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PubMed1998

Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle.

BACKGROUND: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings. METHODS AND RESULTS: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure. CONCLUSIONS: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2000

Correctness of local probability in graphical models with loops.

Graphical models, such as Bayesian networks and Markov networks, represent joint distributions over a set of variables by means of a graph. When the graph is singly connected, local propagation rules of the sort proposed by Pearl (1988) are guaranteed to converge to the correct posterior probabilities. Recently a number of researchers have empirically demonstrated good performance of these same local propagation schemes on graphs with loops, but a theoretical understanding of this performance has yet to be achieved. For graphical models with a single loop, we derive an analytical relationship between the probabilities computed using local propagation and the correct marginals. Using this relationship we show a category of graphical models with loops for which local propagation gives rise to provably optimal maximum a posteriori assignments (although the computed marginals will be incorrect). We also show how nodes can use local information in the messages they receive in order to correct their computed marginals. We discuss how these results can be extended to graphical models with multiple loops and show simulation results suggesting that some properties of propagation on single-loop graphs may hold for a larger class of graphs. Specifically we discuss the implication of our results for understanding a class of recently proposed error-correcting codes known as turbo codes.

Bayes Theorem↗

PubMed2001

A spike-train probability model.

Poisson processes usually provide adequate descriptions of the irregularity in neuron spike times after pooling the data across large numbers of trials, as is done in constructing the peristimulus time histogram. When probabilities are needed to describe the behavior of neurons within individual trials, however, Poisson process models are often inadequate. In principle, an explicit formula gives the probability density of a single spike train in great generality, but without additional assumptions, the firing-rate intensity function appearing in that formula cannot be estimated. We propose a simple solution to this problem, which is to assume that the time at which a neuron fires is determined probabilistically by, and only by, two quantities: the experimental clock time and the elapsed time since the previous spike. We show that this model can be fitted with standard methods and software and that it may used successfully to fit neuronal data.

Animals↗

PubMed1992

A probability nomogram to predict rectal temperature in children.

The relationship between rectal and peripheral-site temperature was investigated to achieve two objectives: 1) to evaluate a prevailing practice of intersite adjustment by use of an invariant temperature difference; and 2) to develop a statistical method for intersite temperature predictions in the individual child, especially for fever as defined by rectal measurement. Rectal, oral, axillary, left abdomen skin, and forehead skin temperatures (degrees F) were measured with an electronic thermometer in 257 children. Objective 1 was not achieved because a simple temperature difference between a peripheral site and the rectal site could not be used to predict rectal temperature reliably. For objective 2, intersite differences met three statistical criteria so that normal distribution theory could be used to derive the probabilities for occurrence of each difference. Accordingly, cumulative probability nomograms were constructed to estimate rectal-site fever from measurements at peripheral sites. This nomogram method produces a clinically reliable prediction of rectal-site fever from temperature measurement at peripheral sites, especially the oral and axillary sites. These predictions offer useful assessments of febrile illness severity when rectal temperature is not available.

Abdomen↗

PubMed2002

The prosecutor's fallacy--a pitfall in interpreting probabilities in forensic evidence.

Forensic evidence is often given in terms of a mathematical probability. However, it is easy to make a particular type of error, 'the prosecutor's fallacy', in the interpretation of such probability. This paper highlights the source of this error and briefly introduces Bayes Theorem as the correct theoretical basis for interpreting such evidence. The first Californian legal case in which this error was committed is discussed, followed by all cases in the UK in which this error was highlighted and rectified by the Court of Appeal. It is important for all parties concerned--expert witnesses, lawyers and judges--to understand these principles correctly. Furthermore, the criminal courts face dilemmas when juries are involved. This paper concludes by discussing recent guidance from the Court of Appeal on how such evidence should be presented to the jury and the implications of this guidance.

Bayes Theorem↗

PubMed2006

Retributive reactions to suspected offenders: the importance of social categorizations and guilt probability.

In the current research, the author investigates the influence of social categorizations on retributive emotions (e.g., anger) and punishment intentions when people evaluate suspected offenders as independent observers. It is argued that information that guilt is certain or uncertain (i.e., guilt probability) has different consequences for retributive reactions to ingroup and outgroup suspects. In correspondence with predictions, results of four experiments showed that people reacted more negatively to ingroup than outgroup suspects when guilt was certain but that people reacted more negatively to outgroup than ingroup suspects when guilt was uncertain. It is concluded that guilt probability moderates the influence of social categorizations on people's retributive reactions to suspected offenders.

Adolescent↗

PubMedDate not supplied

Patient preference-based treatment thresholds and recommendations: a comparison of decision-analytic modeling with the probability-tradeoff technique.

BACKGROUND: Decision analysis (DA) and the probability-tradeoff technique (PTOT) are patient preference-based methods of determining optimal therapy for individuals. Using aspirin therapy for the primary prevention of stroke and myocardial infarction (MI) in elderly persons as an example, the objective of this study was to determine whether group-level treatment thresholds and individual-level treatment recommendations derived using PTOT are identical to those of DA incorporating the patients' own values. METHODS: Persons in a pilot study of the efficacy of aspirin in the prevention of stroke and MI were asked to participate. Participant values and utilities for pertinent health states (e.g., minor and major stroke, MI, major bleeding episode) were determined. Then, in three hypothetical clinical situations in which the chance of stroke or MI was varied, PTOT was used to directly determine treatment thresholds for aspirin therapy (i.e., the smallest reduction in MI or stroke risk for which participants would be willing to take aspirin). Using DA modeling, with the same probabilities of events as in the PTOT exercise and incorporating participants' own values, treatment thresholds for the three clinical situations were determined. The thresholds determined by the two approaches were compared. Finally, based on these treatment thresholds, using the best estimates of the efficacy of aspirin to prevent first-time stroke and MI, PTOT and DA treatment recommendations for individual participants were compared. RESULTS: The 42 participants reported that a major stroke was the least desirable health state, followed by MI, minor stroke, and major bleeding. The minimum risk reduction required to take aspirin was greater for MI prevention compared with stroke prevention. For the two clinical situations in which the hypothetical efficacy of aspirin to prevent stroke was varied, treatment thresholds for the PTOT versus DA approaches differed (p < 0.04), but this difference was not significant (p = 0.19) for the MI-based clinical situation. Using the best estimate of the efficacy of aspirin to prevent first-time stroke and MI, PTOT and DA treatment recommendations whether or not to take aspirin were discordant for 38% of participants (16 of 42) (p < 0.001). CONCLUSIONS: Patient preference-based group-level treatment thresholds and individual-level treatment recommendations can differ significantly depending on whether PTOT or DA is used, apparently because the two emphasize different aspects of the decision-making process. DA theory assumes that effective therapeutic decision making should maximize both quality and quantity of life; with PTOT, the emphasis for effective clinical decision making allows patients to be fully engaged in the process, thus hopefully leading to fully informed decisions that may result in satisfaction and compliance.

Age Factors↗

PubMedDate not supplied

Hindsight bias: an impediment to accurate probability estimation in clinicopathologic conferences.

Although clinicopathologic conferences (CPCs) have been valued for teaching differential diagnosis, their instructional value may be compromised by hindsight bias. This bias occurs when those who know the actual diagnosis overestimate the likelihood that they would have been able to predict the correct diagnosis had they been asked to do so beforehand. Evidence for the presence of the hindsight bias was sought among 160 physicians and trainees attending four CPCs. Before the correct diagnosis was announced, half of the conference audience estimated the probability that each of five possible diagnoses was correct (foresight subjects). After the correct diagnosis was announced the remaining (hindsight) subjects estimated the probability they would have assigned to each of the five possible diagnoses had they been making the initial differential diagnosis. Only 30% of the foresight subjects ranked the correct diagnosis as first, versus 50% of the hindsight subjects (p less than 0.02). Although less experienced physicians consistently demonstrated the hindsight bias, more experienced physicians succumbed only on easier cases.

Clinical Competence↗

PubMedDate not supplied

Primer on medical decision analysis: Part 3--Estimating probabilities and utilities.

This paper describes how to estimate probabilities and outcome values for decision trees. Probabilities are usually derived from published studies, but occasionally are derived from existing databases, primary data collection, or expert judgment. Outcome values represent quantitative estimates of the desirability of the outcome states, and are often expressed as utility values between 0 and 1. Utility values for different health states can be derived from the published literature, from direct measurement in appropriate subjects, or from expert opinion. Methods for assigning utilities to complex outcome states are described, and the concept of quality-adjusted life years is introduced.

Biopsy↗

PubMed1996

Ultrasound at scintigraphic "intermediate probability of pulmonary embolism".

For diagnosis of pulmonary embolism (PE), ventilation/perfusion lung scintigraphy is routinely used; approximately one-third of the patients will have the diagnosis "intermediate probability of PE" (inconclusive). In this group only about 33% are found to have pulmonary emboli if examined with pulmonary angiography. To evaluate the diagnostic, therapeutic, and economic consequences of ultrasound of the legs as a complementary diagnostic investigation to "intermediate probability", 72 consecutive patients were investigated with bilateral ultrasound of the proximal deep veins of the legs and pulmonary angiography in a prospective study. Ten patients had PE, of whom 7 had deep venous thrombosis, and 62 had no PE, of whom 2 had deep venous thrombosis. The negative predictive value of ultrasound was 0.95. In view of the importance of adequate treatment and rational use of public health care expenditure, complementary diagnostics should be performed, and ultrasound is an adequate complementary investigation.

Adult↗

PubMed2005

Investigation and management of chronic cough using a probability-based algorithm.

Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the management of chronic cough, in which an assessment of clinical probability of disease determines the need to proceed to investigation. In this study, the performance of this algorithm in clinical practice was prospectively evaluated. A total of 131 consecutively referred patients (86 females) whose principal presenting symptom was a cough of duration >8 weeks were studied. Their age (median (range)) was 60 (16-88) yrs and cough duration 5.9 (0.2-65) yrs. A cause of cough was established in 93% of cases. The most frequent diagnoses were asthma (24% of cases), gastro-oesophageal disease (22%), post-viral cough (8%), bronchiectasis (8%) and interstitial lung disease (8%). Primary pulmonary disease was significantly more likely in patients with a productive cough and in patients with an abnormal chest radiograph. Only a small proportion (<8%) of patients had multiple causes of cough. The probability of treatment started on the basis of a high clinical suspicion of either asthma, gastro-oesophageal disease or rhinitis being successful was 74%. Overall, 26% of the patients were managed successfully without the need for any form of investigation other than chest radiography and spirometry. Use of the algorithm resulted in identification of the cause of cough and successful treatment in the large majority of cases. It is concluded that this protocol has the potential to improve management by providing a structured approach, reducing the number of investigations performed, and minimising unnecessary delays in treatment.

Adolescent↗

PubMed2005

Evaluation of gene importance in microarray data based upon probability of selection.

BACKGROUND: Microarray devices permit a genome-scale evaluation of gene function. This technology has catalyzed biomedical research and development in recent years. As many important diseases can be traced down to the gene level, a long-standing research problem is to identify specific gene expression patterns linking to metabolic characteristics that contribute to disease development and progression. The microarray approach offers an expedited solution to this problem. However, it has posed a challenging issue to recognize disease-related genes expression patterns embedded in the microarray data. In selecting a small set of biologically significant genes for classifier design, the nature of high data dimensionality inherent in this problem creates substantial amount of uncertainty. RESULTS: Here we present a model for probability analysis of selected genes in order to determine their importance. Our contribution is that we show how to derive the P value of each selected gene in multiple gene selection trials based on different combinations of data samples and how to conduct a reliability analysis accordingly. The importance of a gene is indicated by its associated P value in that a smaller value implies higher information content from information theory. On the microarray data concerning the subtype classification of small round blue cell tumors, we demonstrate that the method is capable of finding the smallest set of genes (19 genes) with optimal classification performance, compared with results reported in the literature. CONCLUSION: In classifier design based on microarray data, the probability value derived from gene selection based on multiple combinations of data samples enables an effective mechanism for reducing the tendency of fitting local data particularities.

Algorithms↗

PubMed2005

Two novel quantitative trait linkage analysis statistics based on the posterior probability of linkage: application to the COGA families.

BACKGROUND: In this paper we apply two novel quantitative trait linkage statistics based on the posterior probability of linkage (PPL) to chromosome 4 from the GAW 14 COGA dataset. Our approaches are advantageous since they use the full likelihood, use full phenotypic information, do not assume normality at the population level or require population/sample parameter estimates; and like other forms of the PPL, they are specifically tailored to accumulate linkage evidence, either for or against linkage, across multiple sets of heterogeneous data. RESULTS: The first statistic uses all quantitative trait (QT) information from the pedigree (QT-posterior probability of linkage, PPL); we applied the QT-PPL to the trait ecb21 (resting electroencephalogram). The second statistic allows simultaneous incorporation of dichotomous trait data into the QT analysis via a threshold model (QTT-PPL); we applied the QTT-PPL to combined data on ecb21 and ALDX1. We obtained a QT-PPL of 96% at GABRB1 and a QT-PPL of 18% at FABP2 while the QTT-PPL was 4% and 2% at the same two loci, respectively. By comparison, the variance-components (VC) method, as implemented in SOLAR, yielded multipoint VC LOD scores of 2.05 and 2.21 at GABRB1 and FABP2, respectively; no other VC LODs were greater than 2. CONCLUSION: The QTT-PPL was only 4% at GABARB1, which might suggest that the underlying ecb21 gene does not also cause ALDX1, although features of the data complicate interpretation of this result.

Alcoholism↗

PubMed1979

Probability and the brain.

Probability theory asserts the lawfulness of seemingly random events in large populations and seems to be a reasonable approach to a general understanding of the structure and function of the nervous system. The brain, by virtue of the number of its components, the multiplicity of their possible interconnections, and the range and rapidity of their outputs, is almost implausably complex in its over-all design. Probability theory, therefore, is usually applied to (a) descriptions of the behavior of large neuronal populations, (b) statistical analysis of neuronal spike trains, and (c) theoretical models of neuronal interaction. A consideration of each of these subjects is presented, as is a discussion of the most fundamental level of application of the theory to the nervous system: (d) the assertion that the neuron and/or brain is inherently nondeterministic. In practical terms this is shown to be a "nonissue," the uncertainty principle that follows has rather definite philosophical implications.

Auditory Perception↗

PubMed2006

Predicting patients at low probability of requiring postmastectomy radiation therapy.

BACKGROUND: Postmastectomy radiation therapy (PMRT) is recommended for patients with four or more positive lymph nodes (LN+). Given the ramifications of PMRT for immediate reconstruction, we sought to create a model using preoperative and intraoperative factors to predict which patients with a positive sentinel lymph node will have less than four LN+. METHODS: The database from a prospective multicenter study of 4,131 patients was used for this analysis. Patients with one to three positive sentinel lymph nodes (SLN) and tumors < 5 cm (n = 1,133) in size were randomly divided into a training set (n = 580) and a test set (n = 553). Multivariate logistic regression was used on the training set to create a prediction rule that was subsequently validated in the test set. RESULTS: Median patient age was 57 (range, 27-100) years, and median tumor size was 2.0 (range, 0.2-4.8) cm. In the training set, factors associated with having four or more LN+ on multivariate analysis were: tumor size [odds ratio (OR) = 2.087; 95% confidence interval (CI): 1.307-3.333, P = 0.002), number of positive SLN (P < 0.0005), and proportion of positive SLN (OR = 3.602; 95% CI: 2.100-6.179, P < 0.005). A predictive model was established with a point assigned to each positive SLN, T2 (vs. T1), and if proportion of positive SLN was > 50%, for a maximum of five points. In both the training and test sets, patients with one point had a low probability of having four or more LN+ (3.8% and 3.3%, respectively). CONCLUSION: Tumor size, number of positive SLN, and the proportion of positive SLN influence whether patients will have four or more LN+. A simple model can predict the probability of requiring PMRT.

Adult↗

PubMed1990

A probability sample of gay males.

Data are presented from a national probability sample of males interviewed by telephone and asked their sexual orientation. Of these males 3.7 percent reported that they were homosexual or bisexual. Homosexual/bisexual men were compared with heterosexual ones on the demographic variables. This sample produced larger numbers in those groups which appear to be underrepresented in the usual samples drawn from the gay world. These groups include those with little education, married men, older men, minorities, and those living in small towns. It is suggested that probability samples which do not draw directly or heavily from the gay world for homosexual respondents obtain a broader sampling of those having homosexual feelings or behaviors.

Adolescent↗

PubMed2006

On the probability of dizygotic twins being concordant for two alleles at multiple polymorphic loci.

Accurate determination of same-sex twin zygosity is important for medical, scientific and personal reasons. Determination may be based upon questionnaire data, blood group, enzyme isoforms and fetal membrane examination, but assignment of zygosity must ultimately be confirmed by genotypic data. Here methods are reviewed for calculating average probabilities of correctly concluding a twin pair is monozygotic, given they share the same genotypes across all loci for commonly utilized multiplex short tandem repeat (STR) kits. Numerous tools enabling convenient and accurate zygosity probability calculation may be accessed via the ZygProb homepage at http://genepi.qimr.edu.au/general/daleN/ZygProb/

Alleles↗

PubMed2007

Protein library design and screening: working out the probabilities.

In designing protein libraries for selection, we must coordinate our capacity to create a large diversity of protein variants with the physical limitations of what we can actually screen. This chapter aims to bring the language of probabilities into the protein engineer's laboratory to answer some of our common questions: How can we most efficiently design a library? What fraction of the theoretical library diversity have we actually sampled at the end of the day? What is the probability of missing an individual of the library? Are the mutations present in the variants we have selected statistically meaningful or the product of random variation? The computation of these criteria throughout the process of experimental protein engineering will enable us to better design and evaluate the products of our libraries of protein variants.

Combinatorial Chemistry Techniques↗