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PubMed2001

Incorporation of covariates in multipoint model-free linkage analysis of binary traits: how important are unaffecteds?

When the mode of inheritance is unknown, genetic linkage analysis of binary trait is commonly performed using affected-sib-pair approaches. When there is evidence that some covariates influence the phenotype, incorporation of this information is expected to increase the power of the analysis since it allows (1) a better specification of the phenotype and (2) to take into account unaffected subjects. Here, we show how to account for covariates in the sibship-oriented Maximum-Likelihood-Binomial (MLB) linkage method by means of Pearson's logistic regression residuals which are computed using phenotypic and covariate information on both affected and unaffected subjects. These residuals are subsequently analysed as a quantitative phenotype with the corresponding extension of the MLB approach which can be used without any assumption on the distribution of these residuals. Then, a large simulation study is performed to study the relative power of incorporating or not unaffected sibs. To this aim, two different strategies in the multipoint analysis of family data are compared: (1) using residuals of the whole sibships (ie both covariate and genotypic information on unaffecteds is needed), and (2) using affecteds only (no information on unaffecteds is needed), under different generating models according to genetic and covariate effects. The results show that there is a clear increment in the power to detect the susceptibility locus when making use of the information carried by unaffecteds, in particular for dominant mode of inheritance and when values of the covariates influencing the disease are shared by all the members of the family.

Analysis of Variance↗
PubMedDate not supplied

Some neural effects of adenosin.

The possible neural effects of adenosine were investigated by using electrophysiological techniques at the level of some central and peripheral synapses. The evoked potentials in the somatosensorial cerebral cortex are influenced according to both the type of administration and the level of the electrical stimulation. While the local application does not induce significant alterations, the intrathalamic injections and the perfusion of the IIIrd cerebral ventricle do change the distribution of activated units at the level of different cortical layers especially during the peripheral stimulation. The frequency of spontaneous miniature discharges intracellularly recorded in the neuromuscular junction (mepp) is significantly depressed by adenosine. This effect is calcium- and dose-dependent. The end plate potentials (EPP) were also depressed. The statistical binomial analysis of the phenomenon indicated that adenosine induces a decrease if the presynaptic pool of the available transmitter. The data obtained demonstrate a presynaptic inhibitory action of adenosine beside its known vascular and metaholic effects.

Adenosine↗
PubMed2026

Investigating telomere length and hTERT-MNS16A VNTR polymorphism in Bipolar disorder: Insights into clinical features.

OBJECTIVE: To compare leukocyte telomere length (LTL; T/S ratio) and hTERT-MNS16A VNTR polymorphism between patients with bipolar disorder (BD) and healthy controls, and to examine their associations with clinical features in BD. METHODS: A total of 179 participants (100 BD patients, 79 healthy controls) were enrolled. Relative LTL was assessed by qPCR-based T/S ratio; hTERT-MNS16A VNTR genotyping by PCR and gel electrophoresis. Clinical variables including episode frequency, illness duration, age at onset, symptom severity scales, first episode polarity, and family history of mood disorder were evaluated. RESULTS: No significant differences were observed between BD patients and healthy controls in T/S ratio or hTERT-MNS16A VNTR genotype distributions (all p > 0.05). Within the BD group, S allele carriers (L/S or S/S) had significantly more depressive episodes than L/L homozygotes (1.45 &#xb1; 2.58 vs. 0.61 &#xb1; 1.52; p = .040). Significant inverse correlations were identified between T/S ratio and depressive episode count (&#x3c1; = -0.220, p = .028) and total mood episodes (&#x3c1; = -0.207, p = .039). Multivariable negative binomial regression revealed four independent predictors of depressive episode frequency: lower T/S ratio (p = 0.005), S allele carriage (L/S or S/S genotypes) (p = 0.001), first depressive episode polarity (p < 0.001), and family history of mood disorder (p = 0.035). CONCLUSION: Although LTL and hTERT-MNS16A VNTR genotype did not differ between BD patients and healthy controls, shorter telomere length and S allele carriage were independently associated with higher depressive episode frequency within the BD group, implicating telomere biology and hTERT genetic variation in the biological substrate of depressive illness burden.

Humans↗
PubMed2006

Oral lesions in elderly population: a biopsy survey using 2250 histopathological records.

OBJECTIVE: To perform an oral biopsy survey focused on the incidence of oral lesions in Brazilian elderly patients. METHODS: A total of 17 329 oral biopsy records were analysed and divided into two age groups: elderly patients, > or =60 years old; and non-elderly patients, <60 years old. Information about sex, race, age and histopathological diagnosis (categorised in non-neoplastic and neoplastic lesions) was collected. Differences of diagnosis incidence were tested by comparison between two proportions (binomial test). RESULTS: The incidence of epithelial malignant neoplasms and pre-malignant lesions in the elderly group was higher than non-elderly group, as well as autoimmune diseases and salivary gland tumours. The three most prevalent lesions in the elderly group were inflammatory fibrous hyperplasia, squamous cell carcinoma, and fibroma. CONCLUSION: The distribution of oral diseases using biopsies allows greater accuracy in data about oral health of elderly patients, especially when considering malignant and pre-malignant lesions.

Age Distribution↗
PubMed2003

Dealing with discreteness: making 'exact' confidence intervals for proportions, differences of proportions, and odds ratios more exact.

'Exact' methods for categorical data are exact in terms of using probability distributions that do not depend on unknown parameters. However, they are conservative inferentially. The actual error probabilities for tests and confidence intervals are bounded above by the nominal level. This article examines the conservatism for interval estimation and describes ways of reducing it. We illustrate for confidence intervals for several basic parameters, including the binomial parameter, the difference between two binomial parameters for independent samples, and the odds ratio and relative risk. Less conservative behavior results from devices such as (1) inverting tests using statistics that are 'less discrete', (2) inverting a single two-sided test rather than two separate one-sided tests each having size at least half the nominal level, (3) using unconditional rather than conditional methods (where appropriate) and (4) inverting tests using alternative p-values. The article concludes with recommendations for selecting an interval in three situations-when one needs to guarantee a lower bound on a coverage probability, when it is sufficient to have actual coverage probability near the nominal level, and when teaching in a classroom or consulting environment.

Biomedical Research↗
PubMed2001

Age distributions of horses with strangulation of the small intestine by a lipoma or in the epiploic foramen: 46 cases (1994-2000).

OBJECTIVE: To test the hypothesis that strangulation of the small intestine by a lipoma or in the epiploic foramen is more common in older horses. DESIGN: Retrospective study. ANIMALS: 46 horses. PROCEDURE: Ages of horses with strangulation of the small intestine by a lipoma (n = 29) or in the epiploic foramen (17) were compared with ages of 79 horses with miscellaneous small intestinal lesions. Effects of increasing age on risk of the diseases of interest were examined by use of logistic regression and a 1-sided trend test for binomial proportions. RESULTS: Mean age of the horses with strangulation in the epiploic foramen (9.6 years) was the same as that for the horses with miscellaneous small intestinal lesions (7.7), but mean age of the horses with strangulation by a lipoma (19.2) was significantly greater than that for the other groups. The proportion of horses with lipoma increased significantly with increasing age, but the proportion with strangulation in the epiploic foramen did not. CONCLUSIONS AND CLINICAL RELEVANCE: Results refute the current suggestion that increasing age predisposes horses for strangulation of the small intestine in the epiploic foramen but support the suggestion that the risk of strangulation of the small intestine by a lipoma increases with age.

Age Distribution↗
PubMed1998

Exact tests of equivalence and efficacy with a non-zero lower bound for comparative studies.

Exact tests of equivalence and efficacy with a non-zero lower bound based on two independent binomial proportions for comparative trials are proposed. These exact tests are desirable for studies with small sample sizes. They generalize classical methods to include testing of null hypotheses of prespecified differences and can be used to demonstrate a new treatment's efficacy or its equivalence to a standard treatment. The proposed exact tests use unconditional distributions of the test statistics. Variances of test statistics are estimated via a constrained maximum likelihood method (Farrington and Manning). Data from oncology and vaccine clinical trials are used to illustrate the exact tests.

Child↗
PubMed1992

Modeling of the quantal release at interneuronal synapses: analysis of permissible values of model moments.

A theoretical study of effects of the different factors on fluctuation of post-synaptic potential (PSP) amplitudes was undertaken, using computation of regions of permissible values (RPV) of the ratio between the variance and the mean number of the quanta released (R1) and the ratio between the third moment and the variance (R2). The RPVs of these indexes for the binomial model were compared with regions determined for a number of models incorporating several factors. It has been shown that the involvement of temporal non-uniformity of transmitter release probability, decremental spreading of potentials along dendrites, and failure of spike propagation give the values of skewness index R2 less, compared to the binomial model. Simultaneously, a number of other factors, especially spatial non-uniformity of release probabilities in single release sites, would give amplitude histograms with high positive values of the index. The values of R1 and R2, calculated for 21 samples of sensorimotor EPSP amplitudes, were biased from RPV of these parameters constructed for the binomial model. The scattergram of R1 and R2 can be explained by the presence of two kinds of contacts which release quantum with different probabilities. The same was true for the beta-model based on the assumption that probabilities of quantal release are a sample of values of random variable that has beta-distribution. From analysis of the distribution of individual release probabilities, obtained from evaluation of beta-model parameters, is concluded that a greater part of boutons in the sensorimotor synapses release transmitter with very low probabilities, there being, however, a few boutons with probabilities close to 1.

Animals↗
PubMed2004

Improved confidence intervals for a binomial parameter following a group sequential phase II clinical trial.

Group sequential procedures are widely employed in phase II clinical trials. It is often desirable to provide an interval estimate of the true response rate upon termination of a group sequential phase II clinical trial. The confidence intervals proposed by Jennison and Turnbull (Technometrics 1983; 25: 49-58) are conservative. Utilization of auxiliary statistics based on the overall disease status is proposed to reduce the discreteness of the underlying distribution. Confidence intervals generated by the proposed methods have confidence coefficients closer to the nominal level and have shorter average lengths than JT.

Antineoplastic Agents↗
PubMed2006

Bayesian sample size calculations in phase II clinical trials using a mixture of informative priors.

A number of researchers have discussed phase II clinical trials from a Bayesian perspective. A recent article by Mayo and Gajewski focuses on sample size calculations, which they determine by specifying an informative prior distribution and then calculating a posterior probability that the true response will exceed a prespecified target. In this article, we extend these sample size calculations to include a mixture of informative prior distributions. The mixture comes from several sources of information. For example consider information from two (or more) clinicians. The first clinician is pessimistic about the drug and the second clinician is optimistic. We tabulate the results for sample size design using the fact that the simple mixture of Betas is a conjugate family for the Beta- Binomial model. We discuss the theoretical framework for these types of Bayesian designs and show that the Bayesian designs in this paper approximate this theoretical framework.

Algorithms↗
PubMed1991

Relation between structural and release parameters at the young rat sensorimotor connection.

The present work was carried out on isolated spinal cords of young rats. The aim of this study was the combined morphological and electrophysiological investigation of sensorimotor connections labelled with horseradish peroxidase and the evaluation of the relationship between their structural and functional properties. Sensorimotor contacts were widely distributed along the postsynaptic cell: from the soma and juxtasomatic dendrites to distal dendrites. The number of contacting boutons in the connection of a single afferent fibre and an individual motoneuron was about 10. The amplitude fluctuation patterns of the unitary and the minimal excitatory postsynaptic potentials of the motoneurons fitted with predictions based on a binomial model. A close correspondence was found between the estimated number of binomial release sites, n, and the number of contacting boutons. The calculated size of the quantal potential was about 100 microV. The difference in the organization of sensorimotor connections of the young rat and the frog is discussed.

Afferent Pathways↗
PubMed1998

Prevalence estimation under heterogeneity in the example of bovine trypanosomosis in Uganda.

We examine variance estimators of a binomial parameter established under cluster sampling using data from a cross-sectional study of bovine trypanosomosis in Mukono County, Uganda. Fifty farms (referred to as clusters), were sampled with a total sample size of 487 cattle. Trypanosomes were found in 17.9% (87/487) of the total sample. The cluster-level (CL) prevalences were not homogeneously distributed. According to maximum-likelihood parameters established by mixture-distribution analysis, 18% of the cluster had 0% prevalence whereas 48% and 34% of the clusters could be allocated to subpopulations of clusters with mean prevalences 11.6% and 31.9% respectively. We show that this form of heterogeneity invalidates the applicability of the Beta distribution as a model for the distribution of CL prevalences. Furthermore, we provide empirical evidence for a variance inflation due to heterogeneity (inflation factor 2.07) that exceeds the design-based variance inflation due to clustering alone (inflation factor 1.82). The variance inflation due to heterogeneity is given in a closed form so that the approach can be conveniently applied to survey data that involve cluster sampling under heterogeneity.

Animals↗
PubMed2002

[Variability of the number of chloroplasts in a population of stoma guard cells in the sugar beet (Beta vulgaris L.)].

Diploid sugar beet plants demonstrate a broad variability of the number of chloroplasts in stoma guard cells, which is related to myxoploidy of cell populations in leaf apical meristems (epigenomic variability). In addition to random organelle segregation between daughter cells, this variability is affected by factors disrupting the mitotic cycle: (1) plant treatment with a mitotic poison, such as colchicine; (2) duration of the life cycle of a plant; the variability in second-year plants is greater than in first-year ones; (3) the mode of plant reproduction; the variability in inbred plants is greater than in the initial population. Treatment of germinating seeds with a diluted colchicine solution increases the number of organelles in cells in the myxoploid generation (generation C0) and the variance of the distributions in the first vegetation year. The variability in the organelle number in stoma cells correlates with that in maternal meristem cells. It is concluded that the epidermal cell monolayer (including stoma guard cells) keeps record of the epigenomic and epiplastome variability in meristem cells. The variability of the number of chloroplasts in stoma guard cells is approximated by binomials with negative powers.

Beta vulgaris↗
PubMed1990

Structure-distribution relationship studies of 99mTc-2,3-dioxime complexes.

The structure-distribution relationship studies of a homologous series of anionic 99mTc-2,3-dioximinoalkanes in mice, showed very low specific organ uptakes due to a combination of rapid clearance and excessive blood binding factors as found for the cationic 99mTc-diamine analogues (Salako and Theobald, Nucl. Med. Biol. 17, 437-441; 1990. The dioxime complexes showed a preference for hepatobiliary clearance unlike the diamine complexes which were cleared through the renal tract. The relationship between the amount cleared through the biliary tract and molecular weight of the dioxime complexes is binomial, with the optimum about the C-8 chain homologue. The hepatobiliary clearance model which was discovered for these complexes follows a multiple correlation equation which has a combination of four physico-chemical properties in the order: log P, charge, protein binding and molecular weight. It was observed particularly that the log P and charge have broadly similar magnitudes (to those in the urinary model of the diamine complexes) but reversed signs. The sign on the charge coefficient is negative, indicating that an overall negative charge is required for efficient hepatobiliary extraction and excretion of these Tc-complexes.

Animals↗
PubMed1989

Estimating the size of the dividing stem cell pool after allogeneic bone marrow transplantation.

Currently the problem of estimation of the number of pluripotent stem cells reconstituting marrow grafts following bone marrow transplantation, or studies looking at questions of clonal dominance in hematopoietic cell populations, rely on indirect measurement and a simple application of the formula for the sampling variation of a binomial proportion. This approach, from a statistical viewpoint, can be seen to be flawed. It is very easily remedied though and only requires appropriate use of variance stabilizing transformations. These lead to a very simple estimator for the number of hematopoietic stem cells involved in repopulating the marrow and require little in the way of additional calculation. We give the distribution theory for this estimator as well as simple approximations for practical application. As an illustration we rework data recently gathered to address the question as to whether or not reconstitution of marrow grafts in the clinical setting is oligoclonal.

Bone Marrow Transplantation↗
PubMed2006

Quantifying genomic imprinting in the presence of linkage.

Genomic imprinting decreases the power of classical linkage analysis, in which paternal and maternal transmissions of marker alleles are equally weighted. Several methods have been proposed for taking genomic imprinting into account in the model-free linkage analysis of binary traits. However, none of these methods are suitable for the formal identification and quantification of genomic imprinting in the presence of linkage. In addition, the available methods are designed for use with pure sib-pairs, requiring artificial decomposition in cases of larger sibships, leading to a loss of power. We propose here the maximum likelihood binomial method adaptive for imprinting (MLB-I), which is a unified analytic framework giving rise to specific tests in sibships of any size for (i) linkage adaptive to imprinting, (ii) genomic imprinting in the presence of linkage, and (iii) partial versus complete genomic imprinting. In addition, we propose an original measure for quantifying genomic imprinting. We have derived and validated the distribution of the three tests under their respective null hypotheses for various genetic models, and have assessed the power of these tests in simulations. This method can readily be applied to genome-wide scanning, as illustrated here for leprosy sibships. Our approach provides a novel tool for dissecting genomic imprinting in model-free linkage analysis, and will be of considerable value for identifying and evaluating the contribution of imprinted genes to complex diseases.

Biometry↗
PubMed1993

Statistical considerations for cross-sectional data relating to tracheal reconstruction over time.

Complementary statistical analyses are performed on data concerning tracheal reconstruction in rats. The principal response criterion is vessel area as defined by the area of a graft onto the trachea covered by blood vessels. Postoperatively, this vessel area changes in a nonlinear fashion over time. Starting at 0% immediately postoperation, the vessel area increases to a peak and then sharply decreases to a certain level at which it remains. A total of 64 independently observed cross-sectional pairs (postop day, vessel area) are distributed among four treated groups. Analysis consists of two-way analysis of variance and piecewise linear regression under the usual assumptions of normality and variance homogeneity. Other analyses that relax these assumptions are also considered; treatment differences are established by nonparametric tests, and a quasi-likelihood analysis of the piecewise linear regression model is applied under the assumption of a binomial-like variance function. The resulting fit of the normal-theory-based piecewise linear model is compared to that of a nonlinear model whose shape is that of a gamma function integrand.

Analysis of Variance↗
PubMed1986

Probabilistic determination of synaptic strength.

This work was carried on to analyze the presynaptic components of synaptic efficacy, which is designated by the term of synaptic strength. To assess the relations between synaptic strength and innervation density, the properties of unitary Cl(-)-dependent inhibitory postsynaptic potentials (IPSPs) evoked in the potentials (IPSPs) evoked in the goldfish Mauthner (M-) cell by single impulses in individual presynaptic cells, including quantal release parameters, were compared with the histological features of the same neurons, determined from their reconstructions after intracellular injection with horseradish peroxidase (HRP). Because the M-cell is a stereotyped target neuron, comparison of the synaptic strength from different experiments was accomplished by using as a quantitative measure of this parameter the mean unitary IPSP amplitude normalized with respect to the reversal potential for Cl- (i.e., the driving force). In 108 experiments at low stimulus frequency, the majority of the normalized responses (63%) were grouped in a rather narrow range, varying about fourfold, or from 1.5 to 6% of the driving force, with results from stained (n = 46) and unstained (n = 62) cells being the same. In contrast, for the same restricted set of responses, the number of presynaptic terminals (histological n) encompassed a larger range, varying from 3 to 52. Impulses in neurons with quite different complements of terminal boutons could evoke similarly sized, normalized IPSPs, and these two parameters were poorly correlated, with there being, at most, a tendency for the responses to increase with histological n for small values of the latter. Quantal fluctuations in IPSP amplitudes were analyzed according to a binomial model having three parameters, p, which is the probability of release, n, which is the number of releasing units and was previously shown to equal the number of presynaptic boutons or active sites, and q, or the quantal size. The normalized quantal size varied randomly, with a mean value of 0.51% (SD = 0.20) and was relatively independent of n. In contrast, the distribution of p, which ranged from 0.17 to 0.74 (mean = 0.40, SD = 0.155), was skewed to the right; this parameter tended to decrease as a function of increasing n. The normalized unitary inhibitory conductance (g'IPSP) underlying an IPSP is equal to the product of npg'q, where g'q is the normalized quantal conductance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗