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PubMed1983

Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population.

The population distribution of bronchial responsiveness to inhaled histamine was examined in 300 randomly selected caucasian college students (aged 20 to 29 years). Bronchial responsiveness was measured as the histamine threshold, defined as the concentration producing an FEV1 fall greater than 2 SD below the mean of five prehistamine FEV1 measurements. The cumulative prevalence of asthma was 9.3 percent, including 2.7 percent with current asthma, 3.3 percent with asthma following allergen exposure only, and 3.3 percent with remote asthma. Allergic rhinitis was present in 10.7 percent; nonallergic rhinitis in 16.3 percent; 63.7 percent had neither asthma nor rhinitis. Histamine threshold ranged from unmeasurable (greater than 8 mg/ml) in 36 percent to 0.125 mg/ml in 0.3 percent. The distribution of histamine threshold values in the responsive range was unimodal, the asthmatic subjects representing a subgroup within the hyperresponsive distribution tail rather than a separate distribution peak. Examination of the FEV1 response to 8 mg/ml showed a range between 2.8 SD increase and 100 SD reduction; the population distribution of this variable was unimodal and log normal. We concluded that there is a continuous unimodal log normal distribution of bronchial responsiveness to inhaled histamine in a random human population. Rather than representing a separate (bimodal) peak or a sharp cutoff (of a unimodal tail), the asthmatic subjects show substantial overlap with the remainder of the population.

Adult↗
PubMed2003

Laterality in bovine behavior in an extensive partially suckled herd and an intensive dairy herd.

Cattle exhibit behavioral laterality, but the consistency and correlation between behaviors are unknown. Behavioral laterality was recorded in two herds of contrasting management intensity. The first was a small, extensively managed herd in Brazil, with cows and calves on rangeland, except when removed for handmilking in stalls. The second was a large, intensive British herd, with cows fed mostly indoors and calves removed for individual rearing soon after birth. In herd 1, the side of the body on which the following behaviors were performed was recorded: rumination (rumination), tail waving (tail), tongue protrusion during the initiation of a feeding bout (feeding), hind leg placement when lying (lying), and front leg initiating walking (walking). The distribution of left and right side dominance was normal for all behaviors, with positive correlations between walking and rumination, tail, and feeding, and between lying and rumination. In herd 2, rumination, feeding, and lying behaviors were similarly recorded, as well as parlor side-preference (parlor) and the side of a track chosen when returning to pasture (track). For all behaviors except track, the extent of left- and right-side dominance was not normally distributed, and more cows than expected showed strong laterality on the right or the left side. Parlor and track lateralities were correlated, indicating that cows that entered one side of the parlor also tended to choose the same side of the track. Strong laterality in the intensively managed herd therefore contrasted with that observed in the extensively managed herd and the reasons for such differences in laterality are uncertain.

Animals↗
PubMed1976

The tuberositas tibiae and extension in the knee joint.

In all 56 tibiae from Lapps and 56 from Norwegians have been studied. These ethnic groups represent different weight bearing situations. Variables dealing with the extension in the knee joint are dealth with. The bone is mainly studied in the AP and the ML planes. The material is analyzed statistically. The distribution form is examined and the deviations from normality are found to be moderate. Chiefly positive skewness occurs. Platykurtosis is found equally often as leptokurtosis. The deviations from a standard normal distribution are not supposed to affect the results significantly. There is a non-systematic pattern of distribution. The variability is generally lower in Lapps than in Norwegians. The variability is about the same in linear and angular variables and in indices. In linear variables females and Lapps show lower mean values than males and Norwegians, respectively. Lapps show the largest indices. In linear variables, contrary to in angular variables and indices, the sex differences exceed the differences between the ethnic groups. As a rule sex differences are largest in Lapps. The variations of the tuberositas tibiae are supposed to be in particular the results of muscular forces in bone remodeling. The relationship between the habitual knee position and extension is discussed.

Computers↗
PubMed1976

Variations in the relationship between the diaphysis and the epiphyses of the tibia.

In all 56 tibiae from Lapps and 56 tibiae from Norwegians have been studied. These ethnic groups represent different weight bearing situations. Variables expressing adaptation to non-axial loading are dealt with. The bone is mainly studied in the AP and the ML planes, as well as in the three dimensional space. The material is analyzed statistically. The distribution form is examined and the deviations from normality are found to be moderate. Mainly positive skewness occurs. Platykurtosis is found as often as leptokurtosis. The deviations from a standard normal distribution are not supposed to affect the results significantly. There is a non-systematic pattern of distribution. The variability is generally lower in Lapps than in Norwegians. The standard deviation shows highest numerical values in indices, lowest in linear variables. Systematic group differences, especially in similar variables, are supposed to be of greater importance than isolated differences. The variables giving deviations from the reference planes or the diaphyseal axis, show the largest and the consistent left-right differences. In linear variables Lapps and females show lower mean values than males and Norwegians, respecitvely. In linear variables giving deviations from the reference planes, in angular variables and in indices, Lapps usually show the highest mean values. Lapps tend to show larger sex differences in variables giving deviations from the reference planes or the diaphyseal axis. However, the sex differences within the Lapps are small. The variations of the tibia are supposed to be the results of mechanical factors in bone remodelling. The epiphyseal-metaphyseal parts tend to have a constant shape, the adaptations to non-axial loading predominantly appearing in the diaphysis. The relation between the weight bearing line and the diaphyseal axis is discussed, particularly regarding the ML stability mechanism of the knee joint. The occurrence of torsion and its influence upon the AP and ML projected values regarding the relationship between the epiphyses and the diaphysis are discussed.

Biometry↗
PubMed2002

Rasch-transformed raw scores and Two-way ANOVA: a simulation analysis.

This article demonstrates, through the exposition of underestimated variable effects or spurious interaction effects, the inherent inadequacy of untransformed 0-1 raw scores for analysis via Two-Way analysis of variance (ANOVA). The pioneering work in this field, conducted in the 1990's by Dr. Susan Embretson of the University of Kansas, USA, is highlighted, and the eminent suitability of Rasch transformations of 0-1 raw scores for analysis via Two-Way ANOVA is also demonstrated. In this study Monte Carlo techniques or simulations are utilized to determine the precise psychometric conditions under which differences between raw scores and Rasch transformations of those raw scores are detectable via Two-Way ANOVA. This study partially replicates Dr. Embretson's studies, and also defines the extent of underestimation and spuriousness which ensue when uniform or skewed distributions of item difficulties are used instead of normal distributions, and misfitting raw data are utilized instead of fitting data.

Analysis of Variance↗
PubMedDate not supplied

Kinematic analysis of chemotaxis of fresh and stored neutrophils.

When neutrophils are isolated from the circulation the first function to begin to deteriorate is chemotaxis. To characterize the loss of chemotaxis that occurs during storage, a computer-assisted video motion analysis of neutrophils responding to formyl-methionyl-leucyl-phenylalanine (FMLP) was used in an agarose assay. The chemotactic speed, velocity, and orientation angle were measured, and a persistence of locomotion index (velocity/speed) and chemotropic index (cosine of the orientation angle) were calculated for fresh neutrophils and neutrophils stored in plasma at 20 to 22 degrees C for 24 hours. The data reveal that: (1) the frequency distribution of speed for individual stored cells had a different shape than that of fresh cells owing to a subpopulation of stored cells (approximately 35 percent) which migrated at a slower mean speed; (2) the frequency distribution of orientation for fresh cells is not normally distributed and contains a subpopulation (approximately nine percent of the total) of cells which orient at random in a gradient; (3) the precision of orientation of the majority of stored cells is comparable to that of fresh cells, but approximately 35 percent of the stored cells orient at random in a chemoattractant gradient; (4) neither the persistence index nor the orientation of both fresh and stored cells were correlated with speed; (5) the chemotropic index and persistence index are correlated, and this correlation is not altered by storage suggesting that stored cells which show decreased persistence also show a decreased chemotropic index. It is proposed that neutrophils respond to a gradient of fMLP with either fast, persistent, accurately oriented locomotion or slower, less persistent, randomly oriented locomotion. In addition to those neutrophils which do not migrate in response to fMLP, it is proposed that there are two subpopulations of motile neutrophils. Storage at 20 to 22 degrees C induces shifts between these three modes of behavior.

Blood Preservation↗
PubMed1989

Clinical application of electrocardiographic computer model.

A three-dimensional computer model was developed to stimulate the ventricular depolarization and repolarization in a clinical setting. The ventricle is composed of approximately 50,000 units arranged in a cubic close-packed structure and the specialized conduction system is distributed so as to obtain the excitation sequence resembling normal ventricular depolarization. The normal distribution of action potential waveforms with the longest duration on the endocardium and the shortest on the epicardium is used in the model. The heart model is mounted in a homogeneous torso model, and the body surface potential distribution generated by the electric dipoles is calculated using the boundary element method. The QRST waveforms corresponding to the normal and some abnormal heart conditions, such as bundle branch block, myocardial infarction, apical hypertrophic cardiomyopathy, and Wolff-Parkinson-White syndrome, is obtained by assuming the abnormal area with altered electrical properties. Thus the three-dimensional computer model may provide further insight into the genesis of the clinical electrocardiogram.

Bundle-Branch Block↗
PubMed2005

An age-adjusted bootstrap-based Poly-k test.

The assumption of an asymptotic normal distribution of some test statistics may be invalid in certain dose-response trend tests. For instance, the survival-adjusted Cochran-Armitage test, known as the Poly-k test, is asymptotically standard normal under the null hypothesis. However, the asymptotic normality is not valid if there is a deviation from the tumour onset distribution that is assumed in this test or if the competing risks survival rates differ across groups. We develop an age-adjusted bootstrap-based method to assess the significance of assumed asymptotic normal tests for animal carcinogenicity data. The proposed method differs from conventional bootstrap methods in the aspect of preserving the mortality rate in each dose group under the null hypothesis of equal tumour incidence rates among the groups. We investigate an empirical distribution of the Poly-3 (P3) trend test statistic using the proposed age-adjusted bootstrap-based method and compare it with the P3 test statistic referenced to the assumed standard normal distribution. A simulation study is conducted to evaluate the robustness of these tests to various Weibull-family tumour onset distributions. The proposed method is applied to National Toxicology Program data sets to evaluate a dose-related trend of a test substance on the incidence of neoplasms.

Age Factors↗
PubMed1983

Parametric estimation of ventilation-perfusion ratio distributions.

We present a model and rigorous statistical approach for recovery of ventilation-perfusion ratio (V/Q) distribution parameters from multiple inert gas elimination data. We model the lung as a parallel combination of shunt, dead space, and one to three log-normal distributions of gas exchange units. This model provides a natural set of parameters for characterizing V/Q distributions. The log-normal terms are adjustable to represent smooth or sharp peaks in the distribution. Since the peak locations and widths are explicit in the model, very few parameters are needed. We select and estimate the significant parameters of the model by use of standard statistical tests and constrained least squares. This method provides two major advances in V/Q distribution estimation: 1) it allows flexible pooling and statistical comparisons of multiple experiments, and 2) it simultaneously gives both point estimates and 95% probability intervals for the V/Q distribution parameters. We present results of our procedure for data from humans in health, stress, and pulmonary disease. A program package, VQPAR, in FORTRAN is available for implementing the procedure.

Bayes Theorem↗
PubMed2006

Precision and bias of a normal finite mixture distribution model to analyze twin data when zygosity is unknown: simulations and application to IQ phenotypes on a large sample of twin pairs.

The classification of twin pairs based on zygosity into monozygotic (MZ) or dizygotic (DZ) twins is the basis of most twin analyses. When zygosity information is unavailable, a normal finite mixture distribution (mixture distribution) model can be used to estimate components of variation for continuous traits. The main assumption of this model is that the observed phenotypes on a twin pair are bivariately normally distributed. Any deviation from normality, in particular kurtosis, could produce biased estimates. Using computer simulations and analyses of a wide range of phenotypes from the U.K. Twins' Early Developments Study (TEDS), where zygosity is known, properties of the mixture distribution model were assessed. Simulation results showed that, if normality assumptions were satisfied and the sample size was large (e.g., 2,000 pairs), then the variance component estimates from the mixture distribution model were unbiased and the standard deviation of the difference between heritability estimates from known and unknown zygosity in the range of 0.02-0.20. Unexpectedly, the estimates of heritability of 10 variables from TEDS using the mixture distribution model were consistently larger than those from the conventional (known zygosity) model. This discrepancy was due to violation of the bivariate normality assumption. A leptokurtic distribution of pair difference was observed for all traits (except non-verbal ability scores of MZ twins), even when the univariate distribution of the trait was close to normality. From an independent sample of Australian twins, the heritability estimates for IQ variables were also larger for the mixture distribution model in six out of eight traits, consistent with the observed kurtosis of pair difference. While the known zygosity model is quite robust to the violation of the bivariate normality assumption, this novel finding of widespread kurtosis of the pair difference may suggest that this assumption for analysis of quantitative trait in twin studies may be incorrect and needs revisiting. A possible explanation of widespread kurtosis within zygosity groups is heterogeneity of variance, which could be caused by genetic or environmental factors. For the mixture distribution model, violation of the bivariate normality assumption will produce biased estimates.

Analysis of Variance↗
PubMed2003

Stochastic modeling approach to the incubation time of prionic diseases.

Transmissible spongiform encephalopathies are neurodegenerative diseases for which prions are the attributed pathogenic agents. A widely accepted theory assumes that prion replication is due to a direct interaction between the pathologic (PrP(Sc)) form and the host-encoded (PrP(C)) conformation, in a kind of autocatalytic process. Here we show that the overall features of the incubation time of prion diseases are readily obtained if the prion reaction is described by a simple mean-field model. An analytical expression for the incubation time distribution then follows by associating the rate constant to a stochastic variable log normally distributed. The incubation time distribution is then also shown to be log normal and fits the observed BSE (bovine spongiform encephalopathy) data very well. Computer simulation results also yield the correct BSE incubation time distribution at low PrP(C) densities.

Animals↗
PubMed1995

Immunocytochemical study of choline acetyltransferase in Drosophila melanogaster: an analysis of cis-regulatory regions controlling expression in the brain of cDNA-transformed flies.

We have analyzed the cis-regulatory regions in the 5' flanking DNA of the Drosophila melanogaster choline acetyltransferase (ChAT; E.C. 2.3.1.6) gene by using germline transformants. These transformants are carrying wild-type ChAT cDNA fused to different lengths of 5' flanking sequence of the ChAT gene. Appropriate genetic crosses were used to introduce the transgene into animals with a presumptive null genetic background for endogenous ChAT. Expression of ChAT protein could thus be attributed exclusively to the transgene. Using a monoclonal antibody against Drosophila ChAT, we have investigated the spatial distribution of transgenic ChAT and compared it to the normal distribution of ChAT protein in wild-type animals. The brains of 7.4 kb cDNA transformants showed a ChAT expression pattern similar to that of wild-type animals in the first- and second-order sensory neuropil but reduced expression in other highly ordered neuropil. Several lines that were transformed with 1.2 kb or 0.8 kb of 5' flanking DNA demonstrated relatively normal expression in sensory neuropil. In addition, these lines also showed ectopic expression in higher order neuropil. In the optic lobe, the expression pattern directed by 7.4 kb of 5' flanking DNA was very similar to that of wild-type ChAT expression. In contrast, 1.2 kb or 0.8 kb transformants showed reduced levels of expression and a more limited pattern of distribution in the optic lobe. Our results suggest that the 5' flanking DNA of the ChAT gene can be divided into several separable positive and negative regulatory regions, which define various subsets of cholinergic neurons in the nervous system.

Animals↗
PubMed2000

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.

BACKGROUND: Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. METHOD: Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. RESULTS: At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. CONCLUSION: Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.

Adolescent↗
PubMed1981

An alternative model for the evaluation of antitumor activity.

To date, in cancer clinical trials, treatment programs have been evaluated using objective tumor response as the primary means to demonstrate antitumor activity. This measure, which is based upon a dichotomous outcome whether or not a 50% decrease in tumor area has occurred, is complemented by the alternative measure of the distribution of the ratio of the tumor area taken at a fixed time point compared to the tumor area at the start of protocol treatment. It is inferred that the distribution of the tumor area ratio obeys a log-normal distribution for advanced gastric cancer and that this result may hold for many advanced measurable cancer studies. The identification of this distribution allows for the evaluation of treatment programs using parametric tests. In situations where log-normality does not apply, a Normal Scores test is recommended. This concept may be applied to completed studies to gain additional perspective regarding antitumor activity. A marked reduction in sample size requirements can be achieved when the tumor area ratio is used as a study design criteria. This approach is especially recommended in the phase II setting.

Antineoplastic Agents↗
PubMed1992

Model-based screening by risk with application to Down's syndrome.

Screening for a disorder may be carried out by assessing the risk that an individual is affected given the values of variables whose distributions alter when the disorder is present. An optimal screening policy is obtained by identifying those individuals whose risk is greater than some cut-off value. This paper summarizes the way in which risk is derived from the likelihood ratio of being affected by the disorder, and compares three different methods of estimating the likelihood ratio, namely direct estimation, logistic regression and distribution modelling. For continuous variables that have a multivariate normal distribution, screening by risk is equivalent to the use of quadratic discrimination. The paper shows how estimates of the risk and associated detection and false positive rates can be derived for a screening policy which uses specified risk cut-offs. Screening by risk has the counter-intuitive property that as the separation in the distribution of screening variables between affected and unaffected individuals increases, the detection and false positive rates may both increase. The approach is explored using data on antenatal screening for Down's syndrome. The method of choice is model-based; the model is described and tested for goodness of fit. Complications arising from outliers and non-normality must be overcome before an appropriate assessment of risk can be made. The concept of shrinkage is used to estimate the detection of false positive rates that may be expected in a new data set.

Confidence Intervals↗
PubMed2005

Validation of a method for estimating long-term exposures based on short-term measurements.

A method for estimating long-term exposures from short-term measurements is validated using data from a recent EPA study of exposure to fine particles. The method was developed a decade ago but long-term exposure data to validate it did not exist until recently. In this article, exposure data from repeated visits to 37 persons over 1 year (up to 28 measurements per person) are used to test the model. Both fine particle mass and elemental concentrations measured indoors, outdoors, and on the person are examined. To provide the most stringent test of the method, only two single-day distributions are randomly selected for each element to predict the long-term distributions. The precision of the method in estimating the long-term geometric mean and geometric standard deviation appears to be of the order of 10%, with no apparent bias. The precision in estimating the 99 th percentile ranges from 19% to 48%, again without obvious bias. The precision can be improved by selecting a number of pairs of single-day distributions instead of just one pair. Occasionally, the method fails to provide an estimate for the long-term distribution. In that case, a repeat of the random selection procedure can provide an estimate. Although the method assumes a log-normal distribution, most of the distributions tested failed the chi-square test for log-normality. Therefore, the method appears suitable for application to distributions that depart from log-normality.

Air Pollutants↗
PubMed1988

What is schizophrenia? Changing perspectives in epidemiology.

The psychotic syndrome at the core of schizophrenia appears to be invariable across cultures. The risk of morbidity also seems to vary very little from country to country and over medium periods of time. Moreover, apart from gender differences in first onset, the cumulative lifetime risk is the same in females and males. A similar epidemiological pattern is only found in pathological conditions that are characterized by a precisely defined section of a psychopathological dimension with a continuous distribution in the population, e.g. severe mental retardation being the extreme section of normally distributed IQ values. The interpretation of schizophrenic psychosis as the extreme section of a psychopathological dimension or disposition that is almost evenly distributed in all populations is supported by the fact that milder psychiatric disorders occur more frequently before the onset of the psychosis and in close relatives of schizophrenic patients. The psychopathological heterogeneity of these disorders argues against the assumption of a manifest psychopathological dimension with a continuous transition from the schizophrenic psychosis to the "normal" schizothymic personality. More probable is a continuously distributed latent vulnerability to schizophrenia--with or without a threshold effect--which in severe degrees disposes to the uniform reaction pattern of the schizophrenia syndrome. Smaller degrees of vulnerability are associated with an increased risk for milder patterns of disturbances, which are also more strongly determined by environment and personality and therefore are rather heterogeneous. These assumptions lead to other epidemiological and genetic models than Kraepelin's early concept of a disease entity does.

Female↗