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PubMed2006

Lymph nodes in colorectal carcinoma. The Poisson probability paradigm.

This article introduces use of the Poisson probability density function and Bayes probability rule to understand and analyze lymph nodal metastases in colorectal carcinoma. We apply these models to 370 patients who underwent resection of their tumors. In 213 cases with negative lymph nodes, we found that the Bayes-estimated probability of missed metastases was related significantly to subsequent survival (P = .0006). In 157 cases with lymph nodal metastases, we found that the estimated value of the Poisson parameter a was associated more closely with subsequent survival than pN stage (P = 9 10(-6)). Consequently, we believe that the Poisson model provides insight and useful results in colorectal carcinoma.

Adenocarcinoma↗

PubMed2004

Probable vancomycin-induced neutropenia.

OBJECTIVE: To report a case of vancomycin-induced neutropenia and provide a review of the literature. CASE SUMMARY: A 64-year-old white man was treated with intravenous vancomycin 1.5 g/day for finger osteomyelitis. He developed neutropenia after 21 days of vancomycin therapy. The absolute neutrophil count reached a nadir of 418 cells/mm(3) during vancomycin use and returned to normal 7 days after its discontinuation. The eosinophil count was also elevated during the neutropenic episode and probably related to vancomycin. Based on the Naranjo probability scale, the reaction was probably related to vancomycin use. DISCUSSION: Articles describing cases of vancomycin-induced neutropenia were identified. All patients developed neutropenia as a result of vancomycin therapy >/=12 days. Neutrophil counts generally increased following discontinuation of vancomycin. One article reported successful resolution of neutropenia and infection by switching the patient's therapy to the structurally related antibiotic agent teicoplanin. Other patients were continued on vancomycin therapy, and neutropenia was treated with moderate to good success with filgrastim. Rechallenge was not generally attempted. The mechanism of neutropenia caused by vancomycin is unclear, but appears to be immune-mediated. CONCLUSIONS: Vancomycin therapy should not be prolonged unless absolutely necessary, and therapy should be reserved for patients with clear indications for the drug, such as infections due to gram-positive organisms resistant to other therapies. Patients should have periodic assessment of white blood cell and neutrophil counts with consideration to discontinue vancomycin if neutropenia develops.

Adult↗

PubMed2005

Acute seizures due to a probable interaction between valproic acid and meropenem.

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

Acute Disease↗

PubMed2006

Analysis and comparison of impairments in differential phase-shift keying and on-off keying transmission systems based on the error probability.

The effect of nonlinear phase noise in dispersion-managed optical transmission systems is studied. The variance of the nonlinear phase noise in systems based on differential phase-shift keying (DPSK) in the presence of dispersion is examined analytically, and a semianalytical expression to calculate the error probability including intrachannel four-wave mixing, linear phase noise, and nonlinear phase noise for systems based on DPSK is derived. In addition, for the on-off keying (OOK) format, the formula for the error probability including amplified spontaneous emission noise and intrachannel nonlinear effects has been given. On the basis of the semianalytical expressions, we have compared the error probability of systems based on DPSK and OOK, and the results show that, to reach a given bit error rate of 10(-9) for a specific long-haul system, the difference between the signal-to-noise ratio required by the DPSK format and that required by the OOK format is around 6 dB for the launch power of 0 dBm, and the difference becomes larger as the launch power increases.

Journal Article↗

PubMed1983

Spatial-frequency adaptation affects spatial-probability summation.

The effects of spatial-frequency adaptation on spatial-probability summation were investigated by two techniques: the measurement of the dependence of cosine grating sensitivity on the number of cycles presented and the determination of the frequency-of-seeing curve for a cosine grating. Both measurements indicate that the contribution of spatial-probability summation to adapted grating thresholds is reduced in comparison with unadapted conditions. This reduction in the effects of spatial-probability summation, together with the decrease in local sensitivity, which depends on the spatial inhomogeneity of the visual system, is sufficient to account for the threshold elevation aftereffect measured when adapting and testing with cosine gratings.

Adaptation, Ocular↗

PubMed2004

Non-Maxwellian probability density function of fibers with lumped polarization mode dispersion elements.

We give an analytical expression for the probability density function of the differential group delay for a concatenation of Maxwellian fiber sections and an arbitrary number of lumped elements with constant and isotropically oriented birefringence. When the contribution of the average squared of the constant birefringence elements is a significant fraction of the total, we show that the outage probability can be significantly overestimated if the probability density function of the differential group delay is approximated by a Maxwellian distribution.

Journal Article↗

PubMed1999

Frequency of pulmonary embolism in patients with low-probability lung scan and negative lower extremity venous ultrasound.

STUDY OBJECTIVES: To define the prevalence of pulmonary embolism (PE) in patients who are undergoing pulmonary arteriography because of a high clinical suspicion for PE but who have had a low-probability lung scan and a negative lower extremity venous ultrasound examination. DESIGN: A retrospective review of the medical records of 365 consecutive patients who underwent pulmonary arteriograms for suspected PE was undertaken. RESULTS: Of the 365 pulmonary arteriograms, 62 were performed in patients with suspected PEs despite a low-probability lung scan and a negative lower extremity venous ultrasound examination. In the latter group, five patients (8%; 95% confidence interval, 2.7% to 18%) had PEs revealed on the arteriogram. CONCLUSIONS: In patients whose presentation provokes a high clinical suspicion for PE despite having had a low-probability lung scan, a negative lower extremity venous ultrasound examination is insufficient to preclude proceeding to pulmonary angiography.

Adult↗

PubMed2005

Brain-derived neurotrophic factor enhances GABA release probability and nonuniform distribution of N- and P/Q-type channels on release sites of hippocampal inhibitory synapses.

Long-lasting exposures to brain-derived neurotrophic factor (BDNF) accelerate the functional maturation of GABAergic transmission in embryonic hippocampal neurons, but the molecular bases of this phenomenon are still debated. Evidence in favor of a postsynaptic site of action has been accumulated, but most of the data support a presynaptic site effect. A crucial issue is whether the enhancement of evoked IPSCs (eIPSCs) induced by BDNF is attributable to an increase in any of the elementary parameters controlling neurosecretion, namely the probability of release, the number of release sites, the readily releasable pool (RRP), and the quantal size. Here, using peak-scaled variance analysis of miniature IPSCs, multiple probability fluctuation analysis, and cumulative amplitude analysis of action potential-evoked postsynaptic currents, we show that BDNF increases release probability and vesicle replenishment with little or no effect on the quantal size, the number of release sites, the RRP, and the Ca2+ dependence of eIPSCs. BDNF treatment changes markedly the distribution of Ca2+ channels controlling neurotransmitter release. It enhances markedly the contribution of N- and P/Q-type channels, which summed to >100% ("supra-additivity"), and deletes the contribution of R-type channels. BDNF accelerates the switch of presynaptic Ca2+ channel distribution from "segregated" to "nonuniform" distribution. This maturation effect was accompanied by an uncovered increased control of N-type channels on paired-pulse depression, otherwise dominated by P/Q-type channels in untreated neurons. Nevertheless, BDNF preserved the fast recovery from depression associated with N-type channels. These novel presynaptic BDNF actions derive mostly from an enhanced overlapping and better colocalization of N- and P/Q-type channels to vesicle release sites.

Analysis of Variance↗

PubMed2004

What is the probability of a patient presenting a pleural effusion due to tuberculosis?

INTRODUCTION: In Rio de Janeiro, in almost half of the cases of pleural tuberculosis (PT) treatment begins without substantiation of diagnosis. We examined variables associated with this disease. METHOD: We studied 215 consecutive patients; 104 had tuberculosis (TB) and 111 did not (NTB): 41 neoplasms, 29 transudates, 28 para-pneumonic and 13 other etiologies. Clinical and laboratory variables were assessed in a combined manner using likelihood ratios (LR) and Bayes' theorem to determine the probability of PT. RESULTS: Among the variables examined, adenosine deaminase (ADA) levels, lymphocyte cell percentage, protein and age were the best indicators for the diagnosis of PT. Association of ADA with any of the other variables led to a LR+ higher than 10 and a LR- lower than 0.1, indicating the presence or absence of PT, with an individual probability of more than 90% or of less than 10% considering that there was a 50% initial probability associated with the presence of PT. CONCLUSIONS: Since ADA is highly sensitive, we can practically exclude TB as the cause of effusion when there are low ADA values. However, to confirm the possibility of TB we recommend that other variables, such as prevalence of lymphocytes (higher than 90%), and high protein levels (more than 4 g/dL); low age (less than 45 years) also should be considered.

Adenosine Deaminase↗

PubMed2000

Tumor control probability model for alpha-particle-emitting radionuclides.

Alpha-particle emitters are currently being evaluated for the treatment of metastatic disease. The dosimetry of alpha-particle emitters is a challenge, however, because the stochastic patterns of energy deposition within cellular targets must be taken into account. We propose a model for the tumor control probability of alpha-particle emitters which takes into account these stochastic effects. An expression for cell survival, which is a function of the microdosimetric single-event specific-energy distribution, is multiplied by the number of cells within the tumor cluster. Poisson statistics is used to model the probability of zero surviving cells within the cluster. Based on this analysis, a number of observations have been made: (1) The dose required to eradicate a tumor is nearly a linear function of the cell survival parameter z(0). (2) Cells with smaller nuclei will require more dose to achieve the same level of tumor control probability, relative to cells with larger nuclei, for an identical source-target configuration and cell sensitivity. (3) As the targeting of alpha-particle emitters becomes more specific, the dose required to achieve a given level of tumor control decreases. (4) Additional secondary effects include cell shape and the initial alpha-particle energy.

Alpha Particles↗

PubMed1992

Effects of high-probability requests on the acquisition and generalization of responses to requests in young children with behavior disorders.

The failure to respond to requests in young children often is maintained by the reactions of the adults that encounter this behavior. This failure to respond to requests has been identified as a primary reason for the children's exclusion from community, social, and instructional opportunities. Numerous interventions that target the failure to respond have consisted of punishment and reinforcement procedures. More recently, antecedent interventions have focused on changing the context in which a request is delivered. In the current study, high-probability requests were provided as an antecedent to delivering a low-probability request. The requests were delivered by multiple trainers in an attempt to produce generalized appropriate responding to adults who did not use the high-probability sequence. Results showed an immediate increase in appropriate responding in 2 children when the intervention was delivered. In addition, when the intervention was implemented by more than one adult, spontaneous increases in responding also were observed toward adults who had never implemented the request sequence. Improvements in responding to requests were maintained after the intervention was discontinued.

Aggression↗

PubMed1969

Probability of reinforcement and the development of stimulus control.

Pigeons were trained with a successive discrimination procedure in which responding during the negative stimulus was never reinforced and responding during the positive stimulus was reinforced according to one of four probability values. This discrimination training followed extensive training with a single, neutral stimulus and the same temporal distribution of reinforcements. The development of stimulus control was studied by tracing the difference in rate of responding between the positive and negative stimuli over the course of discrimination training. Response rate during the positive stimulus remained constant, while that during the negative stimulus decreased to zero. The probability of reinforcement associated with the positive stimulus affected both the total number of responses emitted during the negative stimulus and the number of negative stimulus presentations during which responding occurred. However, the number of reinforcements during the positive stimulus preceding the attainment of various degrees of stimulus control was similar for all probability values.

Journal Article↗

PubMed1976

Elicited responding to signals for reinforcement: the effects of overall versus local changes in reinforcement probability.

Pigeons were studied on a three-component multiple schedule where all reinforcement was independent of responding. Two components were cued by different keylights and were associated with different rates of reinforcement. The third was always a no-key period associated with extinction. After a few sessions, pecking was elicited by the keylights signalling the reinforcement and continued to be maintained indefinitely. The duration and sequence of the three components were varied to determine if the primary controlling variable was differences in the overall probability of reinforcement, or if it was the immediate change in reinforcement signalled by the onset and/or offset of the stimulus. Both variables were found to control behavior. When 30-sec components were used, the primary controlling variable was the overall probability of reinforcement, but when 3-min components were used, overall probability had little effect. Control by local changes in reinforcement also occurred, although the type of local control varied both across subjects and experimental conditions. Some behaviors were controlled more by the change in reinforcement signalled by the onset of the stimulus, while others were controlled more by the change signalled by the offset of the stimulus.

Journal Article↗

PubMed1979

A Markov model description of changeover probabilities on concurrent variable-interval schedules.

The primary data were peck-by-peck sequential records of four pigeons responding on several different concurrent variable-interval schedules. According to the hypothesis that the subject chooses the alternative with the highest probability of reinforcement at the moment, response-by-response performance in concurrent schedules should show sequential dependencies. However, such dependencies were not found, and it was possible to describe molecular-level performance with simple Markov chain models. The Markov model description implies that the momentary changeover probabilities were proportional to the overall relative reinforcement frequencies, and that changeover probabilities did not change as a function of previous responding. A second finding was that although a changeover-delay procedure was omitted, relative response frequencies closely approximated relative reinforcement frequencies.

Journal Article↗

PubMed1994

Precurrent contingencies: Behavior reinforced by altering reinforcement probability for other behavior.

The present study explored the effects of a precurrent contingency in which one (precurrent) activity increased the reinforcement probability for another (current) activity. Four human subjects responded on a two-key computer mouse. Each right-key press was reinforced (points exchangeable for money) with .02 probability. In one condition (no precurrent contingency), pressing the left key had no scheduled consequence; in another condition (precurrent contingency), pressing the left key increased the reinforcement probability for right-key responding to .08 for 15 s. Initial exposure to the precurrent contingency resulted in acquisition of precurrent left-key responding for 3 subjects, but for the 4th subject a special contingency was required. Right-key responding occurred at a high stable rate across the conditions. Changeovers to left-key responding dropped to near zero when the precurrent contingency was absent and were maintained at enhanced levels when the precurrent contingency was present. Contacts with the left key consisted of short response runs. Right-key responses were more frequently emitted within 15 s of a left-key response when the precurrent contingency was present, an efficient adaptation to the contingency. Continued research on precurrent behavior may produce insights into complex phenomena such as autoclitics and self-control.

Journal Article↗

PubMed2004

Augmentation procedures for control of the generalized family-wise error rate and tail probabilities for the proportion of false positives.

This article shows that any single-step or stepwise multiple testing procedure (asymptotically) controlling the family-wise error rate (FWER) can be augmented into procedures that (asymptotically) control tail probabilities for the number of false positives and the proportion of false positives among the rejected hypotheses. Specifically, given any procedure that (asymptotically) controls the FWER at level alpha, we propose simple augmentation procedures that provide (asymptotic) level-alpha control of: (i) the generalized family-wise error rate, i.e., the tail probability, gFWER(k), that the number of Type I errors exceeds a user-supplied integer k, and (ii) the tail probability, TPPFP(q), that the proportion of Type I errors among the rejected hypotheses exceeds a user-supplied value 0<q<1. Existing approaches for control of the proportion of false positives typically rely on the assumption that the test statistics are independent, while our proposed augmentation procedures control the gFWER and TPPFP for general data generating distributions, with arbitrary dependence structures among variables. Applying the augmentation methods to step-down multiple testing procedures that control the FWER asymptotically exactly at level alpha (van der Laan et al., 2004), yields procedures that also provide exact asymptotic control of the gFWER and TPPFP at level alpha. The adjusted p-values for the gFWER and TPPFP-controlling augmentation procedures are shown to be simple functions of the adjusted p-values for the original FWER-controlling procedure. Finally, two simple conservative procedures are proposed for controlling the false discovery rate.

Journal Article↗

PubMed2004

Error-rate and decision-theoretic methods of multiple testing: which genes have high objective probabilities of differential expression?

Given a multiple testing situation, the null hypotheses that appear to have sufficiently low probabilities of truth may be rejected using a simple, nonparametric method based on decision theory. This applies not only to posterior levels of belief, but also to conditional probabilities in the sense of relative frequencies, as seen from their equality to local false discovery rates (dFDRs). This approach neither requires the estimation of probability densities, nor of their ratios. Decision theory can also inform the selection of false discovery rate weights. An application to gene expression microarrays is presented with a discussion of the applicability of the assumption of "clumpy dependence."

Journal Article↗

PubMed2005

Empirical Bayes and resampling based multiple testing procedure controlling tail probability of the proportion of false positives.

Simultaneously testing a collection of null hypotheses about a data generating distribution based on a sample of independent and identically distributed observations is a fundamental and important statistical problem involving many applications. In this article we propose a new re-sampling based multiple testing procedure asymptotically controlling the probability that the proportion of false positives among the set of rejections exceeds q at level alpha, where q and alpha are user supplied numbers. The procedure involves 1) specifying a conditional distribution for a guessed set of true null hypotheses, given the data, which asymptotically is degenerate at the true set of null hypotheses, and 2) specifying a generally valid null distribution for the vector of test-statistics proposed in Pollard & van der Laan (2003), and generalized in our subsequent article Dudoit, van der Laan, & Pollard (2004), van der Laan, Dudoit, & Pollard (2004), and van der Laan, Dudoit, & Pollard (2004b). Ingredient 1) is established by fitting the empirical Bayes two component mixture model (Efron (2001b)) to the data to obtain an upper bound for marginal posterior probabilities of the null being true, given the data. We establish the finite sample rational behind our proposal, and prove that this new multiple testing procedure asymptotically controls the wished tail probability for the proportion of false positives under general data generating distributions. In addition, we provide simulation studies establishing that this method is generally more powerful in finite samples than our previously proposed augmentation multiple testing procedure (van der Laan, Dudoit, & Pollard (2004b)) and competing procedures from the literature. Finally, we illustrate our methodology with a data analysis.

Journal Article↗