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PubMed2005

Sample size calculation should be performed for design accuracy in diagnostic test studies.

BACKGROUND AND OBJECTIVES: Guidelines for conducting studies and reading medical literature on diagnostic tests have been published: Requirements for the selection of cases and controls, and for ensuring a correct reference standard are now clarified. Our objective was to provide tables for sample size determination in this context. STUDY DESIGN AND SETTING: In the usual situation, where the prevalence Prev of the disease of interest is <0.50, one first determines the minimal number Ncases of cases required to ensure a given precision of the sensitivity estimate. Computations are based on the binomial distribution, for user-specified type I and type II error levels. The minimal number N(controls) of controls is then derived so as to allow for representativeness of the study population, according to Ncontrols=Ncases [(1-Prev)/Prev]. RESULTS: Tables give the values of Ncases corresponding to expected sensitivities from 0.60 to 0.99, acceptable lower 95% confidence limits from 0.50 to 0.98, and 5% probability of the estimated lower confidence limit being lower than the acceptable level. CONCLUSION: When designing diagnostic test studies, sample size calculations should be performed in order to guarantee the design accuracy.

Biomedical Research↗
PubMed2005

A Colombian survey found intensive care mortality ratios were better in private vs. public hospitals.

BACKGROUND: Our main outcome was to identify organizational characteristics that help to evaluate the differences between the intensive care mortality ratios adjusted by APACHE II. We incorporated the variation associated with the ranking of institutions simulating its random effects under a binomial distribution. METHODS: A nationwide survey on structure, technology, and staffing resources available in Colombian intensive care units during 1997-1998 was conducted. We collected data on admissions from 20 randomly selected adult medical and surgical intensive care units. RESULTS: The mortality ratio from the 20 intensive care units ranged from 0.59 to 2.36; 80% of the intensive care units had a mortality ratio greater than 1. All four intensive care units with the lowest mortality ratio belonged to private institutions, while four of five institutions with the highest mortality belonged to the public sector. Intensive care units in private institutions also had fewer number of beds, lower median length of stay, lower occupancy rates, higher education training for specialists and nurses and fewer emergency nonelective surgical procedures. CONCLUSION: We successfully accounted for intensive care mortality baseline differences and random effects variations. There were substantial differences between intensive care units in institution type, bed availability, technology, staffing resources, and degree of training, which may have been associated with patient outcome. These results are of crucial importance to track, detect and assess future changes.

Adult↗
PubMed2005

A quantitative description of the binding states and in vitro function of antitermination protein N of bacteriophage lambda.

The N protein of bacteriophage lambda activates transcription of genes that lie downstream of termination sequences by suppressing transcription termination. N binds to specific (boxB) and non-specific sites on the transcript RNA and contacts RNA polymerase via cis-RNA looping, resulting in "antitermination" of transcription. To find the effect of N-boxB binding on antitermination, we quantitatively relate binding measurements made in isolation to in vitro antitermination activity. We measure binding of N to boxB RNA, non-specific single-stranded RNA, and non-specific double-stranded DNA fluorimetrically, and use an equilibrium model to describe quantitatively the binding of N to nucleic acids of Escherichia coli transcription elongation complexes. We then test the model by comparison with in vitro N antitermination activity measured in reactions containing these same elongation complexes. We find that binding of N protein to the nucleic acid components of transcription elongation complexes can quantitatively predict antitermination activity, suggesting that antitermination in vitro is determined by a nucleic acid binding equilibrium with one molecule of N protein per RNA transcript being sufficient for antitermination. Elongation complexes contain numerous overlapping non-specific RNA and DNA-binding sites for N; the large number of sites compensates for the low N binding affinity, so multiple N proteins are expected to bind to elongation complexes. The occupancy/activity of these proteins is described by a binomial distribution of proteins on transcripts containing multiple non-specific sites. The contribution of specific (boxB) binding to activity also depends on this distribution. Specificity is not measured accurately by measurements made in the presence and in the absence of boxB. We find that antitermination is inhibited by non-productive binding of N to non-specific sites on template DNA, and that NusA protein covers RNA sites on the transcript, limiting N access and activity. The activity and specificity of regulatory proteins that loop from high-affinity binding sites are likely modulated by multiple non-specific binding events; in vivo activity may also be regulated by the modulation of non-specific binding.

Bacteriophage lambda↗
PubMed2004

Inbreeding coefficients for stochastically varying small population sizes-bias of calculation based on effective numbers.

The commonly used procedure to calculate inbreeding coefficients by effective population numbers (Ne) by the harmonic mean of generation-by-generation population sizes involves a computational bias. If the individual population sizes are considered as realizations of a binomially distributed random variable with sample size N and probability p, this bias can be investigated for the two cases p = constant and p = variable (Markov chain). The bias is of practical relevance only for small probabilities p, short period of initial successive generations, and small population sizes. The largest values for this computational bias are in the range of 0.05-0.06. It is concluded that for most practical purposes the approximate procedure is appropriate.

Animals↗
PubMed2006

Some properties of a simple stochastic epidemic model of SIR type.

We investigate the properties of a simple discrete time stochastic epidemic model. The model is Markovian of the SIR type in which the total population is constant and individuals meet a random number of other individuals at each time step. Individuals remain infectious for R time units, after which they become removed or immune. Individual transition probabilities from susceptible to diseased states are given in terms of the binomial distribution. An expression is given for the probability that any individuals beyond those initially infected become diseased. In the model with a finite recovery time R, simulations reveal large variability in both the total number of infected individuals and in the total duration of the epidemic, even when the variability in number of contacts per day is small. In the case of no recovery, R=infinity, a formal diffusion approximation is obtained for the number infected. The mean for the diffusion process can be approximated by a logistic which is more accurate for larger contact rates or faster developing epidemics. For finite R we then proceed mainly by simulation and investigate in the mean the effects of varying the parameters p (the probability of transmission), R, and the number of contacts per day per individual. A scale invariant property is noted for the size of an outbreak in relation to the total population size. Most notable are the existence of maxima in the duration of an epidemic as a function of R and the extremely large differences in the sizes of outbreaks which can occur for small changes in R. These findings have practical applications in controlling the size and duration of epidemics and hence reducing their human and economic costs.

Algorithms↗
PubMed2004

Voxel-based homogeneity probability maps of gray matter in groups: assessing the reliability of functional effects.

A subject of increasing importance in magnetic resonance imaging (MRI) is the analysis of intersubject structural differences, particularly when comparing groups of subjects with different conditions or diagnoses. On the other hand, determining structural homogeneity across subjects using voxel-based morphological (VBM) methods has become even more important to investigators who test for group brain activation using functional magnetic resonance images (fMRI) or positron emission tomography (PET). In the absence of methods that evaluate structural differences, one does not know how much reliability to assign to the functional differences. Here, we describe a voxel-based method for quantitatively assessing the homogeneity of tissues from structural magnetic resonance images of groups. Specifically, this method determines the homogeneity of gray matter for a group of subjects. Homogeneity probability maps (HPMs) of a given tissue type (e.g., gray matter) are generated by using a confidence interval based on binomial distribution. These maps indicate for each voxel the probability that the tissue type is gray for the population being studied. Therefore, HPMs can accompany functional analyses to indicate the confidence one can assign to functional difference at any given voxel. In this paper, examples of HPMs generated for a group of control subjects are shown and discussed. The application of this method to functional analysis is demonstrated.

Adult↗
PubMed2004

Estimation of infection prevalence from correlated binomial samples.

Infection prevalence in a population often is estimated from grouped binary data expressed as proportions. The groups can be families, herds, flocks, farms, etc. The observed number of cases generally is assumed to have a Binomial distribution and the estimate of prevalence is then the sample proportion of cases. However, the individual binary observations might not be independent--leading to overdispersion. The goal of this paper was to demonstrate random-effects models for the estimation of infection prevalence from data which are correlated and in particular, to illustrate a nonparametric random-effects model for this purpose. The nonparametric approach is a relatively recent addition to the random-effects class of models and does not appear to have been discussed previously in the veterinary epidemiology literature. The assumptions for a logistic-regression model with a nonparametric random effect were outlined. In a demonstration of the method on data relating to Salmonella infection in Irish pig herds, the nonparametric method resulted in the classification of herds into a small number of distinct prevalence groups (i.e. low, medium and high prevalence) and also estimated the relative frequency of each prevalence category in the population. We compared the estimates from a logistic model with a nonparametric distribution for the random effects with four alternative models: a logistic-regression model with no random effects, a marginal model using a generalised estimating equation (GEE) and two methods of fitting a Normally distributed random effect (the GLIMMIX macro and the NLMIXED procedure both in SAS). Parameter estimates from random-effects models are not readily interpretable in terms of prevalences. Therefore, we outlined two methods for calculating population-averaged estimates of prevalence from random-effects models: one using numerical integration and the other using Monte Carlo simulation.

Animals↗
PubMed2004

Failure to detect norovirus in a large group of asymptomatic individuals.

Noroviruses are a major cause of both sporadic and epidemic gastroenteritis in humans, but the mechanisms by which norovirus circulates within the community are poorly understood. In this study, we examined the hypothesis that asymptomatic people act as a reservoir for norovirus. Faecal specimens from 399 asymptomatic individuals were tested for norovirus by reverse transcription polymerase chain reaction (RT-PCR) methodology, and no norovirus was detected. The failure to detect norovirus was not apparently due to the test sample being resistant to norovirus infection, nor to the presence of PCR inhibitors in the test sample. The findings suggest that, if norovirus is carried by asymptomatic people, the carriage rate is very low; the upper bound (95% confidence interval, binomial distribution) of the carriage rate was only 0.8%. Thus, it is unlikely that asymptomatic people are an important reservoir for norovirus.

Adolescent↗
PubMed2005

Deuteron NMR spectra of ammonium ion isotopomers at low temperatures.

Partially deuterated ammonium compounds contain ammonium ion isotopomers with relative abundances given by the binomial distribution of protons and deuterons. All isotopomers with deuterons contribute characteristic deuteron NMR spectra at 5K. Experimental NMR spectra were separated and respective contributions of isotopomers were determined. The derived contributions agree with expected values for a given deuteration in the case of ammonium hexafluorophosphate. In ammonium hexachlorotellurate both NH2D2+ and about 50% of NH3D+ ions are rigid, while the remaining NH3D+ perform limited jumps. NHD3+ and ND4+ ions undergo tunnelling rotation, NH3D+ ions perform either jumps about C2 axis or limited jumps, but some stay rigid in ammonium hexachlorostannate. NH2D2+, NHD 3+ and ND4+ undergo rotational tunnelling. In the case of ammonium perchlorate, the NH3D+ ions perform either jumps about C3 axis or limited jumps whilst some remain rigid. Very low values of activation energies were derived for all spectral components from the temperature dependence of their spectra, up to about 20K, which indicates an incoherent tunnelling nature of the observed dynamic processes. The diverse mobility of NH3D+ ions appears to be the most interesting and new feature.

Journal Article↗
PubMed2005

Pathways to the analysis of microarray data.

The development of microarray technology allows the simultaneous measurement of the expression of many thousands of genes. The information gained offers an unprecedented opportunity to fully characterize biological processes. However, this challenge will only be successful if new tools for the efficient integration and interpretation of large datasets are available. One of these tools, pathway analysis, involves looking for consistent but subtle changes in gene expression by incorporating either pathway or functional annotations. We review several methods of pathway analysis and compare the performance of three, the binomial distribution, z scores, and gene set enrichment analysis, on two microarray datasets. Pathway analysis is a promising tool to identify the mechanisms that underlie diseases, adaptive physiological compensatory responses and new avenues for investigation.

Algorithms↗
PubMed2004

Transmission dynamics of the Echinococcus granulosus sheep-dog strain (G1 genotype) in camels in Tunisia.

Cystic echinococcosis, caused by Echinococcus granulosus, is highly endemic in North Africa and the Middle East. This paper examines the abundance and prevalence of infection of E. granulosus in camels in Tunisia. No cysts were found in 103 camels from Kébili, whilst 19 of 188 camels from Benguerden (10.1%) were infected. Of the cysts found 95% were considered fertile with the presence of protoscolices and 80% of protoscolices were considered viable by their ability to exclude aqueous eosin. Molecular techniques were used on cyst material from camels and this demonstrated that the study animals were infected with the G1 sheep strain of E. granulosus. Observed data were fitted to a mathematical model by maximum likelihood techniques to define the parameters and their confidence limits and the negative binomial distribution was used to define the error variance in the observed data. The infection pressure to camels was somewhat lower in comparison to sheep reported in an earlier study. However, because camels are much longer-lived animals, the results of the model fit suggested that older camels have a relatively high prevalence rate, reaching a most likely value of 32% at age 15 years. This could represent an important source of transmission to dogs and hence indirectly to man of this zonotic strain. In common with similar studies on other species, there was no evidence of parasite-induced immunity in camels.

Animals↗
PubMed2007

Prevalence and intensity of intestinal helminths found in free-ranging golden lion tamarins (Leontopithecus rosalia, Primates, Callitrichidae) from Brazilian Atlantic forest.

Helminth identification and egg counts were performed in 316 fecal samples during 4 years in 199 golden lion tamarins (GLTs), Leontopithecus rosalia, from two Brazilian conservation units. Tamarin sex and age, area of occurrence and helminth co-infection were tested as potential factors that could affect helminth prevalence and egg shedding in host individuals. Three nematodes species were found at low prevalences but not in both conservation units: Ancylostomatidae (12%), Ascarididae (1%) and Tripanoxyuris minutus, an Oxyuridae (4%). Three other species had high prevalences and were found in both conservation units: one acanthocephalan, Oncicola sp. (30%), and two nematodes, Spiruridae (24%), and Trichostrongylidae (31%). These three latter helminths had distinct prevalences between the conservation units, probably due to differences in availability of helminth infective stages in each area. Prevalences were greater in females for all helminth species; this was especially the case for Oncicola sp. Sex and age differences in helminth prevalence may be associated with changes in sexual steroid levels that accompany age and reproductive status. Frequency of simultaneous infections by the two helminths considered most pathogenic (Oncicola and Trichostrongylidae) were statistically lower than expected; this may be related to: (i) higher tamarin death rate caused by the association; (ii) differences in exposure to helminth infective stages in the various areas of occurrence; (iii) and competition between these helminth species. All helminth species followed a negative binomial distribution, with stronger clumping occurring in Trichostrongylidae and in female GLTs. Distinct transmission strategies of Oncicola sp. and Spiruridae, in contrast with Trichostrongylidae, may partially explain the different clumping levels of these helminths in GLTs. Mean fecal egg counts of all helminths were not different between GLT sexes, ages or areas of occurrence. The three most common helminth species may be a threat to isolated or dense GLT populations.

Aging↗
PubMed1986

Evidence for interactions between batrachotoxin-modified channels in hybrid neuroblastoma cells.

Current records from voltage-clamped membrane patches containing two batrachotoxin-modified sodium channels were analyzed to determine whether these channels are identical and independent. In most two-channel patches, the experimentally observed probabilities that zero, one, or two channels are open differ from the binomial distribution, demonstrating that the two channels are nonidentical or nonindependent or both. From the same current records, we also determined the rate for the transition from two open channels to one open channel and for the transition from one open channel to zero open channels. These data are consistent with closing rates for the two channels that are equal and independent. Both probability and closing rate data can be fit by a model wherein the channels are identical, the closing rates are independent, and the opening rate is greater when the other channel is closed than when it is open. The implications of this model for analyzing noise spectra and current variance are examined.

Animals↗
PubMed1988

Role of single-channel stochastic noise on bursting clusters of pancreatic beta-cells.

To study why pancreatic beta-cells prefer to burst as a multi-cellular complex, we have formulated a stochastic model for bursting clusters of excitable cells. Our model incorporated a delayed rectifier K+ channel, a fast voltage-gated Ca2+ channel, and a slow Cai-blockable Ca2+ channel. The fraction of ATP-sensitive K+ channels that may still be active in the bursting regime was included in the model as a leak current. We then developed an efficient method for simulating an ionic current component of an excitable cell that contains several thousands of channels opening simultaneously under unclamped voltage. Single channel open-close stochastic events were incorporated into the model by use of binomially distributed random numbers. Our simulations revealed that in an isolated beta-cell [Ca2+]i oscillates with a small amplitude about a low [Ca2+]i. However, in a large cluster of tightly coupled cells, stable bursts develop, and [Ca2+]i oscillates with a larger amplitude about a higher [Ca2+]i. This may explain why single beta-cells do not burst and also do not release insulin.

Animals↗
PubMed2001

The effect of nonsteroidal anti-inflammatory drugs on ovulation: a prospective, randomized clinical trial.

OBJECTIVE: To assess the effect of ibuprofen, a nonspecific inhibitor of prostaglandin synthesis, on ovulation. DESIGN: Prospective, randomized, double-blind, placebo-controlled cross-over study. SETTING: University Medical Center. PATIENT(S): Twelve normally cycling women between ages 20 and 40. INTERVENTION(S): Subjects were randomized to either oral ibuprofen (800 mg) or placebo three times per day, beginning when the maximum diameter of the leading follicle reached 16 mm by ultrasound, and continuing for 10 days total. The second cycle was a washout period, and in the third cycle, the subjects were crossed over to the alternate regimen from the first cycle. The probability of delayed follicular collapse was determined using the binomial distribution, and changes in P levels were compared using the paired t test. MAIN OUTCOME MEASURE(S): Urinary LH surge, follicular collapse by serial transvaginal ultrasonography, and serum midluteal P levels. RESULT(S): Eleven of 12 subjects detected an LH surge with both ibuprofen and placebo. Five of 11 women demonstrated a >or=2-day increase in time interval from detection of the LH surge to follicular collapse, and 3 of those 5 had been randomized to ibuprofen. This represents a 27% (3 of 11; 95% confidence limits: 1%, 53%) rate of delay for follicular collapse for ibuprofen. There was no difference in average midluteal P levels for ibuprofen or placebo. CONCLUSION(S): If ibuprofen inhibits follicular collapse, this effect is seen in a small group of study subjects, and this information should be clinically reassuring to patients who take nonsteroidal anti-inflammatory drugs. Serum midluteal P levels were unaffected by administration of ibuprofen.

Adult↗
PubMed1987

Termination of ventricular bigeminy by conversion to concealed forms.

Ventricular bigeminy may be either overt or concealed. In this study, we attempted to determine the frequency with which the overt form converted to the concealed variety. Ambulatory electrocardiographic recordings from 25 patients with greater than 40 episodes of monomorphic ventricular bigeminy were examined. A statistically significant (P less than 0.01, binomial distribution) predominance of odd or even number of sinus beats between the end of a bigeminal episode and the next ventricular premature beat was considered to be evidence for conversion of overt to concealed bigeminy. In 14 of the 25 cases, the number of episodes of bigeminy followed by odd numbers of sinus beats was beyond these statistical bounds. In 74 episodes in 9 patients, progressive prolongation of the coupling interval during bigeminy occurred before termination. These data demonstrate the high prevalence of concealment as a mode of termination of bigeminy. In a small number of episodes, this occurs in a pattern suggestive of progressive delay of conduction in or around an arrhythmogenic locus.

Cardiac Complexes, Premature↗
PubMed2000

Burst properties of a supergated double-barrelled chloride ion channel.

The chloride selective channel from Torpedo electroplax, ClC-0, is the prototype of a large gene family of chloride channels that behave as functional dimers, with channel currents exhibiting two non-zero conductance levels. Each pore has the same conductance and is controlled by a subgate, and these have seemingly identical fast gating kinetics. However, in addition to the two subgates there is a single slower 'supergate' which simultaneously affects both channels. In the present paper, we consider a six state Markov model that is compatible with these observations and develop approximations as well as exact results for relevant properties of groupings of openings, known as bursts. Calculations with kinetic parameter values typical of ClC-0 suggest that even simple approximations can be quite accurate. Small deviations from the assumption of independence within the model lead to marked changes in certain predicted burst properties. This suggests that analysis of these properties may be helpful in assessing independence/non-independence of gating in this type of channel. Based on simulations of models of both independent and non-independent gating, tests using binomial distributions can lead to false conclusions in each situation. This is made more problematic by the difficulty of selecting an appropriate critical time in defining a burst empirically.

Animals↗
PubMed2000

Combinatorics of giant hexagonal bilayer hemoglobins.

The paper discusses combinatorial and probabilistic models allowing to characterize various aspects of spacial symmetry and structural heterogeneity of the giant hexagonal bilayer hemoglobins (HBL Hb). Linker-dodecamer configurations of HBL are described for two and four linker types (occurring in the two most studied HBL Hb of Arenicola and Lumbricus, respectively), and the most probable configurations are found. It is shown that, for HBL with marked dodecamers, the number of 'normal-marked' pairs of dodecamers in homological position follows a binomial distribution. The group of symmetries of the dodecamer substructure of HBL is identified with the dihedral group D6. Under natural symmetry assumptions, the total dipole moment of the dodecamer substructure of HBL is shown to be zero. Biological implications of the mathematical findings are discussed.

Animals↗