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CSF-ACE activity in probable CNS neurosarcoidosis.

OBJECTIVE: To redefine the utility of CSF-ACE as a selective indicator of probable CNS neurosarcoidosis. METHODS: The diagnosis of probable CNS neurosarcoidosis required: (a) biopsy evidence of systemic sarcoidosis, (b) cortical, brainstem, and/or spinal cord deficits, (c) enhancing lesions on brain and/or spinal cord MRI, and (d) exclusion of other etiologies which could account for the neurological deficits. Radioassay measurement of CSF-ACE activity was performed in 11 patients who met our criteria for probable CNS neurosarcoidosis and 207 control patients. RESULTS: The M +/- SD for CSF-ACE activity was significantly higher (p < 0.05) for the 11 probable CNS neurosarcoidosis patients (9.5 +/- 6.9 nmol/mL/min) than for the control patients (2.9 +/- 2.7 nmol/mL/min). The optimal CSF-ACE activity discriminator value was 8 nmol/mL/min. At this value, the sensitivity and specificity of CSF-ACE activity was 55% and 94%, respectively. CONCLUSIONS: CSF-ACE activity is a useful biochemical marker of probable CNS neurosarcoidosis when brain and/or spinal cord MRI show diffuse enhancing lesions.

Adult↗

[Treadmill stress-echocardiography in diagnosis of coronary artery involvement in patients with various probability of ischemic heart disease].

Results of treadmill stress-echocardiography were compared with those of coronary angiography in 153 patients (133 men, 20 women, mean age 55.7-/+8.5 years) with various initial probability of ischemic heart disease (IHD) which was determined for each patient basing on sex, age and status of angina. Probabilities of IHD > or = 75% and >10% but <7 5% were considered high and intermediate, respectively. According to coronary angiography 40 patients had no significant coronary artery stenoses while 32, 36 and 45 patients had hemodynamically significant single, double and triple vessel stenoses, respectively. The use of echocardiographic criteria of myocardial ischemia allowed to increase sensitivity of treadmill test in patients with high IHD probability from 74 to 91% (p<0.01) and its specificity in patients with intermediate IHD probability from 45 to 83% (p<0.001). Value of stress-echocardiography for diagnosis of the presence of stenotic lesions in coronary arteries depended on initial probability of IHD.

Adult↗

A model for malignancy probability prediction of adnexal masses.

OBJECTIVE: To develop a model for pre-operative malignancy probability determination in a patient with an adnexal tumor or tumors by the application of multivariate logistic regression analysis to variables at the time of pelvic sonography. METHOD: Pre-operative ultrasound examination including Doppler analysis was performed on 117 consecutive women scheduled for surgery because of an adnexal mass or masses. Each tumor was classified as probably benign or malignant using a subjective evaluation system on the gray-scale morphological images. Then, Doppler sonography was carried out. The resistance index (RI) and pulsatility index (PI) of the vessel with the highest velocity were recorded. Multivariate logistic regression analysis was performed with the histological outcome as the dependent variable. Independent variables included patient's age, menopausal status, gray-scale morphological data, RI and PI. The probability of malignancy was formulated from statistical analysis. RESULTS: There were 117 women included in the study, 83 (71%) with histologically benign and 34 (29%) with histologically malignant ovarian tumors. Regression analysis on the five variables resulted in the retention of only patient's age, morphological data and RI as significant contributing factors for malignancy prediction. The probability of malignancy was 1/(1+e(-z)) where e was the base value for natural logarithms and z was the regression equation: -3.6355 + 1.8028 (age) + 2.1047 (morphological data) + 2.9816 (RI). CONCLUSION: A model for estimation of probability of malignancy for an adnexal tumor was derived using multivariate logistic regression analysis. The prediction should be more accurate than that from either gray-scale ultrasound imaging or Doppler velocimetry alone. The test of the model is now on-going.

Adult↗

[Functional disorders of FOF1-ATPase in submitochondrial particles obtained from platelets of patients with a diagnosis of probable Alzheimer's disease].

INTRODUCTION: Recent studies indicate that decreased energy generation by mitochondria is a feature that is common across neurodegenerative diseases. PATIENTS AND METHODS: In order to obtain direct evidence that mitochondrial functioning is altered, we measured the hydrolytic activity of F0F1-ATPase and its capacity to generate a stable proton gradient in submitochondrial particles in 29 patients diagnosed with probable Alzheimer's disease (AD). Submitochondrial particles were obtained from platelets of patients with a diagnosis of probable AD and from clinically healthy controls. RESULTS: Data revealed that the hydrolytic activity of F0F1-ATPase increases significantly in patients with probable AD (41.7+/-4.3 nmol PO4 min-1[mg protein]-1, n=29) as compared to the control subjects (29.1+/-1.9 nmol PO4 min-1 [mg protein]-1, n=29). It is important to note that, in the male population with probable AD, we found that hydrolytic activity of F0F1-ATPase increased as cerebral deterioration progressed. We also detected a lower pH gradient in the submitochondrial particles of patients with probable AD (0.28+/-0.08 pH units, n=25) as compared to the controls (0.5+/-0.1 pH units, n=20). CONCLUSIONS: Overall, these data point to an alteration in the functioning of the enzyme.

Alzheimer Disease↗

[Detection of severe acute respiratory syndrome probable patients' virus RNA in Hangzhou by using a two loci and a modified nested real-time reverse transcription polymerase chain reaction].

OBJECTIVE: To detect the RNA of severe acute respiratory syndrome virus (SARS-CoV) by using reverse transcription polymerase chain reaction (RT-PCR) targeted for a two loci and a modified nested real-time RT-PCR as to improving the reliability and sensitivity of tests. METHODS: A nested RT-PCR was used for detecting one fragment of SARS-CoV RNA in oropharyngeal swabs from 3 SARS probable patients, 4 SARS suspect patients and other 27 patients with fever in Hangzhou, and the nested RT-PCR product from one SARS probable patient was sequenced. Meanwhile in these 3 SARS probable patients, other three RT-PCR methods, including a hemi-nested RT-PCR targeted for another fragment of SARS-CoV RNA, a real-time RT-PCR and a modified nested real-time RT-PCR, were employed to detect SARS-CoV RNA. RESULTS: Two positives were found in the 3 SARS probable patients, and none positive in 4 SARS suspect patients and other 27 patients with fever, using the nested RT-PCR. The sequence of the nested RT-PCR product from one SARS probable patient was identified with the counterpart of SARS-CoV genomes published in public database. The results of the hemi-nested RT-PCR, the real-time RT-PCR and the modified nested real-time RT-PCR in the 3 SARS patients were consistent with the one of the nested RT-PCR. During detecting specimen with low copies of RNA, a weak positive signal was produced after about 35 cycles in the real-time RT-PCR, but a strong positive signal was found only after 10 cycles in the modified nested real-time RT-PCR. CONCLUSION: It might improve the reliability of test by employing RT-PCR targeted for two or more fragments in SARS-CoV genome. The modified nested real-time RT-PCR might have higher sensitivity than the routine real-time RT-PCR.

Adolescent↗

Effects of stimulus probability on encoding by mentally retarded and nonretarded persons.

A choice reaction-time experiment was performed in which probe stimulus probability and probe stimulus quality were orthogonally manipulated. Subjects were retarded and nonretarded junior high school students. The stimuli were random forms presented at four probability levels in order to assess the effect of stimulus probability on the encoding process. The results indicated that the retarded subjects appeared to be less sensitive than did the nonretarded subjects to stimulus-probability information, particularly under degraded stimulus conditions. The results were discussed in terms of the relative sensitivity of retarded and nonretarded persons to stimulus-probability information and the effect of such information on the encoding process.

Adolescent↗

Bayesian and threshold probabilities in therapeutic drug monitoring: when can serum drug concentrations alter clinical decisions?

The use of Bayesian and threshold probabilities is examined with respect to the range of probabilities of toxicity for which obtaining a patient's serum drug concentration leads to information that is potentially useful in altering a clinical decision. For the situation of potential drug-induced toxicity, three threshold probabilities are needed to characterize the decision process: the decision threshold for deciding between continuing and discontinuing the drug regimen, the testing threshold that separates the decision to continue the regimen without testing the serum drug concentration from the decision to test before deciding, and the companion testing threshold that separates the decision to discontinue the regimen without testing from the decision to test before deciding. For digoxin, theophylline, aminoglycosides, vancomycin, and phenytoin, three prototypical decision threshold probabilities, 0.33, 0.2, and 0.1, are used, along with published true-positive and false-positive rates, to calculate serum concentration testing thresholds for each drug. Practitioners can be more effective in their use of serum drug concentration data when a Bayesian approach to probability assessment is used in conjunction with testing thresholds.

Bayes Theorem↗

A clinical study of perimetric probability maps.

Perimetric probability maps depict visual field results in terms of the frequency with which the measured findings are seen in a normal population. We tested clinically the importance of the model of the normal visual field used to calculate such maps. Forty-one eyes of 41 normal subjects and 58 eyes of 46 glaucomatous patients were studied. Probability maps were calculated by means of two different models of the normal visual field. The first model assumed gaussian threshold distributions with constant variability across the field. The second used empirically determined nongaussian location-dependent threshold distributions. Probability maps using the empiric model allowed better separation between glaucomatous and normal eyes, and the number of significant points in normal subjects was in better agreement with the theoretically expected number. The gaussian model yielded an unacceptably high frequency of significant points in normal fields, particularly in the midperiphery. The clinical usefulness of perimetric probability maps depends critically on the choice of normal visual field model.

Adult↗

Probability binning comparison: a metric for quantitating multivariate distribution differences.

BACKGROUND: While several algorithms for the comparison of univariate distributions arising from flow cytometric analyses have been developed and studied for many years, algorithms for comparing multivariate distributions remain elusive. Such algorithms could be useful for comparing differences between samples based on several independent measurements, rather than differences based on any single measurement. It is conceivable that distributions could be completely distinct in multivariate space, but unresolvable in any combination of univariate histograms. Multivariate comparisons could also be useful for providing feedback about instrument stability, when only subtle changes in measurements are occurring. METHODS: We apply a variant of Probability Binning, described in the accompanying article, to multidimensional data. In this approach, hyper-rectangles of n dimensions (where n is the number of measurements being compared) comprise the bins used for the chi-squared statistic. These hyper-dimensional bins are constructed such that the control sample has the same number of events in each bin; the bins are then applied to the test samples for chi-squared calculations. RESULTS: Using a Monte-Carlo simulation, we determined the distribution of chi-squared values obtained by comparing sets of events from the same distribution; this distribution of chi-squared values was identical as for the univariate algorithm. Hence, the same formulae can be used to construct a metric, analogous to a t-score, that estimates the probability with which distributions are distinct. As for univariate comparisons, this metric scales with the difference between two distributions, and can be used to rank samples according to similarity to a control. We apply the algorithm to multivariate immunophenotyping data, and demonstrate that it can be used to discriminate distinct samples and to rank samples according to a biologically-meaningful difference. CONCLUSION: Probability binning, as shown here, provides a useful metric for determining the probability with which two or more multivariate distributions represent distinct sets of data. The metric can be used to identify the similarity or dissimilarity of samples. Finally, as demonstrated in the accompanying paper, the algorithm can be used to gate on events in one sample that are different from a control sample, even if those events cannot be distinguished on the basis of any combination of univariate or bivariate displays. Published 2001 Wiley-Liss, Inc.

Algorithms↗

Hierarchical models for the probabilities of conception.

In the last thirty years, there has been considerable interest in finding better models to fit data for probabilities of conception. An important early model was proposed by Barrett and Marshall (1969) and extended by Schwartz, MacDonald and Heuchel (1980). Recently, researchers have further extended these models by adding covariates. However, the increasingly complicated models are challenging to analyze with frequentist methods such as the EM algorithm. Bayesian models are more feasible, and the computation can be done via Markov chain Monte Carlo (MCMC). We consider a Bayesian model with an effect for protected intercourse to analyze data from the California Women's Reproductive Health Study and assess the effects of water contaminants and hormones. There are two main contributions in the paper. (1) For protected intercourse, we propose modeling the ratios of daily conception probabilities with protected intercourse to corresponding daily conception probabilities with unprotected intercourse. Due to the small sample size of our data set, we assume the ratios are the same for each day but unknown. (2) We consider Bayesian analysis under a unimodality assumption where the probabilities of conception increase before ovulation and decrease after ovulation. Gibbs sampling is used for finding the Bayesian estimates. There is some evidence that the two covariates affect fecundability.

Bayes Theorem↗

The equilibrium partition function and base pair binding probabilities for RNA secondary structure.

A novel application of dynamic programming to the folding problem for RNA enables one to calculate the full equilibrium partition function for secondary structure and the probabilities of various substructures. In particular, both the partition function and the probabilities of all base pairs are computed by a recursive scheme of polynomial order N3 in the sequence length N. The temperature dependence of the partition function gives information about melting behavior for the secondary structure. The pair binding probabilities, the computation of which depends on the partition function, are visually summarized in a "box matrix" display and this provides a useful tool for examining the full ensemble of probable alternative equilibrium structures. The calculation of this ensemble representation allows a proper application and assessment of the predictive power of the secondary structure method, and yields important information on alternatives and intermediates in addition to local information about base pair opening and slippage. The results are illustrated for representative tRNA, 5S RNA, and self-replicating and self-splicing RNA molecules, and allow a direct comparison with enzymatic structure probes. The effect of changes in the thermodynamic parameters on the equilibrium ensemble provides a further sensitivity check to the predictions.

Animals↗

Premelting thermal fluctuational base pair opening probability of poly(dA).poly(dT) as predicted by the modified self-consistent phonon theory.

We employ a mean field, modified, self-consistent phonon theory to evaluate the single base-pair opening rate and the probability of a base pair in the amino proton exchangeable state for the homopolymer poly(dA).poly(dT) at temperatures below the helix-coil transition region. Our calculated premelting single base-pair opening probabilities are in general agreement with several available experimental estimates from imino proton exchange and formaldehyde-induced DNA melting measurements. These calculated opening probabilities, however, are in disagreement with the prediction of the helix-coil transition theory. Possible reasons for the differences are discussed, especially the possible different definition of a meaningful open state in the premelting region. The premelting open state of the modified self-consistent phonon approximation theory seems to be appropriate to describe a solvent-accessible open configuration that is sufficient to facilitate important chemical reactions such as imino proton exchange and formaldehyde reaction with the bases. This can be compared with the completely unstacked open state of the helix-coil transition theory originally defined in the helix-coil transition region. We propose that the amino proton exchangeable state is different from the open state associated with melting and only involves the breaking of the amino interbase H bond. The agreement between the calculated and experimentally estimated probability of a base pair in the amino proton exchangeable state seems to support this hypothesis.

Base Composition↗

How useful is the fine-scale mapping of complex trait linkage peaks? Evaluating the impact of additional microsatellite genotyping on the posterior probability of linkage.

The two-stage linkage mapping protocol for complex traits (a primary genome scan with low marker density followed by the high-density genotyping around linkage peaks) is a near-universal practice. The behavior (an increase or a decrease) of the peak upon such fine mapping frequently leads to inferences regarding the veracity of the primary scan finding, namely a true, or a false, positive. We examined by simulation, under the null hypothesis of no linkage and the alternative hypothesis of true linkage, the inferences that can be made regarding the posterior probability of linkage given either a peak increase, or alternatively, a peak decrease, following fine mapping. We considered different models of missing genotype data, fine-mapping LOD score thresholds, and prior probabilities of linkage. Our simulations show that evidence for linkage can increase frequently upon fine mapping under both null and alternative hypotheses, although large increases in LOD scores are more common under the alternative hypothesis. Increased LOD scores accompany an increased posterior probability of linkage, and large LOD score changes and the presence of dominance at the trait locus accentuate this effect. We demonstrate that the greatest changes in the posterior probability of linkage occur when the genotyping data are least complete (and especially when parental genotypes are missing), and the LOD score threshold for fine mapping is relaxed.

Algorithms↗

A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.

Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders.

Adult↗

Computational basis of knowledge-based conformational probabilities derived from local- and long-range interactions in proteins.

The probabilities of the various basins in Ramachandran maps are examined critically. The theoretical basis of probability calculations both from molecular computations and from protein libraries are discussed. The well-defined basins of the Ramachandran maps are treated as rotational isomeric states. Statistical independence and dependence of the states of different residues along the peptide chain are discussed. The Flory isolated pair hypothesis, near neighbor correlations, context effects, and long-range correlations are examined critically. A method of evaluating long-range correlations in helical and extended sequences is introduced in analogy with earlier polymer theory. Three different protein libraries are constructed where data is considered from residues in the (i) coiled regions, (ii) all regions, and (iii) only the helical and extended regions of proteins. Singlet and pairwise dependent probabilities calculated from these libraries are used to predict whether a given sequence is helical or extended. Predictions using pairwise dependence were not better than those using singlet probabilities. Modeling of long-range correlations improved the predictions significantly. Removal of the Chameleon sequences from the data set also improved the predictions, but to a lesser extent.

Amino Acid Sequence↗

Age-conditional probabilities of developing cancer.

We propose an estimator of the probability of developing a disease in a given age range, conditional on never having developed the disease prior to the beginning of the age range. Our estimator improves the one described by Wun, Merrill and Feuer ( Lifetime Data Analysis 1998; 4, 169-186) that is currently used by the U.S. National Cancer Institute for the SEER Cancer Statistics Review. Both estimators use cross-sectional disease rates and provide an interpretation of these rates in terms of the age-conditional probability of developing disease in a hypothetical cohort. The difficulty of this problem is that rates are not available per person-years alive and disease free, but only per person-years alive. Wun et al. used ad hoc methods to handle this problem which did not properly account for competing risks, did not provide a measure of variability, and only allowed age ranges using prespecified 5-year age intervals. Here we solve the problem under a unified competing risks framework, which allows the calculation of the age-conditional probabilities for any age range. We generalize gamma confidence intervals to apply to our new statistic. Although our new method provides estimates which are numerically similar to that of Wun et al., this paper provides a comprehensive theoretical basis for estimation and inference about the age-conditional probability of developing a disease.

Age of Onset↗

Impact of measurement error and temporal variability on the estimation of event probabilities for risk factor intervention trials.

The impact of measurement error and temporal variability of risk factors on estimates of disease probabilities based on the logistic function is discussed. Monte Carlo results and empirical findings from the Multiple Risk Factor Intervention Trial indicate that the degree of attenuation of logistic parameter estimates is well approximated by the reliability coefficient when the errors are assumed to be normal random variates and event probabilities are small. In the design of intervention studies, measurement error and temporal variability of risk factors do not usually influence estimates of the probability of developing the disease in the control group, but can result in mis-estimation of the probability of developing the disease in the experimental group, substantially reducing the statistical power of the clinical trial.

Bias↗

On estimating the probability of aperiodic outbursts of microbial populations from their fluctuating counts.

The irregular sequence of counts of a microbial population, in the absence of observable corresponding environmental changes (e.g., temperature), can be regarded as reflecting the interplay of several unknown or random factors that favor or inhibit growth. Since these factors tend to balance one another, the fluctuations usually remain within bounds, and only by a coincidence--when all or most act in unison--does an 'outburst' occur. This situation can be represented mathematically as a sequence of independent random variables governed by a probability distribution. The concept was applied to reported microbial counts of ground meat and wastewater. It is found that the lognormal distribution could serve as a model, and that simulations from this model are indistinguishable from actual records. The parameters of the lognormal (or other) distribution can then be used to estimate the probability of a population outburst, i.e., an increase above a given threshold. Direct estimation of the outburst probability based on frequency of occurrence is also possible, but in some situations requires an impractically large number of observations. We compare the efficiency of these two methods of estimation. Such methods enable translation of irregular records of microbial counts into actual probabilities of an outburst of a given magnitude. Thus, if the environment remains 'stable' or in dynamic equilibrium, the fluctuations should not be regarded merely as noise, but as a source of information and an indicator of potential population outbursts even where obvious signs do not exist.

Animals↗