical mixture model accounts for differences among genes in their average expression levels, differential expression for a given gene among cell types, and measurement fluctuations. Two distinct parameterizations are considered: a model based on Gamma distributed measurements and one based on log-normally distributed measurements. False discovery rate and related operating characteristics of the methodology are assessed in a simulation study. We also show how the posterior odds of differential expression in one version of the model is related to the ratio of the arithmetic mean to the geometric mean of the two sample means. The methodology is used in a study of mammary cancer in the rat, where four distinct patterns of expression are possible.

Animals↗

PubMed2005

A mixed-effects regression model for three-level ordinal response data.

Three-level data occur frequently in behaviour and medical sciences. For example, in a multi-centre trial, subjects within a given site are randomly assigned to treatments and then studied over time. In this example, the repeated observations (level-1) are nested within subjects (level-2) who are nested within sites (level-3). Similarly, in twin studies, repeated measurements (level-1) are taken on each twin (level-2) within each twin pair (level-3). A three-level mixed-effects regression model is described here. Random effects at the second and third level are included in the model. Additionally, both proportional odds and non-proportional odds models are developed. The latter allows the effects of explanatory variables to vary across the cumulative logits of the model. A maximum marginal likelihood (MML) solution is described and Gauss-Hermite numerical quadrature is used to integrate over the distribution of random effects. The random effects are normally distributed in this instance. Features of this model are illustrated using data from a school-based smoking prevention trial and an Alzheimer's disease clinical trial.

Alzheimer Disease↗

PubMed1992

Application of Bayesian statistics to decision making during a clinical trial.

We describe the application of Bayesian methods to the monitoring and analysis of a trial of treatment for patients with advanced colorectal carcinoma. We discuss the choice of prior distribution and justify the use of a truncated normal distribution with a probability mass at zero difference. The stopping rule, based on the trials of the posterior distribution and a chosen range of equivalence, yields an upper boundary very close to the Pocock group sequential boundary. The Bayes stopping rule is quite sensitive to the amount of probability mass at zero in the prior distribution.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Response fields of intraparietal neurons quantified with multiple saccadic targets.

The activity of each of 99 intraparietal neurons was studied in three awake-behaving rhesus monkeys (Macaca mulatta) while subjects performed 100-900 delayed saccade trials. On each trial, a saccadic target was presented at one location selected randomly from a grid of 441 locations spanning 40 degrees of horizontal and vertical visual space. Individual neurons in our population were sensitive to both the direction and amplitude of saccades. Response fields, which plotted firing rate as a function of the horizontal and vertical amplitude of movements for each neuron, were characterized by a Cartesian two-dimensional gaussian model. The goodness-of-fit of these gaussian models was tested by: (1) comparing observed responses with predicted responses for each movement; and (2) by computing the percentage of variance explained by each model. Cartesian Gaussian models provided a good fit to the response fields of most neurons. Across our population, the Gaussian fit to the response field of each neuron accounted for more of the variance in neuronal activity when the data were plotted with regard to the horizontal and vertical amplitude of the saccade than when the same data were plotted with regard to the position of the saccadic target. The Gaussian functions were used to estimate the eccentricity and spatial tuning breadth of each neuronal response field. Modal response field radius was less than 5 degrees, whereas mean response field radius was about 10 degrees. Linear regression analysis demonstrated that response field eccentricity accounted for less than 30% of the variance in response field radius. Analysis of the horizontal distribution of response field centers showed an approximately normal distribution around central fixation. Most histologically recovered neurons were located on the lateral bank of the intraparietal sulcus, although a small number of saccade-related neurons were recorded from Brodmann's area 5 on the medial bank of the intraparietal sulcus.

Animals↗

PubMed1996

A case of neonatal Bartter's syndrome.

We describe a child with a neonatal presentation of Bartter's syndrome. Unlike infants previously described with a similar clinical presentation, the urinary excretion rate of prostaglandin E2 in this child was similar to normal children and Tamm-Horsfall protein was distributed normally in the thick ascending limb of the loop of Henle. The child failed to respond to indomethacin alone, but thrived after the addition of the angiotensin converting enzyme inhibitor, captopril.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1980

Intracellular oxygen measurements of mouse liver cells using quantitative fluorescence video microscopy.

Our currently developed fluorescence video microscope can measure fluorescence intensities with an error of +/- 1.5% of full scale in 65536 different positions of a microscope field. With a video frame freeze acquisition time of 33 ms, time-dependent changes of this order of time or slower can be followed. Using cells which have absorbed pyrene-1-butyrate to an intracellular concentration of 0.05 to 1 mM, the changes in fluorescence intensity with oxygen concentration are easily measured. The spatial resolution for data collection is 0.5 micron when a 54X objective is used. The individual Stern-Volmer quenching constants of each individual pixel were measured for agar slices and mouse liver cells treated with pyrenebutyric acid. The distribution of quenching constants for agar follows a normal curve about a mean value of 16 . 10(-4) torr-1. The data for mouse liver cells gave a non-normal distribution of quenching constants with a mean value of 18 . 10(-4) torr-1. The greater spread of the data from cells is interpreted as evidence for a real biological variation in the solubility coefficient of oxygen in different locations within the cell. In all the cells examined, this distribution has been observed to be non-random and appears to be associated with specific cell structures.

Animals↗

PubMed1981

Design of a statistical method for the analysis of mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase locus of cultured Chinese hamster ovary cells.

Mutagenesis data collected in the mammalian cell CHO/HGPRT assay were analyzed to study the distribution of the experimental errors associated with the test. The data neither followed the widely assumed Poisson distribution nor satisfied the usual statistical assumptions of normality and homogeneous variance of experimental errors. We transformed the data by using the power formula Y = (X + A) gamma where X is the observed mutation frequency, Y is the transformed frequency, and A and gamma are constants determined by the procedure of Box and Cox. Setting A = 1 and gamma = 0.15 we produced transformed values for which the assumptions of homogeneous variance and normal distribution were satisfied. This transformation enables one to properly use Student's t-test and dose-response analysis of variance to analyze CHO/HGPRT results. The experimental design for CHO/HGPRT mutagenesis assays is also discussed.

Animals↗

PubMed1996

Standard error and sample size determination for estimation of probabilities based on a test variable.

A method of sample size determination for estimation of probabilities based on a test variable is presented. Applications to estimation of sensitivity and specificity of medical tests are the focus of this research, although the methods can be applied to other areas of study such as engineering reliability. Examples are given for determining sample sizes required for the classification of patients with cutaneous lupus erythematosus based on the incidence of several markers. In this example, the test variable is the number of markers present. The methodology employs a weighted average of model-based and non-model-based estimates of the probability with the weights determined by the closeness to or the confidence in the given model. Formulas and charts required for determining sample size are provided for test variables that can be modeled by the binomial, Poisson, or normal distributions, i.e., for the most commonly encountered distributions for counting events (binomial and Poisson) and for measurements (normal). However, the methods given can be applied to any distribution, including multivariate. Especially when relatively small probabilities (the rare events) are being estimated, the techniques provided assistance in safeguarding against undersampling brought on by unwarranted confidence in a test variable distribution and against oversampling required for high accuracy in non-model-based probability estimators.

Epidemiologic Methods↗

PubMed2005

Significance of heritability in primary and secondary pediatric hypertension.

BACKGROUND: Patient weight and family history are significant risk factors for the development of hypertension in children. Multiple genetic factors have been identified in primary (essential) hypertension in adults; however, the delineation of genetic factors in the separate populations of children with primary or secondary hypertension are not well understood. Heritability is the proportion of observed variation in a particular trait that can be attributed to an inherited genetic factor in contrast to environmental factors. In the consideration of hypertension, heritability can be assessed in terms of an underlying continuous gradient of the liability for developing hypertension. With this assumption it is possible to compute heritability using hypertension incidence among relatives and described by Falconer. Heritability values range from 0 (no genetic contribution) to 1 (complete genetic contribution). The aim of this study was to determine the genetic contribution to primary and secondary hypertension in a pediatric population through heritability analysis. METHODS: This was a retrospective case-control analysis of medical records of children (n=276) followed in the Pediatric Nephrology Clinic over a 4-year period from 1999 to 2002. There were 192 children and adolescents with primary hypertension (124 male, 68 female, age 0 to 21 years) and 84 children and adolescents with secondary hypertension (46 male, 38 female, age 0 to 21 years). Each hypertensive group served as the control for the other. Estimates of heritability were made using Falconer's method 2. The model assumes independence between the environment and genetic factors and that the joint distribution of liabilities between parent and child are normally distributed. Problems can arise from computing heritability due to dominance within loci, correlations between nongenetic familial effects, or the presence of a major gene. RESULTS: Of the children and adolescents with primary hypertension, 49% had parents with primary hypertension; and of the children and adolescents with secondary hypertension, 24% had parents with primary hypertension. Of the children and adolescents with primary hypertension, 10% had parents with secondary hypertension; and of the children and adolescents with secondary hypertension, 46% had parents with secondary hypertension. The estimated heritability for primary hypertension was 0.84 (SE=0.21). The estimated heritability for secondary hypertension was 1.14 (SE=0.21). As the value was >1, this indicates that the fit of the liability model is poor and that a few genes, or even one major gene, were significantly involved in the causes of secondary hypertension in the children and adolescents studied. CONCLUSIONS: The results suggest that primary and secondary hypertension do not share the same type of genetic profile. Primary hypertension in children and adolescents is likely due to a large number of additive contributions of genes, although a highly correlated environmental component can not be excluded. The continuous liability model is inappropriate for secondary hypertension because the estimate was substantially greater than one. This study supports the model that secondary hypertension in children and adolescents may be related to just a few genes.

Adolescent↗

PubMed2005

Eliminating bias in the estimation of the geometric mean of HI titres.

The standard test for anti-haemagglutinin antibody titration is the haemagglutination inhibition (HI) test. The HI titre is defined as the dilution factor of the highest dilution that still completely inhibits haemagglutination. If the highest dilution tested (1:2560) still completely inhibits haemagglutination, an HI titre value of 2560 is assigned. Logarithmically transformed HI titres tend to be normally distributed. But because dilutions less than 1:2560 are not tested, the distribution may be truncated and the assumption of normality may not hold. As a consequence, the geometric mean titre (GMT) will be underestimated. Using data from 10 clinical studies, it is shown here that the GMT may be underestimated by 5-13%. An unbiased estimate of the GMT can be obtained by a statistical method that originates from the analysis of survival data: maximum likelihood estimation for censored observations. The maximum likelihood estimate of the GMT of truncated HI titres can be readily obtained using the statistical software package SAS.

Antibodies, Viral↗

PubMed2005

Culturable airborne fungi in outdoor environments in Beijing, China.

Airborne fungi are being proposed as a cause of adverse health effects. They may adversely affect human health through allergy, infection, and toxicity. Moreover, they have a great influence on urban air quality in Beijing. In this study, a systematical survey on the culturable airborne fungi was carried out for 1 year in Beijing urban area. Fungal samples were collected for 3 min, three times each day, and continued for three consecutive days of each month with FA-1 sampler from three sampling sites. Results showed that the culturable fungal concentrations ranged from 24 CFU (Colony forming units) /m3 to 13960 CFU/m3, and the mean and median was 1165 CFU/m3 and 710 CFU/m3, respectively. Fungal concentrations in the greener area around the Research Center for Eco-Environmental Sciences (RCEES) and Beijing Botanical Garden (BBG) were significantly higher than in the densely urban and highly trafficked area of Xizhimen (XZM) (***P<0.001), but no significant difference was found between RCEES and BBG (P>0.05). The variation of fungal concentrations in different seasons was significant in RCEES and BBG, where the concentrations were higher in Summer and Autumn, and lower in Spring and Winter. However, there were no significant differences in fungal concentrations between the Spring and the Winter for three sampling sites (P>0.05). Fourteen genera, including 40 species of culturable fungi, were identified in this study. Penicillium, with the most abundant species, which comprised more than 50% of the total isolated fungal species. Cladosporium were the most dominant fungal group, and contributed to more than one third of the total fungal concentration, followed by non-sporing isolates, Alternaria, Pencillium and Asperigillus. The concentration percentage of Cladosporium was significantly higher in RCEES than in XZM (*P<0.05), and the concentration percentages of Penicillium (**P<0.01) and Aspergillus (*P<0.05) were higher in XZM than in RCEES and in BBG. For other groups' concentration percentages, no significant differences were observed among the sampling sites. The distribution pattern of airborne fungi presented log-normal distribution. The highest proportion of culturable fungi was detected in stage 4 (2.0-3.5 microm), and the lowest was in stage 6 (<1.0 microm).

Air Microbiology↗

PubMed2003

Genotype-phenotype correlation for histamine N-methyltransferase in a Chinese Han population.

BACKGROUND: Two potential single-nucleotide polymorphisms (SNP) (C314T and A595G) exist in the gene for human histamine N-methyltransferase (HNMT). METHODS: A radiochemical microassay was used to measure the erythrocyte HNMT activities, whereas the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to perform the genetic analysis in 247 unrelated Chinese Han subjects. RESULTS: All subjects had detectable HNMT activity. The activity of HNMT was gender related (males>females, p<0.0001), with a 5.5-fold individual variation. The distribution of HNMT activity was compatible with a normal distribution. There were 28 heterozygotes for the variant T314 allele among the 247 subjects, whereas no A595G transition was observed. All heterozygotes for the T314 allele displayed an intermediate or low HNMT activity, with an average HNMT activity being 34.0% lower than those with wild-type genotype (623.1+/-136.0 vs. 944.8+/-249.3 U/ml red blood cells [RBC], p<0.0001). CONCLUSION: The C314T polymorphism was functionally important and contributes in part to phenotypic variance of HNMT activity in Chinese Han population. Additional unknown genetic or epigenetic factors should also play important roles in the regulation of HNMT activity.

Adolescent↗

PubMed1999

Variation of toxaphene indicator compounds in fish from single fishing grounds: conclusions for sampling.

The levels of three toxaphene indicator compounds were determined in individual lots of herring, redfish, Greenland halibut and farmed salmon. Concentration levels of the three marine fish species were characterised by a right-skewed frequency distribution whereas residue concentrations in farmed salmon were normally distributed. The toxaphene concentrations in the edible part of redfish, herring and Greenland halibut were found to be positively correlated to the sizes and thus to age. As results show, for representative sampling of a landed catch, not more than 10 individual fishes from typical size classes of a lot are necessary for a pooled sample.

Animals↗

PubMed2001

Sampling variance and distribution of the D' measure of overall gametic disequilibrium between multiallelic loci.

The development of the theory of estimation of gametic disequilibrium for multiallelic systems is particularly necessary, since a large number of the genetic markers available at present are highly polymorphic multiallelic systems. The D' coefficient is one of the most commonly used measures of the extent of overall disequilibrium between all possible pairs of alleles at two multiallelic loci. Nevertheless, the sampling properties of this measure of overall disequilibrium, are to date, unknown. In this work, we have derived explicit expressions by large-sample theory to compute the approximate sampling variance of Dhat' between pairs of multiallelic loci, when samples of haplotypes are taken from populations. Formulae for calculating the asymptotic sampling variance were checked by Monte Carlo simulation. In addition, the magnitude of the sampling variance of Dhat' was investigated under different scenarios of disequilibrium between multiallelic loci. Extensive simulations were also carried out for describing the sampling distribution of Dhat', conditioned on the sample size, number of alleles and their frequencies, and disequilibrium components. It was found that the sampling distribution of Dhat' generally approaches well the theoretical normal distribution for experimental sample sizes, particularly when loci have many alleles. Disequilibrium data between microsatellite loci of human chromosome 11p are used for illustration. These investigations increase substantially our knowledge about this widely used measure of overall disequilibrium, which is relevant to evaluate disequilibrium between multiallelic loci in populations.

Alleles↗

PubMed1994

Cognitive function in depression: its relationship to the presence and severity of intellectual decline.

Cognitive dysfunction is an integral feature of depression, in some cases of sufficient severity to warrant a diagnosis of dementia. There has been little systematic investigation of whether cognitive dysfunction is an inevitable consequence of depression, or is specific to a subgroup of depressed patients. Related to this is the distribution of cognitive dysfunction, whether there is a continuum of impairment or a distinct demented subgroup. Finally, there is the question of which aspects of cognitive function are most sensitive to the intellectual decline seen in depression. A study is described which addresses these issues. The distribution of global cognition was found to be normally distributed in the sample of 29 patients assessed. Based on this distribution and the scores of a control sample, the patients were classified as unimpaired, borderline or impaired. Two sets of independent comparisons were carried out. First, the unimpaired depressed patients were compared to matched non-depressed controls. Significant deficits were found on a range of neuropsychological measures covering aspects of language function, memory, both recall and recognition, attention and behavioural regulation. These same patients were also compared with two groups of matched depressed patients, with varying degrees of global cognitive impairment. In general, the cognitive measures showed a gradient of dysfunction across the three patients groups. Significant differences between the depressed groups were shown on measures of immediate recall, attention and behavioural regulation. The possible significance of attentional factors for the observed memory dysfunction is discussed.

Adult↗

PubMed1991

Intraocular pressure asymmetry in a population tested with the Pulsair non-contact tonometer.

Intraocular pressure asymmetry as measured by noncontact tonometry (NCT) was analysed in a population of 874 individuals aged over 50 years. In both males and females the intraocular pressure (IOP) measured in the right eye exceeded that of the left. Pressure asymmetry followed a normal distribution in a population subgroup known to have normal fields, discs and pressures. The 95% confidence intervals for the equation R IOP--L IOP in normals were 0.63+ or -5.46 mmHg when the mean of four pulses per eye were used to calculate the IOP, increasing to 0.80+ or -6.56 mmHg for two pulses per eye (thus expanding the limits by 20%). The range of asymmetry for NCT in normals therefore exceeds that reported for Goldmann applanation tonometry. Asymmetry was greater in females than males. Knowledge of the normal range of IOP asymmetry in each sex will help glaucoma screeners using NCT in their decision as to when to refer. A minimum of four pulses per eye should be used to assess the IOP when screening.

Aged↗