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PubMed1989

Discrete visual samples may control locomotor equilibrium and foot positioning in man.

The static or dynamic visual cues required for equilibrium as well as for foot guidance in visually guided locomotion in man were studied using a variety of locomotion supports and illumination and visual conditions. Stroboscopic illumination (brief flashes) and intermittent lighting (longer flashes) were used to control and to vary the visual sampling frequency of static (positional/orientational) visual cues. There were three main findings: First, visual control of foot positioning during locomotion over a narrow support depends mainly upon the availability of high frequency static visual cues (up to about 12 Hz); and third, static visual cues required for equilibrium control are extracted from both the peripheral and the central visual field. Assuming that discrete demands for feedback occur, a simple probabilistic model was proposed, according to which the mean time that elapses following presentation of static visual cues about positions or changes of position accounts for the differences in the difficulty of the various illumination conditions.

Journal Article↗
PubMed2000

How the variability issue was uncovered: the history of the UK residue variability findings.

As a result of routine monitoring data on carrots generated in the 1990s indicating MRL exceedances, further studies showed that residues of organophosphorus compounds in individual roots could vary up to 25 times the levels found in composite samples. Additional work found that this phenomenon also extended to other crops including apples, peaches and celery. Variability (defined as the highest residue level found in any one crop item divided by the level found in a composite sample from the same batch) of up to 34 times mean values was found in one batch of plums. Conventional deterministic methods used in consumer assessments were likely to give gross overestimates of short-term exposure because of the assumptions employed. This led to the development of probabilistic models which made the best use of all available information and was capable of indicating percentages of consumers that could exceed relevant toxicological end points. This indicated that there was unlikely to be serious health effects as a result of ingesting these residues and has subsequently proved to be a useful aid to regulatory decision making.

Food Inspection↗
PubMed2003

Cadmium intake of moose hunters in Finland from consumption of moose meat, liver and kidney.

Although the average cadmium intake in Finland is about 10 microg day(-1), some risk groups can be identified. This study assessed cadmium intake from the consumption of moose meat, liver and kidneys by moose hunters. Consumption data from a postal questionnaire were combined with a representative database on moose cadmium concentrations. Cadmium intakes were calculated as point estimates for all respondents (n = 711), for those consuming moose meat, liver and/or kidneys, and for the highest decile of those. Probabilistic modelling using the Monte Carlo technique was used to simulate the distribution of dietary cadmium exposure. Of the respondents, 69% consumed moose liver and only 23% moose kidneys. The consumption of moose liver or kidneys significantly increased cadmium intake, whereas moose meat (median consumption 17 kg year(-1) person(-1)) contributed only slightly (0.16 microg day(-1) person(-1)) to the daily total cadmium intake. In the simulation, 10% of the moose hunters had an intake of > 8.76 microg day(-1) (14.6% of PTWI for a 60-kg person) from moose. Point estimates provided only a partial understanding of the potential exposure. Simulated distributions of intake were more useful in characterizing exposure. The study revealed that heavy users of moose organs have a relatively narrow safety margin from the levels of cadmium probably causing adverse health effects.

Animals↗
PubMed2004

Dual spatial folds and different local structures of the HIV-1 immunogenic crown in various virus isolates.

Local and global structural properties of the HIV-1 principal neutralizing epitope were studied in terms of NMR spectroscopy data reported in literature for the HIV-Haiti and HIV-RF isolates. To this effect, the NMR-based method comprising a probabilistic model of protein conformation in conjunction with the molecular mechanics and quantum chemical computations was used for determining the ensembles of conformers matching the NMR requirements and energy criteria. As a matter of record, the high resolution 3D structure models were constructed for the HIV-Haiti and HIV-RF immunogenic crowns, and their geometric parameters were collated with the ones of conformers derived previously for describing the conformational features of immunogenic tip of gp120 from Thailand and MN HIV-1 strains. The HIV-1 neutralization site was demonstrated to constitute in water solution highly flexible system sensitive to its environment. This inference is completely valid for the geometric space of dihedral angles where statistically significant differences in local structures of simulated conformers have been found for all virus isolates of interest. In spite of this fact, the stretch analyzed was shown to manifest a certain conservatism in the space of atomic coordinates, building up in four HIV-1 isolates two spatial folds similar to those observed in crystal for the V3 loop peptides bound to different neutralizing Fabs. The results are discussed in the light of literature data on HIV-1 neutralizing epitope structure.

Amino Acid Sequence↗
PubMed2004

Brief but efficient: acute HIV infection and the sexual transmission of HIV.

BACKGROUND: We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV. METHODS: We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. RESULTS: Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. CONCLUSIONS: Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.

Cohort Studies↗
PubMed2005

Social structure, robustness, and policing cost in a cognitively sophisticated species.

Conflict management is one of the primary requirements for social complexity. Of the many forms of conflict management, one of the rarest and most interesting is third-party policing, or intervening impartially to control conflict. Third-party policing should be hard to evolve because policers personally pay a cost for intervening, while the benefits are diffused over the whole group. In this study we investigate the incidence and costs of policing in a primate society. We report quantitative evidence of non-kin policing in the nonhuman primate, the pigtailed macaque. We find that policing is effective at reducing the intensity of or terminating conflict when performed by the most powerful individuals. We define a measure, social power consensus, that predicts effective low-cost interventions by powerful individuals and ineffective, relatively costly interventions by low-power individuals. Finally, we develop a simple probabilistic model to explore whether the degree to which policing can effectively reduce the societal cost of conflict is dependent on variance in the distribution of power. Our data and simple model suggest that third-party policing effectiveness and cost are dependent on power structure and might emerge only in societies with high variance in power.

Animals↗
PubMed2006

Nosocomial pertussis: costs of an outbreak and benefits of vaccinating health care workers.

BACKGROUND: In September 2003, 17 symptomatic cases of pertussis among health care workers (HCWs) resulted from a 1-day exposure to an infant who was later confirmed to have pertussis. These HCWs identified 307 close contacts. The hospital implemented extensive infection-control measures. The objective of this study was to determine direct and indirect costs incurred by the hospital and symptomatic HCWs as a result of the September 2003 outbreak and to estimate possible benefits of vaccinating HCWs from the hospital perspective. METHODS: We determined costs by interviewing infection-control and hospital personnel, reviewing billing records, and surveying symptomatic HCWs. We calculated the benefits and costs of a vaccination program for HCWs, using a probabilistic model to estimate the number of pertussis exposures that would require control measures annually. Sensitivity and threshold analyses were performed. RESULTS: The outbreak cost to the hospital was 74,870 dollars. The total measured cost of the outbreak was 81,382 dollars, including costs incurred by HCWs (6512 dollars). Our model predicted that vaccinating HCWs against pertussis would prevent >46% of exposures from HCWs with pertussis per year and would provide net savings. The benefit for the hospital was estimated to be 2.38 times the dollar amount invested in vaccinating HCWs. The number of exposures prevented and the benefit-cost ratio were sensitive to the number of exposures identified, the incidence of pertussis among HCWs, and HCW turnover. CONCLUSIONS: A single nosocomial pertussis outbreak resulted in substantial disruption and costs to the hospital and to HCWs. Our model suggests that cost savings and benefits could be accrued by vaccinating HCWs against pertussis.

Cost Control↗
PubMed2005

Robust optimization for intensity modulated radiation therapy treatment planning under uncertainty.

The recent development of intensity modulated radiation therapy (IMRT) allows the dose distribution to be tailored to match the tumour's shape and position, avoiding damage to healthy tissue to a greater extent than previously possible. Traditional treatment plans assume that the target structure remains in a fixed location throughout treatment. However, many studies have shown that because of organ motion, inconsistencies in patient positioning over the weeks of treatment, etc, the tumour location is not stationary. We present a probabilistic model for the IMRT inverse problem and show that it is identical to using robust optimization techniques, under certain assumptions. For a sample prostate case, our computational results show that this method is computationally feasible and promising-compared to traditional methods, our model has the potential to find treatment plans that are more adept at sparing healthy tissue while maintaining the prescribed dose to the target.

Algorithms↗
PubMed2005

Action levels for automatic gamma-measurements based on probabilistic radionuclide transport calculations.

In the event of a nuclear or radiological emergency resulting in an atmospheric release of radioactive materials, stationary gamma-measurements, for example obtained from distributed, automatic monitoring stations, may provide a first assessment of exposures resulting from airborne and deposited activity. Decisions on the introduction of countermeasures for the protection of the public can be based on such off-site gamma measurements. A methodology is presented for calculation of gamma-radiation action levels for the introduction of specific countermeasures, based on probabilistic modelling of the dispersion of radionuclides and the radiation exposure. The methodology is applied to a nuclear accident situation with long-range atmospheric dispersion of radionuclides, and action levels of dose rate measured by a network of monitoring stations are estimated for sheltering and foodstuff restrictions. It is concluded that the methodology is applicable to all emergency countermeasures following a nuclear accident but measurable quantities other than ambient dose equivalent rate are needed for decisions on the introduction of foodstuff countermeasures.

Disaster Planning↗
PubMed2003

Monotony of surprise and large-scale quest for unusual words.

The problem of characterizing and detecting recurrent sequence patterns such as substrings or motifs and related associations or rules is variously pursued in order to compress data, unveil structure, infer succinct descriptions, extract and classify features, etc. In molecular biology, exceptionally frequent or rare words in bio-sequences have been implicated in various facets of biological function and structure. The discovery, particularly on a massive scale, of such patterns poses interesting methodological and algorithmic problems and often exposes scenarios in which tables and synopses grow faster and bigger than the raw sequences they are meant to encapsulate. In previous study, the ability to succinctly compute, store, and display unusual substrings has been linked to a subtle interplay between the combinatorics of the subword of a word and local monotonicities of some scores used to measure the departure from expectation. In this paper, we carry out an extensive analysis of such monotonicities for a broader variety of scores. This supports the construction of data structures and algorithms capable of performing global detection of unusual substrings in time and space linear in the subject sequences, under various probabilistic models.

Algorithms↗
PubMed2003

Discovering local structure in gene expression data: the order-preserving submatrix problem.

This paper concerns the discovery of patterns in gene expression matrices, in which each element gives the expression level of a given gene in a given experiment. Most existing methods for pattern discovery in such matrices are based on clustering genes by comparing their expression levels in all experiments, or clustering experiments by comparing their expression levels for all genes. Our work goes beyond such global approaches by looking for local patterns that manifest themselves when we focus simultaneously on a subset G of the genes and a subset T of the experiments. Specifically, we look for order-preserving submatrices (OPSMs), in which the expression levels of all genes induce the same linear ordering of the experiments (we show that the OPSM search problem is NP-hard in the worst case). Such a pattern might arise, for example, if the experiments in T represent distinct stages in the progress of a disease or in a cellular process and the expression levels of all genes in G vary across the stages in the same way. We define a probabilistic model in which an OPSM is hidden within an otherwise random matrix. Guided by this model, we develop an efficient algorithm for finding the hidden OPSM in the random matrix. In data generated according to the model, the algorithm recovers the hidden OPSM with a very high success rate. Application of the methods to breast cancer data seem to reveal significant local patterns.

Algorithms↗
PubMed2003

Picking alignments from (Steiner) trees.

The application of Needleman-Wunsch alignment techniques to biological sequences is complicated by two serious problems when the sequences are long: the running time, which scales as the product of the lengths of sequences, and the difficulty in obtaining suitable parameters that produce meaningful alignments. The running time problem is often corrected by reducing the search space, using techniques such as banding, or chaining of high-scoring pairs. The parameter problem is more difficult to fix, partly because the probabilistic model, which Needleman-Wunsch is equivalent to, does not capture a key feature of biological sequence alignments, namely the alternation of conserved blocks and seemingly unrelated nonconserved segments. We present a solution to the problem of designing efficient search spaces for pair hidden Markov models that align biological sequences by taking advantage of their associated features. Our approach leads to an optimization problem, for which we obtain a 2-approximation algorithm, and that is based on the construction of Manhattan networks, which are close relatives of Steiner trees. We describe the underlying theory and show how our methods can be applied to alignment of DNA sequences in practice, successfully reducing the Viterbi algorithm search space of alignment PHMMs by three orders of magnitude.

Algorithms↗
PubMed1995

Ordering clone libraries in computational biology.

We consider a probabilistic model, due to Lander and Waterman and to Alizadeh, Karp, Newberg and Weisser, for the physical mapping of DNA molecules. Within this model, we answer precisely a question of Alizadeh et al. concerning the minimum number of probes required to reconstruct the entire ordering of a given clone library with high probability. We also examine the related problem of determining the least number of probes required to construct a "tiling" for the library. We give a fairly precise characterization for this number.

Chromosome Mapping↗
PubMedDate not supplied

Identification of protein complexes by comparative analysis of yeast and bacterial protein interaction data.

Mounting evidence shows that many protein complexes are conserved in evolution. Here we use conservation to find complexes that are common to the yeast S. cerevisiae and the bacteria H. pylori. Our analysis combines protein interaction data that are available for each of the two species and orthology information based on protein sequence comparison. We develop a detailed probabilistic model for protein complexes in a single species and a model for the conservation of complexes between two species. Using these models, one can recast the question of finding conserved complexes as a problem of searching for heavy subgraphs in an edge- and node-weighted graph, whose nodes are orthologous protein pairs. We tested this approach on the data currently available for yeast and bacteria and detected 11 significantly conserved complexes. Several of these complexes match very well with prior experimental knowledge on complexes in yeast only and serve for validation of our methodology. The complexes suggest new functions for a variety of uncharacterized proteins. By identifying a conserved complex whose yeast proteins function predominantly in the nuclear pore complex, we propose that the corresponding bacterial proteins function as a coherent cellular membrane transport system. We also compare our results to two alternative methods for detecting complexes and demonstrate that our methodology obtains a much higher specificity.

Bacterial Proteins↗
PubMed2006

Towards an integrated protein-protein interaction network: a relational Markov network approach.

Protein-protein interactions play a major role in most cellular processes. Thus, the challenge of identifying the full repertoire of interacting proteins in the cell is of great importance and has been addressed both experimentally and computationally. Today, large scale experimental studies of protein interactions, while partial and noisy, allow us to characterize properties of interacting proteins and develop predictive algorithms. Most existing algorithms, however, ignore possible dependencies between interacting pairs and predict them independently of one another. In this study, we present a computational approach that overcomes this drawback by predicting protein-protein interactions simultaneously. In addition, our approach allows us to integrate various protein attributes and explicitly account for uncertainty of assay measurements. Using the language of relational Markov networks, we build a unified probabilistic model that includes all of these elements. We show how we can learn our model properties and then use it to predict all unobserved interactions simultaneously. Our results show that by modeling dependencies between interactions, as well as by taking into account protein attributes and measurement noise, we achieve a more accurate description of the protein interaction network. Furthermore, our approach allows us to gain new insights into the properties of interacting proteins.

Algorithms↗
PubMed2006

A reversible jump Markov chain Monte Carlo algorithm for bacterial promoter motifs discovery.

Effective probabilistic modeling approaches have been developed to find motifs of biological function in DNA sequences. However, the problem of automated model choice remains largely open and becomes more essential as the number of sequences to be analyzed is constantly increasing. Here we propose a reversible jump Markov chain Monte Carlo algorithm for estimating both parameters and model dimension of a Bayesian hidden semi-Markov model dedicated to bacterial promoter motif discovery. Bacterial promoters are complex motifs composed of two boxes separated by a spacer of variable but constrained length and occurring close to the protein translation start site. The algorithm allows simultaneous estimations of the width of the boxes, of the support size of the spacer length distribution, and of the order of the Markovian model used for the "background" nucleotide composition. The application of this method on three sequence sets points out the good behavior of the algorithm and the biological relevance of the estimated promoter motifs.

Algorithms↗
PubMed1994

The influence of the reference mean prothrombin time on the international normalized ratio.

The International Normalized Ratio (INR) is a mathematical transformation of the prothrombin time (PT). The transformation requires a laboratory to compute the geometric mean of its own reference population. In this paper, the authors examine how the reference mean PT influences the INR accuracy and precision using a validated probabilistic model. The variance of the geometric mean of reference populations in three laboratory settings was determined. Because the variance of an individual laboratory geometric mean is not directly determinable by simple parametric equations, its variance is estimated using bootstrap analysis. The geometric mean is compared to the computationally simpler arithmetic mean for effects on accuracy and precision of the resulting INR. The study shows mathematically and empirically that using the arithmetic mean biases INR determinations so that patients tend to be over-anticoagulated. However, in the laboratory settings examined, the amount of bias was both statistically and clinically insignificant. An analysis of the effect on the INR of errors in estimating the geometric mean reference PT also is performed. For large biases in estimating the reference mean, the INR can be significantly affected and can trigger inappropriate clinical actions in patients. The authors demonstrate empirically and mathematically that biases in the geometric mean reference PT do not affect the INR coefficient of variation. However, they produce significant differences in confidence intervals for INR determinations. Laboratories must exercise care in determining specific reference means to ensure that biases do not occur in geometric mean reference PT determinations. This can be achieved by circumspection in the selection of normal subjects for the reference population, carefully reviewing the data, and performing the proper calculations on the data.

Female↗
PubMed2006

When is quarantine a useful control strategy for emerging infectious diseases?

The isolation and treatment of symptomatic individuals, coupled with the quarantining of individuals that have a high risk of having been infected, constitute two commonly used epidemic control measures. Although isolation is probably always a desirable public health measure, quarantine is more controversial. Mass quarantine can inflict significant social, psychological, and economic costs without resulting in the detection of many infected individuals. The authors use probabilistic models to determine the conditions under which quarantine is expected to be useful. Results demonstrate that the number of infections averted (per initially infected individual) through the use of quarantine is expected to be very low provided that isolation is effective, but it increases abruptly and at an accelerating rate as the effectiveness of isolation diminishes. When isolation is ineffective, the use of quarantine will be most beneficial when there is significant asymptomatic transmission and if the asymptomatic period is neither very long nor very short.

Communicable Diseases, Emerging↗