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[The determination of the upper limits of year-round morbidity].

The use of K. Pearson's criterion has made it possible to establish that the empirical rows presenting the annual data on dysentery morbidity for each month during the period of many years correspond to binomial distribution. For this reason, the calculation of the highest limit of annual morbidity for many years should be made with the use of the formulae of great radices of quadratic inequation [formula: see text] used in mathematical statistics for the determination of the highest limits in binomial distribution. For the number of observations (n) not the number of inhabitants (which contradicts to the notion of observation in the theory of probability), but the number of minimal values of monthly morbidity, used for the calculation of the minimal average morbidity value omega or theta*, should be taken. To obtain objective results, the minimal average value omega or theta* and the ratio t2/2n must be of the same order, where t is the critical value of Student's criterion equal to 1.96.

Bacterial Infections

On the regularities of distribution of Hypoderma bovis De Geer larvae parasitizing cattle herds in different parts of the range of this warble fly.

The type and parameters of the distribution of the second and third instar larvae of Hypoderma bovis in cattle herds in Czechoslovakia (54 herds, 7233 head), Mongolia (20 herds, 1809 head) and the USSR (48 herds, 4978 head) were studied. A statistical analysis showed a) that in the majority of cases negative binomial distribution serves as a model of the distribution of larvae with sufficient reliability; b) that the regularity of dependence of the distribution exponent k of the negative binomial distribution on the incidence of infestation remains constant in different parts of the range of this warble fly. The latter fact indicates that the regulatory systems limiting the population numbers of this warble fly are associated with host-parasite relationships and do not depend on a complex of conditions specific for various natural zones. In order to understand the regulatory processes in parasite populations it is necessary to study equally the regulatory mechanisms operating primarily on the level of specimens as well as the regulatory systems operating on the level of populations.

Animals

On the regularities of distribution of Hypoderma bovis De Geer larvae parasitizine cattle herds in different parts of the range of this warble fly.

The type and parameters of the distribution of the second and third instar larvae of Hypoderma bovis in cattle herds in Czechoslovakia (54 herds, 7233 head), Mongolia (20 herds, 1809 head) and the USSR (48 herds, 4978 head) were studied. A statistical analysis showed a) that in the majority of cases negative binomial distribution serves as a model of the distribution of larvae with sufficient reliability; b) that the regularity of dependence of the distribution exponent k of the negative binomial distribution on the incidence of infestation remains constant in different parts of the range of thes warble fly. The latter fact indicates that the regulatory systems limiting the population numbers of this warble fly are associated with host-parasite relationships and do not depend on a complex of conditions specific for various natural zones. In order to understand the regulatory processes in parasite populations it is necessary to study equally the regulatory mechanisms operating primarily on the level of specimens as well as the regulatory systems operating on the level of populations.

Animals

Doxapram dosage regimen in apnea of prematurity based on pharmacokinetic data.

To 18 premature apneic patients refractory to theophylline, doxapram (0.5-2.5 mg/kg/h) was administered in combination with therapeutic doses of theophylline. Doxapram concentrations in serum were measured 48 h after commencement of the infusion and then in 2-hour intervals during a 6-8 h withdrawal. Total body clearance (dose/Css) of the drug ranged from 0.20 to 0.56 liter/h in 13 patients and 1.14 to 1.75 liter/h in 4 patients suggesting a binomial distribution in the disposition kinetics of the drug. Other pharmacokinetic indices, although variable, did not exhibit binomial distribution. The mean volume of distribution and half-life of doxapram were 7.33 +/- 4.55 liter/kg and 8.17 +/- 4.13 h, respectively. Based on our calculations to accelerate the attainment of a steady-state plasma concentration (Css) of approximately 1.5 mg/l, a loading dose of 5.5 mg/kg and a maintenance dose of 1 mg/kg/h along with serum concentration monitoring are recommended.

Apnea

Estimation and analysis of the concentration-response surfaces associated with multiple-agent combinations.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU) and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantified as measures of genotoxicity of the two agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with both agents simultaneously. Response surface methodology, using a polynomial model based on a negative binomial distribution of SCE events, was employed for analysis of the interactions of the two genotoxic agents. The negative binomial distribution, a generalization of the Poisson distribution, is required since SCEs are discrete variables which, under the conditions of these experiments, have a distribution which exhibits extra-Poisson variability. The model of the ENU/DDP combinations indicated an increasingly less-than-additive effect resulting from increasing concentrations of each agent in the combination. The analysis of these experiments demonstrates the usefulness of a powerful statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Cells, Cultured

The distribution of fetal death in control mice and its implications on statistical tests for dominant lethal effects.

In dominant lethal testing fetal death is generally assumed to follow either a Poisson or binomial distribution. However, both of these models were found to be inappropriate when three large sets of mouse control data and other data sets from the literature were examined. The validity of statistical test procedures based on these inappropriate models was then studied in detail. It was found that chi-square tests (which assume an underlying binomial distribution) may seriously exaggerate the level of significance and hence should not be used. In contrast, the inappropriateness of the underlying Poisson or binomial model appeared to have little effect on the validity of pairwise comparisons by analysis of variance procedures. Unlike chi-square, these procedures regard the pregnant female rather than the individual implant as the experimental unit. However, a statistical analysis of dominant lethal data generally involves more than a series of pairwise comparisons, and it is unclear how an invalid underlying model may affect statistical test procedures in this more complex situation. Moreover, it is difficult to justify the use of statistical models that are demonstrably invalid when a reasonable alternative exists. Thus, until a satisfactory parametric model can be found and appropriate test procedures derived, we prefer to analyze dominant lethal data by non-parametric (distribution-free) methods. Proportion of dead implants per female appears to be a more meaningful measure of fetal death than number of dead implants per female for several seasons which include (1) analyses based on proportions take the total number of implants per female into account and (2) analyses based on proportions make more reasonable assumptions concerning pre-implantation losses and are more powerful when such losses occur. Despite our concern with the appropriateness of the underlying model, in practice we have found few instances in which non-parametric and analysis of variance procedures have led to markedly different conclusions.

Animals

[Radiation damages in human lymphocytes studied by micronucleus and chromosomal analysis].

It was shown that the dependence of the micronucleus number and chromosome aberration on irradiation dose is linear quadratic, the values of linear coefficient being different. The distribution of ameliorators and children from the areas with higher irradiation level by micronucleus test conforms to Poisson distribution, while the distribution by chromosomal analysis approaches to binomial distribution.

Adult

Quantitative analysis of intercellular adhesive specificity in freshly explanted and cultured cells.

A new method is presented for the quantitative analysis of intercellular adhesive specificity. In this assay, two cell types are mixed, one unlabeled and the other labeled with the fluorescent dye, fluorescamine [4-phenylspiro(feran-2[3H],1'-phthalan)-3,3'-dione]. The resulting aggregates are analyzed by fluorescence microscopy to determine the number of labeled and unlabeled cells per aggregate. Random (nonspecific) aggregation was characterized by a binomial distribution, and adhesive specificity was accordingly quantified by the deviation (as determined by a chi-square test) from the calculated binomial distribution. The labeling procedure was simple and rapid, and experiments with 18 different cell types showed that it did not affect cell viability, morphology, rate and extent of adhesion, plating efficiency, and the capability of myogenic cells to undergo terminal differentiation. Most important, assays with morphologically identifiable cell pairs indicated that the fluorescent label neither induced apparent nor destroyed existing adhesive specificity. The most pronounced adhesive specificities were observed with freshly explanted cells from adult tissues and also with mixtures of simian virus 40-transformed and nontransformed BALB/c 3T3 cells. A glucosamine-6-phosphate N-acetylase-deficient mutant 3T3 line (AD6), however, aggregated randomly with parental 3T3 cells. Lectin-resistant mutant Chinese hamster ovary (CHO) cells displayed marginal adhesive specificity when mixed with normal CHO cells.

Adipose Tissue

Non-random chromosome loss in PHA-stimulated lymphocytes from normal individuals.

31773 lymphocyte metaphase cells from 280 karyotypically normal men aged 18-46 were examined for chromosome gain or loss. Chromosome loss was much more common than chromosome gain. Frequency of chromosome loss did not conform to a binomial distribution. There is a striking non-linear, inverse relationship between likelihood of loss and chromosome length. Chromosome gain shows a near binomial distribution between cells and no clear relationship to chromosome length. These facts indicate that the hypodiploid cells mostly arose as technical artefacts during slide preparation but that hyperdiploid cells were mainly due to non-disjunctional gain.

Adolescent

The statistical analysis of graft patency data in a clinical trial of antiplatelet agents following coronary artery bypass grafting.

Because most coronary artery bypass patients receive more than one graft at surgery, it is most important to determine whether statistical analysis of graft patency should be performed on the premise that the multiple grafts within patients are dependent or independent experimental units. Veterans Administration Cooperative Study No. 207 was a multicenter clinical trial comparing four different antiplatelet regimens to placebo in the prevention of graft occlusion following coronary artery bypass grafting. Using the results from the 1-week postoperative angiograms from the Veterans Administration Cooperative Study No. 207, in which there were 3.2 distal anastomoses per patient, we have tested the hypothesis that grafts within patients tend to act dependently with respect to patency or occlusion by comparing the graft patency data to a binomial distribution (i.e., that distribution that would have been manifest if grafts were independent). Because the graft patency results in Study No. 207 significantly deviated from the binomial distribution (p = 0.0003), a more appropriate analysis for graft patency data was applied using a ratio estimate as applied to cluster sampling. The statistical methods used in 11 previous clinical trials of antithrombotic therapy after coronary artery bypass grafting were examined. Only one of the previous studies used such an analysis, and three additional reports attempted to correct for dependency of grafts within patients in their analyses using other statistical methods. In seven of the studies the investigators did not address the potential problem of a dependent relationship between multiple grafts within patients. We conclude that grafts within patients act as dependent experimental units and that the ratio estimate as applied to cluster sampling may be appropriately applied to these data.

Clinical Trials as Topic

[Falsely positive values in multi-channel analysis: An iniquiry into reference and patient groups (author's transl)].

The number of falsely positive values occurring in 12-channel analysis was determined in two groups of patients and reference individuals. It revealed that the portion of falsely positive values actually found was statistically significant beyond that calculated on the assumption of a binomial distribution. Partly distinct correlations of the parameters combined to a profile as well as clear deviations from the normal distribution have to be taken into consideration as reasons for this discrepancy between theory and reality. The results show that the application of the binomial distribution leads to statements which significantly differ from the conditions actually present.

Autoanalysis

A reappraisal of the use of multiple choice questions.

The terms Multiple True/False and Best Answer deserve wider applicability than at present when discussing multiple choice questions (MCQs). They describe the truthfulness of the choices and distinguish between the question types. The choice which matches the key in a MCQ is best called the correct answer. Multiple True/False questions contain either true (accepted) or false (unaccepted) ideas in the correct answers while in the Best Answer type, all choices are true. Using a complex recording procedure to indicate the selections already made, as in the K-type MCQ, does not assess any additional abilities. Candidates answering Multiple True/False MCQs should be asked to respond to each choice as either true or false. This helps to discriminate between those who can detect the falsity of a false choice from those who cannot. When dealing with guessing, examiners need to be cognizant of issues such as blind guessing and informed guessing, proclivity for risk-taking, extension of the marking range and probabilities according to the binomial distribution.

Binomial Distribution

Substitution rate variation among sites in hypervariable region 1 of human mitochondrial DNA.

More than an order of magnitude difference in substitution rate exists among sites within hypervariable region 1 of the control region of human mitochondrial DNA. A two-rate Poisson mixture and a negative binomial distribution are used to describe the distribution of the inferred number of changes per nucleotide site in this region. When three data sets are pooled, however, the two-rate model cannot explain the data. The negative binomial distribution always fits, suggesting that substitution rates are approximately gamma distributed among sites. Simulations presented here provide support for the use of a biased, yet commonly employed, method of examining rate variation. The use of parsimony in the method to infer the number of changes at each site introduces systematic errors into the analysis. These errors preclude an unbiased quantification of variation in substitution rate but make the method conservative overall. The method can be used to distinguish sites with highly elevated rates, and 29 such sites are identified in hypervariable region 1. Variation does not appear to be clustered within this region. Simulations show that biases in rates of substitution among nucleotides and non-uniform base composition can mimic the effects of variation in rate among sites. However, these factors contribute little to the levels of rate variation observed in hypervariable region 1.

Biological Evolution

Dispersion statistics and sample size estimates for house fly (Diptera: Muscidae) larvae and Macrocheles muscaedomesticae (Acari: Macrochelidae) in poultry manure.

The precision of the density estimate for a given population depends upon the population's density and degree of clumping and upon sampling characteristics, such as the number and surface area of the quadrats. The parameters k of the negative binomial distribution and b of Taylor's power law (s2 = a mean b) were determined for third instars of the muscaedomesticae (Scopoli), which were sampled by random quadrats at two shallow-pit, caged-layer poultry houses. Most calculated values of k were < 1, but agreement with the negative binomial distribution was found only in 4, 18, and 14 of the 27 weekly samples for house fly larvae, female mites, and male mites, respectively. Taylor's power law provided the best fit for the distribution (P < 0.01 for all regression coefficients) with s2 = 9.08 mean 1.83 (r2 = 0.97) for third-instar house flies and s2 = 4.65 mean 1.76 (r2 = 0.97) for both sexes of M. muscaedomesticae. Two ecological processes, social clustering and environmental heterogeneity, were hypothesized as the mechanisms determining aggregation of house fly larvae and the macrochelid mites. Regardless of the biological model influencing their distributions, Taylor's power law provided a reliable index for measuring their degree of aggregation. Reliability defined by the coefficient of variability and Taylor's regression coefficients was used to calculate optimum sample size-density estimates for each species with coefficients of variability of 10, 15, 20, and 25%.

Animals

Subclass approach for mutational spectrum analysis.

Analysis and comparison of mutational spectra represents a burning question in molecular biology. We report an algorithm based upon the SEM subclass approach (SEM--stochastique, estimations, maximizations). Any real mutational spectrum is regarded as a mixture of standard binomial distributions. The separation procedure is run by rounds. Each iteration includes simulation, maximization and estimation. The algorithm has been checked on random spectra with the preset parameters and on real mutational spectra. As has been shown, any real mutational spectrum can be represented as a mixture of two and more binomial distributions, of which one contains hotspots of mutation.

Algorithms

Random partitioning of cytoplasmic organelles at cell division: the effect of organelle and cell volume.

When a cell divides, some cytoplasmic organelles may be partitioned randomly between the daughters. The number of organelles in each daughter is usually calculated from the binomial distribution, which assumes that the organelles occupy zero volume. We developed equations to predict numerical partitioning taking the volume of the organelles and of the cell into account. The effect of large organelle volume is that daughter cells receive equal or nearly equal numbers of organelles more often than predicted by the binomial distribution. However, numerical solutions show that volume effects are very small unless the number of organelles is very small or they occupy more than about 50% of the available cell volume.

Cell Compartmentation

The question of the total gene number in Drosophila melanogaster.

A statistical analysis has been carried out on the distribution and allelism of nearly 500 sex-linked, X-ray-induced, cytologically normal and rearranged lethal mutations in Drosophila melanogaster that were obtained by G. Lefevre. The mutations were induced in four different regions of the X chromosome: (1) 1A1-3E8, (2) 6D1-8A5, (3) 9E1-11A7 and (4) 19A1-20F4, which together comprise more than one-third of the entire chromosome.--The analysis shows that the number of alleles found at different loci does not fit a Poisson distribution, even when the proper procedures are taken to accommodate the truncated nature of the data. However, the allele distribution fits a truncated negative binomial distribution quite well, with cytologically normal mutations fitting better than rearrangement mutations. This indicates that genes are not equimutable, as required for the data to fit a Poisson distribution.--Using the negative binomial parameters to estimate the number of genes that did not produce a detectable lethal mutation in our experiment (n0) gave a larger number than that derived from the use of the Poisson parameter. Unfortunately, we cannot estimate the total numbers of nonvital loci, loci with undetectable phenotypes and loci having extremely low mutabilities. In any event, our estimate of the total vital gene number was far short of the total number of bands in the analyzed regions; yet, in several short intervals, we have found more vital genes than bands; in other intervals, fewer. We conclude that the one-band, one-gene hypothesis, in its literal sense, is not true; furthermore, it is difficult to support, even approximately.--The question of the total gene number in Drosophila will, not doubt, eventually be solved by molecular analyses, not by statistical analysis of mutation data or saturation studies.

Alleles

Evaluation of a measure of neonatal morbidity.

The neonatal risk score of Hobel et al. was evaluated as a measure of neonatal morbidity in a sample of 1,600 singleton infants born alive at two institutions. The score was evaluated for internal consistency, the appropriateness of weight assigned to factors, criterion validity, and conformity to the negative binomial distribution. The results are encouraging for the use of the score as a measure of neonatal morbidity. It appears internally consistent. All risk factors occur with some frequency with at least one other and, in most instances, with several others. With one exception, all factors distinguish infants with high and low scores. The neonatal score, defined by a weighted score and by the number of factors, is highly correlated with length of infant stay in the nursery. Correlations are higher for scores of events measured after birth than for scores of events measured directly at birth. The authors recommend that the number of risk factors be used in preference to the weighted neonatal score since it conforms to the negative binomial distribution and is simpler to calculate. The potential uses of a quantitative, comprehensive measure of neonatal morbidity ar discussed.

Apgar Score